dr Milan Ignjatović
IGNJATOVIĆI 40GODINAUPSIHIJATRIJI
Vršac 2017
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Posvećeno mojim roditeljima. 2
IGNJATOVIĆI 40GODINAUPSIHIJATRIJI
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AGORAPHOBIA WITH PANIC DISORDER - FAMILY PSYCHOPHARMACOTHERAPY BY PAROXETIN AUTHORS Milan Ignjatovič, MD, Psychiatric Medical Office, Health Care Center, Banská Bystrica MUDr. Dana Ignjatovičová, Psychiatric Department, F. D. Roosevelt›s Hospital, Banská Bystrica
SUMMARY 4 women – 55-year-old mother and her two daughters: 38 and 34 years old and one stepdaughter 20 year old were followed and used in casuistics. To make good quality family anamnesis is very impotant for risks family factors and for detection of psychical disorders. The ways of heredity are: polygenic modeli, model of the dominant gene with incomplete penetration, autosomal dominant model and the others. There are many genetic hypothesis about genesis of the psychical disorders and genetics markers like: yohimbin, clonidin, coffein, infusion of natrium lactatum, hyperventilation, L-tryptofan, benzodiazepin’s receptors, continuity between mitral prolaps and panic disorder, positive response on antidepressants, personality studies of the patients with panic disorder (Erič Lj., 1991). The problem is that patients didn’t know about their disorder, about treatment, etiology, complications and consequences. Treatment by psychopharmacotherapy confirms some of genetic hypothesis connected with correct diagnosis. These 4 women were diagnosticated and adequately treated in our Psychiatric Medical Office, Health Care Center.
KEY WORDS Agoraphobia with panic disorder, paroxetinum, genetic studies
INTRODUCTION Long time ago, in the past century, when genetic research was not carried out, Beard wrote about “consequent predisposition for the occurrence and development of neurasteny.” Freud came up with similar experience and he pointed out the fact that neurosis of fright has the same symptoms among several family members. Oppenheimer and Rothshild found out that family history of neurosis existed among 45% of observed World War I soldiers who were diagnosed with Da Costa syndrome. Some time later, during the World War ll, Wood found positive family history among 25% patients treated on heart neurosis. Subsequent researches showed that panic disorder is a disease, which cumulates in the family.
METHODOLOGY AND GROUP OF PATIENTS 4 female patients were chosen for the casuistic study on the basis of 5 including criteria: 1. Biographical anamnesis, 2. Forgoing diariosis„ 3. Current diagnosis, 4. Therapy, 5. Family relationship. Observation and evaluation of results was carried out from October 1999 to March 2000, while all of the female patients continue will the therapy and they are registered in our medical office.
OBSERVATION The results are based on retrospective clinical observation of patients medical records where the focus was on the biographical anamnesis, diagnosis, therapy and family relationship. The core of the study is formed by 4 casuistic cases which draw the importance of genetic factors for the occurence and development of panic disorder.
CASUISTIC No. 1 55 years old woman, worker, mother of three daughters, long term treated in different medical offices with diagnosis of neurasteny. She visited our medical office on the recommendation of both of her daughters. She describes her first panic attack as the situation when she had her middle daughter and she couldn’t go for a walk with the buggy (in the year 1966), she was dizzy and weak, she couldn’t take anything into her hands, she had palpitations, was stifled, sweated, had pins and needles in her hands, felt a node in her throat and she helped herself by giving snow on her head. Afterwards she was scared to go for a walk. Physicians prescribed chlordiazepoxidum (Radepur) and ergotamini tartas, belladonnae radicis, phenobarbitalum (Bellaspon) for her and symptoms were gone for one or two days. Her husband didn’t believe her that she was ill and he was furious of her status. That all enhanced her tension and the patient was not even able to stand up from her bed because of the dizziness. She was scared to visit a physician in the psychiatry ward at that time. First time she visited psychiatric medical office in Brezno 20 years ago, she was taking chlordiazepoxidum (Elenium), ergotamine tartas, belladone radicis, phenobarbitalum (Bellaspon) and diazepanum (Seduxen). When her youngest daughter was born, she felt quite well during the daytime but she got an attack after night shift. She described the attack like is: she woke up in the night, didn’t know where she was, what she
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was doing, she was steamy and very afraid. When her husband was close to her, she composed herself but in spite of this she was not able to leave the bed. She had to be very responsible in her job, millions were at stake, fortunately nothing happened. She was treated in the spa town of Vyšné Ružbachy since 1992. She felt very well in the baths because it was a peaceful place. She was sent to visit a primary doctor 5 years ago who prescribed alprazolam (Neurol) and fluoxetinum (Prozac) for her. She felt better, even though she still used to have panic attacks which were more mild and weaker. She concluded the combination of noted drugs because her physician changed one drug to fluoxetinum (Deprex). She had strong diarrhea, strong headache and she felt sick after using this drug. The patient visited our medical office on December 12, 1999 with no psychopharmacological medication. We prescribed lire medication of paroxetinum and clonazepamum for her. The patient’s status improved very quickly (in 2 weeks time), she didn’t have any attacks any more, her mood brightened, she slept all the night, and she hasn’t been scared of people any more. After one month the dermatologist diagnosed her with allergy to paroxetinum. That’s why this drug was replaced by citalopramum. Tte patient canceled the medication of citalopram by herself and on the recommendation of her three daughters she started taking paroxetinum and clonazepamum during the last control visit on the March 16, 2000. No allergy to paroxetinum occurs at present and previous allergic reactions are thought to be possible comorbidity with allergy e.g. to another drugs or food. The patient evaluates her status as excellent and she assesses the current therapy as the most sufficient and the most successful in 30 years of treatment.
CASUISTIC No. 2 38 years old female patient, single, lives with her partner who is addicted to alcohol and is aggressive when drunk. Currently the patient tries to evacuate him from her flat a legal way. The patient was treated by psychiatrist for a long time. She was not satisfied with the treatment and that’s why she visited our medical office on other patient’s recommendation. The memories of her childhood are connected to her mother who lived with the children alone, she was divorced, she raised the children quite strictly. The patient’s father drank a lot of alcohol, she remembers that he even attacked them with a gun and he threatened to shoot them all. Her mother was very sick, she moved to her grandmother and she got married for the second time. The patient couldn’t sit down under the facts the underwent in her childhood. When she cut adrift she got a flat and she took an alcoholic man to her flat. She wants to get him away in a legal way now. When the patient visited our medical office for the first time, she had the following symptoms: palpitation, exudation, fear that disallowed her to go to the work, trepidation of hands, s le had as well as her mother a node in the throat. She got the first attack in 1994 at home, she didn’t know what that was, she felt worse and worse. Her status was so had that she couldn’t even watch TV, she was even scared of the people in TV shows. Her mother had similar symptoms. She felt a noise in heir head, she had to go to bed, couldn’t go for a shopping to the moles where a lot of people are. She stayed in the bed very often and didn’t talk to people. One psychiatrist prescribed chlordiazepoxidum (Defobin) for her. When she didn’t get enough, she visited another psychiatrist, who gave her maprotilinum (Ludiomil), alprazolamum (Neurol). In spite of that she had to call the emergency very often or had to visit the emergency by herself, she got hypertension, couldn’t compose herself. We registered her with the diagnosis of neurasteny and put her on paroxetinum and clonazepamum right after her first visit in our medical office. Between the first and the second week her health status improved, attacks receded, she started to go for a shopping, wasn’t scared of people anymore. She also attended the group therapy in our medical office. When she started to have conflicts will her partner, her health status got worse. The patient received shoots of progesterone and estradioli benzoas from the year 1980 because sometimes she didn’t have menstruation up to 3 months. Since she has been treated by paroxetinum, her menstruation is periodical. Meanwhile the patient received the verdict which states that her partner has to move from her flat. The patient is looking for a new job because nobody believed in her invisible illnesses in her former job. She evaluates her status as good, stabilized and the treatment as successful.
CASUISTIC No. 3 34 years old female patient, previously unemployed, married. For the first time she got palpitation after the wedding in 1986. She couldn’t breathe and her health status started to worsen after 3 years. She started to feel sicker since she became unemployed. Since she finished only elementary school, she studied at the school for waiters but in fact she had stage fright and was very self-centered, she didn’t finish the school for waiters. She doesn’t remember her father because her parents got divorced when she was 4 years old. She describes her symptoms as weakness, shakiness, vertigo, chest pains, shaking of her legs. She feels better when she stays at home in silence. Her husband drinks alcohol and when drunk, he upbraids her the fact that she is unemployed. She adds to her symptoms that she couldn’t breathe; she felt the way she would suffocate. These symptoms appeared when her daughter, who had legs desjointedness and didn’t sleep at night, was born. That was a huge endurance for her. When the patient tended her daughter to the school, she felt she wouldn’t return home and would vomit. There were more panic attacks upraised during one week and she felt she would get heart attack. When she worked as a cleaner in an elementary school, she felt good in a collective of colleges. She felt the worst when she had to stay at home alone. She underwent different medical examinations but nothing was found. Afterwards she started to be scared of people and that’s why she didn’t go abroad (she didn’t travel by bus, didn’t go for a shopping). There is comfort at home, it’s worse when the husband gets drunk and offends her. The neurologist put her on paroxetinum. Even though her health status improved, the patient stopped the treatment by herself because the period of menstruation shortened up to 15 days. The patient was examined in our medical office for the first time on the recommendation of her mother and two sisters in February and she had the following symptoms: hands shakiness, enhancing anxiety, node in the throat, she was scared of going 6
outside, felt better at home. After the introductory interview we agreed on be therapy of paroxetinum and clonazepamum.. After one month the patient notes that her health status improved, she has no panic attacks, she meets people and she evaluates the treatment as the best one so far.
CASUISTIC No. 4 20 years old female patient, trained tailor, the youngest one in the proximity. After the childbirth in 1988 she began to have vertigo, palpitation, body shakiness and was scared of going out for a shopping. She had these attacks more than 4 times a month. Unlike her mother and stepsisters, she didn’t have a node in her throat. When she restored from the smallpox in her childhood, she was diagnosed with the epilepsy. The patient states that she used to faint, she sensed everything around but couldn’t respond. She visited a neurologist who put her on phenytoinum and carbamazepinum. Then the pediatric neurologist put her on natrium valproate when she was 12 years old. Gradually acidum valproicum + natrii valproas (Depakine Chrono 500) of a dose of 1 tablet in the morning - 1 tablet in the noon - 1 tablet in the evening were added to the therapy management. Phenytoinum was rejected, natrium valproat (Orfiril 300 mg in one tablet) of a dose of 1 tablet in the morning - no tablet in the noon - 1 tablet in the evening was kept. When the patient attended the 7th grade of the elementary school, she had vertigo during the lessons, she asked for going to the toilet very often and she felt very badly during the biology classes when they learned about blood. She was hospitalized during that period of time. When medical staff told her about the blood sample testing, she fainted. She was scared of going to school, her classmates laugh at her because of her epilepsy and she didn’t remember anything after each attack. At home the attacks started to appear during the night. She got shakiness and her mother had to wake her up. She had vertigo in the classroom very often. Moreover she fabled and fell down at home. She used to faint more often in school, especially in the period of examinations; she fainted more often at home as well at that time. She has never had enuresis and has never bitten her tongue. The epileptic attack lasts for 1 minute and she has never slept after the injection of diazepamum or after the attack. When she got very painful menstruation, she felt she would suffocate and they called the ambulance immediately. The patient had no attacks at the secondary school. No attacks were present at home at that time either. She visited a pediatric neurologist for the first time when she was 11, panic attacks uprose when she was 12 years old. Even though she was taking phenytoinum and carbamazepinmu, she fainted at home as well as at school. She felt badly all the time. Suddenly, the attacks were gone when she was in the 8th grade of the elementary school. Palpitation appeared at home when she was 12 years old, she didn’t tell her parents about it, she just retired to her room and went to bed. She lists more exact medication since her age of 16, when she received natrium valproas (Orfiril 300 mg in each tablet) in a dose of 1 tablet in the morning - no tablet in the noon - 1 tablet in the evening. When she was 18 years old she was taking acidum valproicum + natrii vaiproas (Depakine Chrono 500) in a dose of 1 tablet in the morning - 1 tablet in the noon -1 tablet in the evening. The attack uprose in the dormitory when she was 16 years old. It was seldom and as she states further, there have been no more attacks at home or at secondary school. She got married at the age of 18; she gave birth to a daughter in 1983 and 3 days after the childbirth she fainted lying in the bed. Wien she rinsed pampers or when she woke up to get pills, the attacks returned. She got “aura” and consequently fainted when she saw the strips on the tiles. Prolonged observation of the blue strips on the tiles provoked this kind of schism. After that accident her mother didn’t let her staying at home alone, she was with her daughter even when she was having a shower. To help herself, the patient doesn’t look at those strips when she is in the bathroom. When her oldest sister remembered the incidents with the bathroom, we found out that she used to lock the patient in the bathroom as a punishment when she behaved badly in her childhood. She haunted the patient to leave her inside the bathroom for good in this time of her childhood. This fact was confirmed also by the middle sister. The patient is 20 years old now, last time she fainted in maternity hospital one year ago. Approximately half year after her child was born she began to have vertigo, uncertain walking, everything was spinning around her, she sweated. These feelings attacked her 4 times a month. Since the patient milked her child, her health status worsened during each menstruation period. She visited our medical office on the recommendation of her stepsister on the November 3, 1999. Her stepsister suggested her to visit the psychiatrist for a long time. The patient’s status improved after two weeks of medication of paroxetinum and clonazepamum, she has had no more anxiety nor panic attacks. Whereas the patient is listed in neurological office, we mutually consulted the therapy and recommended to reduce eventually to cancel their therapy. After the arrangement we stopped the management of natrium valproas (Orfiril), we reduced the dose of acadum valproicum + natrium valproas (Depakine Chrono 500) up to 1/2 tablet in the morning - no tablet in the noon - 1 tablet in the evening. Patient feels good, the health status is stabilized, she takes care of her daughter with joy, handles with common activities without any probifems, she evaluates the treatment as being successful. Each of these 4 patients evaluated the treatment of their mothers, sister and stepsister separately, so besides subjective evaluation we have heteroanamnestic (heterologic history) evaluations as well.
SUMMARY 4 women, a mother and 3 daughters who were chosen according to 5 including criteria are inncluded in the casuistic study, whereas 2 sisters were their own, one was a stepsister. The average age was 36,75 years. Symptoms were present in average of 16,25 years and treatment in our medical office tasted 3 months in average. There has been used paroxetinum in a dose of 30 mg per day and clonazepamum in a dose of 0,5 up to 1,5 mg per day individually in the treatment. The results were analyzed on the basis of patients’ subjective evaluation as well as according to the heteroanamnestic evaluation.
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DISCUSSION Family studies and studies realized on twins who suffer from anxiety and panic attacks show that panic disorder is familiar disease. However, family cumulation is neither sufficient nor necessary condition to confirm that the disorder is congenital. It is necessary to look through the exact pathway of genetic transmission, but we have not reached definitive conclusion up to now. There are several models available; polygenous model, model of dominant gene with incomplete penetration, autozom dominant model. The results of the researches done up to now show that the model of dominant gene with incomplete penetration is the most feasible way of genesis and development of panic disorder, but the model of polygenous heredity is also not definitely rejected. We have investigated the model of polygenous autozom dominant heredity in our study. The results we have reached suggest that panic disorder is transmitted as an autozom dominant disorder (1). Family studies of the panic disorder realized in 1980’s show that the risk of uprise is 17,3% in first grade relatives and added risk from 7,4% for possible panic disorder (which uprises with 2,3 rarely with 4 symptoms of the panic disorder criteria). Some authors have found out high risk of panic disorder in both groups of relatives in a case of panic disorder (17,3%) and in groups of relatives in a case of agoraphobia (8,3%), compared to 4,2% in control group. (2) Other studies found out from 4 to 8 higher risk of panic disorder in the group of first grade relatives of patients with panic disorder diagnosis compared to first grade relatives of patients with other psychical disorders. (3) Having gone through the all aspects of genetic research of anxiety and panic disorder, the problem how to explain them still remains. In spite of evidences that panic disorder is family disease, as well as there is high concordance in monozygote twins, pathophysiological mechanisms of panic disorder development have been determined. We don’t have sufficient feasibility to define the role of genetic factors in panic disorder etiology for certainty. What is really proved is the fact that anxiety and panic disorder are not inherited by the simple principle of Mendelejev heredity rules. It is proved that a lot of anxious conditions occur in the participation of psychological, social and cultural factors without the visible contribution of genetic factors. There is a model of possible panic disorder uprise and development, in which the biological, psychological and social factors are comprehensively present and the model is based on those proved facts. Truly, nonspecific genetic predisposition in cooperation with psychological factors leads into the uprise and development of anxious conditions. In this kind of explanation the questions about the nature, noted genetic predisposition come out. In other, more simple, words, what is inherited in the case of anxious conditions and panic disorder and if children of patients with panic disorder inherited the same disorder. The majority of research scientists suggest that the cacoethes and hypersensitiveness for the uprise and development of anxious conditions are inherited and they are based on enhanced autonomous nervous system reactivity or on the unstableness of neurotransmitter system that determines the global organism reactivity. Meanwhile, the existence of cacoethes and hypersensitiveness for the anxious conditions suprise and development doesn’t mean sure disease development. Maybe the cacoethes is anchored in development basement of known personality of type A, by whom the essential hypertension is developing. The essential hypertension could be followed by the existence of anxiety but it couldn’t be as well. It is also possible that the cacoethes just reduces threshold for specific senses and activities which, in cooperation with psychological factors, lead into the disease onset. This kind of explanation can be only the “peak” of the enhanced reactivity basement to the stress or can bean anxiety manifestation. It was proved by many researches that only features of personality, such as flap, tendency to react anxiously, hypersensitiveness and shyness are inherited. It is proved that neuroticism as personality feature is inherited. Other authors have found out that personality feature highly correlates in twins couples, no matter if they have grown up together or not. The high correlation of personality features for anxiety in monozygote twins couples have been proved, meanwhile it hasn’t been proved in dizygote twins couples. A personality that has anxious features (anxious character) goes through unpleasant psychosocial factors or through stress with anxious reactions. The way to the symptoms of panic attacks and panic disorder is very short when a long term and intensive fear comes out. Finally, children of patients who are diagnosed with panic disorder do not straightaway inherit the same disorder. However, even this fact can’t he certainly confirmed. 50% of daughters and 10% of sons who suffer from panic disorder have symptoms which permit to make the right diagnosis. In conclusion, we have to state that geneticists have not said the final word on the confirmation of basement for panic disorder uprise and development. Researches in the area of molecular biology are at the center of attention. Preliminary results of 29 genetic markers of 26 families with positive history of panic disorder have been reported and they have shown that there is a connection between panic disorder and patient’s chromosome status, especially in chromosome 16 and 22. Implementation of this new technology into genetic research of patients with panic disorder and twin couples with certain disease has allowed us to accept genetic basement of panic disorder uprise and development as comprehensive problem. The results that should be found out are expected with great attention.
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CONCLUSION Thanks to patients who suffer from panic disorder and thanks to enthusiasm in psychiatry, positive family history of certain disorder, disease can be helpful for early diagnostic testing and for sufficient therapy. Everything we are supposed to do is to get quality family history.
BIBLIOGRAPHY 1. Erič Lj., 1991: Pričina stanja, II dopunjeno i prošireno izdanje, Beograd- Zagreb, 1 309: 56- 57, 67- 69 2. Hales R.E., Yudovsky S.C., Talbott JA., 1994 Textbook of psychiatry, 2-nd Edition, The American Psychiatric Press, 1-, 1608, 37- 71 3.Raboch J., Praško J., Seifertová D., 1999: Panické stavy II díl, vyd. SKB, 6- 56: 29
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ACAMPROSATE FOR OUT-PATIENT ALCOHOL DEPENDENCE TREATMENT AUTHORS Dana Ignjatovićová, 1, M.D. Milan Ignjatović, 2, M.D. Jasmina Janković-Gajić, 3, M.D. 1- Psychiatric Out-Patient Clinic, Health Centre Banská Bystrica, Slovakia 2- Psychiatric Out-Patient Clinic, Health Centre Banská Bystrica, Slovakia 3- Dragiša Mišović’s Psychiatric Clinic KBC, Belgrade, Yugoslavia
SUMMARY The number of patients treated for the alcohol dependence syndrome at the psychiatric clinic increases. Their drinking has a serious impact on their families and professional lives and it represents a complex medical, social, and economic problem. Various methods of treatment of the alcohol dependence syndrome have been used in psychiatry, and currently we can combine them or use new preparations, designed specially for specific kinds of dependence. One of the latest substances used as anti-craving agents is calcium acetylhomotaurinate, also known as calcium acetyl aminopropanesulfonate or acamprosate. In our study, we have tried to establish whether acamprosate can be helpful in the treatment of the alcohol dependence syndrome. We have included 23 patients into our study, 9 women and 14 men, who were monitored from 1st January 2001 to 31st October 2001. The average period of drinking was 10.47 years (the shortest one 2 years, the longest one 39 years), with an average duration of abstinence of 7.52 months (the shortest one 58 weeks, the longest one 10 months). The average age of the patients was 43.26 years (ages ranging from 27 to 59 years). 5 patients interrupted their abstinence after they had started to use acamprosate, 3 of them after less than three months of abstinence and 2 patients after longer than 3-month abstinence. None of the patients interrupted their treatment by acamprosate due to adverse side effects of the drug.
KEY WORDS alcohol dependence syndrome, acamprosate, SSRI, period of drinking, duration of abstinence. break of abstinence, relapse
INTRODUCTION The alcohol dependence syndrome includes a number of physiological, behavioural and cognitive phenomena, in which the use of a certain substance or substances by an individual becomes more significant than any other behaviour patterns that were previously of a higher value. The basic described characteristic of the alcohol dependence syndrome is the longing or craving (often strong, almost unbearable) for the use of a drug (which is or is not medically prescribed), like alcohol or tobacco. There is evidence that the resumption or the use of the substance after a period of abstinence leads to faster re-discovering of the developed manifestations of the syndrome when compared to individuals who are not addicted. The following are diagnostic criteria for the dependence syndrome according to ICD- 10:final diagnosis of dependence should be made only when 3 or more of the following nenomena have been experienced or have manifested themselves in the past year: Strong longing for or temptation to use a substance; More difficult control over own behaviour, linked with the use of the substance in terms of the start of the use, end of the use, or quantity of the used substance; Physiological abstinence syndrome after the use of the substance ended or was decreased, proved by an abstinence syndrome characteristic for that substance, or when the same (or similar) substance is used with the intention to reduce or overcome abstinence symptoms; Proof of the tolerance in a way in which increased doses are necessary to achieve effects (results) that were previously achievable by lower doses (a good example of that is people dependent on alcohol or opiates, who can used daily doses of such substances that would be sufficient for devastating or killing other users without developed tolerance); Progressive neglecting of alternative ways for satisfying interests due to the use of the substance, increasingly longer time necessary for the obtaining and use of the substance, as well as for resting an recovery from its effects; Carrying on with the use of the substance despite the awareness of clear facts about its harmful consequences, like liver damage due to excessive use of alcoholic drinks, depressive mood that follows periods of intensive use of the substance or damage of the cognitive functioning connected with the use of drugs. It is necessary to insist it is specified whether the user has realized or it can be expected he/she will realize the basis as well as the mechanism of the harmful effect of the substance.
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The decrease of the personal repertoire of patterns for the use of a psychoactive substance is also described as a typical characteristic (e.g. tendency to drink alcoholic drinks in the same way during week days as during weekends, irrespective of social limitations that set norms for behaviour connected with drinking); The basic characteristic of the alcohol dependence syndrome is the existence of a substance that is used or the existence of a desire, craving for using the drug. We meet with an individual’s subjective realization that he/she is tempted to use a substance most frequently during a test aimed at ending or controlling the use of the substance. Such a diagnostic procedure excludes, for example, surgical patients who are administered pain relieving opium preparations and who may show symptoms of opiate abstinence syndrome after the administering of drugs has been interrupted, and who are do not crave for further use of the given therapy. The dependence syndrome can be characteristic for a certain substance (like, for example, tobacco, diazepam) for a group of substances (e.g. opiates, opiate drugs), or for a wider range of different substances, like in the case of some individuals who feel temptation to take any substance (drug) that is available for them, which is manifested by their restlessness, agitation or physical symptoms of the abstinence syndrome when they do not take the drug. According to Otto M. Lesch, there are 4 subtypes of alcoholism that are significant for diagnosing and therapy of the alcohol dependence syndrome. The least possible to influenceand treat are the 4th type (connected with organic brain disorders) and the 3rd type (connected with severe mental disorders), while the 2nd type (connected with anxiety) and the 1 st type (connected with habits in the population) are most easily possible to diagnose and treat. There are also other classifications, in which development stages are specified, from the initial one, through the prodromal one and the crucial one, to the terminal (chronic) one (according to professor Dobiáš), as well as the division of dependences according to Jellinek into the alpha, beta, gamma (most frequently dealt with at the psychiatric clinic), delta and epsilon types (Skalá 1987). Psychopharmacotherapy of the alcohol dependence syndrome has its history, including substances ranging from those with an aversive effect to those with an anti-craving effect, and recording a lot of contradictory results (Bankole A. Johnson, 2000). Large studies with acamprosate, including thousands of patients, have been conducted (Mason B. et al., 2000), and there have also been some others that included more than 100 patients (Pelc 1., 1997). Sociotherapeutical meetings, as an auxiliary method, have been reported. Substances that have been used in the treatment of the alcohol dependence syndrome include opioid receptor antagonists (naltrexone, nelmefene) (Wilde, 1997), NMDA antagonists (calcium acetylhomotaurinate - acamprosate (Monografia, 2000), serotonergic substances, including SSR1, out of which fluoxetine (Naranjo CA, 1990), fluvoxamine and citalopram (Naranjo CA., 1987, Naranjo CA, 1992), 5HT1 partial agonists (buspirone), 5HT2 antagonists (ritanserine, amperozide), 5HT3 antagonists (ondansetron) (Bankole A. Johnson, 2000, Wilde, 1997), dopamine antagonists (haloperidol, tiaprid), which can be used for relieving abstinence symptoms, (Evens M., 1980), or completely new substances that influence delta receptors (ICI 174864, naltriben and naltrindole) (Froehlich JC, 1991), or other μ-opioid antagonists (nalmefene), have been used in most studies. Furthermore, calcium channel blockers (isradipin) (Rush CR, 1998), natural preparations from the roots of a Chinese plant peuraria lobata (puerarin), with which no trials have been conducted on people yet, as well as neuropeptide Y, which shows anxiolytic effects in animal studies (Ehlers CL, 1998), have been used. Combinations of various psychopharmaceuticals, like acamprosate with disulfiram, are also used, but the combination of naltrexone with disulfiram is not recommended, while, on the theoretical level, there are some views in favour of combining naltrexone with fluoxetine and SSRI with naltrexone in the case of patients who suffer from a depressive disorder in co-morbidity. Some pre-clinical studies point out the combination of ondansetron and naltrexone (Bankole A. Johnson, 2000). Acamprosate (Campral) = calcium acetylhomotaurinate is a non-aversive drug, acting on the CNS, and specially developed for maintaining long-term abstinence. Its chemical structure is similar to that of pharmacologically active arninoacids, such as taurine, gamma-aminobutyric acid (GABA) and glutamate. Since hypoactivity of the GABA-ergic system occurs during the chronic consumption of alcohol, acamprosate increases the number of GABA receptors, increases GABA transmission (Monografia, 2000), and causes a reduction of the number of calcium channels, which are the probable mechanisms of its effect (Wilde, 1997).Acamprosate is the first specifically acting drug for patients with alcohol dependence syndrome after detoxification. The drug does not cause any potential acute or chronic toxic effects. It is not addictive. Acamprosate has been approved for prescription in France since 1989, and, since later, in many European countries (in Slovakia since 2000), as well as in Latin America, Australia, South Africa, and Hong-Kong. More than 4 million people have been treated by it (Mason 2000). The preparation could help to treat patients dependent on alcohol. The main goal of the study was to specify an average duration of abstinence after starting to use acamprosate during a 10-month follow-up period. Other objectives included: Finding out an average period of drinking before an examination at a psychiatric clinic; Time to the first drink after the start of the use of acamprosate; Monitoring or the patients’ families’ burdening; Completion of an anti-alcoholic treatment before an examination at a psychiatric clinic; Monitoring of the patients’ personality characteristics; Psychiatric co-morbidity; Psychiatric therapy;
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Adverse effects at the start of the use of acamprosate and during its use; Physical illnesses (epileptic seizures, liver function disorders, post-traumatic brain damage with unconsciousness and concussion, ischemic heart disease, polytopic vertebrogenous algesic syndrome); Occurrence of palimpsests, alcoholic delirium and hallucinosis; Preference of alcohol. As a shortcoming of this work we consider the fact that the patients started to use the drug during a 6-month period, which is a long starting period, but which, however, was not possible to shorten in our clinical conditions; Another shortcoming of the work is the fact that the patients’ GMT was not monitored or evaluated in precisely specified time intervals; it was done only at the beginning, in the mid- term, and at the end of the 10-month monitoring of the patients. We have not monitored the patients MCV. The third shortcoming of the work is a relatively small group of monitored patients.
POPULATION AND METHODOLOGY 23 patients (9 women and 14 men), meeting the MKCH-10 DSM-IV criteria for the alcohol dependence syndrome - chronic, continual condition F.I0.25 (Smolik, 1994), were identified in the patient records of two psychiatric clinics. Patients with another psychiatric co-morbidity (F.06 - 1 patient, F.32 - 9 patients, F.34.1 - 1 patient, F.40.01 - 3 patients, F.43 - 2 patients, F.60 - 1 patient, 6 patients without any other psychiatric co-morbidity) were not excluded. The average age of the patients was 43 26 years (from 27 to 59 years), the average period of drinking was 10.47 years (from 2 to 39 years). The average period of drinking was 10.47 years (from 2 to 39 years). The patients were monitored from 1st January 2001 to 31st October 2001; they started to use acamprosate between 1st January 2001 to 30th June 2001. The treatment of their alcohol dependence was monitored at the psychiatric clinics for the period of 10 months. Its successfulness was evaluated by the duration of abstinence, time to the first drink, break of abstinence, and occurrence of adverse effects during the treatment with acamprosate -- interruption of treatment due to adverse effects of the preparation. To carry out an evaluation, we have compiled a questionnaire, which was completed by each patient included into the study.
RESULTS The results are shown in Tables 1, 2, 3, and 4. The average duration of abstinence of the monitored patients was 7.52 months, which can be considered as a treatment success (according to Mason et al., 2000, who define a treatment success as complete abstinence for more than 3 months, established by a clinical interview, normal GMT and decreased MCV). Out of 23 patients, we have identified family burdening in 22 cases; one patient’s family burdening was not confirmed. 10 patients underwent detoxification at a psychiatric ward, 13 were detoxified as out-patients. Adverse effects at the start of using acamprosate are summarized in Table 5. None of the patients had suffered from hyper-kinetic disorder in their childhood or had previously been treated at a psychiatric clinic due to an anti-social personality disorder. One patient had been treated for a limit personality disorder. 3 patients had previously been treated for anxiety disorders. 12 patients had been treated for affective disorders. One patient had been treated as a F.06.4., and 6 patients had not been treated at a psychiatric clinic before. 14 patients suffered from physical diseases caused by their long-term consumption of alcohol. 9 patients did not. 21 patients had palimpsests and only two patients did not have them.9 patients had overcome alcoholic delirium, 14 did had not. 2 patients suffered from alcoholic hallucinations. 21 did not. As far as the preference of specific kinds of alcoholic drinks is concerned, 8 women preferred wine, 1 woman drank wine and vodka, 3 men drank beer, 4 men drank beer and spirits, 2 men drank beer and wine, and 5 men preferred spirits.
DISCUSSION Our knowledge of various classifications of the alcohol dependence syndrome that we used before 1994 and the ones we use in today’s practice, like DSM-III-R, DSM-1V, ICD-9, 1CD- 10 alcoholism subtypes according to Otto M. Lesch, or alcoholism types according to Dobiáš or Jellinek, allowed us to do make more precise diagnoses and better consideration of further continuation of treatment. Some patients are helped by outpatient treatment, combined with anxiolytics, SSRI, SNRI or atypical antipsychotics, but other patients are not clinically motivated to abstinate after detoxification treatment, and in such cases their treatment requires hospitalization. After the return from treatment, there are also crisis periods, which can be decisive for further abstinence (Ignjatović M., Ignjatovićová D., 2001 ). In out-patient treatment, sociotherapeutical groups, support psychotherapy, psychoeducation, and A-clubs can be helpful. There is similar experience elsewhere at the home as well as abroad. Combined treatment is currently being offered as an advantage. We can realize the detoxification treatment of the patient, subsequently prescribe an anti-craving drug, and include the patient into psychotherapeutical treatment, which can result in a much better effect (Robert M. Swift, 1999, Melchior J. A., J. M. Hoes, 1999, Bankole A. Johnson, 2000, Pelz I. et al., 1997).
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There are different ways through which abstinence translates itself. Hoes specifies that a break of abstinence that lasted less than 4 months it considered as a relapse, while a break of a longer than 4-month abstinence it called a recurrence. He also specifies a possibility of treatment with aversive or anti-craving substances (Hoes 1999). Other authors consider abstinence longer than 3 months as a successful one (Mason et al., 2000). When all these views, although mutually differing, are learned, they allow better diagnosing, treatment, and support of longterm abstinence. Besides psychosocial possibilities to understand the issue of dependence, there are also biological aspects of the alcohol dependence syndrome, in which the decisive role is played by the treatment with psychopharmaceuticals. Their mechanisms of action are known, like, for example, a GABA-ergic effect, an inhibitive effect on the glutamate system, and influencing of calcium channels (Michelle l. Wilde et al., 1997, Dahchour A., 2000, Bankole A. Johnson, 2000). By using the biopsychosocial model of the illness (Ďurčik V,, 2001) in the diagnosing and treatment of the alcohol dependence syndrome, the possibilities of learning about it basis and achieving long-term abstinence are widened.As it is pointed out in our study, patients need to he cared for individually, examined thoroughly and recommended for adequate treatment. The result is the duration of their abstinence as well as the subsequent improvement of the quality of their lives. In comparison with the previous methods of treatment, for example by disulfiram, serotoninergic substances, or naltrexone, acamprosate has proved be a promising drug (Pelc, 1977). When compared with naltrexone, the long-term use of acamprosate with naltrexone in the acamprosate group resulted in abstinence lasting for 12 months during which acamprosate was taken and beyond, while in the case of naltrexone, recidiving and a break of abstinence occurred earlier. Both preparations were more successful than the placebo (Melchior J. A., J.M. Hoes, 1999). According to B. Mason, in 14 out of 16 studies conducted in different European countries it was found out that patients dependent on alcohol and treated with acamprosate showed significantly better results in terms of the time to the first drink, abstinence score, and cumulative abstination time than patients treated with the placebo (Mason, 2000).
CONCLUSION The discovery of new preparations that can help to treat the alcohol dependence syndrome is not just a good motivation for patients to abstinate, but also for doctors themselves to widen their knowledge of the possibilities of treatment. It is not just about simple offering of a tablet to the patient that will help him/her to get rid of his/her problems, but complex treatment, in which each new substance, verified in double- blind, placebo controlled perspective studies, should also be proved by the doctor’s personal experience. The experience we have presented in our work is not absolute, but it assesses the way though which we have tried to help the patient in the best possible way. In this process, the anti-craving substance acamprosate has been of substantial help.
LITERATURE Bankole A. Johnson, Nassima Ait- Daoud: Neuropharmacological Treatments for Alcoholism: scientific basis and clinical findings, 2000, psychopharmacology, 149, 327-344 Besson J, Aeby F., Kasa A., Lehert P., Potgieter A.: Combined Efficacy of Acamprosate and Disulfiram in the Treatment of Alcoholism: a controlled study. Alcohol Clin. Res., 1998, 22: 573-579 Dahchour A., Witte P. De: Ethanol and Aminoacids in the Central Nervous System: assessment of the pharmacological actions of acamprosate, 2000, Neurobiology, 60, 343-362 Ďurčik V., About the Role of the Ecology and Psychology on the Threshold of a New Millennium. In: Reforma psychiatrickej starostlivosti, Československá konferencia, 19. - 21. april, 2001, Michalovce Ehlers Cl.,Li TK, Lumeng L , HwangBH, Somes C, Jimenes P., Mathe AA/1998/Neuropeptid Y Levels in Ethanol in Naive AlcoholPreferring and Non-Preferring rats and in Wistar Rats after Ethanol Exposure. Alcohol Clin. Exp res. 22: 1778-82 Evens M: Tiapridal and Alcoholic Detoxification/author’s transla./Acta Psychiatr. Belg, 1980.80: 149-155 ICD-10 Klasifikacija mentalnih poremećaja i poremećaja ponašanja, Klinički opisi i dijagnostička uputstva, WHO, 1992, Beograd, 327: 65-78 Ignjatović M., Ignjatovićová D., Krizové obdobia v liečbe syndrómu závislosti od alkoholu na psychiatrickej ambulancii, Zdravotnicke noviny, ZdN č.5, febr. 2001, in annex Lekárske listy, 1-8: 5 Kolibáš E. Priručka klinickej psychiatric, ASKLEPIOS, 1996, 7-240, 95 118 Kunda S: Klinika alkoholizmu, 1998, Osveta, 5-248 Lesch Otto M., Walter H.. Subtypes of Alcoholism and Their Role in Therapy, Alcohol and Alcoholism, 1996, Vo1.31: Suppl.1, p. 63-67 Lovinger D M., High Ethanol Sensitivity of` Recombinant AMPA-type Glutamate Receptors Expressed in Mammalian Cells, 1993, neurosci Lett, 159, 83-87 Mason BJ, Ownby LR: Acamprosate for the Treatment of Alcohol Dependence: A review of Double-Blind , Placebo-Controlled Trials, Feb. 2000., CNS SPECTRUMS, Vol. 5, No2 Mason B.J., Goodman A.M.: Cognitive Effects of Naltrexone and Acamprosate Administered Alone and in Combination, presented in: Annual meeting or the Research Society on Alcoholism /RSA/June 27-July 1, 1999/Santa Barbara, California/ Melchior J.A., J.M. Hoes: Relapse Preventions in Alcoholics, A review of Acamprosate versus Naltrexone, 1999, Clin. Drug Invest., 17/3/, 211-216 13
Monografia. Campral v liečbe alkoholizmu, 1999, Farmakologický a klinicky prehlad, GROUP LIPHA, 7-6 Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K., Sykora K. /1987/Serotonin Uptake Inhibitor Citalopram Attenuates Ethanol Intake. Clin. Pharmacolog. Ther 41: 266-274 Naranjo CA, Kadlec KE, Sanhueza P, Woodley - :Remus D, Sellers EM/1990/: Fluoxetine Differentially Alters Alcohol Intake and Other Consumatory Behaviors in Problem Drinkers, Clin. Phamracol. Ther 47: 490-498 Naranjo CA., Poulos C.X., Bremner KE, Lanctot KL/I992/Citalopram Decreases Desirability, Liking, and Consumption of Alcohol in Alcohol-Dependent Drinkers, Clin. Pharmacol. Ther, 51: 729-739 Pelc Verbank P, Le Bon P, Gavrilović M, Lion K, LehertP/1997/Efficacy and Safety of Acamprosate in the Treatment of Detoxified Alcohol-Dependent Patients, Br J Psychiatry, 171: 73-77 Rush CR, Pazzaglia PJ/1998/Pretreatment with lsradipine, a Calcim-channel Blocker, Does not Attenuate the Acute Behavioral Effects of Ethanol in Humans. Alcohol Clin. Exp Res22: 539-547 Smolik P: Duševni a behaviorálni poruchy MAXDORF , JESENIUS, 1996, 9-487, 112- 131 Suchopár J.: REMED1A, COMPENDIUM, 3. vydanie, PANAX, 1999, 1 743: 251-252 Swift RM: Drug Therapy for Alcohol Dependence, 1999, The New England Journal of Medicine, 1482-1489 Wilde MI, Wagstaff AJ: Acamprosate A review of its Pharmacology and Clinical Potential in the Management of Alcohol Dependence After Detoxification, Drugs, 1997, Jube, 53/6/, 1038-1053 TABLE I: OVERVIEW OF PATIENTS THAT USED ACAMPROSATE
Number of patients
23
Women Men
9 14
TABLE 2: CHARACTERISTICS OF THE PERIOD OF DRINKING, DURATION OF ABSTINENCE, DETOXIFICATION, AND BREAK OF ABSTINENCE Average age in years Average period of drinking in years Average duration of abstinence in months Detoxification before the start of the use of acamprosate at a psychiatric ward Detoxification before the start of the use of acamprosate at a psychiatric out-patient clinic Break of abstinence within 3 months after the start of the use of acamprosate Break of abstinence later than 3 months after the start of the use of acamprosate Non-relapsing or recidiving patients
43 26 (27 - 59) 10.47 (2 - 39) 7.52 (5 weeks 10 months) 10 patients 13 patients 3 patients 2 patients 18 patients
TABLE 3: PSYCHIATRIC CO-MORBIDITY WITH F.10.25 DIAGNOSIS F.06 F.32 F.34.1 F.40.01 F.43 F.60 Without any other psychiatric co-morbidity
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NUMBER OF PATIENTS 1 9 1 3 2 1 6
TABLE 4: OVERVIEW OF PSYCHIATRIC PSYCHOPHARMACOMETRY THERAPY: ACAMPROSATE ACAMPROSATE + FLUVOXAMINE ACAMPROSATE + FLUOXETINE ACAMPROSATE + CITALOPRAM ACAMPROSATE + PAROXETINE ACAMPROSATE + CLONAZEPAM ACAMPROSATE + CITALOPRAM + CLONAZEPAM ACAMPROSATE + PAROXETINE + CLONAZEPAM
NUMBER OF PATIENTS: 23 5 3 1 1 2 2 7 2
TABLE 5: OVERVIEW OF ADVERSE EFFECTS OF ACAMPROSATE BY SYSTEMS YES NO GASTROINTESTINAL SYSTEM/NAUSEA, DIARRHOEA, ABDOMINAL PAIN/ 1 0 DERMATOLOGICAL/RASH, PRURITUS/ 1 0 MUSCLE SYSTEM /PAIN IN LIMBS / 1 0 NEUROLOGICAL 0 0 GENITOURINARY SYSTEM/IMPOTENCE 1 0 CARDIOPULMONARY SYSTEM 0 0 TIREDNESS 0 0 INCREASED TASTE FOR SWEET THINGS 10 0 INCREASED OR DECREASED BODY WEIGHT 0 0 TOTAL: 14* 0 * NONE OF THE 14 PATIENTS WHO SHOWED THE SPECIFIED ADVERSE EFFECTS INTERRUPTED THEIR TREATMENT WITH ACAMPROSATE
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OUTPATIENT PSYCHIATRIST ACTIVITIES OF CONSULTATIONS IN DIAGNOSTING PROCESS AND TREATMENT OF PSYCHOSOMATIC DISORDERS AUTHORS MUDr.Milan Ignjatović, Psychiatric Medical 0ffice, Health Care Center, Banská Bystrica MUDr. Dana Ignjatovičová, Psychiatric Department, F. D. Roosevelt›s Hospital, Banská Bystrica
SUMMARY 65 patients, 47 females and 18 males aged from 18 to 72 years were treated within consultations on various departments of hospital in Brezno. The most frequent diagnosis for being hospitalized are: chronical vertebrogenous algic polytopic syndrom, hypertension, chronical ischemic heart disease and others. They were diagnosed ex-post in psychiatric medical office and the most frequent diagnosis were psychosomatic disorders. Thereafter the psychiatric therapy had started according to psychiatric algorythm, the most frequent managed treatment was sulpriridum with SSRI’s and combination of benzodiazepins and another drugs. The effectivenes of the treatment was evaluated by patients subjectivelly, while the condition of more than half of all patients improved.
KEY WORDS Outpatient psychiatrist activities of consultation, psychosomatic diseases, sulpiridum, SSRI, benzodiazepins
INTRODUCTION It was Freud who laid the basis of psychosomatic medicine, and in the fifties of the last century came its boom thanks to Franz Alexander /1/. Majority of his researches were formed by psychosomatic disorders with apparatus lesion, which used to be called psychosomatosis in that time /4/. This increase of interest in the fifties of the last century helped to found special psychosomatic departments in some hospitals. It also helped to develop psychosomatic medicine as an interdisciplinary one. Many patients with this diagnosis stay permanently in the care of district GP, internal medicine doctor, neurologist and also of surgeon and finally they need to visit psychiatrist, when their condition is already chronificated and refractory. The patients come there with headaches, insomnia and tension. The psychic symptoms scale is very wide. There are psychic disorders with or without somatisation but of non-organic base, psychosomatic disorders with apparatus lesion and other somatopsychic symptoms /3/. The above quoted doctor continues in his article: „The doctor makes diagnoses of disorders or diseases which he thinks of.” He confirmed by this sentence that the patient’s symptoms should not be evaluated separately but totally within bio-psycho-social model.
METHOD AND GROUP OF PATIENTS The group consisted of 65 patients chosen on the basis of 5 including criteria: 1. somatic diagnosis, 2. psychiatric diagnosis according to ICD 10 (mainly anxious in clinical picture, anxiously depressive syrnptomatology with or without somatisation, disorders such as dissociative, somatoforrn and psychosomatic), 3. therapy before psychopharmacotherapy management, 4. continuation in psychopharmakological treatment (mainly sulpiridum, citalopram, paroxetinum and cionazepainum treatment monitoring), 5. patient’s subjective valuation of treatment.
OBSERVATION The results are based on retrospective evaluation of patients medical records, where focus was on diagnosis of somatic and psychiatric psychopharmacotherapy and patients evaluation of psychiatric treatment. Monitoring and scoring of results were realised in psychiatric medical office from the February 1, 1999 to February 29, 2000. We have chosen two casuistic cases for illustration.
CASUISTIC No. 1: This patent was not included in the study because she has been taking sulpiridum, paroxetinum, clonazepamum for two years of her treatment and patients included in the study were monitored only for period of one year. Since the patient subjectively feels good, we objectively assess that her condition has improved and we chose the patient as a casuistic case. The patient is a 48 years old woman, single, with positive family history, father has undergone surgery 9 times, e. g. ileus, prostate, during the patient’s treatment her father died. Mother is after ventricule resection and agranulocytosis, brother has undergone ventricule resection.
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In her personal history: she vomited once, was treated by her GP without any success for three months. There are also megrimous headaches in her personal history as well as long-term management of alprazolarnum. Social history: single, lives with her parents who she has to take care of, hard working and having troubles with her sick parents (patient’s father died subsequently). She complains on vertebral column pain, insomnia followed by tension in the ventricule area. Last 3 months she had very bad headaches. Fluvoxarninum 50 mg in 1 tablet in the evening. Alprazolamum 0,5 mg in 1 tablet in dose of 0,5 tablet in the morning - no tablet in noon - 0,5 tablet in the evening was long-term managed and within the first revision sulpiridum 50 mg in 1 tablet in dose of 1 tablet in the morning - no tablet at noon - 1 tablet in the evening had been added. After sulpiridum management the condition of patient had improved, she continued treatment. Patient’s father died after 3 montits, the condition got worse, she became to fail in her new work. We excluded alprazolamum and managed clonazepamum 0,5 mg in 1 tablet in the evening. Fluvoxaminum was excluded and substituted by paroxetinum 20 mg in 1 tablet in the morning. Since the patient changed the job and failed in the new one, the requirements were too high, and the charge was growing. She gave a notice from work and is unemployed at the moment. Now she subjectively evaluates her health condition as good and stabilised. Headaches aregone, ventricule is without symptoms. She does not mention any unacceptable effects of the therapy. Sleeping has improved and internal tension is gone. We chose this case as the patient is under sulpiridurn management without evident unacceptable effects, and with combination of another psychopharmatics. Current therapy is: sulpiridium 50 mg in 1 tablet in dose of no tablet in the morning, one tablet at noon, no tablet in the evening, paroxetinum 20 mg in one tablet in dose of one tablet in the morning, no tablet at noon, no tablet in the evening, clonazepamun 0,5 mg in one tablet at the night. The patient is currently taking care of her very sick mother and keeps looking for a new job.
CASUISTIC No. 2: 72 years old patient; female, married, pensioner, long-term treated on: I 25 chronical ischemic heart disease, algic form, hemodynamically. compensated I 10. hypertension WHO II, stabilised I 83 varixy of inferior extremities with the sign of chronical venous insufficiency K 80 status post cholecystectomiam propter lithysiasis in 1990 K 83 postcholecystectomic syndrome K 86 pancreatophaty K 43 status post hemioplasticam in cicatricae post cholecystectomiam M 54 vertebrogenous algic syndrom of cervical and thoracal vertebral column with vertigo J 42 chronical bronchitis currently in remission E 66 exogenous obesity Z 88 personal allergy history on drugs and biological substances The patient visited an internal medicine office very often last year. She was also frequently hospitalised, complaining on nauzea, vertigo, palpitation and epigastric sharp pains. The patient says that her condition improved after being hospitalised and managed infusion, and so she was released from the hospital and sent home. Hospitalisations were short-time and the psychiatrist who had seen her before recommended the patient maprotilinum. This treatment was evaluated by the patient as insufficient. The patient was sent to our psychiatric medicine office in December of last year and we could see that the gastrointestinal symptoms with vegetative disorder were not treated adequate. From the patient’s documentation brought by her we found out that there was not described family, personal or social history in any of these documents. Family history showed us that mother died of kidney failure, her brother died of cerebral failure and her sister is treated on hypertension. Going further in exploration we found out matrimonial problems of the patient with her husband, who often got drunk. Tension was subsequently occurring in the family. We re-evaluated patient’s treatment whose therapy consisted of glyceroli trinitras, isradipinum, pancreatinum, cisapridum, hymecromonum, maprotilini hydrochloridum. Since the patient was considered to have neurastenic syndrome with depressive symptomaticity, later on as pseudoneurastenic syndrome, we made the final diagnosis as a psychosomatic disorder. We excluded maprotilinum and at first recommended revaluation of the treatment by other drugs, reducing or eventually excluding of procineticum and enzyme therapy. We managed sulpiridum 50 mg in 1 tablet in dose of 1 tablet in the morning - no tablet at noon - 1 tablet in the evening, citalopramum 20 mg in 1 tablet in the morning and clonazepamum 0,5 mg in 1 tablet in dose of 1 tablet in the morning - no tablet at noon - 1 tablet in the evening. The patient was sent home and recommended examination the following week, as she was again ready to go home and expected to be hospitalised in the Internal Department. She accepted our assurance with disbelief and after one week came satisfied because in spite of existing family problems the gastrointestinal symptoms have gone, sleep was qualitative,anxiety lost its intensity and vegetative symptoms receded,. The patient came twice for examination and she evaluates her condition as good.
RESULTS There were 65 patients in the group, 18 males (27,69%) and 47 females (72,30%), see Table No. 1. The average age of patients was 47,66 years, the youngest patient was 18 years old, the oldest was 72 years old. The average age of symptoms onset was 43,30 years, see Table No. 2.
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The average duration of symptoms was 4,4 years, the longest duration was 22 years, the shortest one was 6 months, see Table No. 3. The average duration of treatment in the psychiatric medical office was 6,81 months, the longest duration was 15 months, the shortest one was 2 months, see Table No. 4. Thirty seven patients (56,92%) out of 65 still continue in the treatment and 27 patient do not continue the treatment (41,53%) and one patient does not continue the treatment because of hospitalisation (1,53%), see Table No. 5. The list of patient’s diagnosis before the treatment is shown in Table No. 6. We have chosen only one diagnosis, the main one from the group of patients with several somatic diagnoses. The most frequent diagnosis was M 53 (vertebrogenous algic syndrome) in 6 patients, I 11 (hypertension) in 6 patients, I 25 (chronic ischemic heart disease) in 4 patients and the others as well. Thirteen patients were without previous diagnosis. The list of diagnoses in the psychiatric medical office is given in Table No. 7. The most frequent diagnosis was F 45 (psychical and behavioural factors related to disorders or diseases classified elsewhere) in 31 patients, F 45 (somatoform disorders) in 15 patients. Patients followed up in the study were diagnosed and treated with sulpiridum, SSRI drugs (most frequently with citalopramum and paroxetinum), benzodiazepins (clonazeoamum) either in monotherapy or in combination of noted drugs and other psychotropic drugs. The list of therapy is in Table No.8. The evaluation of treatment effectiveness was based on patients’ subjective evaluation, where 31 patients evaluated their condition as good (47,69%), 29 patients didn’t evaluate their condition (44,61 %), 1 patient evaluated his condition as partly improved, but the pain remained, 1 patient felt partial palliation, 2 patients evaluated their condition as partly improved and 1 patient didn’t evaluate has condition as good, see Table No. 9.
DISCUSSION Outgoing from previous classifications, new ICD 10 classification divided all psychosomatic disorders into 3 bigger groups which are dissociative disorder (converse disorder, F 44), somatoform disorder (F 45) and psychical and behavioral factors related to disorders or diseases classified elsewhere (F 54). In our work of consulting experts we mostly come across disorders classified under F 54 which F. Alexander understood as “psychosomatic disorders with apparatus lesion” and he used to call them psychosomatosis. We come across somatoform disorders and dissociative disorders in smaller amount as well. There are various names of factors that can lead into this kind of disorder in different studies. Some authors mention biographical factors for psychosomatic disorders uprise (4) which are listed in ICD 10 as “Z” codes (7). Another authors agree but in different way- there isa psychic conflict in pathogenesis of somatic symptoms. The conflict undergoes a process ofsomatisation and leads into ulcerous disease in some cases. The difficulties are dependent on exacerbation of psychic conflict at the beginning, dissociation of psychosomatic simultaneity may occur afterward (according to Mitscherlich) and so, some kind of somatic autonomy occurs (3). “A long-way” from one medical office to another is written in some patients history and treatment is long termed and complicated in some point. Sulpiridum is often recommended in psychopharmacotherapy, what is based on its biphasic effect. Specific neuropharmacological profile of sulpiridum is predominantly explained by sulpiridum’s blockade of especially D-2 dopaminergic receptors in mesolimbic structures. By its selective bound on presynaptic dopaminergic receptors sulpiridum works as their agonist which leads into greater liberation and turn over of dopamine. Sulpiridum has activating eftect in low doses (tymoanaleptic effect) because of inhibition of dopamine secretion negative feedback, in higher dosage, it has neuroleptic effect which is atypical, especially antipsychotic without any significant influence on mobility (6). Sulpiridum effectiveness on ventricular and duodenal ulceration is related to direct activity of bowel physiologic process. Sulpiridum helps to set psychological stability when patient is under the influence of stress. This is the main reference in discussion about the topic of extensive tasks of sulpiridum in psychosomatic disorders broadly. Diagnosis such as megrim, asthma, dermathosis, rheumatic diseases, urogenital diseases and cardiovascular diseases are arranged in that group (5). Paunovič has the same opinion about the psychopharmacotherapy of those disorder, he adds ulcerous colitis, pruritus, insomnia and allergies to mentioned group (6). Psychosomatic research also showed protective factors that protect people against uprise of psychogenous and psychosomatic disorder, e.g.: 1. long term and good attitude with at least one suitable person, 2. big family, compensatory unloading of mother and others (4). Others put stress on the contact between patient and physician and mention in what the psychosomatic attitude of physician is manifested in the practice: 1. Content of history, 2. Method of history interview, 3. The way of minipsychotherapeutic conversations during control visits (3). Of course, when appropriate diagnosis and well done management of treatment are made and adequate psychopharmacotherapy of e.g. sulpiridum is initiated, the adjuvant therapy of SSRI (8), benzodiazepins, tymoprofylactics and other drugs can be considered. Resolution about the kind of psychopharmacotherapy is based on main and accessory symptoms. The clinical picture is not simple very often as well and its consecutive treatment can be complicated. This could be covered depressions (3), reactive depression with somatisation (5), where sulpiridum can exhibit the same effectiveness as oxazepamum and is more effective than diazepamum and tianeptinum as well (5). Options of psychotherapy are wide as well, like e.g. deeply oriented individual psychotherapy, KBT and especially Balint’s groups that allow to get better view of attitude between physician and patient. 18
CONCLUSION The problem of psychosomatic disorders is quite wide and interdisciplinary. Philosophical debates can lead into better and more successful understanding of these disorders because human being actively affected the nature and “disturbed a contract with the nature” from the beginning of his existence (2). Of course afterward, it was reflected in the relationship with ecological and social factors that can be a predisposition for psychosomatic disorder uprise. The most complex model we should follow in the process of diagnosis and treatment is bio-psycho- social model. We convicted ourselves about this fact very often in the practice- our patients who were long term treated at other departments, missed basic information about family, personal and social history and that is why it was difficult to understand symptoms repeating and frequent hospitalizations. After biographical histories were discovered we successfully understood given patient, identified a diagnosis and managed the therapy. Thereby, psychiatrist activity of consultations represents important part of patient’s treatment who are hospitalized at other departments. On the contrary, good history discover and diagnosis of somatic disorders that are made by other colleagues can help us to solve these kind of patients quickly and successfully.
BIBLIOGRAPHY Alexander F., Benedek Th., 1992: Psychosomatická medicina. Jej princípy a aplikácie, Psychosomatic Medicine, Its Principles and Applications, W. W. Norton and Comp., New York, 1987, 1- 178 Ďurčík V., 1995: Etický aspekt interakcie spoločnosti a prirody, Zbornik symposia ,, Úcta k životu”, TU, Zvolen, s. 1- 113, 109 Gregor O., 1996: Psychosomatický pacient, Praktický Lékaŕ (Praha), 76, 1996, supp. 21-28, 14-15 Haštová M., Hašto J., 1999: Klasifikácia psychosomatických porúch v ICD 10. Porovnanie s klasickými pojmami, Slovenský Lekár 4-5/’99, 175-177 Johnson H and Johnson F.N., 1996: Sulpirid in neurotic, psychofunctional and affective disorders associated with somatoform disorders, overview, Rev. Contemp. Pharmacother., 1996, 7:299-312 Paunovič V. 1996: Sveske iz kliničke psihofarmakologije, (Beograd), 330:96, 244-245 Smolík P., 1996: Duševní a behaviorální poruchy, MAXDORF (Praha), 7-504:48-50 Švestka J. a kol., 1995: Psychofarmaka v klinické praxi, Avocenum (Praha), 249:93-96 Table No. 1 - The number of patients examined and consulted by psychiatrist Absolute numbers 65
The number of patients
Percentage 100
Table No. 2 - The age of patients and average age of difficulties’ beginning
Males Females
18 47
27,69 72,30
The average age of patients The oldest patient The youngest patient The average age of difficulties beginning
47,66 years 72 years 18 years 43,30 years
Table No. 3 - Duration of difficulties The average duration of difficulties The longest duration of difficulties The shortest duration of difficulties
4,4 years 22 years 6 months
Table No. 4 - Duration of treatment in psychiatric medicine office The average duration of treatment The longest duration of treatment The shortest duration of treatment
6,81 months 15 months 2 months 19
Table No. 5 - Continuation in psychiatric treatment
Continued in treatment Did not continued in treatment Hospitalized Total
Absolute numbers 37 27 1 65
Percentage 56,92 41,53 1,53 100
Table No. 6 - Diagnosis before attending the psychiatric medical office Diagnosis, ICID 10 B 49
The number of patients 1
Diagnosis in words Non-specified mycosis
C 53 D 34 E 03 E 04 E 11 E 28 F 48 G 40 G 43 G 45 G 50 G 61 G 99 I 11 I 25 I 51 I 83 J 30 J 45 K 25 K 35 K 51 H 16 M 53 M 54 M 82 N 18 R 10 Z 88 No diagnosis Total
1 1 1 2 1 1 2 2 1 1 1 1 1 6 4 2 1 1 3 2 1 1 1 6 3 1 1 1 1 13 65
Uterus malignance Thyroid benignance Other hypothyreosis Other non-toxical Derbyshire neck Noninsulindepedent DM Functional disorders of ovaries Other neurotical disorders Epilepsy Megrim Transtory ischemic attacs and related syndroms Neuralagy of n. trigeminus Inflammatory polyneuropathy Other NS disorders by diseases classified elsewhere Hypertension Chronical ischemic heart disease Cardiovascular diseases and vaguely described heart diseases Varixy of inferior extremitatis Vasomotoric and allergic coryza Asthma Ulcus ventriculi Appendicitis acuta, st. post APE Ulcerous colitis Coxarthrosis Vertebrogenous algic syndrome Dorsalghia Ostheophorosis Chronical kidney failure Abdominal pain and per-menstruation syndrome Personal allergy history on drugs and biological substances -
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Table No. 7 Survey of diagnosis in psychiatric medical office ICD 10 diagnosis F 06
Absolute numbers 6
Percentage 9,23
F 19 F 40 F 41 F 43 F 44 F 45 F 54 F 61 Total
1 7 1 1 2 15 31 1 65
1,53 10,76 1,53 1,53 3,07 23,07 47,69 1,53 100 Table No. 8 --- Survey of theraphy in psychiatric medical office
Generic name of the medicament Sulpiridum Paroxetinum Tianeptimum natricum Fluoxetinum Sulpiridum + citalopramum Sulpiridum + clonazepamum Sulpiridum + other medicament Sulpiridum + other SSRI Citalopramum + clonazepamum Paroxetinum + clonazepamum Tianeptimum natricum + clonazepamum Dibenzepini hydrochloridum + clonazepamum Sertralinum + alprazolamum Oxazepamum + prochlorineperazinum Sulpiridum + citalopramum + clonazepamum Sulpiridum + paroxetinum + clonazepamum Citalopramum + clonazepamum + other medicament Sulpiridum + clonazepamum + other medicament Sulpiridum + citalopramum + other medicament Sulpiridum + 2 other medicaments Sulpiridum + paroxetinum + acidum valprocium, natrii valproas Sulpiridum + citalopramum + clonazepamum + acidum valprocium, natrii valproas Sulpiridum + clonazepamum + natrii valproas + carbamazepinum Risperidonum + sertralinum Risperidonum + sertralinum + clonazepamum Risperidonum + tianeptimum natricum + bromazepamum
Number of patients 2 2 1 1 5 7 1 5 1 1 1 1 1 1 8 9 1 5 3 1 2
Total
65
1 1 2 1 1
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Table No.9 – Subjective evaluation of treatment
Partly improved condition but pain chronicity
Absolute numbers 1
Percentage 1,53
Partly relief Condition is improved Condition is good Non-valuation of condition Treatment was not good Total
1 2 31 29 1 65
1,53 3.07 47,69 44,61 1,53 100
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POSSIBLE ADVERSE EFFECTS IN THE TREATMENT OF AGORAPHOBIA WITH VALPROIC ACID AND NATRIUM VALPROATE- OUR ONE YEAR EXPERIENCES AUTHORS MUDr. Milan Ignjatovitć 1 MUDr. Dana Ignjatovićová 2 MUDr. Jasmina Janković- Gajić 3 Psychiatric medical office, Health Care Center, Banská Bystrica, Slovak Republik Psychiatric medical office, Heaith. Care Center, Banská Bystrica, Slovak Republik Psychiatric medical office, KBC D. Mišković, Beograd, Yugoslavia
SUMMARY Valproic acid and natrium valproate have accurately defined diagnostic area in psychiatry which are mostly affective disorders. Their indication was enlarged latterly by panic disorder which hasn’t responded to the conventional therapy. Patients with panic disorder have tried different kinds of drugs very often and there were diagnosis such as polytopic vertebrogenous algic syndrome, epilepsy, megrim, vertigo and others in their medical history. Within these kinds of diagnosis, they were given different kinds of drugs that could mutually interact. The main goal of the study was to verify if there is a hepatotoxic effect after one-year management of valproic acid and natrium valproate combination. We checked the hepatotoxicity by common biochemical parameters which are available at psychiatric medical office (Bilirubin, ALT, AST, GMT, ALP) without the assessment of serum level of managed drugs. Noted biochemical parameters were assessed before the treatment of valproic acid and natrium valproate, and then one month, six months and twelve months after the treatment. The treatment was assessed retrospectively during the period of time of one year from March 1, 2000 to March 31, 2001 in the group of 9 patients (women N= 8) at the psychiatric medical office of the first author. The average age of patients was 47,7’7 years. The results of this study show that although there was mild elevation of enzymes (aminotransferases) after the management of valproic acid and natrium valproate, these levels didn’t exceed the physiological levels.
KEY WORDS Panic disorder, valproic acid, natrium valproate, possible adverse drug effects concerning Hepatotoxicity
INTRODUCTION Valproic acid and natrium valproate are used in psychiatric patients for their antidepressive (Calabrese J.R., 1993, Swann A.C., 1997) antimanic (Pope H.G., 1991, Bowden Ch.L., 1994, McElroy S.L., 1996) and antiagressive effect (eventually in personality disorders) as well as in cases of pharmacoresistance to others antidepressive drugs, such as lithium (Pope H.G., 1991) and karbamazepinum. It is used successfully with patients with short cycling (Švestka J., 1995, Calabrese J.R., 1993, Bowden Ch.L., 1994). Besides, its usage is recommended in cases of anxious disorders, especially in case of panic disorder with no respond to conventional therapy (Baetz M., 1998). There are different theories on panic attack origin; serotonin theory is one of them. Even though all the theories are not expressly confirmed in clinical practice (Charney D.S., 1986). There are speculations about connection between attack affections (narcolepsy, epilepsy) and panic disorder in domestic scientific area. Comorbidity of panic disorder with various affections (mitral valve prolapses, asthma, depression) is listed. There is another hypothesis on the connection between panic disorder and megrim based on serotonin neurotransmitter system dysfunction (Kukumberg P., 1999). The usage of natrium lactate for panic attack induction is known in experiments. There are experiments of usage of valproate as an anticonvulsive drug for panic attacks (antipanic effect). There are several reasons for that: it improves GABA activity in brain it has anxiolitic effect in animal experiments it was reported as an effective drug in case of panic attack in some preliminary studies but it has not been systematically assessed in prevention of panic attack inducted by natrium lactate (Keck P.E., J., 1993). There is comorbidity and consequently polyprogrnasy seen in the case of panic disorder at the psychiatric medical office very often. In consideration of possible interactions between managed drugs the development of functional or morphological apparatus damage that participate on drug biotransformation is possible as well (Majkić- Singh N., 1993), including apparatuses that don›t directly participate on drug biotransformation (e.g. polycystic ovarian syndrome in women with epilepsy). Direct contingency between management of sodium valproate and polycystic ovarian syndrome has not been proved in this trial; more prospective trials must be realized (Duncan S., 1998).
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The apparatus that is directly involved in drug biotransformation is liver and its function can be impaired by the management of these drugs. (Jiminez - Rodriguezvila, 1995). The hepatotoxicity is manifested by biochemical as well as by morphological changes of liver tissue. The most frequent changes are elevation of ALT and AST (Kriška M., 2000). We know from various bibliografical sources that there are more than 200 different clinical- chemical methods which are used for liver impairment testing. Liver is the greatest gland in the body and it is used as the central metabolic apparatus. The first diagnostic step of apparatus damage confirmation is detection of enzymes and their izoenzyrnes in the serum. Hepatitis caused by drugs and other chemical substances is known as toxic hepatitis. Liver is the main location of drug metabolism and hepatocellular effects caused by the drugs are regarded as direct toxic effects (predictable, direct hepatotoxic) and Flosyncratic (unpredictable, hepatitis alike). (Majkić- Singh N., 1993).
THE GOALS OF THE STUDY The main goal of the study was to follow up possible biochemical parametens changes that should suggest drug hepatotoxicity. The parameters were checked before management of valproic acid and sodium valproate, after one month of the management, after 12 months and after 1 year of noted drug management with combination of other psychotropic drugs. We have followed up the level of cumulative Bilirubin, AST, ALT ALP, GMT.
SET AND METHODICS We have retrieved patients who suffer from agoraphobia with panic disorder that is resistant to conventional psychopharmacotherapy in the cardfile of psychiatric medical office of the first author. Noted mental disorder has been diagnosed according to DSM IV classification (Kaplan et al., 1994) and MKCH - 10 classification. Patients with psychiatric comorbidity were excluded from the observation. The overall amount of evaluated patients reached the level of 9, one from the group was male. The average age of the group members was 47,77 years (at the interval from 21 to 57), the patients were monitored in the psychiatric medical office of the first author during the interval of one year from the March 1, 2000 to March 31, 2001.In the treatment of all patients valproic acid and sodium valproate with combination of other psychotropic drugs in all cases were used. The treatment of patients and possible hepatotoxicity were observed during the interval of one year. No patient noted any adverse effects of valproic acid and sodium valproate (e.g. gastrointestinal system, headache, somnolence and others). Clinical status (condition) of all 9 patients has markedly improved (no panic attacks, no agoraphobic behavior nor anticipate anxiety) and has been subjectively evaluated by patients as good. We have followed up biochemical parameters which indicate possible hepatotoxicity before the management of valproic acid and sodium valproate with combination of other psychotropic drugs and after noted management. The study has not been submitted to the ethic committee for approval because the study was the retrospective evaluation of medical documentation.
RESULTS The results are stated in Table No. 1 and Table No. 2. Whereas these were cases of resistant statuses of agoraphobia with panic disorder, valproic acid and sodium valproate in combination with other psychotropic drugs were used in the treatment of all 9 patients. Valproic acid and sodium valproate were used in cases of: 2 patients who received SSRI with high potent benzodiazepin 4 patients who received SSR1 with neuroleptic drug and benzodiazepin 1 patient who received SSRI with TCA and benzodiazepin 1 patient who received SSRI with TCA, benzodiazepin and neuroleptic drug and 1 patient who received SSRI with benzodiazepin and tymoprophylactic drug From the group of SSRI 6 patient received paroxetinum, 2 patients received sertralinum and 1 patient received citalopramum. 9 patients received clonazepamum, 1 patient received suipiridum, 1 patient received haloperidolum, 1 patient received prochlorperazinum and 2 patients received risperidon. One patient received maprotilinum, 1 patient received dosulepinurn with combination of SSRI, high potent benzodiazepin, valproic acid and sodium valproate. 1 patient received carbamazepinum with combination of SSRI, high potent benzodiazepin, valproic acid and sodium valproate. We followed up biochemical parameters which suggest possible hepatotoxicity. We didn’t find any abnormality in previously noted data in any of our patient in the interval of one year combined therapy of valproic acid and sodium valproate. Changes of biochemical parameters were in the interval of normal levels.
DISCUSSION Liver - our the greatest biochemical factory processes huge amount of chemical substances and drugs. Drugs and chemical substances which can lead to hepatocellular impairment depending to their dose belong to the group of direct hepatotoxins. Clinical picture is variable and depends on the origin and dose of toxin. If the management of drug is excluded, liver completely restitutes.
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Idiosyncratic, hepatitis alike reactions can occur after the management of e.g. MAP inhibitors, antituberculotic drugs, sulfonamides, metyldopa, after halotane anesthesia (Majkić- Singh N., 1993).In the treatment of agoraphobia with panic disorder antidepressive drugs of the SSRI group are mostly used (Praško J., 1995) and possible interactions between this group of drugs and other drugs are hypothetical in most cases. The process of metabolism runs through izoenzymes. This substances react as substrates, inductors or inhibitors of other drugs metabolism in noted pathway (Švestka J., 1998). Sodium valproate should be inhibitor of CYP 450, it inhibits SSRI metabolism what can also influence their metabolism. That in clinical practice means possible adverse effects uprise that can be severe in some cases (Švestka J., 1998). Biotransformation of sodium valproate runs through CYP 2C19. The majority of SSRI is CYP 450 inhibitor and their biotransformation runs through different CYP 450 (e.g. CYP 2D6 metabolize paroxetinum). Moreover, drugs can be hepatotoxic and various liver tissue impairment can cause changes in serum enzymes levels. According to internationally accepted nomenclature, liver impairment is classified as hepatocellular (acute and chronic hepatitis and cirrhosis), cholestatic (e.g. obstructive disease of biliary tract) neoplastic and infitrative diseases. Serum enzymatic profiles present in cases of drug inducted liver impairment vary a lot and imitate practically each kind of liver disease. That is why it is very difficult to detect and classify the manifestation that was caused by some kind of drug. To simplify the diagnostic process, the following rules were made: activity of GMT is unequally elevated and 3 factors are excluded - alcohol, obstruction of biliary trot and invasive processes of liver normal GMT activity, other enzymes are elevated (AST, ALT, ALP...) cholinestherasis activity quickly droops or is the only one that is low if liver enzymes activities are pathological in serum and histopathological picture is normal (Majkić- Sinhg N., 1993). Hepatotoxicity can be manifested by elevation of ALT, AST (Kriška M., 2000). At the same time the author notices that the elevation of ALP is important as well and depression of albumin is more serious because from the view of possible developing liver lesion the diagnosis is more severe. In the study where 1172 epileptic patients received slowly soluble valproate (Bergmann A., 1999) as monotherapy or in combined therapy with other antiepileptic drugs or other drugs was fond that valproate is well tolerated and effective in all types of epileptic seizures in monotherapy management and polytharapy management as well. We didn’t find such voluminous studies on valproic acid and sodium valproate in psychiatry relative to agoraphobia with panic disorder nor the studies on their hepatotoxic influence. The usage of valproate in cases of resistant panic disorders (Baetz M., 1998) and management of valproate in cases of sodium lactate inducted panic attacks was published (Keck P.E., 1993). Whereas these were resistant types of disorders valproate was not managed in monotherapy but in combination with SSRI, TCA, high potent benzodiazepin, neuroleptic drugs and tymoprofylactic drug in all patients in our study. We didn’t find changes in biochemical parameters besides their drift in the interval of physiological levels. From the previously stated data about possible hepatotoxic effects we didn’t find abnormalities, which should confirm hepatotoxic effects in the group of our patients who received valproate in combined therapy during one-year interval. Our study has the following shortcomings: low number of patients polytherapy impossibility to evaluate serum level of managed drugs according to unavailable laboratory tests subjective evaluation of patient’s condition improvement without aggregate scales of appraisal
CONCLUSION Even though valproate is more frequently used in neurology, its usage is effective in the treatment of resistant agoraphobia with panic disorder in psychiatry. We found valproate as well tolerated, effective and without any adverse effects connected to possible hepatotoxicity during its management in cases of agoraphobia with panic disorder resistant to conventional therapy.
BIBLIOGRAPHY Baetz M., Rudradeo C. Bowen, FRCPC, Efficacy of Divalproex Sodiumin Patients with Panic Disorder and Mood Instability Who Have Not Responded to Conventional Therapy, Can J Psychiatry, Vol. 43, February 1998, 43: 73- 77 Bergmann A., Schmidt P., Hutt H-j, Elger C.E., Epilepsy Treatment with a Sustained- Release 2. Bowen L. Ch., Brruger A., Swann A.C., Efficacy of Divalproex vs Lithium and Placebo in the Treatment of Mania. Journal of the American Association, march 23- 30, 1994, Volume 271 Calabrese J.R., Woyshvilli M.J., Kimmel S.E., Rapport D.J., Predictors of Valproate response in Bipolar Rapid Cycling, Journal of Clinical Psychopharmacology, 1993, Vol. 13, No 4, 280- 283 Chaney D.S., Heninger G.R., Serotonin Function in Panic Disorder, Arch gen Psychiatry, 1986, 43: 1059- 1065 Duncan S., Polycystic Ovarian Syndrome in Women with Epilepsy, Aspects of Epilepsy, 9, Oct., 1998, 1- 5 Jiminez- Rodriguezvila M., Caro- Paton A., Conde M et al: Side effects of sodium valproate, mainly related to its hepatic and pancreatic toxicity, Int J Clin Pharm Res 6, 1986, 217- 224 Keck P.E. Jr, Taylor V.E., Tugrul K.C., McElroy S.L., and Bennett J.A.: Valproate Treatment of Panic Disorders and LactateInduced Panic Attacks, Biol. Psychiatry, 1993, 33: 542- 546 25
Paško J., Agorafobie In” Raboch J. ed. Psychiatrie. Doporučené postupy psychiatrické péče. Praha: Česká psychiatrická společnost, Galén, 1991, 41- 61 Kukumberg P., Panická porucha a migréna, Čes. a Slov. Neurol. Neurochir., 62/ 95, 1999, No 1, p. 57- 59 Kriška M a kol., Rizoko liekov v medicínskej praxi, Slovak Academic Press, 2000, Bratislava, 474: 307 Majkić- Singh N., Klini6ka enzimilogija, Univerzitet u Beogradu, Farmaceutski fakultet Zavod za Medicinsku Biohemiju, Klinički Centar Srbije,. Institut za Medicinsku Biohemiju, Beograd, 1993, 875: 225, 257, 269, 272, 273 McElroy S.L.,Keck P.E., Stanton S.P., Turgul K.C., Bennett J.A., Strakowski S.M: A Randomized. Comparison of Divalproex Oral loading Versus Haloperidol in the Initial Treatment of Acute Psychotic Mania, J Clin Psychiatry 1996, 57: 142- 146Pope H.G., McElroy S.L., Keck P.E., Hudson J.I: Valproate in the treatment of Acute Mania, arch. Gen Psychiatry- Vol 48, january 1991 Swann A.C., Bowen Ch.L., morris D., Calabrese J.R., Petty F., Small J., Dilsaver S.C., Davis J.M> Depression During Mania, Arch. Gen Psychiatry, Vol 54, January 1997 Švestka J. a kol., Psychofarmaká v klinické praxi, Grada Publishing, 1995, 241, 117 Švestka J.: SSRI léky prvé volby, MAXDORF JESSENIUS 1998, 153: 83, 93 TABLE NO.1 - AVERAGE LEVELS OF IOCHEMICAL PARAMETERS TESTED IN PSYCHIATRIC MEDICAL OFFICE DURING ONE YEAR INTERVAL
AST ALT ALP GMT Prote-ins total
0 month
1st month
6th month
12th month
0,13 0,16 1,46 0,36 8,93
0,22 0,36 1,23 0,34 8,24
0,29 0,30 1,47 0,36 7,33
0,28 0,33 1,43 0,34 8,26
Physiol-ogical level 0,0-0,65 0,0-0,7 0,57-1,57 0,17-1,12 5,0-20,5
TABLE NO. 2 - LIST OF PSYCHOPHARMACOLOGIC MANAGEMENT
val-proic acid* sodium valp-roate
SSRI* BD**
SSRI NL*** BD
SSRI TCA*** BD
2
4
1
SSRI TCA BD NL 1
SSRI BD tymopofyl-active drug**** 1
* 6 patients received paroxetinum, 2 patient sertralinum, 1 patient citalopramum ** BD = high potent benzodiazepin- clonazepamum which was received by 9 patients *** NL = sulpiridum 1 patient, haloperidolum 1 patient, prochlorperazinum 1 patient, risperidon 2 patients **** TCA = maprotilinum I patient, dosulepinum 1 patient **** tymoprofilactive drug = carbamazepinum 1 patient
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THE EFFICACY OF DEPRESSION TREATMENT WITH MILNACIPRAN (A SIX- MONTH EXPERIENCE) AUTHORS Dana Ignjatovičová, M.D. (1) Milan Ignjatović, M.D. (2) Silvia Beatriz Schweitzer, M.D. (3) (1, 2) Private Psychiatric Outpatient Surgery, Cesta k nernocnici 1, Banska Bystrica, Slovak Republic (3) Psychiatric Department, Cespedes, Buenos Aires, Argentina
Summary Depression represents one of the most frequent and grave psychical alienations. It manifests itself by tiredness, sleeping malfunction, headaches, loosing or putting on weight, and failure of sexual function. Bad mood, however, is not necessarily the most dominant symptom G. N. Christodoulou, 2002] It means that together with the establishment of the right diagnosis it is very important to manage an adequate treatment of depression. Some of the key points, not only in the conditions of outpatient treatment, are anamnesis exploration of previous depressive episodes, family anamnesis of affective diseases, and clinical exploration in relatives. Depression today represents the 4th most frequent cause of health damage or loss of life due to early affection or mortality. It is expected that depression will become the 2nd in 2020 [G.N.Christodoulou, 2002]. In the U.S.A., yearlong prevalency represents 12.9% in women and 7.7% in men [Kessler et al., 1994). In Europe, prevalency is 17% [Lepine et al., 1997]. Our 6-month follow-up included 12 patients using milnacipran 100 mg per day. We made evaluations of HAMID and HAMA at the start (it means on the first day of the follow-up) and used the CGI scale. Two patients were discarded from our followup: one patient had discontinued the medication on her own in the 4th month of the course of treatment and the other one was hospitalized due to a high risk of suicidal tendencies (HAMD-39 points, HAMA-28 points). We have evaluated HAMD on the first day of treatment, then one month later, and then half a year after the setting up of milnacipran 100-mg per day. In the 2nd month we did not observe any kind of strong amelioration (HAMD-19.8 points), but in the 6th month HAMD reached to 7.1 points.
Key words Depression, HDRS (Hamilton Depression Rating Scale), CGI (Clinical Global Impression), milnacipran Introduction The development of new antidepressive drugs in last fifty years has come through the complicated way which was started by the antidepressive effects discovery of iproniazid (an antituberculotic agent) in 1950 and imipramine (an antihistamine) in 1955 [David J. Nutt, 2002]. The progress has finally resulted in the present very effective and strongly selective antidepressive medicaments accompanied by a minimum of undesirable effects - venlafaxin, milnacipran [S.M. Stahl, 1997]. Tricyclic antidepressives (TCA) are strongly effective, especially in the treatment of harder depressions [P. Boyer and M. Briley, 1998, S. A. Montgomery, 1999], but they are characterized by a large number of undesirable effects. At the same time, it must be said that SSRI have at least the same efficacy as TCA [J. Švestka, 1998]. SSR1 are safer and better accepted by the patient. Nevertheless, they are not so effective for grave depressions [M. Briley, 1997], but they have their own exceptional position in the treatment of depressions, especially those connected with anxiety. SNRI antidepressives are more effective compared with the effect of placebo in a big depression episode treatment [Y. Lecsubier, 1997] and have the same effect as TCA, but theyare much better accepted by the patient [Kasper, 1996]. The effect of SNRI in comparison with SSRI is almost on the same level [P. Boyer and M. Briley, 1998, M. Briley, 1997], but their dual effect on noradrenergical and serotoninergical neurotransmission foreshadows higher effectiveness than in SSRI. Thanks to this fact, SNRI have become very promising antidepressants [P. Boyer and M. Briley, 1998]. Depression represents a heterogeneous unit with a different variety of forms. It ranges from a light depressive episode, through dysthymia to grave depression, which requires hospitalization [S.A. Montgomery, 2001]. Symptoms of depression change according to the functional activity of the neurotransmitter system. Considering this, we can divide the symptoms of depression into two groups. The first one is serotoninergic and the second one is noradrenergic. It corresponds generally with the concept of impulsiveness, aggressivity, lower sexual appetence (5-HT system), and lack of motivation and energy (NA system), or when mixed, with anxiety, irritability, bad humour, and failure of cognitive functions [S.A. Montgomery, 2001]. It means that antidepressives with a dual effect (venlafaxin, milnacipran) show a theoretical promise to suppress, by their dual effect, the symptoms of depression. The catecholaminal hypothesis [Schmidtkraut and Kety, 1967] assumes that depression results from an insufficient activity of central noradrenergic neurons, whereas the indolaminal hypothesis [Van Praag, 1982] talks about a deficit of the activity of central serotoninergic neurons [Moret, 1985].
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Milnacipran is a new antidepressant inhibiting the reuptake of serotonin and noradrenaline in vitro and in vivo without an effect on the reuptake of dopamine. Microdialyses confirmed a higher extracellular level of serotonin and noradrenaline. Milnacipran does not show any evidence of interaction with known neurotransmitter receptors. In comparison with TCA, chronic milnacipran administration does not modify the linkage to beta-adrenoreceptoral sites or the function of the second messengers [P. Boyer and M. Briley, 1998]. Observed group and methodology The group under observation included 12 patients. Women (n = 8, average age = 41.33 years, age interval, 22y-60 years). Two female patients were rejected out of the follow-up. One has discontinued the treatment at her own request (but not due to undesirable effects) and the second one was hospitalized (HAM:D-39 points, HAMA-28 points). We have made HAMD and HAMA evaluations on the first day, then after one month and then in the sixth month of the followup. We have evaluated CGI, too. All patients took milnacipran in a dose of 100 mg per day. Criteria for insertion: age 18 - 60 years MKCH-10 and DSM-IV diagnostic criteria for an intermediately grave (F.32. I) to a grave episode of depression without psychotic symptoms (F.32.2) HAMD up to 18 points 6 months follow-up Criteria for rejection: comorbidity together with other psychical diseases organic psychical affects mania, hypomania dysthymia schizophrenia, schizoaffective failures alcoholism and other kinds of dependence pregnancy epilepsy in anamnesis cardiac rhythm failures in anamnesis important somatic diseases A certain shortage of this study could be a small group of patients in whom we observed the clinical status and evaluated HAMD and HAMA scales. But we did not make MADRS evaluation, which is frequently used in control studies. Another shortage of this paper is the duration of the study. The follow-up lasted only for six months and we did not make HAMD and MAHA evaluations in the third month. There were only three evaluations — on the first day, after one month, and on the last day of the follow-up.
Goals of study: to compare the results of HAMD on the first day, after one month, and in the sixth month of the follow-up using milnacipran in a dose of 100 mg pro die to note any undesirable effect of milnacipran during a six months lasting follow-up
Results We have included 12 patients into the follow-up, using the criteria of inclusion (Table 1). We used HAMD, HAMA (Table 2), and CGI for the evaluation. We rejected two patients. The averageHAMD on the first day of the follow-up was 21.5 points, HAMA15.4 points. After one month, the average was HAMD-19.8 points (only 1.7 points amelioration) and HAMA-12.4 points. After a six-month follow-up, it was HAMD-7.8 points (13.7 points amelioration) and HAMA-7. 1 points. Three of the 10 patients under observation had already been treated for an episode of depression in the past. All of them used SSRI and anxiolytic agents. In the patients we found the following undesirable effects: dryness in the mouth - 2 patients, dysuria - 3 patients, GIT troubles - 1 patient (Table 3). For complex evaluation of treatment efficiency, we used CGI (Clinical Global Impression).
Discussion Clinical studies are a suitable source of information about new preparations, but physicians have to verify their effect when prescribing them to patients [S.A. Montogomery, 1999]. Noradrenergic and serotoninergic neurons take the most important part in the mechanism of the effect of neurons. /S. Kasper, 2002/. We can say that medicaments in which two or more synergic effects are combined together might have a higher therapeutic effect and toleration comparable to the therapeutic mechanism of the effect of highly selective substances (S.M. Stahl, 1997). Milnacipran is a cyclopropane derivative which inhibits noradrenergic and serotoninergic reuptake in the presynaptic area. No activity of postsynaptic receptors was observed. The most frequently used dose is 50 mg of milnacipran two times per day [C.M. Spencer and M. Wilde, 1998]. A dose of 100 mg of milnacipran pro die manifested a sufficient effect in our six-month follow up. Amelioration appears mostly in the second week of therapy [Spencer and Wilde, 1998] with a daily dose of 100 mg (4 weeks - 3 months follow up). We observed not so marked amelioration after one-month therapy (HAMD 1=21.5 points, HAMD2=19.8 points - 1.7 points difference).
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Milnacipran had an equal effect to those of imipramine and clotnipramine, 150 mg pro die in Japanese patients [Spencer and Wilde, 1998]. Milnacipran was less effective than clomipramine in our 6 months study. A comparison was carried out concerning the effects of milnacipran 50-100 mg and 20 mg fluoxetin pro die, 200mg fluvoxamin pro die and rnianserin 30-60mg pro die in the 4th and 12th week. Milnacipran had the same effect on hard depression as TCA and SSRI during the 4-12 week follow-up. Milnacipran was very well tolerated with a minimum of undesirable effects dysuria 7% [Spencer and Wilde, 1998]. According to the study of Kasper et al., 1996, one of the most frequent undesirable effects during milnacipran therapy is dysuria (2.1%). Pending our follow-up of undesirable effects occurrence, dysuria appeared in three patients, dry mouth in two patients, tremor in two patients, gastrointestinal troubles in one patient, and obstipation in one patient. These results are comparable with the international studies [Spencer and Wilde, 1998; Kasper, 1996]. The reported undesirable effects did not result in discontinuation of milnacipran therapy. A very important thing for the effect comparison of medicines is comparative studies, multicentred and placebo-controlled. In our study we focused on the results of a six-month milnacipran therapy course in ambulatory conditions but we did not compare it with placebo and SSRI. It would be desirable to do it in the future. Several studies were published in the United States which covered 527 ambulatory patients (131 patients used milnacipran 25mg pro die, 130 patients used milnacipran 50mg pro die, 133 patients milnacipran 100mg pro die, and placebo was used by 133 patients). The follow-up included HAMD results with more than 22 points (average entering HAMD in our study was 21.5 points), MADRS, and CGI. The results of milnacipran 100mg per day were significantly better than placebo (p < 0.01). There were about 64% responding patients pending 8 weeks’ follow-up with a milnacipran dose of 100 mg per day [Y. Lecrubier, 1997]. The follow-up included 68 patients with a milnacipran dose of 50mg in comparison with 49 patients treated with placebo in Europe. HAMD was higher than 22 points --and according to the results the differences were not statistically significant. [Y. Lecrubier, 1997]. A milnacipran dose of 50mg in 29 patients and placebo in 29 patient were compared in the third study. Together there were 58 hospitalized patients and after 4 weeks’ follow-up HAMD changed from 18.7 to 7.1. We observed HAMD, which at the beginning of study was 21.5 points. After a month, HAMD became 19.8 points, which means only 1.7 points amelioration. At the end of the 6th month, HAMD was 7.8 points. Amelioration was thus 13.7 points compared with the first of the follow-up. We also evaluated global clinical impression. The grade of illness importance on the first day of the follow-up: intermediate (6 patients), hard (4 patients). Grade of illness importance at the end of the 6th month was: normal, no evidence of illness (5 patients), marginal evidence of illness(5 patients). Very clearly global amelioration appeared in all 10 patients. During the four months lasting follow-up of patients with a milnacipran dose of 50mg per day, all patients were evaluated as very clearly ameliorated [Rouillon, 2000]. Although a group of 10 patients is small, the results show that our experience is comparable to the studies made in the US and Europe (France and Sweden), which demonstrate that new SNRI medicaments specifically affecting serotonin and noradrenaline are more effective on hard depression than SSRI and possess the same effect as TCA with a smaller number of undesirable effects {Briley, 1998]. Another six-month study made on a small group of 41 patients and comparing 100mg milnacipran to 75 mg clomipramine showed a 50% reduction of HAMD. But there were no significant differences in MADRS and CGI scales [P. Boyer and M. Briley, 1998]. Many studies confirmed milnacipran effectiveness in the therapy of depression compared to other antidepressive agents [Hndmarch,1997, Kasper, 1996, Spencer, 1996]. These published studies helped us to understand the theoretical basis of milnacipran role in hard depression episode treatment which we verified in practice. Conclusion Depression is very a heterogeneous unit [S.A. Montgomery, 2001]. It has various manifestations requiring complex and adequate antidepressive therapy. Milnacipran exerts its effect on basic depression symptoms including anxiety, sleeping malfunction, and psychomotoric retardation. It does not affect memory functions. Milnacipran does not have any interaction via the cytochromic system P-450 and could be effective in patients with concomitant pharmacotherapy. It does not affect the cognitive functions and that is why it is very suitable for the use by older and anxiety patients. Although it has no sedative effect, it adjusts sleeping malfunctions. Milnacipran seems to be a safe, well tolerated, and highly effective antidepressant in the treatment of intermediate to hard depressive episodes with minimal undesirable effects. It depends on our clinical experience whether milnacipran will become the medicament of the first line in depression treatment [S. A. Montgomery, 1999]. Literature Boyer P., Briley M.: Milnacipran , a New Specific serotonin and noradrenaline reuptake inhibitor, Drugs of Today, 34/8/,709-720,1998. Briley M.: From Dirty Drugs to Hyperselectivity and Part Way Back Again, Human Psychophartnacology,Vi1.12,S121-S125,1997. Briley M.: Milnacipran, a Well Tolerated Specific Serotonin and Norepinephrine Reuptake Inhibiting Antidepressant, CNS Drug Review,Vol.4, No2, pp137-148,1998. Hindmarch I.: Do we need New Antidepressants?, Human Psychopharmacology,Vo1.12, S115-S119,1997.
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Christodoulou G.N., Kontaxakisová Beata J.Havali, Kontaxakis Vassilis P.: Prevecnia depresie, WPA buletin o depresie, Roč.5-č.24, 2002, 3-9. Kasper S.: Optimizing antidepressant treatment :are two actions better than one?, International Clinical Psychopharmacology,Vol.17, June 2002. Kasper S., Pletan Y., Solles A., Tournoux: Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results, International Clinical Psychopharnracology,1996,vol.11/ suppl. 4/ 35 39. Kessler RC ,McGonagle KA, Zhao S., Nelson CB, Hughes M, Eshleman S, Wittchen Hu, Kendler KS: Lifetime and 12 months prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.ArchGen Psychiatry 51,8-19,1994. Lecrubier Y: Milnacipran: The Clinical Properties of a Selective serotonin and Noradrenaline Reuptake Inhibitor SNRI/, Human Psychophamracology, Vol.12,S127 S134,1997. Lépine JP, Gastpar M., Mendlewicz J., Tylee A: Depression in the community: the first pan-European study DEPRES/Depression Research in European Society/Int.Clinical Psychopharmacol.,12,19-29,1997. Montgomery SA: From the theory to practice-everyday use of milnacipran, International Journal of Psychiatry in Clinical Practice, Vol.,3,Suppl.2, PS29-S33,1999. Montgomery SA: Dual action antidepressants in clinical practice, Drugs, 3,1,P43 P49,2001. Moret C., Charveron M., Finberg J.P.M., Couzinier J.P., Briley M.: Biochemical Profile of Midalcipran/F2207/,1-Phenyl-1Diethyl-aminocarbonyl-2-aminomethyl- cyclopropane/Z/Hydrochloride, a potential fourth generation antidepressant drug, Neurophamracology, Vol.24,Nol2pp 1211-1219, 1985.Nutt D.J.: The neuropharrnacology of serotonin and noradrenaline in depression, International Clinical Psychopharmacology,17,Suppl.,S1-S12,2002. Poirier M.F,Galinowski a.,Longevialle R.,Loo H.: Comparative study of rnilnacipran versus placebo on cognitive function in healthy volunteers,. 3 erne Conférence Vigilance et Performances Psychomotorices Annecy,8-9-avril,1991. Rouillon F.,Warner B.,Pezous N.,Bisserbe J.C., and the Milnacipran recurrence prevention study group, International Clinical Psychopharnracology,15,133-140, 2000. Spencer C.M., Wilde M.I.: Milnacipran: A review of its Use in Depression, Adis Drug Evaluation, Drugs, 56/3/, 405-427,1998. Stahl S.M.:Are two antidepressant Mechanisms Better Than One?, Clinical Psychiatry, 58,8,1997. Smolik P.:Duševní a behaviorálni poruchy, prúvodce klasifikací, nástin nozognózie, diagnostika, Maxdorf-Jesenius,487: 1996. Suchopár J.: Remedia,Compendium, Tretie vydanie,Panax ,743 1999. Švestka J.: SSRI lieky prvej volby, Maxdorf,Jesenius, 153,9,46-55,74-92, 1998. HAMD, HAMA Scores
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Ave-rage
1st day of study
After one month of milnacipran therapy
After six months of milnacipran study
HAMD 24 25 23 18 18 18 18 25 18 28 21.5
HAMD 22 18 18 16 10 16 12 18 6 22 19.8
HA-MA
HAMD
HAMA
20 18 18 8 6 10 7 10 6 21 12.4
12 11 10 6 6 8 6 0 5 12 7.8
10 6 15 6 6 6 5 0 12 11 7.1
HA-MA 22 23 18 8 8 10 7 10 10 38 15.4
Table 1 PATIENT LIST
Men Woman Total
30
Number 4 6 10
Avg.age 44,25 40.66 41,33
Table 2 HAMD, HAMA Scores
Avg.points
1st day of study HA- HA-MA1 MD1 21,5 15,4
After one month of milnacipran therapy HAMD2 HA-MA2 19,8 12,4
After six monts of milnacipran therapy HAHA- MA3 MD3 7,8 7,1
TABLE 3 List of undesirable effect of medicament Vertigo Dry mouth Anxiety Obstipation Dysuria GIT malfunctions Tremor Palpitation Nausea Somnolence
0 2 0 1 3 1 0 0 0 0
CASUISTICS Recent findings of Alzheimer’s Dementia – possibilities and treatment in a psychiatric outpatient’s department Ignjatovičová D., Ignjatović M. Psychiatric Outpatient ‹s Department, Policlinics in Banská Bystrica
FROM HISTORY TO THE LATEST FINDINGS Dementia comes from a Latin word de-mens, without mind, is deterioration of intellectual capabilities and other cognitive skills leading to decrease the capability to perform the common daily activities. The findings of senile plaques in 1892 was first described by Blocq and Marinesco, but the beginning of the era of Alzheimer ‘s dementia is considered a clinical and pathological finding of pre-senile dementia in a 52-years old woman, who died four years after demonstrating clinical symptoms of mental disorder and paranoid symptoms. The principal histological feature was finding of plaques without neuro-fibral changes in cortex, hipocampal formation was not involved in diagnostics at that time. This case was later studied using modern histological and molecular-genetic analysis, involving screening for amyloid and precursor protein APP and apolipoprotein E /APO E/. In 1910 Bonfiglio, Percusini and Kraepelin proposed differentiation of the Alzheimer’s disease form the “common” senile dementia. In 1976 Katzman proposed unification of the term pre-senile Alzheimer disease and senile dementia of Alzheimer type to one nozologic unit. From 1980 the era of molecular pathogenesis of Alzheimer ‘s dementia starts, from 1997 symptomatic treatment of dementia and the year 2000 brings new modifications in treatment of Alzheimer ‘s dementia. The new researches /Winblad, Bogdanovic, O’Brien, Lovestone/ prove, that Alzheimer’s disease is and it will be an illness of the future and they try to clarify the pathogenesis of this serious progressing disease and also the new trends in treatment of this third most frequent disease in the world. A professor of psychiatry in Munich and neuropathologist Hans Frostl marked the three main strategies in treatment of patients with dementia: Management of somatic situation Influencing the cognitive functions Influencing the behavioural disorders. Different diagnostic criteria were created and accepted for Alzheimer ‘s dementia, e.g. Khatchaturian’s , CERAD /Consortium to Establish a Registry for Alzheimer ‘s disease/, criteria, Tien’s criteria, Braak and Braak classification. Khatchaturian and Tierny present plaques and girdles in cortical and/or hipocamal part, while CERAD prefers semi-quantitative estimation of the maximum cortical affection with critical plaques. The significant difference between Khatchaturian and CERAD criteria was, that the estimation of the number of plaques can be done only from neuritic plaques, which results in the fact that neuritic pathology in clinical-pathological studies is more significant in relation to occurring of dementia.
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The third group pd diagnostic criteria was presented by NINCDS - ADRDA /the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer Disease Related Disorders Association/ a working group for clinical diagnosis of Alzheimer’s Dementia and it was published by Tierny and col. in 1988. They establish clinical criteria without neuropathological criteria for Alzheimer’s dementia based on finding pathologic changes in hipocampus and/or neocortex. They also established excluding criteria for vascular disorders. Criteria for involving and excluding Alzheimer’s dementia are variable, hipocampal and neo-cortical changes involving clinical-pathological approval. Sjogren and col. Divided in 1952 disorders and decrease of the function of memory into several grades of importance for clinical practice: the first grade = the loss of episodic memory accompanied by progressive deterioration, problems in finding words, oscillation of moods, changes of personality, problems in performing daily activities, like e.g. check book balancing, deposits, withdrawals etc. In the medium grade the progress of the disease is obvious - recognition of the family environment, learning new information, repaint of individual events / semantic memory/ starts to be progressively affected. Memorising of distant events is not quite lost. However, if the patients lose sense of time and space, they show agitation, and fail to interact with their environment. In the last or terminal grade the new memory and old memory are quire disturbed, the patient is unable to perform the common daily activities, he is unable to walk by himself, to chew, to eat, he becomes quite dependent of his nurses. The final stage of Alzheimer’s dementia is coma and death, commonly as a result of infection /Gustaffson and col./
CASUISTICS Patient E.M., born 30th of January 1923 Valid anamnestic data received from the daughter and the son in law of the patient -she overcame common infant diseases, childhood was harmonic. Probably no hereditary disease occurred in the family, mother overcame lung tuberculosis, sister died of a carcinoma of abdominal cavity. Family without dementia symptoms. The patient completed eight grades of a grammar school, she worked as an independent employee in the State forests, later at the commercial department, in the Slovak Bookshop, in Stavoprojekt and as an accountant of the Slovak Film Renting Company. She got married as 22 years old, her husband died 74 years old, they had four children, one died of meningitis, other children live. She had no operations, four child-births were normal, without complications, she did not use contraception. She does not mention head injuries, she was never unconcious, she had no concussion, no fractures, she fell twice on an icy pavement, without a fracture. From her 73 years of age treated for the ischernic heart disease, compensated, she uses matipranolum and rutosidum. Her character is rather calm, serious, slow. From 1998 her daughter observed slowly developing memory and attention disorders. The patient started to forget, where she put the things of daily use like a pen or glasses. At first she was not aware of it herself. Later she had worse orientation in space, she got lost when she went to see her visitors off, she could not get back. For disorders in orientation, memory and for the tremor of upper extremities the patient was sent by the general practitioner to a neurological outpatient ‘s department, where they expressed suspicion of morbus Parkinson. She was given biperidenum, which was nottolerated well by her, for getting worse she was hospitalised at neurological department in January 1999, where her dose of biperiden was changed and selegilin hydrochloride was added to the therapy. The patient was released in a stabilised situation with the conclusion extra pyramidal hyper tonic hypo tonic syndrome. On 5th of May a CT examination of the brain was performed with the conclusion of a finding corresponding to the age in the inter-cranial structures without pathosmorphologic changes. At the beginning of May 2000 the status of the patient worsened concerning memory disorders, orientation disorders, intellectual deterioration, paranoid persecution hallucinations occurred in her mind and pseudo hallucinations in perception. The patient was examined at a psychiatric out patient ‘s department, we do not have the conclusion and she was recommended for hospitalisation. The patient was hospitalised at the psychiatric department from 13th of May to 7th of June 2000 with the diagnostic conclusion paranoid syndrome with dementia. She was given taiprid, biperidenum, metipranolum, rutosidum, thioridazini hydrochloridum. She was first time examined at our psychiatric outpatient ‘s department on 27th of June 2000 with the diagnosis probably Alzheimer ‘s dementia with later onset, differentially diagnostically atypical or combined type of Alzheimer ‘s dementia, dementia at Parkinson ‘s disease and Lewy body dementia. We tested the patient by the series of tests where MMSE was 21 points. Differentially diagnostically we excluded depression, where creeping onset, lasting over 6 months, variable mood, worsened performance in the evening, bagatelisation of the disorder, answers on the kind “a little bit outside the point”, worsened expression, meaning and worsened fluency of speech confirmed dementia. Shortened questionnaire of geriatric depression according to Yesevage was 3 points /0- 5 points within limit/, i.e. did not confirm depression. The assessment scale ADL /Activity of Daily Living/ = 6 points, still complete self sufficiency. Assessment scale IADL / Instrumental Activities of Daily Living/ = 7 points, /8 points = complete self sufficiency/. The scale of self sufficienecy of a patient with Alzheimer’s disease - Psychical Self - Maintenance Scale /PSMS/ = 13 points, score 6 means, that the patient can perform all the common daily activities, score 30 means that the patient is quite dependent of the assistance of his environment and requires daily care. Ischemic score of Hachinski and co. was 4 points, with score 0-4 points proves dementia of Alzheimer ‘s type. Clock test according to Schuman and co. We assessed by 3 points /mistakes in marking the time required/. 32
We kept therapy with tiaprid, thioridazini hydrochloridum, metipranolum and rutosidum, we stopped biperidenum and we started donepezil HCl in the initial dose 5 mg in the morning. After three weeks of treatment we checked MMSE = 26 points /17/7/2000/. The patient subjectively reported improvement of her memory /as if her memory came back”, as the side effects she reported vomiting in the first two days. Hetero-amnesteticaly according to her daughter ‘s report she consider ably improved. In the therapy we kept donepezil HCl 5 mg in the morning. The rest of the therapy idem. We ordered the patient for a check up in four months. During telephone consultations the patient ‘s daughter complained of bad daily regime, that she eats little, she drinks only 4 dcl of water during the whole day, she has somaticproblems, she vomits and she has diarrhoea. We recommended to observe drinking regime and nutrition of the patient. The check up on 13th of October 2000 - MMSE = 26 points. Abbreviated questionnaire of geriatric depression according to J.A. Yesevage was 10 points, / 10- 15 points for manifest depression. The assessment scale ADL = 3 points, /self maintenance of the patient worsened/. PSMS =22 points. Clock test = 5 points /severe disorders – de organisation/ The patient subjectively reported worsened mood, worse self maintenance, increased tremor of the upper extremities and feeling like vomiting. We gave her donepenzil for night in the same dose, we stopped thiorazin and we added maprotilinum hydrochloridum. We recommended to hydrate the patient, to check the drinking regime and nutrition. In three days the daughter of the patient consulted the situation of the patient on the phone, she reported worsening, the patient is weak, she cannot walk, she falls, she cannot eat or drink. We recommended the patient for hospitalisation at the psychiatric department, where she was not admitted. She was sent to internal department, where she was admitted for the suspicion of metabolic failure and dehydration. The patient was hydrated but for economic reasons psychiatric medication was stopped, amentiforrn status appeared, which was stressed by behavioural disorders and her daughter assessed the situation as “the worst for the last three years of life” After re-hydration of the patient and internal treatment she improved, the amentiform status was not dominating in the clinical picture. During hospitalisation in the internal department the psychiatrist was not consulted. During the hospitalisation of the patient we were in a constant telephone contact with the patient’s family and after finishing hospitalisation and re-convalescence in a family we called the patient on 14th March 2001 /10th month from the beginning of treatment by dopenzil HCl for checking psychiatric examination, where according to subjective reports the patient now feels much better, she communicates better with her environment, she can go for walks accompanied by a family member. According tot he data of her grand son “her character is the same as it was before, she is calm, serious, and according to her son in law she is more independent, she solves crosswords by herself and she goes for walks, and she also cooks by herself.” We assessed MMSE = 29 points, Clock test = 3 points /mistakes in marking time required/, we assessed an abbreviated questionnaire of geriatric depression according to J.A.Yesevage, which was 5 points /0 -- 5 points within limits/, ADL = 6 points /complete self maintenance, IADL = b points, with 8 points = complete self maintenance, PSMS = 10 points /6 points mean that the patient cal perform all the common daily activities without help, at 30 points he is quite dependent of the help and requires daily care/. Actually the patient ‘s therapy involves donepenzil HCl in the dose 5 mg pro die, maprotilinum 37,5 mg pro die and risperidon 0,5 mg pro die.
DISCUSSION As with the improving care for old people the age limit moves upwards, there are more dement patients. Also there are more patients with Alzheimer ‘s dementia, which is the third most frequent disease after cardiovascular diseases and cancer according to WHO 1999. That is why an out patient psychiatrist faces responsible and very time demanding diagnostics of the patients with dementia and their following treatment. Maybe the best aid in diagnostics is taking anamnesis, MMSE, Clock test, Hachinski Iscemic Score and geriatric depression test.As the most significant and the most simple indicator of the course of Alzheimer’s dementia MMSE and Clock test proved, which is the most used one also in outpatients departments /80 - 90% validity/. Finding in CT, MNR, is a very good aid in differential diagnostics, but not always the finding is significant and it is not decisive in determining diagnosis. In out patient there was a CT finding without patho-morphological changes. As the casuistic case we selected a patient with the probable Alzeimer ‘s dementia of later type, in whom we diferentially diagnostically considered also atypical or combined type of Alzheimer ‘s dementia, eventually dementia in Parkinson ‘s disease. Symptoms of tremor of upper extremities, probably bad toleration ofneuroleptic therapy, therapy by biperidon and virtual pseudo hallucinations as well as the negative CT finding lead us to considering Lewy body dementia. After starting donepezil HCI , compared to the starting MMSE = 21 points there was improvement of 5 points after three weeks from the beginning of treatment and after four months of treatment MMSE was the same. That means that cognitive skills did not worsen any more, but we marked worsening in performing common daily activities, when after four months observation there was considerable worsening of the patient ‘s self maintenance, which proved progress of the disease, or for worsening somatic status of the patient as a result of dehydration , also subjective experience of the patient worsened, which we observed also in the questionnaire of geriatric depression according to Yesevage, which increased from 3 to 10 points. The patient subjectively did not complain of memory disorders, but of the weakness, feeling like vomiting, no appetite, arm tremor worsened. 33
Nutrition of old people, keeping drinking regime, above all in patients with Alzheimer dementia are hard to observe, mainly if the patient has no permanent nurse and family is not instructed on all that. This lead us to consideration of dehydration of the patient with the following states of confusion and behavioural disorders. That is why we recommended the patient for hospitalisation at the psychiatry where she was not admitted. For the suspicion of metabolic failure she was admitted to internal department. After applying adequate treatment, intersinic rehydration and after using psychiatric medication the situation of the patient improved and stabilized. In 10th month of observing the patient MMSE = 29 points, which is improving of 8 points, compared to the first examination, Clock test = 3 points, improvement of 2 points compared tot he examination in the 4th month and the same status as in the first examination. The questionnaire of the geriatric depression was in the 10th month of observation of the patient 5 points /within limits/, ADL = 6 points, improvement of 3 points compared to the 4th month and the same as in the first examination. IADL = 6 points /with 8 points meaning complete self maintenance/ and PSMS= 10 points in 10th month of observing compared to 13 points in the first examination and 22 ppoints in the 4th month of observing, which would prove improved self maintenance of the patient and skills to perform all the common daily activities without help. As Alzheimer ‘s dementia is a life - long and fatal disease and besides the patient himself it also concerns the patient ‘s family members and nurses of the patient from 19th of March 2001 the family members of the patient actively participate of therapeutic groups of Alzheimer ‘s foundation in Banská Bystrica. That means that not only good diagnosis, quality treatment with the latest medication But also co-operation between specialists and family «can ensure good care for the patient in the old age».
CONCLUSION Alzheimer ‘s disease is a serious degenerative progressing brain disease which unites work of psychiatrists, neurologists, gerontologists, internists, pathologists, immunologists, genetics and also nurses and the patient ‘s family themselves. Alzheimer ‘s disease means disease of the new millennium and a great challenge for all the specialists in finding new medication which enable to improve the life quality of patients with Alzheimer ‘s dementia.
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RIVASTIGMINE EFFICACY ON BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF ALZHEIMER’S DISEASE- FINDINGS FROM A 12-MONTHS OUT- PATIENTS’ STUDY. Authors MUDr Milan Ignjatović, Psychiatric Medical Office, Health Care Centre, Banská Bystrica, Slovakia MUDr Dana Ignjatovičová, Psychiatric Medical Office, Health Care Centre, Banská Bystrica, Slovakia MUDr Zeljko Tutujević, Huddinge universitets jukhus, Behoendecentrum, Stockholm, Sweden
Summary The number of patients suffering from Alzheimer’ s Dementia is increasing with the age of their life and is becoming one of the important economic, medical, and social problems. The diagnostics of this disease is not complicated, but it requires a good cooperation both of the patient and his family or those taking care of him. In psychiatry different ways of Alzheimer’s Disease’s therapy are used. Nowadays we use not only nootropic substances, vasodilators, but also depenesil and rivastigmine. Galantamin registered in the Czech republic is being prepared for the market. In our study we monitored the clinical symptoms of BPSD and with the help of MMSE we evaluated the cognitive functions. Sixteen patients were observed / women N=12/ taking rivastigmine in average daily dosage from 9 mg to 12 mg pro die, in the period from January 1, 2001 to January 31, 2002, that is during 12 months. The average age of the patients was 79.88 years / from 71.0 up to 93.0 years of age/. Fourteen patients met diagnostic criteria according to MKCH-10 and DSM- IV for Alzheimer’s Disease’ s dementia, atypical or mixed type and two patients met diagnostic criteria according to MKCH-10 for Alzheimer’s Disease’ s Dementia with a late start. MMSE in the zero- day / the initial examination/ was on average 15.75 points, in the sixth month = 21.75 points, and in the twelfth month = 21.75 points. The average improvement was 6 points during the 12 months monitoring. The improvement of behavioral and psychological symptoms of dementia was evident in the 2-nd and the 6-th month of monitoring with the average daily dosage of rivastigmine from 9 to 12 mg pro die / table 3/. Key Words Alzheimer’s Disease /AD/, rivastigmine, Behavioral and Psychological Symptoms of Dementia, Mini Mental State Examination /MMSE/ Introduction Alzheimer’s Disease is a chronic and progressive neurodegenerative disease which is characterized by the reduction of activity of daily living, behavioral disorders and diminution of cognitive functions /Mateffly I.,2001/. More than two million people in the European Union suffer from Alzheimer’s Disease /Rocca WA, 1991/ .Amyloid plaques and neurofibrillary balls are supposed to be responsible for an attack of Alzheimer’s Disease. Beta- amyloid is derived both from beta- amyloid precursor protein and mutation on gene which is situated on chromosome 21. These changes could be in connection with an early beginning of this disease in families with the genetic predisposition. Alpha, beta, gamma- secretasies are involved in the process of beta- amyloid creation from the beta- amyloid protein precursor. It is also supposed that the early attack of Alzheimer’s Disease in families is caused by mutations on presenilin, the gene bound to chromosome 14. Presenilin is an integral membrane protein, whose exact function is not knowisi yet. It is also supposed that a small amount of beta- amyloid experimentally can start a proinflammation response in vascular tissue and Dr Mullan alleges that vascular diseases could be connected with Alzheimer’s disease. As presenilin 2 is concerned, the gene on chromosome 1, it is well- known that it is connected with familial occurrence of an early form of Alzheimer’s Disease. Presenilin 2 is highly homologous with presenilin I. Also APO E4 and specific allele of APO E gene is often conected with sporadic form of Alzheime’s Disease and the late beginning of familial form of Alzheimer’s Disease / Mullan M.,2000/.Cholinergic theory, which takes part in explanation of the occurrence and development of Alzheimer’s Disease is based on cholinergic deficit. There is the progressive loss of cholinergic neurons, especially in cortex and hippocampus, which leads to diminution of available acetylcholine and later to reduction of activity of daily living, behavior disorders and diminution of cognitive functions of the patient. Physostigmine was introduced among the first substances of cholinergic type but it is not in use now because of its short half-life period. Subsequently tacrin was introduced but is not used due to its hepatotoxicity and discontinuous syndrome with dosage several times per day as well as interaction potential. /Schneider LS, 1998, Changiz G., 2000, Corey- Bloom J., 1998/. It is also the substance with dual effect which means that it has a central effect on AchE / acetylcholinesterase/ and BuChE / butyrylcholinesterase/ similarly to rivastigmine. It means that the loss ofacetylcholinesterase is important in Alzheimer’s Disease and at the same time butyrylcholinesterase is enhanced in cortex and hippocampus in 40 or even 60 percent of the whole cholinesterase activity. This activity is partly the consequence of enhanced secretion of glia’s cells which are the main source of BuChE in the brain. The rise of BuChE activity appears in those parts of brain which are mostly affected by Alzheimer’s Disease and is correlated with the increase of markers of the disease progression/ one of them is also beta- amyloid delosition/.
35
Dr Enz explains that it could be the evidence of the important role of BuChE in the course of the disease. Findings of the author are that BuChE influences the transformation of benign beta- amyloid to neurotoxic plaques and inhibition BuChE can reduce disease’s progression /Mullan M., 2000/. The group of patients and methodology The group consisted of 16 patients, women N= 12, the average age 79.88 years / from 71.0 to 93.0 / with average MMSE = 15.75 points on the day of the initial examination, MMSE in the 6-th month was 21.75 points and in the 12-th month MMSE was 21.75 points. Classifying criteria MMSE in the range from 10 to 25 points The age over 50 MKCH-10 and DSM- IV diagnostic criteria for Alzheimer’s Disease dementia with late occurrence and for Alzheimer’s Disease dementia of atypical or mixed type. the average changeable dose of rivastigmine from 9 to 12 mg pro die the presence of BPSD and evident clinical symptoms of BSPD monitoring during 12 months To make the work simpler we did not use any structured scale - PDS/ Progressive Deterioration Scale/, CIBIC, ADAS-Cog., what can be considered as a shortcoming of the Work. The other shortcoming was the small number of patients. The aims of the study To find out the changes in the cognitive functions of patients with Alzheimer’s Disease by long- lasting monitoring. We evaluated MMSE on the zero-day/ the day of the initial examination/, the l-st month, 2-nd month, 6-th month and the 12-th month. To monitor the symptoms, development and eventual diminution of BPSD of patients with Alzheimer’s Disease. For evaluation we used the scale for monitoring BPSD altered on the 7-th international congress of the International psychogeriatric association /IPA/ in 1996/Benesova V.,2000.
Results The results are shown in tables 1,2,3,4 and 5. For the study we chose 16 patients with diagnosis F.00 and F.00.2 / Alzheimer’s Disease dementia/ who were taking rivastigmine 9-12 mg per day. They were chosen according to classifying criteria and they were monitored from 1 January 2001 up to 31 January 2002. With the help of MMSE we evaluated their cognitive deficit which was recorded on the zero day/ the day of the initial examination/, the 1-st month, 2-nd month, 6-th month and the 12-th month from the administration of rivastigmine. At the same time we monitored occurrence, development and amelioration of behavioral and psychological symptoms of dementia in the connection with administration of rivastigmine and antipsychotic and other psychopharmacologic therapy. The age of the patients was from 71.0 to 93.0 years, the average age was 79.88 years. All monitored patients were polymorbid patients with polypharmacotherapy. In most cases cardiotonics and other drugs for cardiovascular diseases’ treatment were administrated as well as diuretics and nonsteroidal antiflogistics. No patient taking rivastigmine noted any adverse reaction. These by effects occurred most often: diarrhea, nausea and dyspepsia but there was no reason to discontinue the rivastigmine treatment. Rivastigmine proved to be a safe drug not only for reduction of the cognitive deficit but also for diminution of behavioral and psychological symptoms of dementia what considerably improved the quality of life of the patients with low doses of taken antipsychotic drugs. Discussion The studies which were monitoring the influence of rivastigmine on cognitive functions of the patients suffering from moderately severe to severe form of Alzheimer’s Disease showed that after half- a year or one year of monitoring rivastigmine was significantly more effective than placebo / Changiz G., 2000/. It positively influenced not only the cognitive deficit but also the activities of daily living which in milder forms of Alzheimer’s Disease are money operations, time determination, in moderately severe form of Alzheimer’s Disease the ability to dress oneself, in severe forms the ability to have a bath, to eat, to give a telephone ring. Certainly the behavioral symptoms were also improved/ Changiz G.,2000, Corey- Bloom J., 1998, Farlow M., 2000/. We found out that in our monitored group MMSE was improved in 6.0 points from average 15.75 points on the zero- day/ the day of initial examination/ to 21.75 points in the 6-th month and after one year of monitoring MMSE was the same as in the 6-th month. Siinilar findings were mentioned in the foreign literature, too/Schneider LS,1998/. In our study the improvement of BPSD was noticed mainly between the 2-nd and the 6-th month with the average daily dosage from 9 to 12 mg of rivastigmine per day. Similar results are noted in the studies from abroad, but they were evaluated with PDS scale which included activities of daily living - ADL/Corey- Bloom J.,1998/. It was proved that patients who were taking daily dose from 6 to 12 mg were significantly in better clinical state in comparison with patients who were taking from 1 to 4 mg of rivastigmine per day or placebo. The evaluation was done in the 26-th week and it also referred to MMSE which was significantly improved in comparison with patients who had 1-4 mg of rivastigmine or placebo. It is important to mention that preceding
36
Alzheimer’s Disease’s attack there can be a slight cognitive deficit which is reflected in the rate of MMSE and patients’ complaints of dysmnesia. Subsequently this disorder can be changed to Alzheimer’s Disease/Changiz G.,2000/. There can be auxiliary methods in diagnosing of disorders of mind: functional MRI, then MRI aimed at hippocampu.s where the athropy can be found. The athropy of hippocampus was found in Lewy body dementia, vascular dementia and Parkinson dementia. Dr Scheltens supposes that all these diseases contain the elements of Alzheimer’s Disease/Changiz G.,2000/.It was found out that with the presence of BPSD administration of antipsychotic drugs can cause an impairment of Lewy body dementia and in most cases drugs for cardiovascular diseases and neurological diseases dominate in the therapy/Grossberg G.T.,2000/. In our work we most often used antipsychotics e.g. risperidon /average daily dose 0.85 mg/, tiaprid / 100 mg per day/, haloperidol /1.15 mg per day/ and from antidepressive drugs citalopram/ 20 mg per day/, sertralinum /25 mg per day/ and concomitant therapy aimed at the polymorbid patients. The patients were taking mostly drugs for the diseases of cardiovascular system, diuretic stimulants, antiflogistic agents and others. We did not note any pharmacodynamic interactions and adverse reactions while taking rivastigmine in combination with other drugs/KVS, neurological/ what is mentioned also in foreign studies/ Grossberg G.T.,2000, Mullan M.,2000/. There were some by- effects with the dose 6 mg per day like nausea, diarrhea, dyspepsia but they did not lead to the discontinuance of the therapy. This has also correlation with foreign studies/Corey- Bloom J.,1998/. Older patients are a big load for those who take care of them and inadequately treated patients are a risk for their surroundings. Real gerontopsychiatric pathology is situated mainly in nursing homes where the responsibility is put on the staff. Thanks to new cholinergic substances - rivastigmine, we help those who take care of patients with Alzheimer’s Disease and are directly involved in BPSD treatment. Rivastigmine improves the behavioral symptoms of patients with Alzheimer’s Disease up to the stage which is similar to taking antipsychotics. It can be recommended as a drug which can be used in the future in therapy of patients with behavioral disorders /Cummings J.,2000/. Conclusion According to the fact that the number of patients suffering from Alzheimer’s disease is increasing annually an early diagnostics and establishment of appropriate treatment enables the solution of this problem in a dignified way. When BPSD appear different psychopharmaceuticals are used e.g. antipsychotics, antidepressants, bensodiazepins and hypnotic agents .The antipsychotics can certainly cause impairment in some types of Lewy body dementia. We welcome every possibility of treatment of these disorders with cholinergics.Previous studies as well as our work proved that they have good influence on BPSD and thus they reduce prime and total costs on treatment of these patients what is a bennefit to those who take care of them. In our case the patients can get much benefit from dual effect of rivastigmine, its low interaction potential and good influence on BPSD and activities of daily life /ADL/ as well as on limitation of cognitive deficit. Table No. 1 - Monitoring the cognitive deficit according to scales of appraisal of MMSE MMSE 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Average value
day 12 10 14 16 10 10 16 24 17 14 22 11 16 22 20 18 15.75
1-st month 19 17 22 16 16 12 20 24 19 20 24 16 17 19 20 18 18.58
2-nd month 23 20 22 17 16 18 22 27 20 19 20 16 19 22 24 20 20.31
6-th month 23 21 24 20 18 20 24 30 22 14 24 20 22 22 24 20 21.75
12-th month 25 15 24 20 18 20 24 29 24 14 25 20 22 24 23 21 21.75
37
Table No.2 - Psychological symptoms of dementia day
1-st month
2-nd month
6-th month
12-th month
present
absent
present
absent
present
absent
present
absent
present absent
Delu-sion
7
9
7
9
7
9
0
16
0
16
Hallucinations
7
9
7
9
6
10
0
16
0
16
Paranoia
8
8
8
8
6
10
0
16
0
16
Depresion
4
12
4
12
3
13
1
15
1
15
An-xiety
7
9
7
9
6
10
1
15
1
15
Miside-ntification
1
15
1
15
1
15
0
16
0
16
Table No.3- Behavioral symptoms of dementia
0- day
1-st month
2-nd month
6-th month
12-th month
present
absent
present
absent
present
absent
present
absent
present
absent
Aggresiveness
5
11
5
11
4
12
0
16
0
16
Confu-ssion
6
10
6
10
5
11
0
16
0
16
Dysso-mnia
10
6
10
6
8
8
0
16
0
16
Inadequate behavior when eating
2
14
2
14
0
16
0
16
0
16
Inadequat sexual behaviour
2
14
2
14
0
16
0
16
0
16
38
Table No.4 - medicines used in the treatment of BPSD Symptom Psychotic symptoms
Agitation/aggressiveness Anxiety Depression
Dyssomnia
Pharmaceuticals Risperidon Tiaprid Haloperidolum Olanzapinum Risperidon Haloperidolum Clonazepamum Alprazolamum Maprotilinium Sertralinum Citalopramurn Zolpidem Nitrazepamurn
Average daily dosage 0.85 mg 100 mg 1.15 mg 1.15 mg 1.16 mg 10 gtt. 0.5 mg 0.5 mg 10 mg 25 mg 20 mg 10 mg 5 mg
Table No. 5 - Survey of cardiovascular pharmacotherapy and neurological therapy and other pharmacotherapy used in patients with Alzheimer’s Disease: Pharmaceuticals used in therapy of the diseases of cardiovascular system
Diuretics Cardiotonics NSA/nonsteroidal antiflogistics Insulins Others
Isosorbidi mononitras/monosan/Sorbimon Glyccroli trinitras/Nitromack Nifedipinum/Corvaton,Corinfar Verapamili hydrochloridum/isoptin Diltiazemi hydrochloridum/Blocalcin Isradipinum/Lomir Pentoxiffilinum/Agapurin/Trental Furosemidum/Furon/Furosemid Digoxinum/Digoxin Diclofenacum natricum/Dixlofenac Inflamac, Vral, Voltaren Insulini suspension/Insulin Vitamins E,B,C
Bibliography Benešová V., Behaviorálne a psychologické priznaky demencie, Čes. a Slov. Psychiat., 96,20000.No.1.pp.30-37 Costa Jermone F.,Ravi Anand, Neal R. Cutler, Richard Hartmann, Linda Manclone, John J.Sramek, Amy Veroff: Correlation Between Cognitive Effects and Level of Acetylcholinesterase Inhibition in a Trial of Rivastigmine in Alzheimer›s Patients ,Poster Presentation No.561, Convention center,Lower Level, Hall D, Wednesday, May 19,3.00-5.00 PM. Corey- Bloom J.,R. Anand, Veach J.: A Randomized Trial Evaluating the Efficacy and Safety of ENA 713/rivastigmine tartrate/, a New Acetylcholinesterase Inhibition in Patients with Mild to Moderately Severe Alzheimer›s Disease, International Journal of Geriatric Psychopharmacology 1998, 1,55-65. Cummings Jeoffrey, Ravi Anand, Barbara Koumaras, Richard Hartmann: Rivastigmine Provides Behavioral Benefits to Alzheimer›s Disease PatientsResiding in a Nursing Home: Findings from a 26-week Trial,Neurology 2000, Vol, 54/7 suppl.,3,pA4 68/Abs.S 79.002. Farlow Martin,Ravi Anand, John Messina Jr., Richard Hartmann,Jeoffrey Veach: A 52-week Study of the Efficacy of Rivastigmine in Patients with Mild to Moderately Severe Alzheimer›s Disease,Eur. Neurology 2000,44,236-241. Grossberg G.T.,Hannes B. Stahelin,John C. Messina, Ravi Anand and Jeoffrey Veach: Lack of Adverse Pharmacodynamic Drug Interactions with Rivastigrnine and Twenty-two Classes of Medications. Changiz Guela, Farlow Martin, Cummings Jeoffrey, Morris John,Scheltens Philip, Ravi Anand: Alzheimer› s Disease: Translating Neurochemocal Insights into Clinical Benefits, Journal of Clinical Psychiatry, 2000,Vo1.61,p.791-802. Kriška M.: Bezpečnost› liekov v terapii Alzheimerovej choroby,Nové trendy v liečbe Alzheimerovej choroby,3.12.2001,Bratislava, ústna prezentácia,Novartis.
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Mátéffy l.,: Duálna inhibícia rivastigminom, nové trendy v liečbe Alzheimerovej choroby,Bratislava,3.12.2001, ústna prezentácia, Novartis. Mulian Michael, Grossberg George, Albert Enz: New Insight into Genetics and Patophysiology of Alzheimer›s Disease: What are the Clinical and Therapeutical Implications?, Journal of Clinical Psychiatry,2000,Vol.61,p.307-315. Suchopár J., Remedia,Compendium,tretie vydanie,Panax1999,743,47-125,155-257.Rocca W.A. ,Hofman a Brayne C et al.,Frequency and Distribution of Alzheimer` s Disease in Europe- a collaborative Study of 1980-1990 Findings,the Eurodem - Prevalence Research Group, Ann Neurol.,1991,30,381-390 Petr Smolík: Duševni a behaviorální poruchy ,pruvodce klasifikaci nástin Nozologie,diagnostika, Maxdorf,Jessenius,1996,487:62-108. Schneider L.S.,R. Anand, Farlow M.R.:Systematic review of the Efficacy of Rivastigmine for Patients with Alzheimer›s Disease,International Journal of Geriatric Psychopharmacology, EXL 1998,Vol.I.,/Suppl1/p.S26-S34.
40
CHRONIFICATED AGORAPHOBIA WITH PANIC DISORDER MONITORING DURING ONE YEAR INTERVAL AND ASSUMPTION OF COMORBIDITY WITH DEPRESSION UPRISE AUTHORS MUDr. Milan Ignjatovič, Psychiatric Medical Office, Health Care Center, Banská Bystrica MUDr. Dana Ignjatovičová, Psychiatric Department, F. D. Roosevelt›s Hospital, Banská Bystrica
SUMMARY We chose 16 patients, 11 women and 5 men from the group of patients who were monitored in the psychiatric medical office with diagnosis of agoraphobia with panic disorder that lasted for more than 2 years. Thirteen of them continued in the treatment for 1 year and 3 patients didn’t finish the therapy. From the patients who didn’t finish the therapy, 2 patients were excluded after 1 month and they weren’t diagnosed with comorbidity of depression and patient didn’t visit medical office after 1 year even though she was diagnosed with comorbidity of depression (HAMD- 17= 25 points). We diagnosed comorbidity of depression in the study base-line in 3 men and 6 women who represent the majority of patients who finished the study. The rate of comorbidity was 2 men and 5 women after 1 month therapy, 1 man and 2 women after 3 months therapy and there was no occurence of comorbidity of depression after 1 year. Depression was evaluted according the HAMD-17 scale, when HAMD= 7 and more (3). Eminent occurence of depression comorbidity in patients who suffer from agoraphobia with panic disorder after one year therapy suggests that new drug therapy of SSRI, specifically of paroxetinum with additional management of clonazepanum and good compliance is successful in this case.
KEY WORDS Chronificated agoraphobia with panic disorder, comorbidity of depression, SSRI, paroxetinum, clonazepamun
INTRODUCTION Disorder that lasts for more than 2 years and is exacerbated for more than 2 months in one year interval is defined as chronic. In regard to continuous misunderstandings or unwillingness to make a compromise between Anglo-Saxon and American authors who are involved in this problem, agoraphobia with panic disorder is differently listed in DSM-IV and ICD-10 classifications. The question is, if the panic attack uprose as the first one (DSM- IV) and agoraphobia is developing afterward or agoraphobia is the first diagnosis and panic attack uprise afterward (ICD-10). Of course, if authors would make a compromise, great amount of our disorders became chronic, as well as according to the first sentence in our study, where the definition of chronic disorder was noted (it’s related e.g. to the chronic obstructive lung disease and as well as other somatic disorders). Following criteria are listed in evaluation of development, uprise, crest, retreat and recovery of agoraphobia with panic disorder: attacks rate, anticipatory anxiety intensity, comorbidity and patient’s personality. We focused on possible depression comorbidity in the process of agoraphobia with panic disorder chronification. Amer V. Starčević et al (4), panic attack precedes the depression uprise in majority of all cases. But agoraphobia with panic disorder uprose after depression uprise in high percentage of patients (40%) (4). When there is comorbidity of agoraphobia with panic disorder and depression, the percentage interval is 24- 91% and the disorder uprise path is very important- depression mostly uprises after agoraphobia with panic disorder development (5). Afterward author notices that comorbidity can be in % described as interval from 25 to 68% of cases with generalized anxious disorder, with specific phobias from 20 to 50% of all cases, with social phobia from 9-64% of all cases as well as with alcoholism from 5 to 41% of all cases. It is important to notice that these kind of panic disorder are listed in DSM- IV: 1. small (abortive) panic attacks, 2. panic attacks with no clinical signification (non-clinical attacks), 3. panic attacks during a sleep (night panic attacks), 4. panic attack without anxiety sensing( 6). Differential diagnosis of agoraphobia with panic disorder is quite difficult, especially when we take into consideration the above stated facts, dynamics of disorder and comorbidity as well. Disease process is connected to appropriate diagnosis and treatment in the majority of all cases. We can be restricted by pharmacological and economical conditions and by the influence of health insurance companies on the reduction of drug prescription (2). But important fact is that pharrnacoeconornics is just introducing itself into clinical practice and it will be important in the future. That’s why drugs should not be chosen according to pharmaceutical companies advice nor restrictions but according to availability and effectiveness in concrete cases (2).
GOAL To reach the knowledge about paroxetinum effectiveness in chronificated agoraphobia with panic disorder conditions in the case of comorbidity of depression, eventually compliance.
41
HYPOTHESIS Paroxetinum should be effective drug in a case of agoraphobia with panic disorder as well as in a case of depression comorbidity.
METHOD Outpatients who suffer from agoraphobia with panic disorder for more than 2 years and who developed comorbidity of depression were involved in the study.
INVOLVING CRITERIA: men and women older than 18 yearspatients who suffer from agoraphobia with panic disorder according to DSM- IV and ICD-10 possibility of depression comorbidity uprise, HAMD- 17= 7 and more patient’s informed written agreement to be involved in the study
EXCLUDING CRITERIA: men and women older than 70 years history of schizophrenia organic disorder mental retardation personality disorder pregnancy alcohol addiction and other addictions The study was permitted by Ethic Committee of NsP Brezno on the 3rd of August 1999. Patients were involved in the study during one year interval from the day, when the study was ratified by Ethic Committee, i.e. from 03.08.1999 till 03.08.2000. Tests such as HAMA, API (acute panic inventory test) HAMD- 17 (3) were realized before management of paroxetintun and clonazepamum in some cases as well. Wash-out was interval of 3 days in case of previous psychopharmacotherapy (in case of unsuccessful treatment in others psychiatric medical offices). All the tests were repeated after 1 month, 3 months and after 1 year. All obtained data underwent statistical analysis and were prepared for presentation.
MODALITY OF TREATMENT After 3 days wash-out period patients received 20 mg of paroxetinurn at the beginning, dosing was various up to maximal dose of 40 mg per day. Whereas the goal of study was monitoring of agoraphobia with panic disorder improvement and in cases with depression comorbidity monitoring of depression improvement as well, we didn’t count the average dose.
EVALUATION HAMA, HAMD- 17, API- 0., 1st, 3rd month and one year evaluation
CASUISTIC 49 years female patient, married, in partial disability annuity, half time employed as governess, with diagnosis F.40.01, suffers from symptoms for 7 years. She was treated in psychiatric department and frequently checked in psychiatric medical office during noted time, almost everything was tried in the treatment, starting with benzodiazepins, SSR1 and finally RIMA (moclobemid) which she stopped to receive by herself because she was despairing from the “experiments”. Her condition was confirmed by HAND- 17= 21 points, HAMA= 25 point; API= 30 points. Patient was sent by neurologist who monitored her for suspect psychomotoric epilepsy which never really uprose, besides non- significant EEG result because of which she received carbamazepinum (Biston 200 mg in the dose of 1 tablet in the morning- no tablet in the noon- 1 tablet in the evening.) Neither this treatment satisfied her. We suggested the diagnosis from patient’s first sentence when she said that she has vertigo, palpitation, can’t breath, sweats and has needles and pins in her hands and suffers from headache as well, when she travels by bus to visit primary doctor. She recovers during one day, lying in bed with severe non- responding tension headaches after noted control visits. We consulted the patient’s case with neurologist, reduced carbamazepinum up to half dose, managed paroxetinurn (20 mg per tablet) in dose of 1 tablet in the morning and clonazepamum (0,5 mg per tablet) in dose of 2 mg per day. HAMD-17 score fell down to 20 points, HAMA to 22 points, API to 28 points and after 3 months HAMD- 17 was 19 points, HAMA= 18, API= 26. After one year HAMD-17 was 9, HAMA= 11, API= 14 points. After long term persisting anticipating anxiety patient after the initiating of treatment visited her daughter in Austria, traveling by bus by herself. She repeated the visit this year as well. She was not even able to travel because of her disorder in previous time. From the group of symptoms that patient had in our first meeting, she still has mild, rare tension headaches responding to common analgesics which uprise especially when she is exhausted.
42
RESULTS There were 16 patients involved in the study, 11 women and 5 men, table 1. The youngest patient was 28 years old, the oldest one was 56 years old, average age was 39,68 years, table 2. Obtained education is listed in table 3, 3 women finished elementary school, 5 women and 5 men finished specialized secondary school, no patient finished secondary grammar school and 3 women graduated the university. The list of diagnosis that were made in our psychiatric medical office is in table 4. The average time of symptoms duration was 8,06 years, the longest duration was 16 years and the shortest one was 2 years- table 5. Thirteen patients continued the treatment, 3 patients didn’t finish the treatment, table 6. From the group of 13 patients who finished the treatment the comorbidity of depression was diagnosed in 3 men and 6 women, comorbidity of depression was diagnosed in 2 men and 5 women after 1 month, in 1 man and 2 women after 3 months and no patient has depression after one year, table 7. Average HAMD- 17 score was 18,84 at the beginning of the study, afterward HAMD-17 was 15,07 after 1 month, HAMD- 17= 10,76 after 3 months and HAMD- 17= 7,92 after 1 year. There was improvement in the HAMD- 17 scores up to 3,77 points, i.e. up to 20,01% in first testing according to the treatment of agoraphobia with panic disorder and depression comorbidity. The HAMD- 17 scores improvement was up to 4,31 points, i.e. 22,87% in the second testing and up to 2,84 points, i.e. up to 14,86% in the third testing. The final improvement (comparing the first and the last HAMD- 17 scores) was up to 10,92 points, i.e. up to 57,96%, table 8. The average HAMA scores were 25,92 points at the beginning of treatment, HAMA= 21,76 after one month treatment, HAMA= 20,53 after 3 months and HAMA= 14,07 points after one year treatment. The improvement of HAMA was up to 4,16 points, i.e. up to 16,04% in the first testing, up to 1,23 points, i.e. up to 4,74% in the second testing and up to 6,46 points, i.e. up to 24,92% in the third testing. The final improvement comparing the first and the last HAM.A scores was up to 11,85 points, i.e. up to 45,71 points, table 9. There are average scores of API tested at the beginning of the treatment, one month and one year later in the table 10. The improvement of API was up to 2,00 points, i.e. up to 8,93% inthe first testing, up to 3,77 points, i.e. up to 16,84% in the second testing and up to 4,46 points, i.e. up to 19,92% in the third testing. The final improvement of API (comparing the first and the last API scores) was up to 10,23 points, i.e. up to 45,71% in average.
DISCUSSION According to Erić (1), necessary factors for panic attack prognosis are: 1. Biological bases of panic condition, especially intensity and uprise rate of panic attacks, 2. Patient’s age, when disorder uprose, 3. Disorder duration, 4. Disorder process, 5. Existence of specific intrapsychic and interpersonal conflicts, 6. Patient’s motivation for treatment, 7. Hypersensitiveness and reactivity of patient to managed drugs (1). The advantages of SSRI in compare with other classical drugs, e.g. imiprarninum which used to be managed in a case of agoraphobia with panic disorder in previous time, are hidden in point 6. Panic attack is a disorder which follows agoraphobia very often. According to Starević, it happens in 91% of all cases and it can be complicated by others disorders within comorbidity afterward. According to ICD-10, agoraphobia with panic attack is classified as residual diagnostic category that can be used only in case it fulfils own criteria. In case depression would uprise we should use the diagnosis of affective disorder and agoraphobia with panic disorder should be classified as comorbidity. It is different in DSM- IV classification, where panic disorder with or without agoraphobia can be assigned to the group I of other disorders like depression, alcoholism, isolated phobias. Panic disorder in DSM- IV classification was not assigned as self- existent unit. This fact reflects different modalities between DSM- IV and ICD- 10. This fact should not make our workshop more difficult because both classifications are available. Appropriate diagnosis and treatment can be a problem. Daily practice experiences show that paroxetinurn is effective in a case of agoraphobia with panic disorder, as well as that terminal phase of this disorder in the process of chronification is an affective disorder- depression. The primary disorder in our patients was agoraphobia with panic disorder but high HAMD-17 scores which were 18,84 in average at the beginning, were in normal level of 7,92 points after one year, table 8. That was the same in case of anxiety, when HAMA was 25,92 points in average at the beginning and 14,08 points which is a normal level after one year, table 9. API was reduced from 22,38 points at the day zero to 12,15 points after one year, table 10. Thereby the hypothesis that paroxetinum is effective in the treatment of agoraphobia with panic disorder as well as in cases of depression comorbidity was confirmed. Of course the therapy algorithms of one or another disorder must be used and the dose of paroxetinum must be sufficient (whereas, patients often receive insufficient dose of paroxetinum because of physicians fear of overdosing stimulation at the beginning of therapy, what can be amplified by the usage of benzodiazepin, e.g. clonazeparnurn in low dose of 1- 2 mg per day). Sufficient and qualitative patient’s compliance is necessary as well. Supporting psychotherapy is welcome in each of these cases.
43
CONCLUSION Sixteen patients were chosen from the group of patient who were monitored in psychiatric medical office because of diagnosis of agoraphobia with panic disorder that lasted for more than 2 years, 11 women and 5 men. Thirteen of them continued the treatment during one year, 3 patients didn’t finish the treatment- 2 patients who have not been diagnosed with comorbidity of depression were excluded after one month. One female patient who was diagnosed with depression comorbidity didn’t come for control checking after one year (HAMD-17= 25 points). We confirmed comorbidity of depression in the majority of patients who stayed in the study at the base- line of study, what is represented by 3 men and 6 women. There was comorbidity of depression in 2 men and 5 women after 1 month, in 1 man and 2 women after 3 months and there was no patient with depression comorbidity after 1 year. Depression was evaluated by HAMD- 17 scale, where HAMD-17 was 7 points and more. Higher occurence of depression comorbidity in patients who suffer from agoraphobia with panic disorder for more than 2 years suggests that new drug therapy of SSRI, of paroxetinum with additional clonazepamum therapy and good compliance is successful in this case. BIBLIOGRAPHY Erić Lj., Panična stanja II, dopunjeno i prošireno izdanje, Beograd- Zagreb, 1991, 1-331, 215 Hosák L., Farmakoekonomika v psychiatrii, Galén 2000, 7- 133, 111, 112, 107, 108 Paunović V., Tirnotiević I., (1992): Instrumenti kliničke procene u psihiatriji, Izdavač IDP naučna knjiga Beograd, 1- 151, 116, 117 Starčević V., Uhlenhuth EH, Kellner R., Pathak. D. 1993a: Comorbidity in panic disorder: II Chronology of appearance and pathogenic comorbidity. Psychiatry Reasearch, 46: 285- 293 Starčević V., Uhlenhuth EH., Kellner R., Pathak D. 1992a: Patterns of comorbidity in panic disorder and agoraphobia. Psychiatry Research, 42: 171- 183 Starčević V. Beograd, 1997: Stanja stracha u kliničkoj praksi, 1- 234, 37, 129- 130, 132- 134 TABLE 1 - SURVEY OF PATIENTS
Number of patients Women Men
Absolute number 11 5 16
Percentage 68,75 31,25 100
TABLE 2 - AGE OF PATIENTS The youngest patient The oldest patient The average age of patient
28 years old 56 years old 39,68 years
TABLE 3
Elementary School Specialized Secondary School Secondary Grammar School University Total
44
Number 3 5 3 11 women
% 18,75 31,25 18,75 68,75
Number 5 5 men
% 31,25 31,25
TABLE 4 - SURVEY OF PATIENT’S DIAGNOSIS IN PSYCHIATRIC MEDICAL OFFICE Women 9 1 1
F.40.01 F.40.2 F.41
Men 4 1
TABLE 5 - DURATION OF DIFFICULTIES The average duration of difficulties The longest duration of difficulties The shortest duration of difficulties
8,06 year 16 years 2 years TABLE 6 - END OF TREATMENT Number 13 3
Continued in treatment Did not continued in treatment
Percentage 81,25 18,75
TABLE 7 - COMORBIDITY WITH DEPRESSION
Men
Women
Other patients without comorbidity with depression
At the beginning of examination
3
6
4
After 1 month
2
5
6
After 3 months
1
2
10
After 1 year
-
-
13
TABLE 8 - HAMD- 17 TESTS EVALUATION The average values HAMD-17 at the beginning of examination The average values HAMD-17 after 1 month The average values HAMD-17 after 3 months The average values HAMD-17 after 1 year
HAMD1 = 18,84
HAMD1-HAMD2 = 3,77 point, i.e. average improvement by 20,01%
HAMD2 = 15,07
HAMD2-HAMD3 = 4,31 point, i.e. average improvement by 22,87%
HAMD3 = 10,76
HAMD3-HAMD4 = 2,84 point, i.e. average improvement by 14,86% HAMD1-HAMD4 = 10,92 point, i.e. average improvement by 57,96%
HAMD4 = 7,92
TABLE 9 - HAMA TESTS EVALUATION The average values HAMA at the beginning of examination The average values HAMA after 1 month The average values HAMA after 3 months
HAMA1 = 25,92
HAMA1-HAMA2 = 4,16 point i.e. average improvement by 16,04%
HAMA2 = 21,76
HAMA2-HAMA3 = 1,23 point i.e. average improvement by 4,74%
HAMA3 = 20,53
The average values HAMA after 1 year
HAMA4 = 14,07
HAMA3-HAMA4 = 6,46 point, i.e. average improvement by 24,92% HAMA1-HAMA4 = 11,85 point, i.e. average improvement by 45,71%
45
TABLE 10 - API (ACUTE PANIC INVENTORY) TESTS EVALUATION The average values API at the beginning of examination
API1 = 22,38
The average values API after 1 month
API2 = 20,38
The average values API after 3 month
API3 = 16,61
The average values API after 1 year
API4 = 12,15
46
API1-API2 = 2,00 point, i.e. average improvement by 8,93% API2-API3 = 3,77 point, i.e. average improvement by 16,84% API3-API4 = 4,46 point, i.e. average improvement by 19,92% API1-API4 = 10,23 point, i.e. average improvement by 45,71%
PSYCHOPHARMACOTHERAPY OR PSYCHOTHERAPY OF ANXIETY DISORDERS- ONE YEAR RESULTS AUTHORS Milan Igniatović (1) Dana Ignjatović (2) Psychiatric out Department of Policlinic, Banská Bystrica, Slovak republic Psychiatric out Department of Policlinic, Banská Bystrica, Slovak republic
PURPOSE The puropose of our one year study was a comparison of psychopharmacotherapy and psychoterapy of acute out-patients with anxiety disorders during crises periods
PATIENTS AND METHODS We had 20 patients/ 16 female/ they used psychopharmacotherapy and psychotherapy very individually for 12 weeks. Patients used hydroxizin/50 mg pro die for two weeks,with flexible dose titration during 12 weeks and decreasing to minimum/. 10 patients finished their psychotherapy and 10 patients didn’t finish the psychotherapy. We made standard psychological tests- API/ acute panic inventory test/, HAM-A, HAM-D,BECK.
KEY INCLUSION CRITERIA: male and female out - patients aged 18 years DSM —IV diagnosis and ICD - 10 classification for panic disorders, phobic disorders, reactive depression, adaptation disorders, personality disorders, somatoform disorders Patients had been treated in our out - patient department during one year without controlled group and without placebo double - blind group
SUMMARY AND RESULTS We compare our one year experiences with treatment of out-patients with anxiety disorders. After a short time therapy the effect was significant- the improvement of the clinical symptoms and successful „ come back” to every day life activities. Patients, that have finished their treatment by „alliance” were without reziduum by treatment with benzodiazepins and treatment without relevant psychotherapy. Combination of psychopharmacotherapy and psychotherapy results in decreasing of clinical symptoms of anxiety disorders. Diagnosis of our patients- table No 1 Using psychotherapy in the first week of treatment 100% of our patients had been participated, in the 4 th week it had been 60% of them and in the 8 th week it had been only 15 patients.Table No2 Using psychopharmacotherapy in the first week 100% of our patients used hydroxizin, in the 4 th week it had been 45% and in the 8 th week all of our patients had been without psychophamracotherapy.Table No 3. Decreasing of clinical symptoms had influence to psychopharmacotherapy and psychotherapy.
CONCLUSION In acute anxiety disorders first step to be successful in the treatment is adequate initial psychopharmacotherapy/hydroxizin was tolerated by patients during initial crises, without sedation and cognitive disturbance/. In psychotherapy are the most important first 6 weeks of therapy and very important is an “alliance”:patient-psychiatrist. At the end we would like to thanks to prof.Gillieron and prof. Schneider from Policlinique Psychiatrique Universitaire in Lausanne and Dr. Eva Bryois-Hanic to understand dynamic short-time psychotherapy.
References Eva Bryois-Hanic,MD:Intervention Psychoterapique en Quatre Seances, 1994 J.C.Samuelian:Effects on the cognitive functions of two anxiolytical treatments in patients,who suffer from general anxiety A.De Brabander:Effects of hydroxizin on Attention and Memory, 1990 M.Slabý:Preparat Atarax v perorálnej medikácii u detí,1997 M.Ferreri:A multicentre double -blind placebo controled study investigating the anxiotytic efficacy of hydroxizin in patients with generalized anxiety, l995
47
week 1
2
3
4
5
6
7
x
x
x
x
x
x
K
x
x
x
x
x
D
x
x
x
D
x
x
x
S
x
x
x
-
D
x
x
x
x
x
x
K
x
x
x
S
x
x
-
-
-
-
x
x
x
x
x
x
x
K
x
x
x
x
x
x
K
x
x
x
x
D
x
x
x
x
x
x
K
x
x
x
x
x
x
x
x
x
x
x
K
x
x
x
x
x
x
K
x
x
x
x
x
x
x
x
x
S
x
x
x
8
9
x
S
x
x
x
K
10
DG F.32.1 F.32.2
F.32.2 F.40 F.40 F.40 F.40.1
F.41 F.41.1 F.41.1 F.41.1 F.41.1
F.41.2 K
F.43.2
F.43.2
F.45.3
F.60 F.60
F.60 F.60 %
48
S
x
-
-
x
x
H
100
95
80
x
H
60
45
40
15
15
5
11
12
Psychotherapy during 12 weeks
Week
1
2
3
4
5
6
7
8
9
x
x
x
x
x
x
K
F.32.2
x
x
x
x
x
D
F.32.2
x
x
x
D
F.40
x
x
x
S
x
x
x
sine th
D
F.40
x
x
x
x
x
sine th
K
F.40.1
x
x
x
S
x
x
-
-
-
-
sine th
sine th
S
x
x
sine th
sine th
sine th
sine th
K
F.41.1
x
x
x
sine th
sine th
sine th
K
F.41.1
x
x
x
sine th
D
F.41.1
x
x
x
x
sine th
sine th
K
x
x
x
x
x
sine th
sine th
sine th
sine th
F.43.2
x
x
x
sine th
K
F.43.2
x
x
x
x
x
x
K
F.45.3
x
x
x
x
x
x
x
sine th
K
x
x
S
x
x
x
S
x
-
-
x
H
x
x
H
100
95
75
45
30
15
5
0
0
10
11
12
DG F.32.1
F.40
F.41 F.41.1
F.41.2
F.60 F.60 F.60 F.60 %
K
Psychopharmacotherapy during 12 weeks
49
The way how patients finished their therapy
Table 4
The number of weeks Male Agreement
1
2
3
4
5
6
Dg.
F.32.2
%
5
Dg.
F.32.2 F.40, F.41.1
%
5
Female
7
8
9
10
11
12
All patients % 1 5 3
10
15
Dg.
F.43.2
%
5
1
Male
Contact
5
Dg.
F.41.1
F.32.1, F.40, F.41.1 -3x
F.41.1 F.41.1
%
5
25
5
Female
Dg.
F.40.1
%
5
8
5
40 1
Male By patient
F.41
Dg.
F.60
F.40
F.60
%
5
5
5
Dg.
F.60
%
5
5
5
4
Female 20 1
Male Hospitalisation
5
Dg.
F.60
%
5
1
Female 5
All patients
2
3
4
2
6
2
1
Total %
10
15
20
10
30
10
5
50
20 100
Table 5
Psychopharmacotherapy we used during 12 weeks –male Week 1
2
3
4
5
6
Alprazolam (0,5) 1tbl.v. Citalopram (20) 1-0-1
Alprazolam (0,5) 0-1/2-1 Citalopram (20) 1-1/2-0
Alprazolam (0,5) 0-1/2-1 Citalopram (20) 1-1/2-0 Maprotilin (25) 1-1-1
Alprazolam Alprazolam (0,5) (0,5) 0-1/2-1 0-1/2-1 Citalopram (20) Citalopram D 1-1/2-0 (20) Maprotilin (25) 1-1/2-0 1-1-1 Maprotilin (25) 1-1-1
Haloperidol gtt. 5kv./noc
Haloperidol gtt. 5kv./noc
7
8
9
10
11
12
DG
F.32.2
S
F.40.1
Hydroxizine 1/2-1/2-1
Hydroxizine 1/2-0-1
Hydroxizine 1/2-0-1
S
Fluoxetin 1-0-0
Fluoxetin 1-0-0
Fluoxetin 1-0-0
Fluoxetin 1-0-0
Fluoxetin 1-0-0
Fluoxetin 1-0-0
F.43.2
D - therapy finished by alliance S - therapy finished by patient K - therapy finished by contract Table 6 a - Psychopharmacotherapy we used during 12 weeks-female
Week DG
F.32.1
1
2
3
Citalopram (20) 1-0-0 Zopiklon 1/n
Citalopram (20) 1-0-0 Zopiklon ex Zolpidem 1/n
Citalopram Citalopram (20) Citalopram (20) 1-0-0 (20) 1-0-0 Zolpidem 1/n 1-0-0 Zolpidem 1/n Zolpidem 1/n
Sertralin 1-1-0
Sertralin 1-1-0
Sertralin F.32.2 1-1-0
4
5
6
7
8
9
10
11
12
Citalopram (20) 1-0-0 K Zolpidem 1/n
D
51
Hydroxizine 1/2-1/2-1 Fluoxetin 1-0-0
Hydroxizine 1/2-1/2-1 Fluoxetin 1-0-0
Hydroxizine 1/2-1/2-1 Fluoxetin S 1-0-0
Hydroxizine F.40.0 1/2-1/2-1
Hydroxizine 1/2-0-1
Hydroxizine 0-0-1/2 sine th
Sertralin 1-1-0
Sertralin 1-1-0
Sertralin Fluoxetin 1-0-0
Fluoxetin 1-0-0 Bromazepam (3) 1-0-0
Fluoxetin 1-0-0 Bromazepam (3) 1-0-0
F.40
F.40
F.41
Hydroxizine 1/2-1/2-1
Fluoxetin 1-0-0
Fluoxetin 1-0-0
sine th
K
-
-
-
sine th sine th S
Hydroxizine 1/2-1/2-1
F.41.1
sine th
Hydroxizine 1/2-1/2-1
D
Hydroxizine 1/2-1/2-1
sine th
sine th
sine th
K
sine th
sine th
K
Hydroxizine Hydroxizine ex 1/2-1/2-1/2
F.41.1
D - therapy finished by alliance S - therapy finished by patient K - therapy finished by contract H - hospitalisation Table 1
Diagnosis
The number of patients
%
The number of female
%
F.32.1
1
5
1
5
-
-
F.32.2
2
10
1
5
1
5
F.40.0
3
15
3
15
-
-
F.40.1
1
5
-
-
1
5
1
5
1
5
-
-
F.41.1
4
20
4
20
-
-
F.41.2 F.43.2
1
5
1
5
-
-
2
10
1
5
1
5
1
5
1
5
-
-
F.60*
4
20
3
15
1
5
Spolu pacientov
20
100
16
80
4
20
F.41.0
F.45.3
*pacient with diagnosis F.98.5
52
The number of male %
DIFFERENTIAL DIAGNOSTICS OF PANIC DISORDER AND FOLLOWING TREATMENT AT THE PSYCHIATRIC CLINIC - OUR 1 YEARS’ EXPERIENCE AUTHORS MUDr. Milan Ignjatović, Psychiatric Clinic, NsP Brezno (Hospital with Polyclinic) MUDr. Dana Ignjatovičová, Psychiatric Department, F.D. Roosevelt›s Hospital, Banská Bystrica PhDr:Vladimir Ďurčik, CSc.,Technic University Zvolen, Faculty of Ecology and Environmental, Slovak republic
SUMMARY 44 women and 8 men at the age of 20 to 62 years with chronification of panic disorder have often used to be tediously and hardly diagnosed and on the basis of that also inadequately treated. The diagnoses, which most often appear in case of these patients are: dorsalgia, vertigo, migraine, epilepsy, tachycardia and other disorders. These patients often use to be treated on somatic ailments for many years and in most cases they are recommended to a psychiatrist by chance, many times only after exhausting all possibilities at other colleagues. The patients use to be treated by different preparations, as for psychopharmacotherapy, they most often they get benzodiazepines. A great part of the patients have lost hope that once they would be better. In many cases they have been diagnosed and treated by the psychiatrists themselves as neurastenia. Of course, the therapy remained the same and during many years it has not changed. As today we have a wide pallet of medicaments from SSRI’s and we can use them as causal treatment in case of these patients, we suppose that on the basis of these possibilities a new stage in the treatment of chronificating panic disorder have been opening.
KEY WORDS differential diagnosis, panic disorder, agoraphobia, pseudo-epileptic seizure, migraine, vertigo, SSRI, benzodiazepines
INTRODUCTION The neurosis of fear first time appeared in 1895 and it was named by S. Freud himself and its further development can be monitored till nowadays, when it has been renamed to panic disorder with agoraphobia or without agoraphobia in the latest classifications DSM IV and ICD 10. Marks and Klein belong to physicians who contributed to its introduction in DSM III/ 1980. Also other authors in our country, as well as abroad are engaged in this disorder. As for neurologists, they are: P. Kukumberg, R. Kotas in the Czech Republic, I. Rektor. They are neurologists, who try to find a connection and differences between migraine, epilepsy, panic seizure and other psychic disorders. In Yugoslavia, Erič Lj. is engaged in this problematic and tries to find his own multi-modal method of treatment, by which we can help these patients. In Switzerland, Baumann P. and Bryois Ch. are engaged in rational treatment with benzodiazepines. Diagnosing panic disorders with agoraphobia is sometimes tedious and tiresome for the patient, as well as the physician. Much depends on the patient’s personality, on his/her compliance. The treatment can be long /S. Kasper, 1999/ and in many cases also unsuccessful. The patience can be the only assistant in treatment of such disorders. The patients come with different difficulties, massive therapies, without substantial effect and several diagnoses of somatic character. The most frequent of them are: dorsalgia, migraine, epilepsy, vertigo, tachycardia and others, which cannot be treated in the standard way. The patients already are at the end of their tether after multiple examinations and the long-term treatment. Dysphoric tuning?, neurastenic elements and even depression can appear as co- morbidity. Treatment with clomipramine and denyodiazepines /J. Raboch, 1999/, cognitive-behavioural psychotherapy /J. Praško, 1999/ have been the most frequent treatment of such disorders till the discovery of SSRI’s. These are methods, by connection of which the most successful treatment has been reached. At present, the offer is extended by RIMA and SSRI. Their effect in the practice persuaded not only experts-psychiatrists, but also practical physicians.
METHOD AND GROUP OF PATIENTS 52 patients have been chosen on the basis of 3 including criteria: all answer the diagnosis panic disorder according DSM IV and ICD 10, the disorder has been not lasting less than 3 months and the up-to-now treatment and self-treatment has been not successful. Monitoring and evaluation of the results took place from February 1, 1999 to February 1, 2000 at the Psychiatric Clinic.
MONITORING The results are based on the retrospective clinical monitoring of the patients’ medical records, where the focus has been on diagnosing, differential diagnosis and the therapy. There are 2 casuistic cases for illustration, all patients remained filed at our clinic, the smaller number of patients finished the treatment and the others continue with the treatment.
53
CASUISTIC No. 1: Patient, 32 years old, married, without neuro-psychiatric problems in the family and in case history. She is a teacher, from the beginning of ailments: working disability. Before one and half year she started to feel worse and the physicians during 4-5 months tried to find out the reason of her ailments. She subjectively described the ailments as: reeling in the head, heart beating, hindered breathing, nausea, fear of travelling by bus, later fear of going outside to the street without her husband and often repeating of the above mentioned ailments. She has been examined by internists with a negative diagnosis and she underwent the HEAD-UP TILT test, which has been described by her as an unbearable examination, during which she fell into senselessness. She has been diagnosed as vasodepressoric syncopic state, disposition for vagovagal collapses and vertiginous syndrome and tachykardia. Symptomatic treatment metoprololi tartas has been started and she has been left home. The internist sent her to our Psychiatric Clinic , we diagnosed the panic disorder with agoraphobia, we started with paroxetinum with clomazepamum in small dosage / paroxetinum 20 mg pro die and clonazepamum 1 mg pro die / and the state of the patient has improved. The vertiginous ailments, tachycardia, tachypnoe, as well as the fear of travelling passed away. At present, the patient gets only 10 mg of paroxetinum daily as a maintaining dosage and she is fully addicted to her work duties and family.
CASUISTIC No. 2 The patient, 52 years old, she is a worker, disable to work for a long time because of vertigo, headaches, heart beating, pins and needles in hands and legs, choke feeling, fear of travelling by bus, going outside the house, staying among strangers, fear of going shopping alone, without being accompanied by her daughter or somebody else and frequent repeating of the above mentioned troubles. In the family case history of the patient the mother and the father were alcoholics and the patient, together with brothers and sisters, was placed to an orphanage. The patient first time felt bad before 14 years, when she has been in a spa, she started to pass out, to have head reeling, heart beating, hard breathing. That time nothing was found out, she was treated by neurologists on cervical migraine, vertebrogenous algic polytop syndrome and one time she used 8 types of different drugs. At the entry to out Psychiatric Clinic, the following has been used in her therapy: bisoprololi fumaras, oxetoroni hydrogenofumaras, betahistini dihydrochloridum, diclofenacum natricum, alprazolamum, metamizolum natricum. Either the long term treatment did not improved her state at all. The patient was disable to work for a long time, the medical commission considered her to be a malingerer. It has been problematic for her to explain her troubles and they menaced her that she would lose the financial subsidy. After the first meeting with her we finished the treatment with the exception of bisoprololi fumaras and we started with paroxetinum and clonazepamum /dosage: paroxetinum 30 mg pro die and conazepamum 2 mg pro die/ and we recommended the patient to a group therapy. The treatment at our Psychiatric Clinic begun in April 1999 and during a month the patient’s state improved, the headaches remained, but they have been milder, pins and needles in the hands mildened and the patient started to travel by bus without difficulties and without an accompanying person. The patient did not have vertigos, heart beatings and feeling of choke. At the beginning of the group therapy experienced also several panic seizures among strangers - co-patients, which have been treated with intramuscular injection of diazepam. In August the patient returned to the work, she bears well psychic, as well as physic load. She is fully addicted to her family and the youngest juvenile daughter. At present, the patient’s therapy constists of paroxetinum 20 mg pro die, clonazempamum 1 mg pro die, natrium ? mg pro die and sulphirid 50 mg pro die.
RESULTS The studied group o patients consisted of 52 patients: 44 women and 8 men, the patients have been at the age of 20 to 62 years. The average age of the men has been 35.87 years, the average age of the women has been 39.61 years. The shortest ailments of a patient lasted 3 months, the longest 30 years, the average 6.29 years. The average duration of a treatment at our Psychiatric Clinic has been in average 4.71 months, the shortest 1-day’s /of course unsuccessful/, the longest 11 months. The state of the most patient is stabilized - at 19 patients, the mitigation and reduction of the numbers of panic seizures and withdrawal of agoraphobia at 15 patients, 14 patients independently finished the treatment, most frequently after the first examination. At 4 patients less frequent, but strong panic seizures lasted - they have been suffering from panic disorder with agoraphobia for a long time. In the treatment of these patients we most frequently used paroxetinum - at 38 patients as the basic treatment, clonazepamum as the adjuvant treatment. 9 patients used citalopramum and the rest of patients, with the exepction of one female patient /dosulepinum/ had SSRI as the basic treatment. Besides the biological data we would like to underline also the psychical pre-disposition for the origination of the panic disorder, which is often in the character of the patient, itself, Erič calls it “anxious character” and it is the mixture of characteristics of an evasive and dependent personality. Erič recommends the study of the personality structure and the patient diagnosing of the panic disorder with agoraphobia or without agoraphobia The “anxious character” is not included in any classification, but it helps to understand the disorder in other way, like it is understood in other medicinal fields. He itself states also the multimodal method of treatment and recommends as the treatment of 1st option the drugs from the SSRI’s group and enzodiazepines in combination with the relevant psychotherapy /Erič, Lj., 1991/. Also the Czech authors accept the medicamentous SSRI and RIMA therapy, but they prefer the cognitive-behavioral therapy or the combination of the both.
54
The treatment itself of the patients, who have been suffering of the panic disorder with agoraphobia for many years, is not easy, but after diagnosing or eventually finishing the diagnosing of other disorders, who accompany the panic disorder, a tedious and patient treatment follows. It is recommended to continue with the treatment minimally for one year, then to stop the treatment after an agreement with the patient or to leave the maintaining therapy /Kasper, S, 1999/. Our experience is the necessity of the long-term monitoring of the patient and a careful reduction of the therapy and its finishing. The rational manipulation should above all concern besides SSRI’s also benzodiazepines /Baumann P., Bryois Ch., 1999/. Not only once it happened that the patients, who used bromazepamum, alprazolamum, … and in practice they even did not know, what disorder they are treated on, had abstinent appearances in case of switching to other treatment. In such cases the compliance was not bad and some of these patients decided to be treated at those physicians, who prescribed them benzodiazepine.
CONCLUSION The panic disorder is not a hard disease, even if the clinical picture often seems very dramatically and the diagnostics of the panic disorder is very difficult and delicate medicinal procedure, which requires an experienced and patient physician. / Erič Lj., 1991/. The differential diagnostics of the panic disorder requires to return to the beginning of the disorder itself, to the first discovery of completely first symptoms of panic disorder, as well as to monitor the dynamic course of the disorder during the years. The personality structure at such disorders is very important and besides these psychical basis, the neurobiological serotnoninergous theory is given by us to the connection with complicated revealing and diangostics of the panic disorder /Kukumberg P., 1999, Kotas R., 1999, Rektor I., 1999/. Thanks to psychopharmaca from SSRI’s and the rational therapy with benzodiazepines, the therapy of a diagnosed chronified panic disorder, or its comorbidity with other disorders becomes treatable. The multimodal treatment, including psychotherapy, has an extremely important task in this process. BIBLIOGRAPHY Baumann P., Bryois Ch. /8/ 1999/: Usage rationeell des benzodiazepines, Pharmacia and Upjohn, 4-30 Erič Lj. / 1991/: Panična stanja II. dopunjeno i prošireno izdanje, Medicinska knjiga, Beograd-Zagreb, 153-175 Kasper S./4/1999/: Diagnostics and Pharmacoherapy of Panic Disorder, issue: Psychiarie No.4/1999, 242-247 Kotas R, Ambler Z. /1999/: Serotonine receptors in patophysiology and migraine treatment, Czech and Slovak Neurol. Neurochir., 62/95, 1999 /1/8-12 Kukumberg P./1999/: Panic disorder and migraine, Czech and Slovak Neural. Neurochir., 62/95, 1999/1/57-59 Raboch J., Seifertová D., Praško J./1999/: Panic states, issue SKB, 18-24, 26-52 Raboch J., Seifertová D., Praško J./1999/: Panic states, Part II, issue SKB, 6-17 Rektor I., Tyrtlíková I., Brázdil M./1991: Psychically induced non-epileptic /pseudo-epileptic/ seizures, Czech and Slovak Neural. Neurochir., 62/95, 1999/1/44-49 Škoda Ct./1996: Non-distinguished psychiatric disease in a non-psychiatric surgery, Practical physician 76, 1996, 2-5
TABLE 1. - SOMATIC PATIENTS EXAM INED WITH MRI MRI MALE FEMALE TOTAL %
NUMBER 12 11 23
MEAN AGE OF PATIENTS MALE FEMALE MEAN AGE OF ALL PATIENTS THE YOUNGEST PATIENT THE OLDEST PATIENT
% 52.17 47.82 100
44.33 41.36 42.91 21 63
The second group included 9 patients treated in the psychiatric outpatient clinics, and out of that number 4 were men (44.44%) and 5 women (55.55). The mean age of men was 42 years, of women 35.2 years, the youngest patient was 25 and the oldest was 51 (Table 2).
55
TABLE 2. - REVIEW OF PSYCHIATRIC OUTPATIENTS EXAMINED WITH MRI MRI MALE FEMALE TOTAL %
NUMBER 4 5 9
% 44.44 55.55 100
MEAN AGE OF PATIENTS MALE FEMALE MEAN AGE OF ALL PATIENTS THE YOUNGEST PATIENT THE OLDEST PATIENT
42 35,2 38,22 25 51
Exclusion criteria helped us reduce the comorbidity to the minimum among patients with somatic diseases. Patients with somatic diseases tested with MRI (6 patients) had diagnoses G.00-G.99 (diseases of the nervous system) and M.00-M.99 (diseases of muscular, skeletal and collective tissues (also 6 patients) (Table 3). TABLE 3. - DIAGNOSES OF PATIENTS WITH SOMATIC DISEASES EXAMINED WITH MRI DIAGNOSIS C00-C99 D10-D36 E00-E90
G00-G99 I00-I99 M00-M99
R00-R99
S00-T98
DIAGNOSIS IN WRITING TUMOURS BENIGN TUMOURS DISORDERS OF THE GLANDS OF INTERNAL SECRETION DISORDERS OF THE NERVOUS SYSTEM DISORDERS OF CIRCULATION DISORDERS OF MUSCULAR, BONE AND CONNECTIVE TISSUES SUBJECTIVE AND OBJECTIVE SIGNS, ABNORMAL CLINICAL AND LABORATORY FINDINGS, UNCLASSIFIED ELSEWHERE INJURIES, POISONING AND OTHER COMPLICATIONS
TOTAL %
NUMBER OF PATIENTS 5 1 2
% 21.73 4.34 8.69
6
26.08
1
4.34
6
26.08
1
4.34
1
4.34
23 100
Within M.00-M.99 diagnoses, the ratio of dorsalgia was 50% (M.54) - Table 4; and in the G.00-G.99 group, there was no predominant diagnosis (Table 5). DIAGNOSIS M49 M51 M54 TOTAL %
56
DIAGNOSIS IN WRITING SPONDILOPATIE
NUMBER OF PATIENTS 1
OTHER DISORDERS OF INTERVERTEBRAL DISKS 2 DORSALGIA 3 6
33.33 50 100
% 16.66
TABLE 5. - REVIEW OF THE MOST FREQUENT DIAGNOSES AMONG SOMATIC PATIENTS EXAMINED WITH MRI G00-G99 DISASES OF NERVOUS SYSTEM DIAGNOSIS
DIAGNOSIS IN WRITING OTHER DEGENERATIVE DISORDERS OF NS NOT OTHERWISE CLASSIFIED EPILEPSY MIGRAINE TEMPRORARY BRAIN AND ISHEMIC SEIZURES AND RELATED SYNDROMES OTHER POLENEURO-PATHIES
G32
G40 G43 G45
G62 G81 TOTAL %
HEMIPLEGIA
NUMBER OF PATIENTS
%
1
16.66
1 1 1
16.66 16.66 16.66
1
16.66
1 6
16.66 100
In regard to the number of MRI, the greatest number of patients, i.e., 13 (56.52%) were examined with MRI for the first time (Table 6) which made the group more homogenous and comparable. TABLE 6. - NUMBER OF MRI EXAMINATIONS IN PATIENTS WITH SOMATIC DISEASES SEQUENCE OF MRI NUMBER OF PATIENTS % FIRST 13 56.52 SECOND 7 30.43 THIRD 1 4.34 FOURTH 1 4.34 FIFTH 1 4.34 TOTAL 23 % 100 All patients suffering from agoraphobia with panic disorder (9) were examined for the first time on MRI (Tables 7 and 8). TABLE 7. - REVIEW OF DIAGNOSES OF PSYCHIATRIC OUTPATIENTS EXAMMIED WITH MRI DIAGNOSIS
DIAGNOSIS IN WRITING
NUMBER OF PATIENTS
%
F.40.01
AGORAPHOBIA WITH PANIC DISORDER
9
100
TABLE 8. - NUMBER OF MRI IN PSYCHIATRIC OUTPATIENTS SEQUENCE OF MRI FIRST INVESTIGATION
NUMBER OF PATIENTS 9
% 100
The psychological evaluation before and after non-invasive examination (MRI) was carried out with the use of international scales of API test. After MRI in patients with somatic diseases, their condition improved, on average, by 1 point, i.e. 9.96% (API test), among patients who received paroxetin the improvement after MRI was 4.66 points, i.e. 46,7%. At start, the mean value for both groups on API 1 test was 10 points. This comparison indicated that patients, on average, endured MRI better after they had received premedication with paroxetin. The feeling of tension decreases before the examination, and therefore, hypothesis 2 was confirmed, i.e. that premedication makes the patient more comfortable, reduces the tension and enables completion of MRI.
57
In the group of somatic patients examined with MRI, API 1 or 2, seven patients had scored above 15 and, of this number the improvement occurred only in 3 patients on API 2. One among these 7 patients had the same score on API 1 and API 2 (Table 10) TABLE 10. - REVIEW OF DIAGNOSIS AND MEDICATIONS IN SOMATIC PATIENTS EXAMINED WITH MRI, WITH API 1 OR API 2 SCORE ABOVE 15 MRI/diagnosis C78
Sequence of MRI First
API 1 17
API 2 14
Score -3
G32
first
22
9
-13
G43 M51 M54 M54 R42 Total Mean value
first first second third first
20 22 16 8 21 126 18
29 6 40 22 21 143 20.42
+9 -14 +24 +14 0 +17 +2.42
Therapy Does not know which medication he/she takes No pharma-cotherapy
ketoprofen, B vitamins analgetics, antirheumatics no pharmacotherapy biperiden, lorazepam, antirheumatics does not know
A randomly selected patient with somatic disease, who at the time of MRI examination had G.45 diagnosis scored 10 on API 1, 3 on API 2, and took daily dose of paroxetin 20 mg 1-1- 0 tablets 2 weeks before MRI (Table 9). Even when we consider this randomly selected somatic patient, it was paroxetin up to its daily dose that helped him endure the investigation in a more relaxed manner, although the medication with paroxetin was not planned in the study. TABLE 9a. - RESULTS OF PSYCHOLOGICAL TESTS SOMATIC PATIENTS
NMR/ diagnosis
API 1
API 2
Score
C04 C71 C71 C72 C78 D33 D33 E22 G32 G40 G43 G45 G62 G81 I64 M49 M51 M51 M54 M54
0 3 0 2 17 3 6 9 22 7 20 10 11 9 15 4 5 22 16 14
1 3 0 6 14 3 11 0 9 4 29 3 4 6 8 4 9 6 40 0
+1 0 0 +4 -3 0 +5 -9 -13 -3 +9 -7 -7 -3 -7 0 +4 -16 +24 -14
58
PSYCHIATRIC OUTPATIENTS (who had previously been treated for a long time in order specialized outpatient departments) NMR/ diaAPI 1 API 2 Score gnosis I51 I11 Q23 G43 I11 G99 S01 G43 G43
11 20 19 10 23 2 2 0 3
2 8 5 6 1 0 2 19 5
-9 -12 -14 -4 -22 -2 0 +19 +2
M54 R42 S32 total mean value %
8 21 7 231 10.04
22 21 3 208 9.04
+14 0 -4 -23 -1 9.96
total mean value %
90 10
48 5.33
-42 -4.66 -46.67
TABLE 9b. - RESULTS OF PSYCHOLOGICAL TESTS SOMATIC PATIENTS NMR/ dia-gnosis API 1 C04 0 C71 3 C71 0 C72 2 C78 17 D33 3 D33 6 E22 9 G32 22 G40 7 G43 20 G45 10 G62 11 G81 9 I64 15 M49 4 M51 5 M51 22 M54 16 M54 14 M54 8 R42 21 S32 7 total 231 mean value 10.04
%
API 2 1 3 0 6 14 3 11 0 9 4 29 3 4 6 8 4 9 6 40 0 22 21 3 208 9.04
Score +1 0 0 +4 -3 0 +5 -9 -13 -3 +9 -7 -7 -3 -7 0 +4 -16 +24 -14 +14 0 -4 -23 -1
PSYCHIATRIC OUTPATIENTS NMR/ diagno-sis API 1 F4001 11 F4001 20 F4001 19 F4001 10 F4001 23 F4001 2 F4001 2 F4001 0 F4001 3
API 2 2 8 5 6 1 0 2 19 5
Score -9 -12 -14 -4 -22 -2 0 +19 +2
total mean value
48 5.33
-42 -4.66
9.96
%
90 10
-46.67
In addition, of particular interest were 3 cases with increased score on API 2 (Table 11). One of them was a female patient with diagnosis G.43 and score +9, who had the following experiences during the examination: she did not feel the right part of her body, she had a dry mouth, tremor, arrhythmia, difficulties with breathing, she did not feel well but endured the whole investigation (i.e., her condition detenorated).
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TABLE 11. - REVIEW OF SOMATIC PATIENTS INVESTIGATED WITH MRI WHOSE CONDITION DETERIORATED ON API 2 TEST MRI/ DIAGNO-SIS
API 1
API 2
SCORE
EXPERIENCE OF MRI
G43
20
29
+9
M54
16
40
+24
M54
8
22
+14
arrhythmia, difficulties with breathing, carried the MRI procedure to the end feeling of isolation, MRI procedure discontinued arrhythmia, MRI procedure discontinued
TOTAL MEAN VALUE
44 14,66
91 30,33
+47 +15,65
Another patient with diagnosis M.54 who scored +24 (deterioration during MRI) experienced a very unpleasant feeling of anxiety, he felt as if he was placed in the coffin, he could not move. He experienced the noise as the work of the compressor for breaking the asphalt on the street, and he requested the examination to be discontinued after 30 minutes. He had difficulties with breathing, a feeling that he would suffocate and that he would faint, he felt sick and could not complete MRI to the end. The third patient scored +14 (also deteriorated during the investigation). He had arrhythmia, difficulties with breathing, did not feel well, he was dizzy, and for these reasons he asked, on his own initiative, the investigation to be discontinued after 20 minutes. These patients enabled us to better understand our hypothesis 1, which they confirmed, i.e., about a precipitating MRI effect on the development of panic attack among patients whose diagnosis was still not precisely established. Nevertheless, although there were only few such cases among somatic patients (only the condition of 3 patients deteriorated and was accompanied by panic anxiety) we must take into consideration that this was the number of deteriorations from the total number of investigated somatic patients (23), and the study covered only those who were examined with MRI during one clinical week. There are also some other questions which were left unanswered such as, for example, why some patients were tested with MRI for the second, or third time, and whether the therapy they received during the process of making differential diagnosis was effective or not and whether it was related to their main disease. Of 9 psychiatric outpatients patients who received premedication with paroxetin, 3 scored above 15 on API 1. The mean score was 20.66 and their condition improved, on average, in API 2 by 4.66 points, the mean value of improvement was 16 points. This indicates that the patients waited for the investigation with specific psychological tension and uncertainty that disappeared during the investigation (Table 12 ). Deterioration of one patient who scored 0 on API 1, was 19 on API 2. She had acute panic attack during the investigation, which was resolved with 2 mg of clonazepam (Table 12). TABLE 12. - RESULTS OF PSYCHOLOGICAL TESTS OF PSYCHIATRIC OUTPATIENTS, WHO ARE TREATED WITH PAROXETIN AND EXAMINED WITH MRI, AND WHOSE CONDITION IMPROVED AFTER MRI (ON API 2) MRI/ DIAGNOSIS F.40.01 F.40.01 F.40.01 TOTAL MEAN VALUE
API 1 20 19 23 62 20,66
API 2 8 5 1 14 4,66
SCORE -12 -14 -22 -48 -16
All this illustrates the possible increase of the score on API 2, in which case, it enables the follow-up of precipitation of panic attack in somatic patients, as well as in patients premedicated with paroxetin, which is presented in Tables 11 and 13. TABLE 13. - RESULTS OF PSYCHOLOGICAL TESTS OF THE PSYCHIATRIC OUTPATIENTS, WHO ARE TREATED WITH PAROXETIN AND INVESTEGATED ON MRI, AND WHOSE CONDITION DETERIORATED AFTER MRI (ON API 2) MRI/ DIAGNOSIS F.40.01 TOTAL
60
API 1 0 0
API 2 19 19
SCORE +19 +19
Discussion As we have already mentioned at the beginning of the paper, we could not find similar studies in the literature, and we can only confirm that there are various precipitating factors of panic attack2,3,4 We have found that the patients who did not receive premedication with paroxetin had worse experiences. concerning MRI procedure (Tables 9a, b, 10 and 11), and that they showed increased score on API 2 test. The very experience of MRI procedure was different, they were anxious, weak, they felt as if they were placed in the coffin, could not breathe, as if they would suffocate, they had stomach problems, nausea, urge to vomit, they were unable to complete MRI investigation, they had fear of death, a feeling that they had the cage on their head, a shortage of air as if the air in the room did not change. The very work of the MRI machine they experienced as unpleasant noise, as if compressor machine for breaking the asphalt on the street was right by their ear. The vast majority of diagnoses that the patients brought with themselves (Tables 9a and 9b) were M.54, G.43 which had been most commonly consulted with psychiatrists, but unfortunately for the patients, only after investigations that had lasted for too long at other departments.’ These diagnoses were dorsalgia, migrainous diseases, and other. The patients who received paroxetin which has a strong anxiolytic and sedative effect and reduces the frequency of panic attacks at certain time intervals, endured the investigation, on average, 4 times more easily compared with patients who received no premedication with S.S.R.I group of medications (paroxetin).
Conclusion This was pilot study with a small sample and we are planning to continue the investigation since the findings indicated that paroxetin may be very useful, if not with all patients investigated on MRI, then in patients with psychiatric diagnosis. Furthermore, paroxetin can be useful for somatic patients, for example, patients with insufficiently differentiated diagnosis of dorsalgia and migrainous problems. This could facilitate the work of our colleagues who work with RTG (MRI) and help our patients to endure more easily and without panic attacks these, sometimes, necessary noninvasive (MR1) procedures. References: Timotijević 1, Paunović V. 1nstrumenti kliničke procene u psihijatriji, IDP “Naučna knjiga” Beograd, 1992, 1-151, 116-117. Erić Lj. Panična stanja. II dopunjeno i prošireno izdanje, Medicinska knjiga, Beograd - Zagreb, 1991, 1-309, 7-12,133-152. Raboch J, Seifertová D. Praško J. Panicke stavy, vyd: Psychiatrická společnost české Iíkarské společnosti J.E.Purkyné, 1999, I. čast,1-54, 18-24, 11 čast,1-56, 6-40. Robert E. Hales, Stuart C.Yudovsky, John A.Talbott. Textbook of Psychiatry, 2nd Edition, the American Press, 1994, 1-1608, 495-554. Milan IGNJATOVIC, psychiatrist, Psychiatric Outpatient Clinic, Policlinic, Banska Bistrica, Slovakia
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IS COMBINATION OF PSYCHOPHARMACOTHERAPY AND PSYCHOTHERAPY EFFECTIVE AT TREATMENT OF AGORAPHOBIA WIHT A PANIC DISORDER? AUTHORS MUDr. Milan Ignjatović 1. MUDr. Dana Ignjatovičová 2. 1. Psychiatric out-patients’ department, Policlinic, Horna 60, Banska Bystrica, The Slovak Republic 2. Non-state psychiatric out-patients’ clinic, Cesta k nemocnici I, Banska Bystrica, The Slovak republic
Summary Brief dynamic individual psychotherapy is often used at the psychiatric out-patients’ clinics in treatment of anxiety disorders. “Broad-spectrum” antidepressants of the SSRI (serotonin selective reuptake inhibitors) group contribute profoundly to a combined treatment with psychotherapy. A very important question is whether pharmacotherapy or psychotherapy alone are sufficient in treatment of anxiety disorders. Our 39-month long observation at psychiatric out-patients’ clinics shows that patients who were subjected to a brief dynamic individual psychotherapy in combination with pharmacotherapy had better results after the treatment was finished. They have been without pharmacotherapy for 10.5 months on average after taking pharmacotherapy continuously for 12.25 months. In comparison, the other group members have been subjected only to the ordinary psychiatric interview and have been taking the drugs on average for 25.94 months and they are still taking them.
Key words Brief dynamic individual psychotherapy, psychopharmacothcrapy, agoraphobia with a panic disorder
Introduction Anxiety is a part of a range of natural human emotions. And not only that. Anxiety is the oldest universal emotion of a human kind and a primary emotion of every man. Anxiety has different variations from a slight one to a panic attack /Kalicanin, 1996/. Also with view to such statements it can be concluded that it is desirable to combine pharmacotherapy and psychotherapy within a multimodal way of treatment anxiety disorders with adults. /Eric, 1991/. Some authors recommend combining both therapies also with children /Tadic, 1992/. As to the biological foundations of the psychotherapy’s effect, according to the Kandel’s experiments on animals, psychotherapy is considered to be a form of learning, where the process of learning that occurs in psychotherapy can induce alterations of gene expression and thus also a change of synaptic transmission /Gabbard, 2000/. There are also authors who take into account only biological foundations of agoraphobia with panic disorder, for example due to hypofunctioning of presynaptic noradrenergic receptors and adaptation hypersensitisation of postsynaptic noradrenergic receptors. Naturally, this hypothesis includes also serotoninergic, GABA-ergic, cholecystokinergic systems /Landowski, 1999/. For us, the out-patients’ clinic psychiatrists, the clinic experiences, in addition to the theoretical considerations and experiments on animals, are of utmost importance. In Sweden, 62 patients who suffered from agoraphobia with panic disorder were followed up for 16 years and it was discovered that only 10 patients had not had any anxiety symptoms for the last 10 years and had not had to take psychopharmacotherapy /Andersch, 2002/. A small number of cured patients in this study, frequent changes of psychopharmacotherapy, not utilising psychopharmacotherapy during the 15 years of observations represent the same problems that we encounter in our daily out-patients’ clinic practice. Questions that we often ask ourselves are: What is the most effective therapy for patients with agoraphobia with panic disorder, how long it should last and how long a patient should be in remission following the therapy.
Group and Methodology 8 patients suffering from agoraphobia with panic disorder who took psychopharmacotherapy and at the same time underwent depth-oriented individual psychotherapy were found in the patients’ register of the first author of the study /Group A/. On the other hand there were 15 patients with the same diagnosis who took psychopharmacotherapy and underwent only ordinary psychiatric interview /Group B/. Average age of the patients in Group A was 36.5 and in Grout, B 41.06 years. Follow up and assessments of the patients were done retrospectively from the April 1, 1999 until June 30, 2002, i.e. for the period of 39 months.
62
The criteria for enlistment Diagnosis of agoraphobia with panic disorder according to MKCH-10 and DSM-1V /Smolik, 1996/ -Age of 18 - 65 years -Disqualifying criteria men and women older than 65 years of age -depressive disorder -schizophrenic disorder in anamnesis -organic disorders -mental retardation -personality disorders -addiction to alcohol and other addictive substances -pregnancy -serious somatic diseases
Aims To compare application of psychopharmacotherapy after undergoing psychotherapy – brief dynamic individual psychotherapy /Group A/ with application of psychopharmacotherapy after undergoing ordinary psychiatric interview /Group B/. To evaluate the results of the treatment in both groups of patients A and B /right after the treatment has been finished/.
Results We included 23 patients suffering from agoraphobia with panic disorder, followed up at the out-patients’ psychiatric clinic for 39 months in the study. Subgroup A comprised 8 patients, /women N = 3/, of the average age of 36.5 years, who underwent brief dynamic individual psychotherapy and were taking psychopharmacotherapy continuously on average for 12.25 months. After undergoing the psychotherapy, 6 patients have been without psychopharmacotherapy for 10.5 months on average and only 2 patients continue their treatment by psychopharmacotherapy. These patients evaluated their current mental condition with help of point scale for assessment of psychotherapy according to Kondas, 1988. The average number of points that they reached was 55.6 points. Subgroup B comprised 15 patients suffering from agoraphobia with a panic disorder that went only through ordinary psychiatric interview. The average age of patients was 41.06 years /women N=11/, they were taking psychophannacotherapy continuously for 25.94 months on average, while all of them except one /who has not been taking psychopharmacotherapy for 4 months/, continue in taking psychopharmacotherapy. With help of the point scale for assessment of psychotherapy these patients reached 50.1 points on average. An important finding is that the patients who had gone through brief dynamic individual psychotherapy /while taking pharmacotherapy/, were taking the psychopharmacotherapy on average for a shorter period /12.25 months in comparison with 25.94 months/ and with an exception of 2 patients, they did not have to keep taking the pharmacotherapy any longer. In the subgroup B only one patient has been without pharmacotherapy. As for shortcomings, it is a small number of patients in this study who had undergone a brief dynamic individual psychotherapy, which we consider to be insufficient. The brief dynamic individual psychotherapy, which is highly demanding from both time and finances point of view in the out-patients’ clinic conditions, seems to be in combination with psychopharmacotherapy the most suitable combination at the treatment of agoraphobia with a panic disorder. We consider using only one assessment scale of the psychotherapy with patients as another insufficiency of this work. And, at last, it would certainly be useful to include also the economic result of applying the combined treatment of agoraphobia with a panic disorder.
Discussion Term “anxiety” originates in Latin language - “angere” /depressed, constricted/ and “anxietas” /worry, discontent/. The nearest meaning would be a feeling of an internal tension, expecting that something bad is going to happen, a feeling of undefined fear. The psychiatric dimension of fear is also based on this description, and, according to Freud, it has a signalling function / Kalicanin, 1996/. One-sided application of psychotherapy, for example, results in reduction of anxiety and improvement of patients’ condition /Gillieron, 1990/. Nevertheless, even this procedure does not exclude additional psychopharmacotherapy /Bryois, 1994/. On the other hand, a sole application of psychopharmacotherapy, for example of clomipramine for 8 weeks at the beginning of treatment and then terminating it without a psychotherapy requires adding benzodiazepines to suppress anxiety. In the study of the Swedish authors mentioned above, the benzodiazepines were added to 53 out of 62 patients who were included in the study from the beginning. After 15 years of following up, only 10 out of the total number of patients were in remission, while the number of patients taking benzodiazepines decreased to 10/18%/. However, the number of patients who at the beginning did not take SSRI at all increased /0 patients at the beginning of the study/ to 15 patients /27%/ out of the whole group that have completed the follow up /55 patients/ during the 15 years. They were given alprazolam from benzodiazepines.
63
Taking this biological approach to the treatment of patients we are also aware of certain deficiencies at long-term treatment. Every patient is to be considered an individual, the treatment must be determined with the shortest possible time of taking the drugs and with a view that after the treatment the patient will not be taking psychopharmacotherapy. It is important due to the fact that even highly safe SSRI medicines have adverse effects /Briley, 2000/. Adverse effects of SSRI appear by stimulation of 5 HT2-receptors /agitation, anxiety, panic attacks, insomnia, sexual dysfunction/ and 5HT3-receptors /nausea, gastrointestinal problems, diarrhoea, headaches /Briley, 2000, Suchopar, 1999/. Other adverse effects of the treatment by SSRI are also known, such as extrapyramidal symptoms, more often acute then deferred /tardive/ EPS; in spite of that the SSRI are safe at the long-term treatment provided that the indication and dosage are correct. The most important aspect of all the advantages and disadvantages mentioned above for us was to enable the patient full remission in the shortest possible time. That is why we chose for the patients who could come to the psychotherapy regularly the brief dynamic individual psychotherapy in combination with psychopharmacotherapy. This method was more effective, which was also proven in the tests carried out after the psychotherapy or ordinary psychiatric treatment. Patients who underwent psychotherapy and psychopharmacotherapy - 6 do not take psychopharmacotherapy, whereas the patients who came to ordinary psychiatric check-ups and had only ordinary psychiatric interview and took the psychopharmacotherapy still continue in taking the pharmacotherapy. We would conclude the discussion by saying that SSRI affect impulsiveness, affective unstableness that are parts of the temperament while applying psychotherapy helps in approaching at objective relationships and self-assessment. Applying the combined treatment in a neurobiological way could be crucial in the effectiveness of the treatment /Gabbard, 2000/.
Conclusion Even with a small number of patients the combination of psychopharmacotherapy and psychotherapy proved to be the most effective, bringing permanent remission without possible dependence on drugs as well as reducing the risk of adverse effects of psychopharmacotherapy.
Literature Andersch S., Hetta J.: A naturalistic fifteen-year follow up study of panic disorder patient poster presentation, Stockholm, Sweden, 2000 Berk M.: Paroxetine induces dystonia and parkinsonism in obsessive-compulsive disorder. Hum. Psychopharmacol., 8, 1993, pp. 444-445 Briley M.: Understanding Antidepressants, Pierre Fabre Médicament 81100 Catres, France, 2000, 54, pp. 31-32 Bryois E -Hanic: Intervention psychoterapique en quite seances-These universite de Lausanne-faculte de medicine department universitaire de psychhiatrie adulte, 1994. p. 90 Erič Lj; Panična stanja II-dopunjeno i prošireno izdanje, Medicinska knjiga, Beograd, - Zagreb, 1991, 309, pp. 133-152 Gabbard G.O.: A neurobiologically informed perspective on psychotherapy, British Journal of Psychiatry, 2000, 177, pp. 117-122Gillieron E.: Les Psychothérapies Bréves, Presses Universitaires de France, 2nd Edition 1990, 109, 16-32. 62-86 Goetz M., Hrdlička M., Papežová S., Maršalek M - Extrapyramídové príznaky pŕi terapii SSRI, Čes. a slov. Psychiatr., 98, 2002, No 1, pp. 33-40 (Extrapyramidal symptoms at treatment with SSRI) Kaličanin P.:Anksiozni poremećaji, Stanja patološkog straha, TEHNISS,Beograd, 1996, 185,pp.10-23,35-55,32-35, Kondáš 0.,Bodovacia stupnica na hodnotenie psychoterapie L.R.Tucker, v úprave podl›a Kondáša, ústna prezentácia, cesloštátny tématický kurz v psychoterapii,ILF,Bratislava, 22.5.-26.5.1989 (Pointing scale for evaluation of psychotherapy L.R.Tucker, modified by Kondas, oral presentation, national thematic course in psychotherapy, ILF, Bratislava.) Landowski J.,Lysiak-Szydlowska W.:Low plasma dopamine-b-hydroxylase activity in patients with panic disorder,Archives of Psychiatry and Psychotherapy,1999,Vol.1,Dec.1999,pp.63-68. Smolí P.:Duševni a behaviorální poruchy,Maxdorf - Jesenius,1996,487,pp.243-299 (Mental and behavioural disorders) Suchopár J.:Remedia,Compenditun, Tretie vydání,Panax, 1999,743,pp.180-222 Tadić N.:Psihoanalitička psihoterapija dece i mladih,Naučna knjiga,Beograd, 1992, 445,pp.395-403
CHART No. 1 - COMPARISON OF THE PERIOD OF USING PSYCHOPHARMACOTHERAPY AND THE PERIOD WITHOUT PHARMACOTHERAPY AFTER HAVING UNDERGONE THE BRIEF DYNAMIC INDIVIDUAL PSYCHOTHERAPY /GROUP A/ AND THE EVALUATION OF PSYCHOTHERAPY ACOORDING TO KONDAS. Assessment scale of psychotherapy according to Kondas
Continual use of psychopharmaco-therapy in months
Period in months Age in years without psycho-pharmaceu-ticals
Sex
61 59 54 52 33
11 5 10 24 39
17 6 24 24 39
M M M M F
64
34 45 46 24 43
67 52 66 55.5 /average/
5 2 2 12.25 /average/
5 5 6 10.5 /average/
28 37 31 36.5
F F M
CHART No. 2 - COMPARISON OF THE PERIOD OF USING PSYCHOPHARMACOTHERAPY AND THE PERIOD WITHOUT PHARMACOTHERAPY AFTER HAVING UNDERGONE THE BRIEF DYNAMIC INDIVIDUAL PSYCHOTHERAPY /GROUP B/ AND THE EVALUATION OF PSYCHOTITERAPY ACOORDING TO KONDAS. Assessment scale of psycho-therapy according to Kondas 47 54 57 34 63 60 33 59 40 52 61 52 46 52 32 50.1 /average/
Continual use of psychopharma-cotherapy in months 33 20 8 32 23 9 32 7 30 37 32 32 28 36 30 25.94 /average/
Period in months without psychopharma-ceuticals Using Using Using Using 4 Using Using Using Using Using Using Using Using Using Using 1 not using
Age in years
Sex
49 39 39 50 30 36 29 59 47 43 22 40 36 41 57 41.06
F M F F M F F F M F F F F M F
CHART No. 3 - LIST OF THE PHARMACOTHERAPY OF PATIENTS WHO HAVE UNDERGONE THE BRIEF DYNAMIC INDIVIDUAL PSYCHOTHERAPY /GROUP A/ Name of drug Paroxetinum+sulpiridum+clonazepamum Paroxetinum+clonazepamum
Number of patient 2 2
Mirtazapinum Venlafaxinum Citalopramum+bromazepamum
1 1 1
Alprazolamum
1
CHART No. 4 - LIST OF THE PHARMACOTHERAPY OF PATIENTS WHO HAVE UNDERGONE AN ORDINARY PSYCHIATRIC INTERVIEW /GROUP B/ Name of drug Paroxetinum+clonazepamum Paroxetinum+clonazepamum+valproic acid+natrii valproas Citalopramum+clonazepamum Citalopramum+alprazolamum Paroxetinum+hydroxizinum Paroxetinum+valproic acid+natrii valproas
Number of patients 10 1 1 1 1 1
65
PHARMACOECONOMICS OF THE TREATMENT OF AGORAPHOBIA WITH PANIC DISORDER INTRODUCTION Medication and medical aid costs, which reached total amount of 9,648 billion Sk (Slovak crowns) in 1999, represent second most important item of the health care budget of the Slovak republic (SR). During the same year, only diagnostic and therapeutic services, performed by contractual health institutions, have had higher costs. In 1999, compared with previous year, medication and medical aid costs exceeded the budgetary plan for more than 1,749 billion Sk, while average costs of a single medication package rose by 13 percent (VšZP previous year budget, 2000). According to annual report of Všeobecná zdravotná poist’ovna Slovenskej republiky (VšZP SR), by the end of 1999, average costs of a single medication package reached amount of 140.5 Sk, although by the end of 1998 these costs represented only 117.1 SK (Všeobecná zdravotná poist’ovna, 1999). This development was, among other reasons, caused by increasing prescriptions of modem antidepressants, which have higher institutional costs compared with classical preparations. However, modern antidepressants play a decisive role during the treatment of agoraphobia (Praško, 1999). From epidemiological point of view, agoraphobia with panic disorder is one of the most frequent types of phobia. Total prevalence in average population reaches 5 percent, 3 - 5.2 percent in men›s subgroup, and 1.8 - 23 percent in women›s subgroup, depending on their sociocultural environment (Starčević, 1997). Agoraphobia usually appears in the third decennium, affecting active lives of patients, which is an important factor with regard to productivity of work and indirect costs. In 1980, more than 2 million American citizens, of average age 37 years, suffered from agoraphobia with panic disorder and some other anxiety disorders (Sheehan et al., 1980). Individuals, suffering from panic disorder, have seven times higher usage of all medical services and a double number of inability to work periods, compared with average population (Siegel at al., 1990). The field of anxiety disorders was until now rather forgotten by pharmacoeconomists, because a large number of people, suffering from these diseases, do not visit psychiatric outpatient departments. Frequently, general practitioners misdiagnose such patients as being somatically sick. These patients are then long-term, unsuccessfully, and costly treated for their sickness (Hosák., 2000). In the computer database MEDLINE, there is only a minimum of entries, dealing with pharmacoeconomics of agoraphobia. While searching, «agoraphobia» and «cost» keywords may be used, possibly «benefit», «effectiveness», or «utility». However, some older publications do not meet the criteria, required for modern pharmacoeconomic studies. Above facts suggest, that the necessity to study economical aspect of agoraphobia and its pharmacotherapy, within the frame of Slovak health service is urgent. The main objective of our study was to determine the average daily and total pharmacotherapy costs of agoraphobia with panic disorder when treated by non-psychiatrist outpatient practitioners, compared with accurate diagnostics and treatment in psychiatric outpatient department. Average daily and total number of tablets, taken by patients during the examined period, was also analyzed.
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THE EFFICACY OF DEPRESSION TREATMENT WITH M1LNACIPRAN (A SIX- MONTH EXPERIENCE) AUTHORS Dana Ignjatovičová, M.D. (1) Milan Ignjatović, M.D. (2) Silvia Beatriz Schweitzer, M.D. (3) (1, 2) Private Psychiatric Outpatient Surgery, Cesta k nemocnici 1, Banska Bystrica, Slovak Republic (3) Psychiatric Department, Cespedes, Buenos Aires, Argentina
Summary Depression represents one of the most frequent and grave psychical alienations. It manifests itself by tiredness, troubles with sleeping, headaches, loosing or putting on weight, and failure of sexual function. Bad mood, however, is not necessarily the most dominant symptom [G.N. Christodoulou, 2002]. It means that together with the establishment of the right diagnosis it is very important to manage an adequate treatment of depression. Some of the key points, not only in the conditions of outpatient treatment, are anamnesis exploration of previous depressive episodes, family anarnnesis of affective diseases, and clinical exploration in relatives. Depression today represents the 4th most frequent cause of health damage or loss of life due to early affection or mortality. It is expected that depression will become the 2nd in 2020 [G.N.Christodoulou, 2002]. In the U.S. A., yearlong prevalency represents 12.9% in women and 7.7% in men [Kessler et al., 1994]. In Europe, prevalency is 17% [Lepine et al., 1997]. Our 6-month follow-up included 12 patients using milnacipran 100 mg per day. We made evaluafions of HAMD and HAMA at the start (it means on the first day of the follow-up) and used the CGI scale. Two patients were discarded from our follow-up: one patient had discontinued the medication on her own in the 4th month of the course of treatment and the other one was hospitalized due to a high risk of suicidal tendencies (HAMD-39 points, HAMA28 points). We have evaluated HAMD on the first day of treatment, then one month later, and then half a year after the setting up of milnacipran 100-mg per day. In the 2nd month we did not observe any kind of strong amelioration (HAMD-19.8 points), but in the 6th month HAMD reached to 7.1 points.
Key words Depression, HDRS (Hamilton Depression Rating Scale), CGI (Clinical Global Impression), milnacipran
SAMPLE GROUP AND METHOD In the card files of the psychiatric outpatient department of this study’s first author, all patients, suffering from agoraphobia with panic disorder for longer than two years, were selected, who were previously treated by other therapists than psychiatrists. These patients later joined outpatient psychiatric care, which was carried out during nineteen nineties. Agoraphobia was diagnosed according to DSM-IV classification (Kaplan et al., 1994). Patients with psychiatric comorbidity, together with pregnant women, were excluded from the research. Total number of evaluated individuals reached 28, 25 women and three men. Average age of the sample group members was 41.5 years (from 20 to 62 years, S.D. = 11,4). Their average sickness period, before starting psychiatric treatment, was 10 years (from 2 to 30 years, S.D. = 7,0). Patients were originally treated by outpatient general practitioners, internists, neurologists, and other non-psychiatric specialists, usually without the prescription of psychopharmatics for relieving their physical disorders, for example vertigo, back aches, intense heart beating, digestive tract disorders, and asthma. Prescribed were various types of analgesics, antiphlogistics, vasodilatations, myorelaxants, vitamins, hormonal preparations, antiasthmatics, antimigraine drugs, or prokinetics. Anxiolytics were used only exceptionally. None of the patients used antidepressive medication. When they began with psychiatric treatment, being correctly diagnosed as suffering from agoraphobia with panic disorder, majority of previous medications were discontinued and replaced by psychopharmatics. Thirteen patients then took paroxetine in combination with clonazepam, six patients were treated with paroxetine intermittently with sulpirid and clonazepam, one patient took paroxetine in monotherapy. Five patients were treated with citalopram in combination with sulpirid or clonazepam, one patient took citalopram in monotherapy. One group member was treated with fluoxetine only and another with dosulepin. Outpatient psychiatric treatment then comprised supporting psychotherapy. During the examination period, none of the patients was hospitalized in the psychiatric department. Outpatient psychiatric treatment was monitored for the period of one year. Then, patients subjectively evaluated its effectiveness. Clinical conditions of twelve patients were dramatically improved (absence of panic attacks, agoraphobic behavior, or anticipation anxiety), ten patients have improved (reduced number of panic attacks, decline of agoraphobic symptoms and anticipation anxieties), four patients reported no progress (remaining panic attacks with constant frequency and 67
intensity), while conditions of only two patients worsened. On the basis of these facts, psychiatric treatment can be, as a whole, considered successful. Pharmacotherapy costs were evaluated in reverse, using the open method, from the medical records of the psychiatric outpatient department and other outpatient departments of previous specialists. Defined daily doses (DDD) of medications, according to Suchopár (1999), were taken into account. Prices were calculated in Czech crowns (Kč), because prices in Slovak crowns change frequently, with regard to changes in the classification of drugs in the Slovak republic. For example, DDD of paroxetine (20 mg) was 34.3 Kč, citalopram (20 mg) 32.4 Kč, fluoxetine (20 mg) 44.0 Kč, clonazepam (2 mg) 3.6 Kč and sulpirid (100 mg) 8.7 Kč. Study was not subrnitted for the approval of the ethics commission, as it was a retrospective examination of medical records, without the participation of patients, or any influence on their treatment. For statistical processing of acquired data, NCSS 2000 computer software was used. Distribution normality of acquired values, relating to individual variables, was evaluated using Shapiro-Wilks and Kolmogorov-Smirnov tests. However, because the distribution was abnormal, statistical significance of differences, relating to measured values, was examined by Wilcoxon nonparametric test.
RESULTS Results are stated in the table 1. Although the average daily price of pharmacotherapy was higher in the case of psychiatric treatment of the psychic disorder, average total medication costs were lower, compared with treatment carried out by practitioners-nonpsychiatrists. Significantly lower were also average numbers of tablets prescribed by psychiatrists, opposite to previous medical treatment, whether their daily or total amount was examined. All described differences are statistically highly significant.
DISCUSSION To illustrate the problem in more detail, one casuistic example can be depicted: Forty-seven years old women, ill, married, educated as a waitress, currently unemployed, was originally treated for ten years by the internist and neurologist for vertigo, intense heart beating, breathing problems, pain, tingling of limbs, fear from falling, and loss of self-control. Difficulties occurred during the attacks with frequency of four times monthly, sometimes more often. Diagnostic conclusion was “vertebrogenic algesic syndrome vertigo and hypertension”. Isradipin, enalapril, bromazepam, betahistin, tokoferol, cinnarizin, diklofenak, and metamizol were prescribed gradually. During this period, she had taken 72,000 tablets in total price of 251,209 Kč, however, her treatment was ineffective. She was then diagnosed in the outpatient psychiatric department with diagnosis “agoraphobia with panic disorder”. Pharmacotherapy was changed to paroxetine, clonazepam, enalapril, and isradipin. During one year of psychiatric treatment at the outpatient psychiatric department, 2,520 tablets were prescribed in total price of 8,209 Kč. According to patients subjective assessment, there has been a gradual decrease of panic attacks frequency and a moderation of anticipation anxiety in such an extent, that she was able to start working again. When treating agoraphobia with panic disorder, SSRI (selective serotonin reuptake inhibitors) antidepressants are used more and more frequently (Praško, 1999). This type of treatment is expensive, when considering daily-prescribed dose, however, it generates savings compared with previous long-term unsuccessful therapy, performed by general practitioners and some non- psychiatric specialist without the usage of psychopharmatics. When health insurance agencies evaluate and reduce financial costs of prescriptions in psychiatric outpatient department, they should, at the same time, take into consideration the long-term costs of psychic disorder’s treatment, including all pharmacotherapy prescribed by specialists-nonpsychiatrists for the same patient. Only then, it is possible to objectively prove, which treatment is “expensive” and which, on the contrary, saves finances. This study did not examine the quality of patients’ lives. Nevertheless, there are serious doubts about the satisfactory quality of life, when symptoms of anxiety disorder are not properly treated for several years, and additionally, patient is encumbered by taking thousand of tablets of various medications, especially when considering their negative effects. Our results are in accordance with international studies, which deal with similar problems. Greenberg et al. (1999) have assessed total yearly economic costs of anxiety disorders in the United States of America from the viewpoint of the whole society. In 1990, these costs reached 42.3 billion dollars. 54 percent of these costs represented health care costs outside the field of psychiatry. The highest costs were found for patients suffering from post-traumatic stress disorders and panic disorders. Majority of these costs could be reduced by early diagnostics of the disease and its proper psychiatric treatment. According to the results obtained by Reese et al. (1998), patients with panic attacks statistically and notably seek out the health care more outside the field of psychiatry, compared with patients suffering from social phobia, or psychically healthy individuals. This brings about increased direct medical costs, which could be, again, reduced by proper diagnostics and psychiatric treatment of the disorder. General practitioners, internists, and neurologists should be informed in more detail about the symptoms of agoraphobia with panic disorder, so that proper diagnosis can be determined early, patients being immediately transferred for psychiatric treatment. This would lead to the reduction of total medication costs and suffering of patients. Further studies, dealing with this problem, should also comprise the evaluation of direct costs resulting from the periodical medical examinations and treatment. Monitoring of indirect costs, when treating agoraphobia with panic disorder, would be appropriate especially for those costs, which are the result of the inability to work and the decrease of work productivity of affected individuals.
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CONSLUSION Results of this study prove the lack of economy and ineffectiveness of agoraphobia with panic disorder treatment in outpatient departments of non-psychiatric specialists in the Slovak Republic. Proper diagnostics and psychiatric treatment results not only in improvements of clinical state of patients, but also in savings of total direct treatment costs of pharmacotherapy. Considering historically recent division of the common state of Czechs and Slovaks, authors presume that acquired results can be applied also for the Czech Republic.
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CRISES PERIODS IN THE TREATMENT OF ALCOHOLISM ADDICTION SYNDROM IN PSYCHIATRIC MEDICAL OFFICE AUTHORS MUDr. Milan Ignjatovič, Psychiatric Medical Office, Health Care Center, Banská Bystrica MUDr. Dana Ignjatovičová, Psychiatric Department, F. D. Roosevelt›s Hospital, Banská Bystrica
SUMMARY We found out by multimodal or „complex” way of patient’s treatment in alcoholism addiction syndrome that there is a period of crisis in the limited period of 18 months. Crises periods are expressed by greater amount of non-abstinent patients and patients, who broke abstinence mostly in the first month of outpatient treatment but also in the first month after inpatient treatment. Crises periods of patients are inflicted by psychological motivational factors if psychotherapy has less influence on their abstinence, and it seems to us that the supporting psychopharmacotherapy has the lowest influence.
KEY WORDS alcoholism addiction syndrome multimodal treatment motivational factors psychotherapy psychopharmacotherapy
INTRODUCTION Even if we knew that addictions as such belong to contra-indication for short-time individual deeply oriented psychotherapy, we tried to support patient’s treatment by individual as well as group psychotherapy, eventually by family and marital psychotherapy. On the first time we examined 27 patients in our medical office, the others have already been treated in another medical offices including Alcoholism Addiction Office, as well as hospitalized and frequently inpatient treated - see table 4. According to the authors who are longer concerned of psychotherapy of patients treated for alcoholism addiction syndrome, the object of their interest were patient’s traumatic experience from their childhood and therapeutic alliance. To the dynamic oriented therapy they added behavioral therapy as well as others. None of them list exactly only the way of medicamentous treatment or by psychotherapy, or especially by one or another kind of therapy. All of them agree that the therapy should be „complex” and long-term. There are known some cases of controlled drinking but its rate is very low (1 %, Skála). We could not accept this alternative, and so 10 patients from groups continued in drinking. Sociotherapeutic groups as an important part of long-term treatment for alcoholism addiction syndrom can be seen in the studies of Czech and Yugoslav authors as plumbless facts. We did not practice any reinforcing treatment (repeatings) in our medical of but to offer this possibility to the patients in outpatient conditions, we allowed them to report in the medical office more often during their crisis time. Reinforcing treatment is also meaningful „psychologic medium” for patient, and its advantages describe Nábelek and Vongrej in their study.
GOAL To obtain information after what periods the patients experience psychic crisis during multimodal or „complex” treatment for alcoholism addiction syndrome.
METHODOLOGY AND GROUP OF PATIENTS We used the same way of treatment for all the patients who came to our medical office, including short-time individual deeply oriented psychotherapy (hereinafter as SIDOP) with the first interview. After the first sitting we made the contract with the patient: in the first month we will meet once a week to have psychotherapeutic conversation lasting 50 minutes, in the second and third month once in 15 days, i. e. 8 sittings in 3 months and only once a month afterward. Patients received supporting medicamentous treatment based on abstinence or another symptomatology lasting at least 3 months, what was also the part of therapeutic contract. We did not make any difference between patients examined first time in our medical office and patients treated in other specialistic medical offices or departments. We made the same contract with each of the patients. To the group of patients belonged 55 patients for the period of 18 months.
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The part of contract was also the fact that after break-in of abstinence (any patient froth this group) we send him to the inpatient treatment lasting 3 months and if it is rejected, we recommend him to another psychiatrist, because the patient would not benefit from the therapeutic alliance in this case. Patients were recommended after 3 months of outpatient treatment to the sociotherapeutic groups (sittings), which took place once a month in medical office. As an alternative in the patient’s treatment we accepted only permanent and consistent abstinence what was monitored by every individual visit of patient in medical office by toxicologic examination of alcohol presence in urine. All the patients involved in the study belonged to gama and delta alcoholism type. There were 55 patients in the group, 7 women and 48 men, see table 1. The average age of patients was 44,87 years. Socioeconomic status: 45 patients were employed, 7 were unemployed, 3 were pensioners, see table 2. Education structure: 47 patients finished Specialized secondary school, 3 of them Secondary Grammar School, 5 patients finished University, see table 3.
RESULTS We had 11 relapses in outpatient treatment and 7 relapses after inpatient treatment, see table 5. Crises periods for patients after inpatient treatment were: first month, when 5 patients relapsed, fourth month, when 1 patient relapsed, eighth month, when also 1 patient relapsed. The number of relapses after outpatient treatment is a bit higher, and crises months were close to each other again: in the first month 7 patients relapsed, in the third month 1 patient relapsed, in the fourth month 1 patient relapsed, in the ninth month 2 patients relapsed, see table 6. The adherence or breach of the contract did not substantially influence the abstinence of patients. The number of patients who did not break the contract and are abstainers is 23. Remaining 22 patients broke the contract but are abstainers. Of course, we included possible relapse into our contract as well as the next procedure in this case, so the inscribed relapses were throughout 18 months. Abstinence with adherence or breach of contract was sometimes interrupted by relapse. Group therapy, evaluated after 18 months of outpatient treatment, was also involved. The number of patients who abstained and went to group therapy was smaller than the number of patients who abstained without group therapy (sociotherapeutic groups), see table 8. Crises periods expressed in number of patients were the most significant in the first month in both inpatient and outpatient treatment. The inpatient valuation was realized from July 1, 1997 to December 31, 1998, and only patients breaching the contract were taken into consideration, even though they relapsed and we quantificated their abstinence in a statistical way. Those, who abstain 15 days before the end of eighteenth month from the base line of the project, take the first place. They are followed by patients abstaining 30 60, 90 days, 4, 6, 9 and 12 months to 18 months. Four patients abstained 18 months, five patients abstained 12 months, four patients abstained 9 months, four patients abstained 6 months, five 90 days, four 60 days and three patients abstained 30 days, see table 9. Exactly those numbers show the periods that can be crises, which patients must overcome, many times by their self-motion. We managed the SSRI therapy as a monotherapy of Antabuson, non-benzodiazepin anxiolytics, antipsychotics, tymoprofylactics, nootropics and very rare of benzodiazepins. In SSRI therapy the most frequent drugs were citalopram, from the group of non-benzodiazepin was managed anxiolytics hydroxizin. The pharmaceutical therapy even when used in monotherapy or in combined therapy (with another pharmaceuticals) did not have much influence on patient’s decision whether to abstain or not, see table 10.
DISCUSSION Statistical results and also basis of unbroken therapeutic contract made us to realize that even if we offer multimodal way of treatment for patient, patient’s attitude is the main part of successful treatment. This also shows the difference between those, who did not breach the contract and abstain and those, who did but abstain as well; it is a minimum of 1 patient’s difference. Neither the sociotherapeutic groups influenced patients’ abstinence that much, because 19 patients joined the associated therapy and they abstain, the other 26 patients abstained without the supporting associated therapy. Upon relapses we found out that patients in the first month of outpatient treatment or in the first month after inpatient treatment experience very strong crises periods. In this case number of relapses is the highest. Regarding psychopharmacotherapy, its highest effect is in abstinence symptomathology. The drugs from SSRI group (citalopram) had good influence on patients affecting their impulsivity. By the end of the year 1998 we finished the study with all the patients including those who abstain only 15 days. Statistical results show that the highest number of abstainers is in the 1st, 2nd, 3rd„ 6th, 9th, 12th, and 18th month. These months are psychologically very important for patients. During the periods between these months it is possible the abstinence will be interrupted - patients noted this fact at the psychotherapeutic’s conversations. They stayed or would stay without drinking for a few months (e. g. 3, 6,...), that is why we call those periods crises periods, after them the relief, carelessness, control lose may come, and so the patient might relapse again.
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The patient has to intensify the contact with his therapy specialist during this period of time or to start attending the sociotherapeutic groups regularly. All that has been said are our wishes. But patients rather choose another “self-treatment”, in which “self-motivation” can be involved. When we realize that only as much as patient wants can be done, and if we know months during which the crisis may occure, we can contact him and support his abstinence struggle. As a main factor of good outpatient treatment of patients’ alcoholism addiction we accept the motivation and relatively good social integrity of patients as well as qualitative therapeutic relation.
CONCLUSION After multimodal of “complex” way of patients treatment in acoholism addiction syndrom we found out that there exist crises periods in the limited period of 18 months. Crises periods are expressed by greater amount of non-abstinent patients, who broke abstinence mostly in the first month of outpatient treatment but also in the first month after inpatient treatment. Crises periods of patients are conditioned by psychological motivational factors if psychotherapy has less influence on their abstinence, and it seems to us that the supporting psychopharmacotherapy has the lowest influence.
BIBLIOGRAPHY Doc. MUDr. Jaroslav Skalá a kol.: Závislost na alkohole a jiných drogách. I.Žucha, T. Čaplová: K meta-psychopatológii závislosti (AD, 33-1998/1). L. Kubička, L. Csémy: První zkušenosti s českou verzí EuropASI (AD, 32-1997/4). K. Nešpor, L. Csémy: Souvislosti mezi alkoholem a jinými návykovými látkami, dusledky pro prevenci i léčbu (AD. 32-1997/4). H. Vos, L. Bos (Eds.): Narozený, zlomený a scelený. (Primární vztahy, trauma a závislost), (AD, 324 997/4). M. Galanter: Model komplexní terapie závislosti pro bežnou praxi (Network Therapy for Addiction: A Model for office. Practice, AmJ. Psychiatry 150, 1993, 1, s. 28-36 J. Vongrej, L. Nábelek, D. Krajčírova, I. Šajgalíková: Vplyv opakovanej liečby na prevenciu recidívy alkoholizmu (AD, 33-1998/2). Table 1 - Patients devided according to sex Men Number 48
Woman Number 7
% 87,27
% 12,73
Table 2 - Socioeconomic status
Employed Unemployed Pensioners Total
Number 45 7 3 55
% 81,82 12,73 5,45 100
Table 3 - Educational structure
Specialized secondary school Secondary Grammar School University Total
Number 47 3 5 55
% 85,45 5,45 9,09 100
Table 4.- Patients already treated in other department, PAL inpatient treatment, psychiatric outpatients
Patients already treated in psychiatric medical office
72
Number 1
% 1,82
Patients already treated in the Psychiatric department Repeated PAL inpatients PAL inpatients+outpatients Patients treated in other department – Department of Internal Medicine The others Total
19 2 4
34,55 3,64 7,27
2
3,64
27 55
49,09 100
Table 5 - The number of relapses after inpatient and outpatient treatment Number 7 11 37 55
Relapse after inpatient treatment Relapse after outpatient treatment Others Total
% 12,73 20,00 67,27 100
Table 6 - Relapses after inpatient and outpatient treatment in noted months (the number of patients) Month
1
The number of relapses after inpatients treatment
5
The number of relapses after outpatient treatment
7
2
3
4
5
6
7
1
1
8
9
10
11
12
13
14
15
16
17
18
1
1
2
Table 7 - Patients divided according to contract and abstinence by the end of the 18th month Number Adherence of contract, patient abstains 23 Breach of contact, patient abstains 22 Breach of contract, patient does not 10 abstain Total 55
% 41,82 40,00 18,18 100
Table 8 - Patients divided according to group therapy and abstinence by the end of the 18th month Number 19
Group therapy, patient abstains Group therapy, patient does not 0 abstain Without group therapy, patient 26 abstains Total 10 55
% 34,55 0 47,27 18,18 100
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Table 9 - Crises periods in patients’ abstinence (abstinence evaluation during the period of 18 months)
Total
Period of 15 30 45 60 75 90 4 abstinence days days days days days days (months)
5
6
7
8
9
10 11
12
13
14
15
16
17
18
Number of 1 abstainers
1
4
0
3
4
2
5
0
1
0
0
0
4
3
1
4
2
5
2
3
Others %
45
10 1,82 5,45 1,82
7,27 3,64 9,09 3,64 1,82 7,27 0
5,45 7,27 3,64 5,45 9,09 0
1,82 0
0
0
7,27 81,82 18,18
100
Table 10 - List of psychopharmacotherapy
DisulfiCitalopramum ramum Drugs M
F
Monotherapy 5
0
Combined Therapy
0
4
M – male, F - female
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M F
M F
M F
M F M F
M F M F
M F
M F M F M F M F
AGORAPHOBIA WITH PANIC DISORDER – FAMILY PSYCHOPHARMACOTHERAPY BY PAROXETIN AUTHORS Milan Ignjatovič, MD, Psychiatric Medical Office, Health Care Center, Banská Bystrica MUDr. Dana Ignjatovičová, Psychiatric Department, F. D. Roosevelt›s Hospital, Banská Bystrica
SUMMARY 4 women - 55-year-old mother and her two daughters: 38 and 34 years old and one stepdaughter 20 year old were followed and used in casuistics. To make good quality family anamnesis is very important for risks family factors and for detection of psychical disorders. The ways of heredity are: polygenic model, model of the dominant gene with incomplete penetration, autosomal dominant model and the others. There are many genetic hypothesis about genesis of the psychical disorders and genetics markers like: yohimbin, clonidin, coffein, infusion of natrium lactatum, hyperventilation, L-tryptofan, benzodiazepin’s receptors, continuity between mitral prolaps and panic disorder, positive response on antidepressants, personality studies of the patients with panic disorder (Erič Lj., 1991). The problem is that patients didn’t know about their disorder, about treatment, etiology, complications and consequences. Treatment by psychopharmacotherapy confirms some of genetic hypothesis connected with correct diagnosis. These 4 women were diagnosticated and adequately treated in our Psychiatric Medical Office, Health Care Center.
KEY WORDS Agoraphobia with panic disorder, paroxetinun, genetic studies
INTRODUCTION Long time ago, in the past century, when genetic research was not carried out, Beard wrote about “consequent predisposition for the occurrence and development of neurasteny.” Freud came up with similar experience and he pointed out the fact that neurosis of fright has the same symptoms among several family members. Oppenheimer and Rothshild found out that family history of neurosis existed among 45% of observed World War I soldiers who were diagnosed with Da Costa syndrome. Some time later, during the World War II, Wood found positive family history among 25% patients treated on heart neurosis. Subsequent researches showed that panic disorder is a disease, which cumulates in the family.
METHODOLOGY AND GROUP OF PATIENTS 4 female patients were chosen for the casuistic study on the basis of 5 including criteria: 1. Biographical anamnesis, 2. Forgoing diagnosis, 3. Current diagnosis, 4. Therapy, 5. Family relationship. Observation and evaluation of results was carried out from October 1999 to March 2000, while all of the female patients continue with the therapy and they are registered in our medical office.
OBSERVATION The results are based on retrospective clinical observation of patients medical records where the focus was on the biographical anamnesis, diagnosis, therapy and family relationship. The core of the study is formed by 4 casuistic cases which draw the importance of genetic factors for the occurrence and development of panic disorder. CASUISTIC No. 1 55 years old woman, worker, mother of three daughters, long term treated in different medical offices with diagnosis of neurasteny. She visited our medical office on the recommendation of both of her daughters. She describes her first panic attack as the situation when she had her middle daughter and she couldn’t go for a walk with the buggy (in the year 1966), she was dizzy and weak, she couldn’t take anything into her hands, she had palpitations, was stifled, sweated, had pins and needles in her hands, felt a node in her throat and she helped herself by giving snow on her head. Afterwards she was scared to go for a walk. Physicians prescribed chlordiazepoxidum (Radepur) and ergotamini tartas, belladonnae radicis, phenobarbitalum (Bellaspon) for her and symptoms were gone for one or two days. Her husband didn’t believe her that she was ill and he was furious of her status. That all enhanced her tension and the patient was not even able to stand up from her bed because of the dizziness. She was scared to visit a physician in the psychiatry ward at that time. First time she visited psychiatric medical office in Brezno 20 years ago, she was taking chlordiazepoxidurn (Elenium), ergotamine tartas, belladone radicis, phenobarbitalum (Bellaspon) and diazepanum (Seduxen). When her youngest daughter was born, she felt quite well during the daytime but she got an attack after night shift. She described the attack like is: she woke up in the night, didn’t know where she was, what she was doing, she was steamy and very afraid. When her husband was close to her, she composed herself but in spite of this she was not able to leave the bed.
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She had to be very responsible in her job, millions were at stake, fortunately nothing happened. She was treated in the spa town of Vyšné Ružbachy since 1992. She felt very well in the baths because it was a peaceful place. She was sent to visit a primary doctor 5 years ago who prescribed alprazolam (Neurol) and fluoxetinum (Prozac) for her. She felt better, even though she still used to have panic attacks which were more mild and weaker. She concluded the combination of noted drugs because her physician changed one drug to fluoxetinum (Deprex). She had strong diarrhea, strong headache and she felt sick after using this drug. The patient visited our medical office on December 12, 1999 with no psychopharmacological medieation. We prescribed the medication of paroxetinum and clonazepamum for her. The patient›s status improved very quickly (in 2 weeks time), she didn›t have any attacks any more, her mood brightened, she slept all the night, and she hasn›t been scared of people any more. After one month the dermatologist diagnosed her with allergy to paroxetinum. That›s why this drug was replaced by citalopramum. The patient canceled the medication of citalopram by herself and on the recommendation of her three daughters she started taking paroxetinum and clonazepamum during the last control visit on the March 16, 2000. No allergy to paroxetinum occurs at present and previous allergic reactions are thought to be possible comorbidity with allergy e.g. to another drugs or food. The patient evaluates her status as excellent and she assesses the current therapy as the most sufficient and the most successful in 30 years of treatment.
CASUISTIC No. 2 38 years old female patient, single, lives with her partner who is addicted to alcohol and is aggressive when drunk. Currently the patient tries to evacuate him from her flat a legal way. The patient was treated by psychiatrist for a long time. She was not satisfied with the treatment and that’s why she visited our medical office on other patient’s recommendation. The memories of her childhood are connected to her mother who lived with the children alone, she was divorced, she raised the children quite strictly. The patient’s father drank a lot of alcohol, she remembers that he even attacked them with a gun and he threatened to shoot them all. Her mother was very sick, she moved to her grandmother and she got married for the second time. The patient couldn’t sit down under the facts she underwent in her childhood. When she cut adrift she got a flat and she took an alcoholic man to her flat. She wants to get him away in a legal way now. When the patient visited our medical office for the first time, she had the following symptoms: palpitation, exudation, fear that disallowed her to go to the work, trepidation of hands, she had as well as her mother a node in the throat. She got the first attack in 1994 at home, she didn’t know what that was, she felt worse and worse. Her status was so bad, that she couldn’t even watch TV, she was even scared of the people in TV shows. Her mother had similar symptoms. She felt a noise in her head, she had to go to bed, couldn’t go for a shopping to the moles where a lot of people are. She stayed in the bed very often and didn’t talk to people. One psychiatrist prescribed chlordiazepoxidum (Defobin) for her. When she didn’t get enough, she visited another psychiatrist, who gave her maprotilinum (Ludiomil), alprazolamum (Neural). In spite of that she had to call the emergency very often or had to visit the emergency by herself, she got hypertension, couldn’t compose herself. We registered her: with the .diagnosis of neurasteny and put her on paroxetinum and clonazepamum right after her first visit in our medical office. Between the first and the second week her health status improved, attacks receded, she started to go for .a shopping, wasn’t scared of people anymore. She also attended the group therapy in our medical office. When she started to have conflicts with her partner, her health status got worse. The patient received shoots of progesterone and estradioli benzoas from the year 1980 because sometimes she didn’t have menstruation up to 3 months. Since she has been treated by paroxetinum, her menstruation is periodical. Meanwhile the patient received the verdict which states that her partner has to move from her flat. The patient is looking for a new job because nobody believed in her invisible illnesses in her former job. She evaluates her status as good, stabilized and the treatment as successful.
CASUISTIC No. 3 34 years old female patient, previously unemployed, married. For the first time she got palpitation after the wedding in 1986. She couldn’t breathe and her health status started to worsen after 3 years. She started to feel sicker since she became unemployed. Since she finished only elementary school, she studied at the school for waiters but in fact she had stage fright and was very self-centered, she didn’t finish the school for waiters. She doesn’t remember her father because her parents got divorced when she was 4 years old. She describes her symptoms as weakness, shakiness, vertigo, chest pains, shaking of her legs. She feels better when she stays at home in silence. Her husband drinks alcohol and when drunk, he upbraids her the fact that she is unemployed. She adds to her symptoms that she couldn’t breathe; she felt the way she would suffocate. These symptoms appeared when her daughter, who had legs desjointedness and didn’t sleep at night, was born. That was a huge endurance for her. When the patient tended her daughter to the school, she felt she wouldn’t return home and would vomit. There were more panic attacks upraised during one week and she felt she would get heart attack. When she worked as a cleaner in an elementary school, she felt good in a collective of colleges. She felt the worst when she had to stay at home alone. She underwent different medical examinations but nothing was found. Afterwards she started to be scared of people and that’s why she didn’t go abroad (she didn’t travel by bus, didn’t go for a shopping). There is comfort at home, it’s worse when the husband gets drunk and offends her. The neurologist put her on paroxetimun. Even though her health status improved, the patient stopped the treatment by herself because the period of menstruation shortened up to 15 days. The patient was examined in our medical office for the first time on the recommendation of her mother and two sisters in February and she had the following symptoms: hands shakiness, enhancing anxiety, node in the throat, she was scared of going outside, felt better at home. 76
After the introductory interview we agreed on the therapy of paroxetinurn and clonazepamum. After one month the patient notes that her health status improved, she has no panic attacks, she meets people and she evaluates the treatment as the best one so far.
CASUISTIC No. 4 20 years old female patient, trained tailor, the youngest one in the proximity. After the childbirth in 1988 she began to have vertigo, palpitation, body shakiness and was scared of going out for a shopping. She had these attacks more than 4 times a month. Unlike her mother and stepsisters, she didn’t have a node in her throat. When she restored from the smallpox in her childhood, she was diagnosed with the epilepsy. The patient states that she used to faint, she sensed everything around but couldn’t respond. She visited a neurologist who put her on phenytoinum and carbamazepinum. Then the pediatric neurologist put her on natrium valproate when she was 12 years old. Gradually acidum valproicum + natrii vaiproas (Depakine Chrono 500) of a dose of 1 tablet in the morning - 1 tablet in the noon- 1 tablet in the evening were added to the therapy management. Phenytoinum was rejected, natrium vaiproat (Orfiril 300 mg in one tablet) of a dose of 1 tablet in the morning - no tablet in the noon - 1 tablet in the evening was kept. When the patient attended the 7th grade of the elementary school, she had vertigo during the lessons, she asked for going to the toilet very often and she felt very badly during the biology classes when they learned about blood. She was hospitalized during that period of time. When medical staff told her about the blood sample testing, she fainted. She was scared of going to school, her classmates laugh at her because of her epilepsy and she didn’t remember anything after each attack. At home the attacks started to appear during the night. She got shakiness and her mother had to wake her up. She had vertigo in the classroom very often. Moreover she fainted and fell down at home. She used to faint more often in school, especially in the period of examinations; she fainted more often at home as well at that time. She has never had enuresis and has never bitten her tongue. The epileptic attack lasts for 1 minute and she has never slept after the injection of diazeparnurn or after the attack. When she got very painful menstruation, she felt she would suffocate and they called the ambulance immediately. The patient had no attacks at the secondary school. No attacks were present at home at that time either. She visited a pediatric neurologist for the first time when she was 11, panic attacks uprose when she was 12 years old. Even though she was taking phenytoinum and carbamazepinmu, she fainted at home as well as at school. She felt badly all the time. Suddenly, the attacks were gone when she was in the 8th grade of the elementary school. Palpitation appeared at home when she was 12 years old, she didn’t tell her parents about it, she just retired to her room and went to bed. She lists more exact medication since her age of 16, when she received natrium valproas (Orfiril 300 mg in each tablet) in a dose of 1 tablet inthe morning - no tablet in the noon - 1 tablet in the evening. When she was 18 years old she was taking acidum valproicum + natrii valproas (Depakine Chrono 500) in a dose of 1 table in the morning - 1 tablet in the noon - 1 tablet in the evening. The attack uprose in the dormitory when she was 16 years old. It was seldom and as she states further, there have been no more attacks at home or at secondary school. She got married at the age of 18; she gave birth to a daughter in 1983 and 3 days after the childbirth, she fainted lying in the bed. When she rinsed pampers or when she woke up to get pills, the attacks returned. She got “aura” and consequently fainted when she saw the strips on the tiles. Prolonged observation of the blue strips on the tiles provoked this kind of schism. After that accident her mother didn’t let her staying at home alone, she was with her daughter even when she was having a shower. To help herself, the patient doesn’t look at those strips when she is in the bathroom. When her oldest sister remembered the incidents with the bathroom, we found out that she used to lock the patient in the bathroom as a punishment when she behaved badly in her childhood. She haunted the patient to leave her inside the bathroom for good in this time of her childhood. This fact was confirmed also by the middle sister. The patient is 20 years old now, last time she fainted in maternity hospital one year ago. Approximately half year after her child was born she began to have vertigo, uncertain walking, everything was spinning around her, she sweated. These feelings attacked her 4 times a month. Since the patient milked her child, her health status worsened during each menstruation period. She visited our medical office on the recommendation of her stepsister on the November 3, 1999. Het stepsister suggested her to visit the psychiatrist for a long time. The patient’s status improved after two weeks of medication of paroxetinum and clonazepamum, she has had no more anxiety nor panic attacks. Whereas the patient is listed in neurological office, we mutually consulted the therapy and recommended to reduce eventually to cancel their therapy. After the arrangement we stopped the management of natrium valproas (Orfiril), we reduced the dose of acidum valproicum + natrium valproas (Depaldne Chrono 500) up to 1/2 tablet in the morning - no tablet in the noon - 1 tablet in the evening. Patient feels good, the health status is stabilized, she takes care of her daughter with joy, handles with common activities without any problems, she evaluates the treatment as being successful. Each of these 4 patients evaluated the treatment of their mothers, sister and stepsister separately, so besides subjective evaluation we have heteroanamnestic (heterologic history) evaluations as well.
SUMMARY 4 women, a mother and 3 daughters who were chosen according to 5 including criteria are inncluded in the casuistic study, whereas 2 sisters were their own, one was a stepsister. The average age was 36,75 years. Symptoms were present in average of 16,25 years and treatment in our medical office lasted 3 months in average.There has been used paroxetinum in a dose of 30 mg per day and clonazepamum in a dose of 0,5 up to 1,5 mg per day individually in the treatment. The results were analyzed on the basis of patients’ subjective evaluation as well as according to the heteroanamnestic evaluation.
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DISCUSSION Family studies and studies realized on twins who suffer from anxiety and panic attacks show that panic disorder is familiar disease. However, family cumulation is neither sufficient nor necessary condition to confirm that the disorder is congenital. It is necessary to look through the exact pathway of genetic transmission, but we have not reached definitive conclusion up to now. There are several models available: polygenous model, model of dominant gene with incomplete penetration, autozom dominant model. The results of the researches done up to now show that the model of dominant gene with incomplete penetration is the most feasible way of genesis and development of panic disorder, but the model of polygenous heredity is also not definitely rejected. We have investigated the model of polygenous autozom dominant heredity in our study. The results we have reached suggest that panic disorder is transmitted as an autozom dominant disorder (1). Family studies of the panic disorder realized in 1980’s show that the risk of uprise is 17,3% in first grade relatives and added risk from 7,4% for possible panic disorder (which uprises with 2,3 rarely with 4 symptoms of the panic disorder criteria). Some authors have found out high risk of panic disorder in both groups of relatives in a case of panic disorder (17,3%) and in groups of relatives in a case of agoraphobia (8,3%), compared to 4,2% in control group. (2) Other studies found out from 4 to 8 higher risk of panic disorder in the group of first grade relatives of patients with panic disorder diagnosis compared to first grade relatives of patients with other psychical disorders. (3) Having gone through the all aspects of genetic research of anxiety and panic disorder, the problem how to explain them still remains. In spite of evidences that panic disorder is family disease, as well as there is high concordance in monozygote twins, pathophysiological mechanisms of panic disorder development have been determined. We don’t have sufficient feasibility to define the role of genetic factors in panic disorder etiology for certainty. What is really proved is the fact that anxiety and panic disorder are not inherited by the simple principle of Mendelejev heredity rules. It is proved that a lot of anxious conditions occur in the participation of psychological, social and cultural factors without the visible contribution of genetic factors. There is a model of possible panic disorder uprise and development, in which the biological, psychological and social factors are comprehensively present and the model is based on those proved facts. Truly, nonspecific genetic predisposition in cooperation with psychological factors leads into the uprise and development of anxious conditions. In this kind of explanation the questions about the nature, noted genetic predisposition come out. In other, more simple, words, what is inherited in the case of anxious conditions and panic disorder and if children of patients with panic disorder inherit the same disorder. The majority of research scientists suggest that the cacoethes and hypersensitiveness for the uprise and development of anxious conditions are inherited and they are based on enhanced autonomous nervous system reactivity or on the unstableness of neurotransmitter system that determines the global organism reactivity. Meanwhile, the existence of cacoethes and hypersensitiveness for the anxious conditions uprise and development doesn’t mean sure disease development. Maybe the cacoethes is anchored in development basement of known personality of type A, by whom the essential hypertension is developing. The essential hypertension could be followed by the existence of anxiety but it couldn’t be as well. It is also possible that the cacoethes just reduces threshold for specific senses and activities which, in cooperation with psychological factors, lead into the disease onset. This kind of explanation can be only the “peak” of the enhanced reactivity basement to the stress or can bean anxiety manifestation. It was proved by many researches that only features of personality, such as flap, tendency to react anxiously, hypersensitiveness and shyness are inherited. It is proved that neuroticism as personality feature is inherited. Other authors have found out that personality feature highly correlates in twins couples, no matter if they have grown up together or not. The high correlation of personality features for anxiety in monozygote twins couples have been proved, meanwhile it hasn’t been proved in dizygote twins couples. A personality that has anxious features (anxious character) goes through unpleasant psychosocial factors or through stress with anxious reactions. The way to the symptoms of panic attacks and panic disorder is very short when a long term and intensive fear comes out. Finally, children of patients who are diagnosed with panic disorder do not straightaway inherit the same disorder. However, even this fact can’t be certainly confirmed. 50% of daughters and 10% of sons who suffer from panic disorder have symptoms which permit to make the right diagnosis. In conclusion, we have to state that geneticists have not said the final word on the confirmation of basement for panic disorder uprise and development. Researches in the area of molecular biology are at the center of attention. Preliminary results of 29 genetic markers of 26 families with positive history of panic disorder have been reported and they have shown that there is a connection between panic disorder and patient’s chromosome status, especially in chromosome 16 and 22. Implementation of this new technology into genetic research of patients with panic disorder and twin couples with certain disease has allowed us to accept genetic basement of panic disorder uprise and development as comprehensive problem. The results that should be found out are expected with great attention.
CONCLUSION Thanks to patients who suffer from panic disorder and thanks to enthusiasm in psychiatry, positive family history of certain disorder, disease can be helpful for early diagnostic testing and for sufficient therapy. Everything we are supposed to do is to get quality family history.
BIBLIOGRAPHY Erič Lj., 1991: Pričina stanja, II dopunjeno i prošreno izdanje, Beograd- Zagreb, 1- 309: 56- 57, 67- 69 Hales R.E., Yudovsky S.C., Talbott J.A., 1994: Textbook of psychiatry, 2- nd Edition, The American Psychiatric Press, 1- 1608, 37- 71 Raboch J., Praško J., Seifertová D., 1999: Panické stavy 11 díl, vyd. SKB, 6- 56: 29
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TREATMENT OF SOMATOFORM AND PSYCHOSOMATIC DISORDERS AT OUTPATIENT PSYCHIATRIC CENTER ABSTRACT Somatoform disorders (SFD) refer to a subgroup of mental disorders where physical symptoms are not conditioned by physical structural defect. (F45). Patients with somatoform disorders suffer a wide range of physical symptoms e.g. pain, nausea, fatigue, vegetative symptoms and repeatedly insist on physical examinations although previous examinations were negative (Smolik, 1996). Asthma, dermatitis, eczema, peptic ulcers, mucous colitis and ulcerative colitis belong to a group of psychosomatic disorders classified in psychiatry as mental and behavioral factors attributed to other diseases (F54), (Smolik, 1996). We studied cohort of 46 patients, 21 patients with diagnosis F45 (women N=14 total average age =49 years) and 25 patients with diagnosis F 54 (women N=-17 total average age=53 years). In both groups we observed comorbidity with other mental disorders and made survey of applied theraphy. The most common line of theraphy in patients with somatoform disorders was combination of atypical neurolepticum (sulpirid) + SSRI and anxiolytic agent (8 patients). On the other hand patients with psychosomatic disorders were mostly treated with SSRI + anxiolytic agent (15 patients) or with combination of atypical neurolepticum (sulpirid) + SSRI and anxiolytic agent (8 patients). Patients with somatoform disorders suffered especially from gastrointestinal tract disturbances i.e. neurosis, dyspepsia and psychogenic aerophagia (F.45.31) 10 patients, cardiovascular disorders (F.45.30) 3 patients. 2 patients had unusual feelings of burning skin (F.45.38). Psychosomatic disorders most frequently occurring were asthma, migraine and peptic ulcer disease. All patients suffered from the symptoms for the average of 2 or more years. Key words: Somatoform disorders (F45), mental and behavioral factors attributed to other diseases- psychosomatic disorders (F54), sulpirid.
INTRODUCTION Patients with somatoform and psychosomatic disorders are the most frequent subjects visiting general practitioners. They can experience hypertension, asthma, diverse eczemas, gastrointestinal and urogenital problems. Moreover, physical symptoms can sometimes mask depressive symptoms (formerly known as larval or masked depression, today somatoform disorder) or the physical symptoms occur during depressive episode (somatic syndrome previously referred to as biological, vital, melancholic or endogenomorphous) (Smolik, 1996). Making the diagnosis we should not forget to omit mood disorders in somatic diseases malign tumors, drug-induced depression, infection, etc.). They are very important in differencial diagnosis. Psychosomatic disorders together with psychosomatic medicine form interdisciplinary field that comprises collaboration of general practitioners, internists, cardiologists, gastroenterologists, surgeons, neurologists and psychiatrists. Sulpirid 2- methoxy benzamid in not only used in the treatment of psychotic and depressive disorders but also in somatoform and psychosomatic disorders. The mechanism of action of sulpirid in aforementioned disorders is not explicitly known. Although dopamine agonists (DA) have antidepressive effect, there are certain neuroleptics (DA receptor antagonists) that show antidepressive action, also (Schatzberg, Nemeroff, 2001, Janicak 2001). One of the possible explanations of this paradoxical effect (potency of sulpirid in therapy of depressive and somatoform disorders) is that neuroleptics, in small doses, can have antidepressive effect acting as DA autoreceptor antagonists thus increasing DA turnover (Floyd, 1995). Selective blockade of limbic DA receptors with sulpirid is associated with low incidence of neurologic adverse events. Sulpirid can antagonise DA receptors in blood vessels and gastrointestinal smooth muscles, as well (Turjanski, 1996). Using high doses of sulpirid (400-600mg per day) antipsychotic effect becomes dominant (Janicak, 2001). However, with low doses of sulpirid (150-300mg per day) we manage psychosomatic, neurotic and depressive disorders (Turjanski, 1996). Rimon states that sulpirid is efficacious in the treatment of various psychiatric disturbances. Given dose of 100-150mg per day is applicated in neurotic and depressive disorders. Gastrointestinal symptoms are the most common symptoms in subjects with somatoform disorders (Fraxinos, 1995). Therefore sulpirid represents new therapeutical modality in the management of those disorders where visceral hypersensitivity and somatoform component play crucial role (Fraxinos, 1996). Likewise sulpirid comes with new alternative for the treatment of psychosomatic disorders since psychoemotional background is very significant in the etiopathogenesis of above-mentioned disorders (Lemoine, 1996). Sulpirid does not decrease the amount of gastric acid in stomach, reduces postprandial serum gastrin levels, stimulates muconasal defence factors and basal or histamine-stimulated acid production stays unchanged during the course of long-term theraphy (Lemoine, 1996). Furthermore sulpirid is potent in controlling stress due to its well studied CNS effects (Crismer, 1972).
METHODS We studied cohort of 46 patients, 21 patients with main diagnosis of somatoform disorder and 25 patients with diagnosis of psychosomatic disorder. To interpret comorbidity with other psychiatric diseases and to determine applicated therapy we retrospectively analysed patient’s files without using structural scale. Enrollment criteria: ICD- 10 criteria for somatoform and psychosomatic disorder. Age 18 to 80 years. Treated more then 2 years in an outpatient psychiatric center. 79
OBJECTIVES: To find the most common somatoform and psychosomatic disorders at our outpatient center To map incidence of comorbitity with other psychical disturbances. To carry out a survey of the most frequently applied therapeuticals in somatoform and psychosomatic disorders at our outpatient clinic.
RESULTS We enrolled a cohort of 46 patients, 21 patients with main diagnosis F45 and 25 patients with diagnosis F54. Average age is given in Table 1 and Table lb. The most frequent somatoform and psychosomatic disorders were gastrointestinal disturbances (Tab.2) The comorbidity of somatoform disorders with other mental disorders appeared in the sample of 9 patients, 12 patients did not show evidence of comorbidity (Tab. 2). The most common psychosomatic disorders were asthma, migraine and peptic ulcer disease. 19 patients had comorbidity with other mental disorders, 6 patients were without comorbidity (Tab. 3). The most preferred therapy for somatoform disorders was a combination of atypical neurolepticum (sulpirid) + SSRI + anxiolytic agent (Tab. 4). An overview of SSRI used for this diagnosis is presented in Table 5. Psychosomatic disorders were treated with SSRI + anxiolytic agent (despite of high comorbidity with anxiety and depressive disorders) or with atypical neurolepticum + SSRI + anxiolytic agent (Tab 4b).
DISCUSSION Somatoforrn disorders present heavy therapeutical problem, not only for general practitioners but also for specialised clinicians during patient’s hospital stay , because patients’ symptoms vary widely (Lemoine, 1996). Described disorders cover a vast amount of psychiatric and other conslutation services (Ignjatič). Despite of many repeated examinations, the explanation that the disorder is not conditioned by structural defect, seems to be unsatisfactory and patients are finally placed in psychatric outpatient centers. Correct diagnosis and treatment prevents ongoing symptoms of chronic illness. Depressive symptoms may be evident and attributed to somatic or functional symptoms. On the other hand psychatric symptoms can be sometimes masked by somatic or functional symptoms (Lemoine, 1996). Low doses of sulpirid (100-200mg per day) may be effective in the treatment of various somatoform disorders. In one double blinded study, Nishida et al. (1974) compared efficiency of sulpirid (150-200mg per day) to oxazolam (30-60mg per day) in subjects with somatoform disorders. At the end of 3-week period patients on sulpirid showed significant improvement compared to oxazolam. Chent and Sttenhouver (1972) followed 30 patients with symptoms of tachycardia and dyspnoea. Results indicated reduction of symptoms while treated with low doses of sulpirid. Psychosomatic medicine is an interdisciplinary branch of medicine with „typical” psychosomatic disorders e.g. asthma, peptic ulcer disease, migraine and ulcerative colitis (Smolik, 1994). Because of participation of psychoemotional component in the etiopathogenesis, sulpirid has a significant role in modification and therapy of psychosomatic disorders (Lemoine, 1996). Migraine is also a very common symptom. Many authors tried to use sulpirid to reduce frequency of headaches and migraine (Aschoff, 1997, Barré, 1970). Hakkarainen and Vukari (1973) observed 30 subjects with migraine and 30 subjects with tension headaches, in both groups symptoms were associated with psychosomatic symptoms. Daily dose of sulpirid was 150mg. Compared to placebo the results in sulpirid group were much better and lead to alleviation of migraine and tension headaches (Lemoine, 1996). Application of sulpirid in 20 patients with asthma reduced the rate of attacks. According to Chevalier (1985), although sulpirid has no direct impact on pathophysiology of asthma, it is effective in the blockade of vicious circle of psychosomatic factors that contribute to pathophysiology of asthma. Several studies examined potential role of sulpirid (150-200mg per day) in sexual and urological disturbances (Mazeman,1975). The cons of studies that examined the efficiency of sulpirid in a variety of somatoform and psychosomatic disorders are: short period of examination, there are not double blinded, not placebo controlled and they focused on small number of patients. In spite of this fact, various studies support the application of sulpirid in somatoform and psychosomatic disorders treatment. Our survey did not evaluate efficiency of therapy for F45 and F54, but demonstrates the maximum possible use of combined therapy with atypical neurolepticum (sulpirid) + SSRI + anxiolytic agent is for discussed disorders. Average dose of sulpirid in our cohort was 100-150mg per day which is comparable to studies mentioned above. Given results suggest that therapeutical efficiency of sulpirid is indicated by its significant impact upon psycho-emotional component what might be common for miscellaneous somatoform disorders (Lemoine, 1996). Irritable bowel syndrome is another severe illness with prevalence of 15-30% in our population. It is characterised by abdominal pain, abdominal discomfort (symptoms for at least 3 months and several days in a week) and altered bowel habits. There are three major pathophysiological factors for irritable bowel disease: abnormal motility, sensitivity and a type of personality (Almy and Tulin, 1947). Those patients suffer from anxiety, depression and neurotic comorbidity with anxiety and depressive disorders) or with atypical neurolepticum + SSRI + anxiolytic agent (Tab 4b).
DISCUSSION Somatoforrn disorders present heavy therapeutical problem, not only for general practitioners but also for specialised clinicians during patient’s hospital stay , because patients’ symptoms vary widely (Lemoine, 1996). Described disorders cover a vast amount of psychiatric and other conslutation services (Ignjatič). Despite of many repeated examinations, the explanation that the disorder is not conditioned by structural defect, seems to be unsatisfactory and patients are finally placed in psychatric outpatient centers. Correct diagnosis and treatment prevents ongoing symptoms of chronic illness. Depressive symptoms 80
may be evident and attributed to somatic or functional symptoms. On the other hand psychatric symptoms can be sometimes masked by somatic or functional symptoms (Lemoine, 1996). Low doses of sulpirid (100-200mg per day) may be effective in the treatment of various somatoform disorders. In one double blinded study, Nishida et al. (1974) compared efficiency of sulpirid (150-200mg per day) to oxazolam (30-60mg per day) in subjects with somatoform disorders. At the end of 3-week period patients on sulpirid showed significant improvement compared to oxazolam. Chent and Sttenhouver (1972) followed 30 patients with symptoms of tachycardia and dyspnoea. Results indicated reduction of symptoms while treated with low doses of sulpirid. Psychosomatic medicine is an interdisciplinary branch of medicine with „typical” psychosomatic disorders e.g. asthma, peptic ulcer disease, migraine and ulcerative colitis (Smolik, 1994). Because of participation of psychoemotional component in the etiopathogenesis, sulpirid has a significant role in modification and therapy of psychosomatic disorders (Lemoine, 1996). Migraine is also a very common symptom. Many authors tried to use sulpirid to reduce frequency of headaches and migraine (Aschoff, 1997, Barré, 1970). Hakkarainen and Vukari (1973) observed 30 subjects with migraine and 30 subjects with tension headaches, in both groups symptoms were associated with psychosomatic symptoms. Daily dose of sulpirid was 150mg. Compared to placebo the results in sulpirid group were much better and lead to alleviation of migraine and tension headaches (Lemoine, 1996). Application of sulpirid in 20 patients with asthma reduced the rate of attacks. According to Chevalier (1985), although sulpirid has no direct impact on pathophysiology of asthma, it is effective in the blockade of vicious circle of psychosomatic factors that contribute to pathophysiology of asthma. Several studies examined potential role of sulpirid (150-200mg per day) in sexual and urological disturbances (Mazeman,1975). The cons of studies that examined the efficiency of sulpirid in a variety of somatoform and psychosomatic disorders are: short period of examination, there are not double blinded, not placebo controlled and they focused on small number of patients. In spite of this fact, various studies support the application of sulpirid in somatoform and psychosomatic disorders treatment. Our survey did not evaluate efficiency of therapy for F45 and F54, but demonstrates the maximum possible use of combined therapy with atypical neurolepticum (sulpirid) + SSRI + anxiolytic agent is for discussed disorders. Average dose of sulpirid in our cohort was 100-150mg per day which is comparable to studies mentioned above. Given results suggest that therapeutical efficiency of sulpirid is indicated by its significant impact upon psycho-emotional component what might be common for miscellaneous somatoform disorders (Lemoine, 1996). Irritable bowel syndrome is another severe illness with prevalence of 15-30% in our population. It is characterised by abdominal pain, abdominal discomfort (symptoms for at least 3 months and several days in a week) and altered bowel habits. There are three major pathophysiological factors for irritable bowel disease: abnormal motility, sensitivity and a type of personality (Almy and Tulin, 1947). Those patients suffer from anxiety, depression and neurotic disturbances (Fraxinos) that corresponds with our data (high comorbidity with anxiety and depression). While the efficiency of sulpirid in the treatment of irritable bowel disease is under theoretical investigation, sulpirid may directly modify physiological processes of patients with peptic ulcer disease. Additional sulpirid’s quality is the capability to diminish stress factors. Sulpirid has dual function in reducing stress-induced ulcerations. The local activity normalizes vascularization during pre-ulcerative and ulcerative period and it also indirectly modifies gastric secretion and psychological activity that contribute to formation of gastric ulcerations (Stein et al., 1994).
CONCLUSION Somatoforrn and psychosomatic disorders are very frequent in psychatric outpatient care centers. In differential diagnosis it is quite important to exclude depressive episodes since many patients suffering from depression do not present with any signs of depression. The term „somatization” applies to somatic symptoms that express emotional discomfort and may lead to misdiagnosis. A number of depressive subjects with somatic component really have somatic disease, but treatment is often insufficient. On the other hand many patients with inexplicable diffuse symptoms come to psychiatrist and are diagnosed with anxiety or depressive disorder (Stahl,). Correct diagnosis of somatoform and psychosomatic disorder can help with the choice of pharmacological intervention relevently combined with psychotherapy. One such possibility is represented by combination of sulpirid + SSRI + anxiolytic agent. However this modality needs further clinical studies. LITERATURE Table 1 a Diagnose Number of patients Age F.45 Male Female Total Table 1 b Diagnose Number of patients F.54 Male Female Total Table 2 Diagnose Number of patients F.45 somatoform disorder
Age
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F.45.2 hypochondric disorder F.45.30 cardio and KVS system F.45.31 superior GIT F.45.32 inferior GIT F.45.33 respiratory system F.45,34 urogenital system F.45.38 other apparatus or system F.45.4 chronical somatoform painful disorder Total Table 3 a DO Without cormobidity Table 3 b DG Without cormobidity Table 4 a DG SSRI TCA anxiolytic agent SSRI + anxiolytic agent SSRI + typical neurolepticum Atypical neurolepticum Biston Atypical neurolepticum / sulpirid / + SSRI + anxiolytic agent Total Table 4 b DO SSRI SSRI + anxiolytic agent Atypical neurolepticum / sulpirid / + SSRI + anxiolytic agent Other Total
CASUISTIC A 24-years old patient was examined at our outpatient psychiatric center in February 2003 for the first time. He had the first contact with psychiatric center / paediapsychiatric / at the age of 13 only psychotherapy ,without psychopharrnacotherapy. At the age of 21 he was treated at outpatient psychiatric center with a diagnose of somatoform disorder, gastric neurosis F.45.31 with the following advised therapy: maprotilinum 150mg pro die, advised deep psychotherapy, maprotilinum gradually ex, a change for fluvoxamine. The patient travelled abroad for 2 months - without difficulties, he has commited the therapy. RA: He had been brouht up by his parents until he was 13. Then his father died under unknown circumstances, his family refused the suspicion of suicide, he has an older sister, ocassional depressive episodes, t.b.: 0, DM: grandfather, ICHS: grandfather, IM: grandfather, NCMP: probably the great grandparents, ca: great grand father had bowels cancer, alcohol : 0, neuropsychiatric stress: grand mother was treated at psychiatric center, but he can not name her diagnose, his mother is under monitoring by outpatient neurology center, because of sclerosis multiplex. OA: He cameover usual children diseases, more serious diseases in childhood: at the age of 6 months - coeliakia, operations: APE, TE, injuries: 0, fractures: 0, unconsciousness : 0, concussion of the brain: caused by downfall, there was only RTG done, allergy to medicine or to food not declared. SA: The patient has graduated on secondary industrial school, at this time unemployed, character: rather self-contained, introvert, pesimistic, with schizoid features, he does not go out very often, MS rejected, without seriuos relationship, only temporary occasional relationships. TO: He has been suffering from gastric neurosis from the time of his studies on secondary school, It was bearable till the age of 16, it has been getting worse since 2000. When he was abroad, he had no problems. Last year when he came back, his condition started to get worse, it is critical again, he tends to vomit, he is loosing his weight, aversion to food, he feels sick all the time, he has sleeeping problems, he thinks he is not able to go to meet people, only because he feels sick, not because of his anxiety about meeting people. Psychiatric objective:
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The patient comes to the psychiatric center alone, neat, he accepts social formalities, hygiene kept, mimicry and gesticulation appropriate, psychomotoric tempo is appropriate. Consciousness is clear, orientation by person, place, time, situation is right, mood subdepressive, without suicide tendencies, affectivity oscillates, his thoughts are strongly orientated to his somatic qualitative problems of his gatrointestinal tract, without false contents, perception without qualitative disorders, attention good, IMF appropriate to the age, education, surroundings, personality rather introvert, behaviour appropriate. DG: F.45 F.43.31 Advise: Paroxetin 20 mg pro die Clonazepam 2 mg pro die Sulprid 100 mg pro die ETIOPATHOGENIC VIEW: Psychologically the patient’s self-confidence is lower, psychosocially his gatric problems could indicate the need of father’s love. Psychoanalytically somatic disorder is an expression of patient’s anger against unknown person who is responsibile for the pain caused by father’s death. Behaviouraly, somatic disorder would express an imitation of his mother’s disease (sclerosis multiplex, depressive episodes ) and strict upbringing by one of his parents (mother).
BEGINNING AND DEVELOPMENT OF DISEASE The first symptoms of somatoform disorder occured at the age of 13, in the period of adolenscence, it means before the age of 30, it was in close relation with violent death of his father, which meant heavy stress for the young man, Due to the considerable somatic disorder, the patient was repeatedly examined although with negative diagnose. After 5 years of lasting physical problems without scructual defect, the patient was advised to see a mental specialist. His dignose was somatoform disorder (gastric neurosis) with advised therapy. The patient was working abroad for 2 months, where he did not have any physical difficulties. After his return, his condition got worse: nauzei, vomiting, aversion to food, loosing weight, wind.... In differencial diagnoses, we have tried to eliminate these somatic diseases (collagenoses, S M.,myastenia gravis, AIDS, hypertyreosis, chronical infection diseases ...), whose physical symptoms can also be temporary and changeable. We eliminated heavy depressive disorder with somatic symptoms, as there are depressive episodes in the patient’s family anamnesis ( mother, sister ). We eliminated schizophrenia and other psychotic diseases. Concerning the comorbidity we considered stress and endurance situations. TH: Besides psychopharmacotherapy we have advised the patient for psychotherapy as well ( cognito-behavioral psychotherapy )
1.CHECK UP After a month of treatment , the patient felt better, physical symptoms decreased, at this time the patient is looking for the job in Slovakia.
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COGNITIVE AND BEHAVIORAL PSYCHOTHERAPY OF SPECIFIC PHOBIACASUISTIC AUTHORS Dana Ignjatovic 1. Milan Ignjatovic 1, Silvia Beatriz Schweitzer 2 1,2-Non governmental psychiatric health clinic,Cesta k nemocnici 1,Slovakia 3-Hopital Durand, Buenos Aires, Argentina
ABSTRACT Cognitive and behavioral psychotherapy-Beck, 1967, Ellis, 1962- is a integrion of cognitive and behavioral direstions. Cognitive and behavioral psychotherapy is operational and very empirical, what is very important in the efficacy of psychotherapeutical treatment. I would like to introduce you my patient-24 year young woman. She finished catholic secondary school and private business academy with certificate. She work in a shop, like shop-assistant and she lives with her family /mother, father, younger sister and brother lives alone/. She cames to psychiatrist with many problems. She feels very anxious, perfectionistic, she likes when everything is O.K., she likes to be alone in her room, she contol everything 7 times or more. She can’t travel alone in the bus, or train, she has a diarhoea, tachycardia, tachypnoe, she feels very bad, she doesn’t go to bih shops, big squares, she thinks that everybody are looking for her and she has a phobia from blood and injections, all the time she fall off, she feels, when it comes to her, and she prepares a bottle of water for her. It was really too many problems for the first time... So we made cognitive assesment and we formulated together 8 means problems, and goals of psychotherapy. We start with psychopharmacotherapy, because of a long time of psychical problems.
DIAGNOSIS: F.40.01 agoraphobia with panic disorder F.42 or diferential diagnostics: F.60 with obsedant- compulsive F.40.2 specific phobia Therapy: paroxetin/20mg/ 1-0-0 Clonazepamum/0,5mg/ 1/2-0-1/2
ACCTUALLY PROBLEMS AND SYMPTOMS: She is working in a shop, she has agoraphobia and phobi from squares, big rooms, she can’t travel by bus or by train alone, she had a diarhoea, she control 7 or more times if the doors are closed, she feels very anxious, panic, after getting or seeing injections, she can’t stay in a shop for a long time.
INTERPERSONAL CONNECTIONS: Good connections with her mother, but she did so much for family, she have to do much for herself. Father is dominant, expansive, he never said to her and her mother she is clever and successfull. She doesn’t have many friends, only one, she has problems with communications during basic shool.
BEHAVIOUR DURING THE FIRST DIALOGUE: 24 year young woman, with striking makeup, but with inconspisious behaviour, answer the adequate, not so spontaneous. Intelect is higher. Somatic status and laboratory tests/internal,EEG,laboratory scrrening/ are physiological. Actually problem
1.agoraphobia with panic disorder 2.specific phobia 3.personality disorders with obsedant and compulsive symptomatology Personality Senzitive Pedant Anxious Obsedant and compulsive Cognitive schemata I’m not so good for my father When I start to speak everybody thinks I am not clever... Behavioral actual Ampatia Submission Rationalisation of avoidant behavior We start psychotherapy – cognitive and behavioral psychotherapy during the pharmacotherapy, which tries 1 and a half years.
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It was successfull in combination psychopharmacotherapy and psychotherapy and during this time the patients is without symptoms she has on the begining and without psychopharmacotherapy, and she feels very well.
CONCLUSION The psychotherapy is very important par of the complete therapy of the patients, because the patient is a bio-psycho-social complex/Erič, 1999/., and the most important is combination of psychotherapy and psychopharmacotherapy in the treatment. The treatment of this patient was very complex, and complicated, because of many problems. But the compliance between patients and psychotherapeutist was very good what is important for the next treatment, But it may be some times problematic for the finishing the treatment, when the goals are not clear and strong enough. But from our experiences combination of psychopharmacotherapy and psychotherapy is the most effective in the treatment of agoraphobia with panic disorder/Igjatovic M.,Ignjatovic D.,Luhačovice, poster presentation, 2003/.
THANK YOU FOR YOUR ATTENTION! Presented on EABCT,XXXIII.Annual Congress of the EABECT,Prague, 2003
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PHARMACOECONOMICS OF THE TREATMENT OF AGORAPHOBIA WITH PANIC DISORDER AUTHORS Milan Ignjatović 1 Dana Ignjatovićová 2 Hosák Ladislav 3 1-Psychiatric out Department of Polichnic,Banská Bystrica, Slovak republic 2-Psychiatric out Department of Policlinic,Banská Bystrica, Slovak republic 3-Medical Faculty,Psychiatric Clinic Hradec Králové Czech republic
PURPOSE OF THE STUDY The main objective of our study was to determine the average daily and total phannacotherapy costs of agoraphobia with panic disorder when treated by non- psychiatrist outpatient practitioners, compared with accurate diagnostics and treatment in psychiatric outpatient department. Average daily and total number of tablets, taken by patients during the examined period, was also analyzed.
SAMPLE GROUP AND METHOD in the card files of the psychiatric outpatient department of this study’s first author all patients suffering from agoraphobia with panic disorder for longer than two years, were selected who were previously treatedby other therapists than psychiatrists agoraphobia was diagnosed according to DSM-IV clasiffication patients with psychiatric comorbidity, together preganant women were excluded from the research study was not submitted for the approval of the ethics comission, as it was a retrospective axamination of medical records, without the participation of patients, or any influence on their treatment
SUMMARY OF RESULTS AND STATISTICAL ASSESMENTS for statistical processing og acquired data,NCSS 2000 computer software was used distribution normality of aquired values,relating to individual variables,was evaluated using Shapiro-calks and Kolmogorov-Smirnov tests the distribution was abnormal, statistical significance of differences, relating to measured valeus, was examined by Wilcoxon nonparametric test
RESULTS Results are stated in the table 1. Although the average daily price of pharmacotherapy was higher in the case of psychiatric treatment of the psychic disorder, average total medication costs were lower, compared with treatment carried out by practiocioners-nonpsychiatrists. Significantly lower were also average numbers of tablets prescribed by psychiatrists, opposite to previous medical treatment whether their daily or total amount was examined. All described differencie are statistically highly significant.
CONCLUSION Results of this study prove the lack of economy and ineffectiveness of agoraphobia with panic disorder treatment in outpatient departments of non-psychiatric specialists in Slovak republic. Proper diagnostics and psychiatric treatment results not only in improvements of clinical state of patients, but also in savings of total direct treatment costs of pharmacotherapy. Consodering historically recent division of the common state of Czech and Slovaks, authors presume, that acquired results can be applied also for the Czech republic. TABLE 1 The phartmacotherapy costs and the number of the tablets.they had been taken in the outpatient nonpsychiatrists department and comparation with psychiatric outpatient care Patients suffering from agoraphobia with panic disorder Treatment by nonpsy-*chiatrists outpatients practio-cioners Medián /Min.-Max./
Treatment by psychiatrists Medián /Min.-Max./
Wilcoxon nonpara-metric test /p/
Daily price of medication /Sk/
62,9 /1,0-230,9/
82,0 /40,0-333,1/
0,0493
Total price of pharma-cotherapy
123 372,0 /5400,0-1246 860,0/
10 666,5 /82,0-37824,0/
0,0000
Avarage daily number of tablets
7,0 /1,0-20,0/
2,0 /1,0-7,0/
0,0000
Total number of tablets
14 400,0 /1 170,0-75 600,0/
730,0 /365,0-2 555,0/
0,0000
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PHARMACOLOGICAL TREATMENT OF LATE-LIFE DEPRESSION AUTHORS DANA IGNJATOVIC 1 a MILAN IGNJATOVIC 1 b DAVID J. NUTT 2 1 a- Mentee of CINP Mentor-Mentee Program, Non Governmental Psychiatric out Department, Jaseňová 1,97401 Banská Bystrica, Slovak republic 1 b- Coauthor, Non Governmental Psychiatric out Department, Jaseňová 1,97401 Banská Bystrica, Slovak republic 2- Mentor of CINP Mentor - Mentee Program, Professor of Psychopharmacology ,Head of Department of Community Based Medicine, University of Bristol, Psychopharmacology Unit, Bristol
ABSTRACT Late-life depression is common serious health problem with high pharmacotherapy response rate (Solai 2000). Prevalence of depression is 12-15% (Gottfries 1996, Gottfries 1992), but some authors (Mayon and Hawton 1986, Katona 1994) report higher depression prevalence (11-59%) in elderly patients (Katona 1997). Late-life depression is frequently manifested in atypical form with somatic symptoms (Goftfries 1996, Kurzthaler 2001). Approximately 60% of depressive patients in elderly suffer from somatic disease and beside the antidepressants they are treated with other medication (Gottfries 1996). Pharmaceuticals such as antihypertensive drugs /metyldopa, propranolol/, antiparkinsonics /levodopa, karbidopa, amantadine/, hormones /estrogen, progesteron/, corticoids, antituberculotics and anticancer drugs /vincristine, vinblastinel are very frequently used in elderly and could provoke depressive disorder (Hales 1991, Gottfries 1996, Karlsson 1996, Cooke 2001). Misdiagnosed and untreated late-life depression is very common (Gottfries 1999). Depression can be unrecognized due to other medication, alcohol or cognitive dysfunction (Gottfries 1999). Problems with diagnostics of depression and vague pharmacological guidelines could reduce number of treated patients and efficiency of antidepressive treatment in depressive patients with dementia (Alexopoulos 1996). Very important tool is assessment of severity of depression according depression rating scales: GDS scale /Geriatric Depression Scale, /Zung Self Rating Scale /SDS/, The Dementia Mood Assessment Scale and The Cornell Scale for Depression in Dementia or Hamilton scale /HAMD/ (Alexopoulos 1996). SSRIs (Selective Serotonine Reuptake Inhibitors) citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline represent new group of antidepressants developed in 1980 accepted for treatment of late-life depression (Kurzthaler 2001, Briley 1998). Citalopram is one of the most frequently used SSRIs in the treatment of late-life depression (Jirák 2002). Our study was designed as retrospective assessment of 58 elderly patients in the treatment of depression. Patients fulfilled inclusion criteria for depression with or without dementia. 42 patients were treated with citalopram 20mg daily, 7patients were treated with sertraline 50mg daily and 3 patients with paroxetine 20mg daily, 4 patients used fluvoxamin 50 mg pro die, 1 patient used fluoxetin 20mg pro die,1 patient used trazodon 75mg pro die, 1 patient used maprotilin 75mg pro die and 1 venlafaxin 50mg pro die. Incidence of adverse events during antidepressive therapy was monitored. Citalopram was the most frequently used and best-tolerated antidepressant. 28 patients were treated with anxiolytics-21 used clonazepam 0.5 mg daily for sleeping disorders. Neuroleptics were used in 18 patients with behavioral and psychological symptoms of dementia (BPSD). Each of 58 patients suffered from at least one co-morbid chronic somatic disease.
INTRODUCTION Depression in age over 65 is common (Ragneskog 1998) and became an important medical and social problem. Undiagnosed and untreated depression can lead to suicide (Waern 1996). Elderly patients are treated for various somatic chronic diseases. Another very frequent health problem in elderly is chronic pain. Therapy of somatic diseases itself can lead to depression. Around 63% of Americans over 50 years are treated with drugs for more than one chronic disease (Salzman 1997). Antidepressants were used for the first time for the treatment of chronic pain 40 years ago (Opavský 2002). The results of the treatment are ambivalent. SSRIs seem not to have direct analgetic effect, but they potentiate the effect of analgeties (Opavský 2002). According Stephen C. Cook depression use to be co-morbid to syndrome of chronic pain in cancer or rheumatoid arthritis. More than 50% of patients with chronic pain suffer from depression. Adequate antidepressive therapy reduces chronic pain (Cooke 2001). Atypical symptoms of depression in elderly, presence of somatic disease and cognitive deterioration lead to diagnostic problems (Lovestone 2001). Cognitive impairment can cause problems in evaluation of anamnesis, mainly in patients staying in Elderly homes and Homes of social care. Moreover non-cognitive /psychological /symptoms of dementia can include depressive symptoms (Karlsson 1996).
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Some authors recognized late-life depression with or without dementia as specific disorder with different etiology, symptoms and treatment strategy (Karlsson 1996). Other studies suggest, that sometime depression occurs before cognitive impairment in patients with dementia (Reding 1985). In study of 123 depressive patients Hans Ragneskog found 76% of patients with dementia (Ragneskog 1996). Depression simulating dementia can occur in 4-7% of patients (Koukolík 1999). Incidence of depression among patients with DAT (Alzheimer dementia) is 25-33%. Patients with DAT have significantly lower concentrations of serotonine (5-hydroxytryptamine, 5-HT) in brain (Ragneskog 1996). Decreased concentration of 5-HT and 5-HIAA was found also in patients with VAD (vascular dementia) (Gottfries 1990, Baldin 1987). Pathophysiology of depression in elderly indicates possible association of cognitive impairment with depressive symptoms which both could be symptoms of one degenerative brain disease (Karlsson 1996). Uncertainties in diagnostic, comorbidity of depression allow us to consider broader spectrum of clinical decisions in diagnostic process and at the same time they did it more difficult.Tricyclic antidepressants (TCAs) are not recommended for treatment of late-life depression. TCAs similarly to some neuroleptics have also strong anticholinergic effect. They can cause orthostatic hypotension, confusion and rapid deterioration of cognitive functions (Lovestone 2000, Kurzthaler 2001, Švestka 1995). In contrast to TCAs, SSRIs are drugs of first choice for treatment of late-life depression. Adverse events can include gastrointestinal symptoms such as nausea and vomitus especially during first weeks of treatment (Cooke 2001). Fluoxetine can cause agitation, anxiety, and/or insomnia in elderly patients (Cooke 2001). Fluoxetine, fluvoxamine and paroxetine have significantly more drug-drug interactions in comparison with citalopram a sertraline (Solai 2001). Several studies approved positive effect of citalopram in treatment of depression and other emotional disturbances in elderly patients with low frequency of side effects (Ragneskog 1996). Citalopram is one of the most frequently used drug in geriatric patients (Jirák 2002). Efficacy of citalopram is comparable to that of imipramine. Citalopram has antidepressive and anxiolytic effect and is well tolerated in long-term treatment of elderly patients (Joubert 2000). New perspective in treatment of late-life depression are antidepressive drugs such as bupropione, trazodone, nefazodone, venlafaxine and mirtazapine (Cooke 2001).
METHODS Total number of 58 patients, at least 65 years old with diagnosis of clinical depression with or without dementia were included in study. Examination of patients by initial GDS score and 17 items Hamilton scale for evaluation of depression (H. 1D) was used in study. Patients with somatic diseases were not excluded from the study. All patients have at least one of chronic somatic diseases such as ischemic heart disease, II and III stage of hypertension according WHO criteria, polytopic chronic vertebrogenic algic syndrome, chronic headache, chronic gastritis, ulcus ventriculi, chronic bronchitis, diabetes mellitus, hyperlipoproteinemia, status post myocardial infarction and stroke. Patients with diagnosis of schizophrenia and schizoafective disorders, epilepsy, alcoholism and another drug dependence were excluded from the study.
PATIENTS AND STUDY DESIGN Study was designed as retrospective assessment of pharmacotherapy of depression during one month period at two private psychiatric outpatient units at Slovakia. 58 elderly patients were in the treatment of depression. Patients fulfilled inclusion criteria for depression with or without dementia. 42 patients were treated with citalopram 20mg daily, 7patients were treated with sertraline 50mg daily and 3 patients with paroxetine 20mg daily, 4 patients used fluvoxamin 50 mg pro die, 1 patient used fluoxetin 20mg pro die,1 patient used trazodon 75mg pro die, 1 patient used maprotilin 75mg pro die and 1 venlafaxin 50mg pro die.
CLINICAL INVESTIGATION Diagnosis of depression was based on anamnesis, GDS /Geriatric Depression Scale/, HAMD /Hamilton Scale for Depression/, CGI /Clinical Global Impression/. Rating scales were used only for baseline assessment in this study. Evaluation of treatment efficacy was not the aim of our study.
THE AIM OF THE STUDY Overview of antidepressive therapy in elderly during one month period at two private psychiatric out-patient units. Overview of other psychopharmacotherapy and the undesirable effects of antidepressants.
RESULTS 58 elderly patients who fulfilled the inclusion criteria were included in study. The aim of study was to show overview of used pharmacotherapy. Basic characteristics of study population were: men n=13, mean age 71,5 years /range 65-91/, women n=45 patients, mean age 76,4 years /range 65-93/. We follow the psychopharmacotherapy of 58 depressive patients with or without dementia/Tab. 1./. 88
The most frequent and the best tolerated antidepressant in elderly was citalopram/Tab. 2/. 19 patients used neuroleptics for stabilization behavioral and psychological symptoms of Dementia/tab. 3/ Anxiolytics used 28 patients/tab. 4/. Overview of inhibitors ACHE and nootropics shows table 5.
DISCUSSION Psychopharmacotherapy of late-life depression is challenging problem for physician in management of medication, and assessment of age-modified possible adverse events of drugs. Modification is related to pharrnacodynamics and pharmacokinetics of drugs as well as drug-drug interactions with treatment of somatic diseases (Baumann 1998, Švestka 1995). SSRls- citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are important in treatment of late-life depression (Baumann 1998). The dose has to be adapted to liver and renal injury and other somatic diseases (Guttierez 2000). Several studies approved initial half dose of SSRI during one week, for example 10mg citalopram daily and later 20mg citalopram daily (Kasckow 2001), 20-30mg citalopram daily (Balldin 1987) up to 20-40mg citalopram daily (Guttierez 2000, Ragneskog 1996, Andersen 1994, Kyle 1998, Pollock 2000, Klysner 2000). Efficacy of 20-40mg citalopram daily was compared to placebo (Pollock 2000), and TCA- 50-100mg amitriptyline daily (Kyle 1998, 2000). Efficacy of citalopram was similar to amitriptyline with lower frequency of drug adverse events. In process of selection of antidepressive drug in geriatric patients is necessary to remember general guidelines for treatment with antidepressive drugs. One should consider adverse events, log term safety and safety in overdose, efficacy in treatment of previous episodes, present somatic diseases and concomitant medication (Jirák 2002, Hoschl 2002). In geriatric patients SSRI antidepressants are drugs of first choice because of minimal adverse events (no cardiotoxic effect) and good tolerability (Švestka 1996).The most frequently used antidepressant is citalopram at daily dose of 20-40mg and sertraline (50-150mg daily). Fluoxetine can be also used for treatment of late-life depression, but long half-life and drug-drug interactions via cytochrome system need to be considered. Paroxetine has mild anticholinergic effect (Jirák 2002). In our study, citalopram was used in initial dose of 10mg daily for one week, average dose 20 mg daily, maximal dose 40mg daily. Sertraline was given in initial dose 25mg daily, average dose 75mg daily, paroxetine in average dose 20mg daily, fluoxetine in average dose 20mg daily and fluvoxamine in initial dose of 50mg daily. Mackle et al. evaluated efficacy and safety of citalopram in 98 elderly dement patient with noncognitive symptoms (56 - 94 years old) in double blind placebo controlled multiphasic study. Citalopram was found to have excellent safety profile in elderly patients with various somatic diseases. No adverse effects or rebound phenomena were recorded during treatment with citalopram (Mackle 1998). Several multicentric controlled studies assessing efficacy of citalopram in elderly patients have found significant improvement of confusion, irritability, anxiety, depressive mood and psychomotoric agitation in patients treated with 10-30mg citalopram daily. Efficacy of citalopram is significantly higher than placebo. Citalopram has not only antidepressive but also mood stabilizing effect (Gottfries 1992, Gottfries 1999). Our study has shown important role of SSRIs and especially citalopram in treatment of depressive symptoms. There is evidence on efficiency of citalopram in treatment of major depression or depressive symptoms of Alzheimer dementia (DAT). Our study has found citalopram (at daily dose of 20 mg) as the most frequently used and best tolerated antidepressive drug. Citalopram did not cause sedation, retention of urine, orthostatic hypotension, and was well tolerated in drug-drug interactions. Improvement of emotional disturbances, apathy, irritability, anxiety, depressive mood and psychomotoric agitation was observed in patients treated with citalopram. Adverse effects were found to be minimal and reduced by half dose of SSRI given during first week of treatment. No significant drug - drug interactions were recorded during treatment with citalopram. Assessment of GDS, HAMD, CGI was not the aim of the study. The baseline assessments were used as inclusion criteria and evaluation criteria of adverse events. This could be considered as weak point of the study and need to be completed in new study.
CONCLUSION Depression is very common inelderly people and some people with Alzheimers disease are suffering from depression too. Early diagnostic and adequate treatment of depression in elderly is very important. In our retrospective assessment we studied 58 depressive patients with or without dementia and the most frequent and the best tolerated antidepressant was citalopram.
REFERENCES Alexopoulos GS: The Treatment of Depressed Demented Patients, 1996,J Clin Psychiatry 57,/suppl.14/:14-20 Baldwin RC, Chiu E,Katona C, Graham A: Guidelines on Depression in Older People,Practising the Evidence, 2002, 157:7-39,39-47,57-95 Balldin J,Gottfries CG, Karlsson I, Lindstedt G,Langstrom G,Svennerholm L: Relationship Between DST and the Serotonergic Systém.Results from Treatments with Two 5-HT Reuptake Blockers in Dementia Disorders1988,International Journal of Geriatric Psychiatry,Vol.3,17-26 Baumann P:Care of depression in the elderly: comparative pharmacokinetics of SSRIs,1998,Intemational Clinical Psychopharmacology ,13 Suppl5:S35-S43 Božin A.:
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Briley M, Montgomery S: Antidepressant Therapy at the dawn of the third Millennium, 1998,349:69-87,333-349 Cooke SC, Tucker ML: Geriatric Depression,2001,Journal of Pharmacy Practice,Vol.14 No 6, Flicker C,Gottfries CG,Overa K: Citalopram Treatment of Depression in Elderly Patients with or without Dementia-Results of a Placebo - Controlled Trial,dopilnit’ kedy a kde bol poster prezentovaný Foglia JP,Pollock BG, Kirshner MA et al: Psychopharmacology in Geriatric Populations, 1997,Psychopharmacology Bulletin 33/1/:109-112 Gottfries CG: Scandinavian experience with citalopram in the elderly, 1996 International Clinical Psychopharmacology, 11, Suppl 1,41-44 Gottfties CG,Katisson I,Nynth AL: Treatment of Depression in Elderly Patients With and without Dementia Disorders, 1992,Intemational Clinical Psychopharmacology,6 Suppl. 5,55-64 Gottfries CG: Recognition and management of depression in the elderly ,1997,Intemationai Clinical Psychopharmacology,12,supp1.7,S31-S36 Gottfries CG,Pollock BG: Citalopram:Its Use in Elderly Patients, Review, 1999,Annals of long-Term Care 7/51:181-189 Gottfries CG, Nynth AL: Effect of Citalopram,a Selective 5-HT Reuptake Blocker ,in Emotionally Disturbed Patients with Dementia, 1990,kde to bolo pulikované? Guttierez M,Abramowitz Wattanapom: Steady-State Pharmacokinetics of Citalopram in Young and Elderly Subjects, 2000, Psychopharmacotherapy, 20/12/:1441-1447 Hales RE,Yudovsky SC,Talbott JA: Textbook of Psychiatry, Second Edition, The American Psychiatric Press,562:313-353, 99-100 Hoschl C,Libiger J, Švestka J: Psychiatric, 2002, 855:435-480 Ignjatovic D,Ignjatovic M., Jirák R,Zemková P: Psychofarmaka pro pacienty vyššiho veku, Remedia, 12,6/2002,425-440 Joubert AF, Sanchez C,Larsen F:Citalopram, 2000,Human Psychopharmacology, Clin .Exp.15, 439-451 Kasckow JW, Thalassinos A.Carroll BT: The Use of Citalopram to Treat Minor Depression in the Elderly, 2001,Poster Presentation, AAGP Katona C,Livingston: Comorbid Depression in Older People, 1997,79 Karlsson I: Pharmacologic treatment of noncognitive symptoms of dementia,1996, Acta Neurol Scand ,Supp1.165:101-104 Klysner R,Pleidrup E, Hansen HL, Poulsen DL: The Effectiveness of Citalopram in the Prevention of Depression Recureence in Elderly Patients,2000,Poster Presentation, CINP Koukolík F,Jirák R: Diagnostika a léčeni syndromu demence,Grada Publishing, 1999,152:22 Kurtzhaler I, Hotter A,Miller C,Kemmler G,et al: Risk Profile of SSRI s in Elderly Depressive Patients with Co-Morbid Physical Iiiness,2001, 34,Pharmacopsychiatry,Short Communication Kyle CJ,Hopfner Petersen HE, Overo KF: Comparison of the Tolerability and Efficacy of Citalopram and Amitriptyline in elderly Depresse Patients Treated in General Practice,1998,Depression and Anxiety,8:147-153 Kyle CH,Petersen HE Hopfner: Citalopram Treats Major Depression in the Elderly with Fewer Side Effects Than Amitriptyline, 2000,Poster Presentation, CINP Lincová D,Farghali H: Základni a aplikovaná farmakologic, 2002,567:140-143,164-168172-173,175 Lovestone S, Gauthier S: Management of Dementia, 1999,161:12-13,20-2140-41 Mackie M,Gottfries CG: Citalopram Treatment of Noncognitive Symptoms in Elderly Demented Patients 1998,Poster Presentation, NCDEU Nynth AL,Gottrfries CG: The Clinical Efficacy of Citalopram in Treatment of Emotional Disturbances in Dementia Disorders A Nordic Multicentre Study,1990,British Journal of Psychiatry,157,894-901 Nynth AL,Gottfries CG,Smedegaard-Andersen L et al: A controlled multicenter clinical study of citalopram and placebo in elderly depressed patients with and without concomitant dementia,1992 Acta Psychiatr Scand ,86:138-145 Opavský: Stručný prehled analgeticky účinných lečiv pro klinickou praxi, 12,6/2002,409-423 Pollock BG,Mulsant BH, Sweet R et al: Citalopram Pharmacotherapy for the Behaviorla Disorders of Dementia, 1998,Poster Presentation, AMDA Ragneskog H,Eriksson S,Karlsson I,Gottfries CG: Long-Term Treatment of Elderly Individuals With Emotional Disturbances: An Open Study With Citalopram, 1996, International Psychogeriatrics, Vol.8, No4, 659-668 Roose SP,Devanand:DP: The Interface Between Dementia and Depression, 1999,57 Solai LK,Mulsant BH,Pollock BG: Selective Serotonin Reuptake Inhibitors for Late-Life Depression.A Comparative Review, 2001,Drugs and Aging,18/51:355-368 Švestka J: SSRI léky prvé volby, 1998 153:46-56,63-70,94-102,106-114 Švestka J: Psychofarmaka v klinické praxi 1995, 241:65-132 Waern M,Beskow J,Runeson Bo, Skoog I: High rate of antidepressant treatment in elderly people who commit suicide,1996,BMJ,vol.313:1181
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Table 1 Diagnoses overview Diagnosis F.01 with depressive symptomatology F.00.1 with depressive symptomatology F.00.2 with depressive symptomatology F.06.3
Number of patients 2 1 11 44
Table 2 Overview of antidepressants Drug
Number of patients 42 1 4 3 7 1 1 1
Citalopram Fluoxetine Fluvoxamin Paroxetine Sertralin Trazodon Maprotiline Venlafaxine
AEs*
Mean daily dose in miligrams
5 1 2 1 2 0 1 0
20 20 50 20 50 75 75 50
AEs* adverse events as number of patients Table 3 Overview of neuroleptics Drug Haloperidol Risperidon Tiaprid Sulpirid Zotepin Olanzapin
Number of patients 5 3 5 2 3 1
Mean daily dose in mg 1.5 1 100 50 20,8 2,5
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Table 4 Overview of – anxiolyties Drug Alprazolam Bromazepam Clonazepam Hydroxizin
Number of patients 2 4 21 1
Mean daily dose in mg 0,5 3 0,5 12,5
Table 5 Overview of ACHE inhibitors and nootropics Drug Rivastigmin Galantamin Piracetam Ginko biloba Others -vitamin E
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Number of patients 8 1 23 3 14
Mean daily dose in mg 11,25 16 2400 40 400
THE EFFICACY OF DEPRESSION TREATMENT WITH MILNACIPRAN (A six- MONTH EXPERIENCE) Dana Ignjatovičová, M.D. (I) Milan Ignjatović, M.D. (2) Silvia Beatriz Schweitzer, M.D. (3) (1, 2) Private Psychiatric Outpatient Surgery, Cesta k nemocnici 1, Banska Bystrica, Slovak Republic (3) Psychiatric Department, Cespedes, Buenos Aires, Argentina
Summary Depression represents one of the most frequent and grave psychical alienations. It manifests itself by tiredness, sleeping malfunction, headaches, loosing or putting on weight, and failure of sexual function. Bad mood, however, is not necessarily the most dominant symptom [G.N. Christodoulou, 2002]. It means that together with the establishment of the right diagnosis it is very important to manage an adequate treatment of depression. Some of the key points, not only in the conditions of outpatient treatment, are anamnesis exploration of previous depressive episodes, family anamnesis of affective diseases, and clinical exploration in relatives. Depression today represents the 4th most frequent cause of health damage or loss of life due to early affection or mortality. It is expected that depression will become the 2nd in 2020 [G.N. Christodoulou, 2002] . In the U.S. A., yearlong prevalency represents 12.9% in women and 7.7% in men [Kessler et al., 1994]. In Europe, prevalency is 17% [Lepine et al., 1997]. Our 6-month follow-up included 12 patients using milnacipran 100 mg per day. We made evaluations of HAMD and HAMA at the start (it means on the first day of the follow-up) and used the CGI scale. Two patients were discarded from our follow-up: one patient had discontinued the medication on her own in the 4th month of the course of treatment and the other one was hospitalized due to a high risk of suicidal tendencies (HAMD-39 points, HAMA-28 points). We have evaluated HAMD on the first day of treatment, then one month later, and then half a year after the setting up of milnacipran 100-mg per day. In the 2nd month we did not observe any kind of strong amelioration (HAMD- 19.8 points), but in the 6th month HAMD reached to 7.1 points.
Key words Depression, BDRS (Hamilton Depression Rating Scale), CGI (Clinical Global Impression), milnacipran
Introduction The development of new antidepressive drugs in last fifty years has come through the complicated way which was started by the antidepressive effects discovery of iproniazid (an antituberculotic agent) in 1950 and irniprarnine (an antihistamine) in 1955 [David J. Nutt, 2002]. The progress has finally resulted in the present very effective and strongly selective antidepressive medicaments accompanied by a minimum of undesirable effects - venlafaxin, milnacipran [S.M. Stahl, 1997]. Tricyclic antidepressives (TCA) are strongly effective, especially in the treatment of harder depressions [P. Boyer and M. Briley, 1998, S. A. Montgomery, 1999], but they are characterized by a large number of undesirable effects. At the same time, it must be said that SSRI have at least the same efficacy as TCA [J. Švestka, 1998]. SSRI are safer and better accepted by the patient. Nevertheless, they are not so effective for grave depressions [NI Briley, 1997], but they have their own exceptional position in the treatment of depressions, especially those connected with anxiety. SNRI antidepressives are more effective compared with the effect of placebo in a big depression episode treatment [Y. Lecrubier, 1997] and have the same effect as TCA, but they are much better accepted by the patient [Kasper, 1996]. The effect of SNRI in comparison with SSRI is almost on the same level [P. Boyer and M. Briley, 1998, M. Briley, 1997], but their dual effect on noradrenergical and serotoninergical neurotransmission foreshadows higher effectiveness than in SSRI. Thanks to this fact, SNRI have become very promising antidepressants [P. Boyer and M. Briley, 1998]. Depression represents a heterogeneous unit with a different variety of forms. It ranges from a light depressive episode, through dysthymia to grave depression, which requires hospitalization [SA. Montgomery, 2001]. Symptoms of depression change according to the functional activity of’ the neurotransmitter system. Considering this, we can divide the symptoms of depression into two groups. The first one is serotoninergic and the second one is noradrenergic. It corresponds generally with the concept of impulsiveness, aggressivity, lower sexual appetence (5-HT system), and lack of motivation and energy (NA system), or when mixed, with anxiety, irritability, bad humour, and failures of cognitive functions [S.A. Montgomery, 2001]. It means that antidepressives with a dual effect (venlafaxixt, milnacipran) show a theoretical promise to suppress, by their dual effect, the symptoms of depression. The catecholaminal hypothesis [Schmidtkraut and Kety, 1967] assumes that depression
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results from an insufficient activity of central noradrenergic neurons, whereas the indolarninal hypothesis [Van Praag, 1982] talks about a deficit of the activity of central serotoninergic neurons [Monet, 1985]. Milnacipran is a new antidepressant inhibiting the reuptake of serotonin and nora.drenahne in vitro and in vivo without an effect on the reuptake of dopamine. Microdialyses confirmed a higher extracellular level of serotonin and noradrenaline. Milnacipran does not show any evidence of interaction with blown neurotransmitter receptors. In comparison with TCA, chronic milnacipran administration does not modify the linkage to beta-adrenoreceptoral sites or the function of the second messengers [P. Boyer and M. Briley, 1998].
Observed group and methodology The group under observation included 12 patients. Woman (n= 8, average age = 41.33 years, age interval, 22y-60 years). Rwo female patients were rejected out of the follow-up. One has discontinued the treatment at her own request (but not due to undesirable effects) and the second one was hospitalized (HAMD-39 points, HAMA-28 points). We have made HAMD and HAMA evaluations on the first day, then after one month and then in the sixth month of the followup. We have evaluated CGI, too. All patients took milnacipran in a dose of 100 mg per day.
Criteria for insertion: age 18 60 years MKCH-10 and DSM-IV diagnostic criteria for an intermediately grave (F.32.1) to a grave episode of depression without psychotic symptoms (F.32.2) HAMD up to 18 points 6 months’ follow-up
Criteria for rejection: comorbidity together with other psychical diseases organic psychical affects mania, hypomania dysthymia schizophrenia, schizoaffective failures alcoholism and other kinds of dependence pregnancy epilepsy in ananmesis cardiac rhythm failures in anarnnesis important somatic diseases A certain shortage of this study could be a small group of patients in whom we observed the clinical status and evaluated HAMD and HAMA scales. But we did not make MADRS evaluation, which is frequently used in control studies. Another shortage of this paper is the duration of the study. The follow-up lasted only for six months and we did not make HAMD and MAHA evaluations in the third month. There were only three evaluations - on the first day, after one month, and on the last day of the follow-up.
Goals of study: to compare the results of HAMD on the first day, after one month, and in the sixth month of the follow-up using milnacipran in a dose of 100 mg pro die to note any undesirable effect of milnacipran during a six months lasting follow-up
Results We have included 12 patients into the follow-up, using the criteria of inclusion (Table 1). We used HAMD, HAMA (Table 2), and CGI for the evaluation. We rejected two patients. The average HAMD on the first day of the follow-up was 21.5 points, HAMA15.4 points. After one month, the average was HAMD-19.8 points (only 1.7 points amelioration) and HAMA-12.4 points. After a six-month follow-up, it was HAMD-7.8 points (13.7 points amelioration) and HAMA-7.1 points. Three of the 10 patients under observation had already been treated for an episode of depression in the past. All of them used SSRI and anxiolytic agents. In the patients we found the following undesirable effects: dryness in the mouth - 2 patients, dysuria - 3 patients, GIT troubles – 1 patient (Table 3). For complex evaluation of treatment efficiency, we used CGI (Clinical Global Impression).
Discussion Clinical studies are a suitable source of information about new preparations, but physicians have to verify their effect when prescribing them to patients [S.A. Montogomery, 1999]. Noradrenergic and serotoninergic neurons take the most important part in the mechanism of the effect of neurons /S. Kasper, 2002/. We can say that medicaments in which two or more synergic effects are combined together might have a higher therapeutic effect and toleration comparable to the therapeutic mechanism of the effect of highly selective substances (S.M. Stahl, 1997]. Milnacipran is a cyclopropane derivative which inhibits noradrenergic and serotoninergic reuptake in the presynaptic area. No activity of postsynaptic receptors was observed. 94
The most frequently used dose is 50 rng of milnacipran two times per day [CM. Spencer and M. Wilde, 1998]. A dose of 100 rng of milnacipran pro die manifested a sufficient effect in our six-month follow up. Amelioration appears mostly in the second week of therapy [Spencer and Wilde, 1998] with a daily dose of 100 mg (4 weeks - 3 months follow up). We observed not so marked amelioration after one-month therapy (HAMD1=21.5 points, HAMD2=19.8 points - 1.7 points difference). Milnacipran had an equal effect to those of imipramine and clomipramine, 150 mg pro die in Japanese patients [Spencer and Wilde, 1998]. Milnacipran was less effective than clomipramine in our 6 months study. A comparison was carried out concerning the effects of milnacipran 50-100 mg and 20 mg fluoxeloin pro die, 200mg fluvoxamin pro die and mianserin 30-60mg pro die in the 4th and 12th week. Milnacipran had the same effect on hard depression as TCA and SSRI during the 4-12 week follow-up. Milnacipran was very well tolerated with a minimum of undesirable effects dysuria 7% [Spencer and Wilde, 1998]. According to the study of Kasper et al., 1996, one of the most frequent undesirable effects during milnacipran therapy is dysuria (2.1%). Pending our follow-up of undesirable effects occurrence, dysuria appeared in three patients, dry mouth in two patients, tremor in two patients, gastrointestinal troubles in one patient, and obstipation in one patient. These results are comparable with the international studies [Spencer and Wilde, 1998; Kasper, 1996]. The reported undesirable effects did not result in discontinuation of milnacipran therapy. A very important thing for the effect comparison of medicines is comparative studies, multicentred and placebo-controlled. In our study we focused on the results of a six- month milnacipran therapy course in ambulatory conditions but we did not compare it with placebo and SSRI. It would be desirable to do it in the future. Several studies were published in the United States which covered 527 ambulatory patients (131 patients used milnacipran 25mg pro die, 130 patients used milnacipran 50mg pro die, 133 patients milnacipran 100mg pro die, and placebo was used by 133 patients). The follow-up included HAMD results with more than 22 points (average entering HAMD in our study was 21.5 points), MADRS, and CGI. The results of milnacipran 100mg per day were significantly better than placebo (p < 0.01). There were about 64% responding patients pending 8 weeks’ follow-up with a milnacipran dose of 100 mg per day [Y. Lecrubier, 1997]. The follow-up included 68 patients with a. milnacipran dose of 50mg in comparison with 49 patients treated with placebo in Europe. HAMD was higher than 22 points and according to the results the differences were not statistically significant. [Y. Lecrubier, 1997]. A milnacipran dose of 50mg in 29 patients and placebo in 29 patient were compared in the third study. Together there were 58 hospitalized patients and after 4 weeks’ follow-up HAMD changed from 18.7 to 7.1. We observed HAMD, which at the beginning of study was 21.5 points. After a month, HAMD became 19.8 points, which means only 1.7 points amelioration. At the end of the 6th month, HAM was 7.8 points. Amelioration was thus 13.7 points compared with the first day of the follow-up. We also evaluated global clinical impression. The grade of illness importance on the first day of the follow-up: intermediate (6 patients), hard (4 patients). Grade of illness importance at the end of the 6th month was: normal, no evidence of illness (5 patients), marginal evidence of illness (5 patients). Very kacaig global amelioration appeared in all 10 patients. During the four months lasting follow-up of patients with a milnacipran dose of 50mg per day, all patients were evaluated as very clearly ameliorated [Rouillon, 2000]. Although a group of 10 patients is small, the results show that our experience is comparable to the studies made in the US and Europe (France and Sweden), which demonstrate that new SNRI medicament specifically affecting serotonin and noradrenaline are more effective on hard depression than SSRI and possess the same effect as TCA with a smaller number of undesirable effects [Briley, 1998]. Another six-month study made on a small group of 41 patients and comparing 100mg milnacipran to 75 mg clomipramine showed a 50% reduction of HAMD. But there were no significant differences in MADRS and CGI scales [P. Boyer and M. Briley, 1998]. Many studies confirmed milnacipran effectiveness in the therapy of depression compared to other antidepressive agents [Hindmarch,1997, Kasper, 1996, Spencer, 1996]. These published studies helped us to understand the theoretical basis of milnacipran role in hard depression episode treatment which we verified in practice.
Conclusion Depression is very a heterogeneous unit [S.A. Montgomery, 2001]. It has various manifestations requiring complex and adequate antidepressive therapy. Mihiacipran exerts its effect on basic depression symptoms including anxiety, sleeping malfunction, and psychomotoric retardation. It does not affect memory functions. Milnacipran does not have any interaction via the cytochromic system P-450 and could be effective in patients with concomitant pharrnacotherapy. It does not affect the cognitive functions and that is why it is very suitable for the use by older and anxiety patients. Although it has no sedative effect, it adjusts sleeping malfunctions. Milnacipran seems to be a safe, well tolerated, and highly effective antidepressant in the treatment of intermediate to hard depressive episodes with minimal undesirable effects. It depends on our clinical experience whether milnacipran will become the medicament of the first line in depression treatment [SA. Montgomery, 1999].
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Literature Boyer P., Briley M.: Milnacipran, a New Specific serotonin and noradrenaline reuptake inhibitor, Drugs of Today, 34/8/, 709- 720,1998. Briley M.: From Dirty Drugs to Hyperselectivity and Part Way Back Again, Human Psychopharmacology, Vil.12,S121 -S125,1997. Briley M.: Milnacipran, a Well Tolerated Specific Serotonin and Norepinephrine Reuptake Inhibiting Antidepressant, CNS Drug Review, Vol.4, No2, pp137-148,1998. Hindmarch I.: Do we need New Antidepressants?, Human Psychopharmacology,Vol.12, S 115-S119,1997. Christodoulou G.N., Kontaxakisová Beata J.Havali, Kontaxakis Vassilis P.: Prevecnia depresie, WPA buletin o depresie, Roč.5-č.24 , 2002, 3-9. Kasper S.: Optimizing antidepressant treatment are two actions better than one?, International Clinical Psychophannacology,Vol.17, June 2002. Kasper S., Pletan Y., Solles A., Toumoux: Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results, international Clinical Psychopharmacology,1996,vol.11/ suppl. 4/ 35 39. Kessler RC ,McGonagle KA, Zhao S., Nelson CB, Hughes M. Eshleman S, Wittchen Hu, Kendler KS- Lifetime and 12 months prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.ArehGen Psychiatry 51,8-19,1994. Lecrubier Y: Milnacipran: The Clinical Properties of a Selective serotonin and Noradrenaline Reuptake Inhibitor SNRI/, Human Psychophamracology, Vol.12,S127-S134,1997. Lépine JP, Gastpar M., Mendlewicz J., Tylee A: Depression in the community the first pan- European study DEPRES/Depression Research in European Society/Int.Clinical Psychopharmacol.,12,19-29,1997. Montgomery SA: From the theory to practice-everyday use of miinacipran, International Journal of Psychiatry in Clinical Practice, Vo1.,3,Supp1.2, PS29-S33,1999. Montgomery SA: Dual action antidepressants in clinical practice, Drugs, 3,1,P43-P49,2001. Moret C., Charveron M., Fmberg J.P.M., Couzinier J.P., Briley M.: Biochemical Profile of Midalcipran/F2207/,1-Pheny1-1Diethyl-aminocarbonyl-2-aminomethyl- cyclopropane/Z/Hydrochloride, a potential fourth generation antidepressant drug, Neurophamracology, Vol.24,Nol2pp 1211-1219, 1985.Nutt D. J.: The neuropharmacology of serotonin and noradrenaline in depression, International Clinical Psychophannacologry,17, Suppl., S1-S12,2002. Poirier M.F,Galinowski. a.,Longevialle R.,Loo H.: Comparative study of milnacipran versus placebo on cognitive function in healthy volunteers, 3 erne Conférence Vigilance et Performances Psychomotorices Annecy,8-9-avril,1991. Rouillon F.,Warner B ,Pezous N.,Bisserbe J.C., and the Milnacipran recurrence prevention study group, International Clinical Psychophamracology,15,133-140, 2000. Spencer C.M., Wilde M.I.: Milnacipran: A review of its Use in Depression, Adis Drug Evaluation, Drugs, 56/3/, 405-427,1998. Stahl S.M.:Are two antidepressant Mechanisms Better Than One?, Clinical Psychiatry, 58,8,1997. Smolik P.:Duševni a behaviorálni poruchy, prúvodce klasifikaci, nástin nozognózie, diagnostika, Maxdorf-Jesenius,487: 1996. Suchopár J.: Remedia,Compendium, Tretie vydanie,Panax, 743 1999. Švestka J.: SSRI lieky prvej volby, Maxdorf„Jesenius, 153,9, 46-55,74-92, 1998. HAMD, HAMA Scores
1st day of study
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. ave-rage
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HAMD 24 25 23 18 18 18 18 25 18 18 21.5
HAMA 22 23 18 8 8 10 7 10 10 38 15.4
after one month of milnacipran therapy HAMD HAMA 22 20 18 18 18 18 16 8 10 6 16 10 12 7 18 10 6 6 22 21 19.8 12.4
after six months of milnacipran study HAMD 12 11 10 6 6 8 6 0 5 12 7.8
HAMA 10 6 15 6 6 6 5 0 12 11 7.1
Table 1 PATIENT LIST Number 4 6 10
Men Woman Total
Avg.age 44.25 40.66 41.33
Table 2 HAMD, HAMA Scores 1st day of study
Avg.points
HAMD1 21,5
HAMA1 15,4
after one month of milnacipran therapy HAMD2 HAMA2 19,8 12,4
after six months of milnacipran therapy HAMD3 HAMA3 7,8 7,1
Table 3 List of undesirable effects of medicament Vertigo Dry mouth Anxiety Obstipation Dysuria GIT malfunctions Tremor Palpitation Nausea Somnolence
0 2 0 1 3 1 0 0 0 0
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THE RISK OF SUICIDE IN THE GERIATRIC PATIENTS’ COMMUNITY AUTHORS Dana Ignjatovičová1 M.D. Milan Ignjatovič2 M.D. Michala Knišková3 Mgr. 1, 2, 3 - Non governmental psychiatric health clinic, Cesta k nemocnici, 97401 Banská Bystrica, Slovak republic
Abstract Depression occurs quite often at the older age. The base of the depressive disorder is panthic mood, sadness, reduction of the interest sphere and initiative... In the group of geriatric patients the suicidal thoughts occur very often. They have various thoughts: about fear of death, thinking that it would be better to be dead, the life is not worth to live, up to the precise suicidal plans/suicidal tendencies, or suicidal attempts (Hoschl et al., 2002). In the study we have included 14 gerontopsychiatric patients placed in retirement home in Banská Bystrica and 14 gerontopsychiatric patients who do not live in retirement home. They live at home and they are the patients from our psychiatric clinics. In both groups of the patients we have examined the age, gender, social conditions, degree of education, and occurrence of chronic diseases (somatic). The questioner was used to evaluate the depression - incoming record of the depression - VSTD (Filip - 1997), Geriatric depression scale (GDS) and Beck’s selfevaluation scale to evaluate the depression. All of the patients from the retirement home had good social conditions and they had mostly elementary education. In the group of patients who do not live in the retirement home the social status was assessed as excellent and the level of education was higher - college degree and high school diploma. In spite of our expectations, suicidal thoughts occurred with the same frequency even in the group of the patients who do not live in the retirement home. Even though they have better score in the elevation of depth of the depression (GSD, Beck). Everyone in the group A, 14 gerontopsychiatric patients from retirement home, was treated for symptoms of depression. Five patients had suicidal thoughts, even though all of the patients were monitored and treated for one or more chronic diseases. Group B consisted of 14 gerontopsychiatric patients who do not live in the retirement home. Six patients had suicidal thoughts, even though all of the patients were monitored and treated for one or more chronic diseases. Among major risk factors of depression and suicidal thoughts are emotional problems at the older age and anxiety (Beurs, 1999, 2001) associated with the partner’s or close person’s death, illness, loss of the job and change of the home, for example: placement in the retirement home. We have also endorsed environmental stresors as risk factors of depression and suicidal thoughts in the older age. key words: older age (+55 years of age), suicidal thoughts, social conditions
Introduction The diagnosis of depression is very common in the older age and requires besides patient approach also necessary amount of the knowledge. Problems with the appetite, change of body weight, insomnia, psychomotor agitation or retardation, loss of energy, feeling of useless, guilt, problems with the concentrations, thoughts about death or suicide or suicidal attempts are serious signs of the depression (Hoschl et al., 2002). Depression in the older age is quite often misinterpreted or overlapped by somatic illness, since the patients suffer from one or more chronic diseases (Smolik, ). It is important to distinguish problems with the memory within depressive feelings from starting or from advanced dementia. Higher prevalence of depression was observed in females, who are even more often treated (Beekman et al., 1999). However, in males the depression is more serious risk factor of mortality (Zeng et al., 1997). Chronic depression was not associated with higher mortality of the patients. Based to Jorm et at. it is quite possible that depression is prodrome of cardiovascular diseases or dementia or occurs more often in these conditions (Jorm et al.,2000). Among risk factors of mood disorders (according to WPA, PTD, Educational Program on Depressive Disorders, 1997) are included: divorce, loneliness, being widowed, depression in the past, family history of depression, bad life experiences, drug abuse, somatic disorder, social isolation, poor personal life, changes in social systems, pharmocogenic influence, changes in interpersonal relations (Hoschel et al. 2002). Alarming fact is the finding that the most suicides occur in the group age over 70 years of age, and the strongest predictors of suicidal behavior are the presence of suicidal attempts in the medical history and hopelessness (Hoschel el al., 2002).
Method and group characteristics Examined group consisted of: 14 gerontopsychiatric patients form retirement home treated for symptoms of depression (group A) 14 gerontopsychiatric patients living at home and they were not place in to the retirement home (group B) and they are treated for symptoms of depression in doctor’s office. In both groups of the patients we have examined the age, gender, degree of education, socioeconomic conditions, and family status. The questioner was used to evaluate the depression - incoming record of the depression VSTD (Filly - 1997).
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We have examined the depressiveness using GDS (Geriatric depression scale) and by Beck’s selfevaluation scale to assess the depression. We have examined occurrence of suicidal thoughts during actual psychiatric evaluation as well.
Inclusion criteria: age over 55 years symptoms of depression life in a community (retirement home) or in previous home occurrence of one or more chronic somatic diseases
Exclusion criteria: delirium multiple personality psychotic disease additions
Goals of the study: To compare socioeconomic and family conditions in patients living in the retirement home (group A) and in patients living individually at home (group B) and their influence on the occurrence of suicidal thoughts. To evaluate and compare the experience of depression in the patients living in retirement home (group A) and in the patients living individually at home (group B).
Null hypothesis Occurrence of suicidal thoughts and depression is greater in the patients placed in the retirement homes in comparison with the patients living individually at home and is associated with their living and socioeconomic conditions.
Results Our results did not prove the null hypothesis. Suicidal thoughts have occurred equally in patients placed in the retirement home (5 out of 14 patients) just as in the patients living individually (6 out of 14 patients, Table 7). In the group of patients living in the retirement home, the living conditions were evaluated as good ones, in the group of patients living individually as excellent (Table 3). Marital status is presented in Table 2, education is accessible in Table 5 and employment list is in Table 4. Listing of the diagnosis is presented in Table 6. Results of the test of depressiveness are summarized in Table 8.
Discussion Depression is one of the most often occurring disorders in the older age. Depression very often imitates some of the somatic diseases (Hoschl et al., 2002). Great risk represents suicidal thoughts, which can lead to suicide, especially in the older patients. Suicidal attempts occur three times more often in females than in males. Males commit suicide three times more often than females. In the present group, one patient placed in the retirement home attempted to commit suicidal. The patient attempted to commit suicide in the past, before his/her placement in the retirement home. It is alarming that the number of suicides is increasing in a group of people over 70 years of age. The average age of the patients in the group A was 79.85 years of age and in the group B - 66.85 years of age. With increasing suicide are associated such demographic factors as social isolation, childlessness, not sufficient social integration, serious somatic illness and etc. (Hoschl et. al. 2002). This finding has been also supported by the results from our group of patients. In the group B of patients living in retirement home were more widowed patients (9 patients) and 2 single people. in the group A (living individually at home) were more married patients (7 patients), only 4 patients were widowed. All of the patients were retired, except for one who was working (patient from group A). More studies have shown that clinical depression or depression symptoms are risk factors for higher mortality (from cardiovascular disease) in the sample of psychiatric patients (Kaarin et. al., 2002). All of the included patients are treated for one or more somatic chronic disease. Factors, which lead into depression and mortally in non-psychiatric community were chronic somatic diseases, low BMI, cancer, hear disease, smoking, alcohol abuse. What is interesting is that the depression leads to coronary disease in the middle age in comparison to the older population (Mendes de Leon, 1998). This finding is probable in our group of patients, since prior to the diagnosis of the depression, all of them were treated for cardiovascular disease. Therefore, cardiovascular disease was not the result of the depression. All of the patients included into our study suffered from one or more chronic disease, mostly with cardiovascular disease and vertebral problems of the kinetic apparatus. No one from the examined group had psychiatric treatment in the past. One
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patient had psychiatric examination, after repeated suicidal attempts, however, without recommended psychiatric medication or psychotherapy. The study, which was examining patients with the diagnosis of depression or with the symptoms of depression with or without chronic illnesses showed that the patients with poor psychic status, poor social functioning had greater physical pain and the depression was more severe (Wells et. at 1989). Among our patients we have found that the experience of depression was significantly associated and influenced by these factors. Occurrence of suicidal thoughts was comparable in both groups, living in retirement home (group A) and living individually at home (group B). The experience of depression was worse in the group B, living in the retirement home, GDS = 10 points, in comparison to group A GDS = 7 points and Beck’s = 13 points in group A and Beck’s = 8 points in group B. Long term therapy of the depression is recommended especially in the hospitalized patients (Paykel, 2001). There are several two and more years placebo controlled studies for prevention of recurrence of the depression (Montgomery et. al., 1993, Rouillon et. al. 2000). Unfortunately many studies conducted with older patients do not take into the consideration their social adaptability (Reynolds et. al., 1999), which significantly influences their experience of the depression. This has been demonstrated in the group A of the patients living in the retirement home. Mental stress, marital status, socioeconomic conditions, chronic illness and as well as the age are often the causes of the depression at the older age (Katona et at., 1997). Social isolation, placement into a new surroundings (retirement home), childlessness, evaluation of the meaning the life often lead to suicidal thoughts, and this is only a step from suicidal actions. This borderline is very unclear (Hoschl et al., 2002).
Conclusion Depression represents serious mental problem. It requires besides appropriate diagnostic measures also high quality and long term psychopharrnaco and psychotherapeutic approach (Briley et al., 1998). Active questions concerning the experience of the depression and suicidal thoughts will help us to intensify and improve the patients’ therapy. Intensive and fiddly work of the staff in the retirement home as well as the correct psychopharmacotherapeutic and psychotherapeutic approach to the gerontopsychiatric patients may significantly improve the quality of life and enhance the moments of the senescence. In conclusion we would like to thank Livia Lapšanská, the head nurse in the retirement home and as well as the actual inhabitants of this establishment in Banská Bystrica who have made possible to carry out this epidemiological investigation.
References Beekman A T, Copland J R and Prince M J:Review of community prevalence of depression in later life, The British Thum of Psychiatry,1999,174:307-311 De Beurs E,Beekman AT, Balkom AJ,Deeg DJ,R van Dyck,W van Tilburg:Consequences of anxiety in older persons:its effect on disability,well-being and use of health services,Psychol Med 1999, 29/3/:583-593 De Beurs E,Beekman A,Geerlings S,Deeg D ,R van Thick, W van Tilburg:On becoming depressed or anxious in later life-similar vulnerability factors, but different effects of stressful life events, The British Journal of Psychiatry, 2001,179:426-431 Božin A A:Ličnost i stres,osećaj koherentnosti i prevladavanja stresa u uslovima društvene krize,2001,Vršac, 251 Briley M, Montgomery SA:Antidepressant Therapy at the Dawn of the Third Millenium, Martin Dunitz LtD,1998,349:307-319,319-333 Filip V et al.: Praktický manual psychiatrických posudzovacich stupníc, 1997, 185:95-117 Hoschl C,Libiger J,Švestka J: Psychiatrie,2002,895:234-235,435-452,638-641 Jorm AF:Is depression a risk factor for dementia or cognitive decline? A review.Gerontology,2000,46:219-227 Kaarin J A,Luszcz AM: Mortality Risk Varies According to Gender and Change in Depressive Status in Very Old Adults,Psychosomatic Medicine, 2002,64:880-888 Katona C,Livingston G:Comorbid Depression in Older People,Martin Dunitz Ltd,1997,79 Mendes de Leon CF,Krumholtz HIVI, Seeman TS,Vaccarino V,Wiliams CS,Kasl SV,Berkrnan LF:Depression and risk of coronary heart disease in elderly men and women:New Haven EESE,1982-1991,Established Populations for the Epidemiologic Studies of the Elderly. Arch Intern Med., 1998,158:2341-2348 Montgomery SA Dunbar G:Paroxetine is better than placebo in relaps prevention and the prophylaxis of reccurent depression.Int Clin Psychopharmacol.,1993,8:189-195 Nutt D,Feeney A,Argyropolus S:Anxiety Disorders Comorbid with Depression:Panic disoorder and agoraphobia,Martin Dunitz Ltd , a member of the Taylor and Francis Group, 2002,108 Paykel ES :Continuation and maintenance therapy in depression, British medical Bulletin,2001,57:145-159 Reynolds CF,Frank E,Perel JM et al :Nortriptyline and interpersonal psychotherapy as maintenance therapies for reccurent major depression: a randomised controlled trial in patients older than 59 years.JAMA,1999,281:39-45 Rouillon F,Berdeaux G,Bisserbe JC et al: Prevention of reccurent depressive episodes with milnacipran consequences on quality of life, Jaffect Disord,2000,58:171-180 Wells KB, Stewart A,Hays RD,Bumam MA,Rogers W,Daniels M,Berry S,Greenfield S, Ware J: The functioning and well-being of depressed patients.Results from the Medical Outcomes Study, JAMA, 1989,262/7/:914-919 Zheng D,Macero CA, Croft JB,Giles WH,Davis D, Scott WK:Major depression and all cause mortality among while adults in the United Mates, Ann Epidemilo., 1997,7:213-218 100
Table 1 Group A 79.85 (67 – 90) females N = 10 out of 14
Average age Gender
Group B 66.85 (59 – 70) females N = 9 out of 14
*Group A= gerontopsychiatric patients placed in the retirement home *Group B= gerontopsychiatric patients living individually at home
Table 2 Marital status Single Married Divorced Widowed Total
Group A 2 1 2 9 14
Group B 0 7 3 4 14
Table 3 Present social conditions of the patient Excellent Good Poor Total
Group A
Group B
0 14 0 14
11 3 0 14 Table 4
Employment In the household Studying Manually non-qualified worker Manually qualified worker Clerk Clerk in leading position Disable retired senior Retired senior Other Total
Group A 0 0 0
Group B 0 0 0
0 0 0 0 14 0 14
1 0 0 0 13 0 14 Table 5
Degree of education Unfinished elementary school Elementary school completed, further not qualified
Group A 5 6
Group B 0 3
College diploma High school diploma University Other Total
2 1 0 0 14
6 5 0 0 14
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Table 6 Diagnose F.01 with symptoms of depression F.00.2 with symptoms of depression F.06.3 F.07 F.32 F41.2 Total
Group A 1
Group B 0
2
0
10 1 0 0 14
5 0 8 1 14 Table 7
Suicidal thoughts
Group A 5
Group B 6
Table 8 Evaluating scales GDS (geriatric depression scale) Beck’s selfevaluating scale of depression
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Group A 9.64 points=10 (5-14)
Group B 6.71 points=7 (0-11)
12.5=13 points (2-25)
8 points (2-17)
THE QUALITY OF LIFE IN PATIENTS WITH DEMENTIA OF ALZHEIMER’S TYPE LIVING IN OLD PEOPLE’S HOMES AND NURSING HOMES AUTHORS MUDr. Dana Ignjatović, 1 MUDr. Milan Ignjatović, 1 Mgr. Michala Knišková, 1 MUDr. Tibor Baška, 2 Dr. Silvia Beatriz Schweitzer, 3 Psychomed Svátosávsky, Banská Bystica, the Slovak Republic Institution of Epidemiology JLF, Martin, the Slovak Republic Buenos Aires, Argentina
Abstract: The quality of life of the patients with Dementia of Alzheimer’s type (DAT) in Old peoples’ homes and Nursing homes is determined by different factors, not only endogenous. Even though there is a documented impact on the quality of life of the patients, this problem is not closely monitored in our conditions and therefore we will focus on it in our work. Cognitive symptoms in dementia are rather frequently accompanied by anxiety, depression, delusions and hallucinations (Latas, 2003). One of the biggest problems in taking care of the patients with Dementia of Alzheimer’s type is just a problematic behaviour of the patients (not adequate verbal or motoric activity) (Stegaru, 2003). We have included 19 patients with the diagnosis of Dementia of Alzheimer’s type and 25 patients without a psychiatric diagnosis into the follow-up. All the patients were from two Old peoples’ homes and Nursing homes in Banská Bystrica and there was not a difference between the average age of the patients. The an of this study was to evaluate and compare the quality of life of the clients with Dementia of Alzheimer›s type and the clients without any psychiatric burden living in Old peoples› homes and Nursing homes in Slovakia. The results of this pilot study confirmed that the quality of life in patients with Dementia of Alzheimer›s type is lower compare to the clients without any psychiatric burden living in Old peoples› homes and Nursing homes. We have monitored and evaluated following scales and questionnaires in these patients: ADL - Activities of Daily Living IADL - Instrumental Activities of Daily Living CRICHT - Crichton Geriatric Rating Scale SLAG - Sandoz Clinical Assessment Geriatric Scale NOSGER- Nurse›s Observation Scale for Geriatric Patients There were significant differences except the mood in all evaluated items. The patients with the diagnosis of Dementia of Alzheimer›s type represented more severe patients in all these items whose self-sufficiency in ADL and IADL was lower compare to the patients without any psychiatric burden. In spite of the fact that we have excluded the patients with the severe form of Dementia of Alzheimer›s type from our follow-up, the entry score and results in an area of cognitive disorders, also the interpersonal relations and physical dysfunctions were worse in these patients. Better results were obtained in the clients without any psychiatric burden. In a part dealing with the apathy and in a part dealing with the mood there was not any significant difference which would prove the fact that even the clients without psychiatric burden living in an Old peoples’ home and a Nursing home are more frequently liable to depressive experience (anxiety, depressive mood and lack of motivation). This study represents a pilot study for other similar studies of this kind in Slovakia.
Key words: The quality of life in patients with Dementia of Alzheimer’s type and without any psychiatric burden in Old peoples’ homes and Nursing homes, ADL, IADL, CRICHT, SCAG, NOSGER.
Zero hypothesis: There is not any difference in the quality of life of the patients/clients with the diagnosis of Dementia of Alzheimer’s type (mild and moderately severe degree) and the clients without a psychiatric diagnosis living in Old peoples’ homes and Nursing homes.
Alternative hypothesis: Dementia of Alzheimer’s type is related to lower quality of life of the patients compare to the clients without any psychiatric burden who live in Old peoples’ homes and Nursing homes.
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Group of patients (Subjects): The dwellers of two average standard Old peoples’ homes and Nursing homes in Slovakia were included into the study; into the control study the clients were selected by the systematic selection according to an alphabetical list of the facility dwellers, the first twelve clients from one facility and the first thirteen clients from the other one. Because this was not a case of an invasive intervention which does not change the quality of life of the patients, the physician’s approval of the self-government for a follow-up conduct was not necessary. The patients agreed with the filling in the questionnaire implicitly. The information about the purpose, the paint of the study, assurance about the anonymity and observance of medical ecrecy within the study into which they voluntarily agreed to participate was a part of it. The xecutives of Old peoples’ homes and Nursing homes and head nurses, who actively articipated in a follow-up, agreed with the performance of the follow-up.
Inclusion criteria: mild and moderately severe degree of Dementia of Alzheimer’s type age over 65 years a patient capable of participation in a follow-up (questionnaires) and willing to cooperate placement of the patient in an Old peoples’ home and a Nursing home
Exclusion criteria: severe degree of Dementia of Alzheimer’s type other psychiatric diagnoses severe somatic illnesses
Used tests: ADL (Activities of Daily Living) IADL (Instrumental Activities of Daily Living ) CRICHT (Crichton Geriatric Rating Scale) SCRAG (Sandal Clinical Assessment Geriatric Scale) NOSGER (Nurse’s Observation Scale for Geriatric Patients)
Introduction: Alzheimer’s type of dementia belongs among the most frequent degenerative diseases of the brain (Smolik, 1996). It is also one of the most frequent cases of death. It is ranked on the fourth place after cardiovascular diseases, malignants and acute cerebrovascular accidents (Pidrman, Bouček, Látalová, 2003). And it is also becoming a severe medical and social problem. The most finances are used for the in-patient care of the demented patients. Supporting programmes for the care-givers of the patients with dementia, which arise in many centers specializing in diagnostics and treatment of cognitive disorders, are rather important (Kurz, 2003). The quality of life in a society is evaluated by several measures; one of them is also increasing average age of life and subsequently the number of inhabitants older than 65 years of age as well. With the increase of age there is also the increase in a risk of psychiatric disorders (cognitive decrease, depressive disorders, delirium, behavioral symptoms ...), as well as cardiovascular and neurological diseases (conditions after acute cerebrovascular accidents).Immobility of the patient and incontinence are often associated. This kind of patient is rather demanding as for the care, since considering the comorbidity he becomes the big burden for the care-givers. These patients often live in Old peoples’ homes and Nursing homes. As long as the care-giver or the relative of the demented patient is not educated enough, he can perceive the behaviour of the patient as rather disturbing, many times “as though he was doing the things on the purpose”- repeats the activities, he does not know what he was told a while ago, as soon as he finishes the breakfast he starts verbal attacks that he was not given anything to eat, he does not recognize his own partner, accuses his children that they took his money, messed up with personal things and clothes ... Even the least probable attacks of demented patient can be badly tolerated by the care-giver and also the relatives.
Results: We have included 19 patients with the diagnosis of mild and moderately severe degree of Dementia of Alzheimer’s type (DAT) into the pilot study. The control group comprised of 25 clients without any psychiatric burden. All of them represented the dwellers of the Old peoples homes and Nursing homes (OPS and NH). Because the clients were chosen from two average OPS and NH, a selected sample of people is possible to consider as a representative one. The age is one of the determinants of the quality of life, in a monitored sample there was not a difference between the average age in one and the other group, so it was not necessary to take into account a potential concurrent impact of the age. There were more women than men in both groups. In an evaluating scale ADL (Activity of Daily Living) more than 64% clients (i.e. 16 clients out of 25) without any psychiatric burden were
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completely self-sufficient (6b/6b). However, only 5 patients (i.e.25%) out of 19 with Dementia of Alzheimer’s type were totally self-sufficient. In an evaluating scale IADL (Instrumental Activities of Daily Living) only 3 clients (8b/8b) were fully sells-sufficient from the group without any psychiatric burden and none of the patients with DAT reached a complete self-sufficiency. 8 patients with DAT were not totally self-sufficient and none of the clients without any psychiatric burden. We have used a CRICHT scale (Crichton Geriatric Rating Scale) for an evaluation of the impact of the treatment on patients’ behaviour. This scale evaluates mobility, orientation, communication, cooperation, uneasiness, and self-service activities getting dressed and eating, incontinence,. sleep, and mood objectively and subjectively. 17 clients without any psychiatric burden reached the score value from 10 to 20 points which indicates a mild deterioration, only one client reached the score of 31 points which reflects a severe deterioration. In patients with DAT 8 patients reached the score over 31 points and only 6 patients had a score indicating a mild deterioration which would represent the fact that the patients with DAT have more problems with communication, are less mobile, suffer from sleep disorders and incontinence more often. Geriatric scale of the firm SANDOZ SCAG (Sandoz Clinical Assessment - Geriatric) is used especially in the in-patient conditions or facilities for pensioners with the aim of observing the changes in a course of therapy. We have assessed 5 monitored variables: cognitive disorders, interpersonal relations, mood, apathy and physical dysfunctions. In the first assessed item - cognitive disorders a significant difference appeared in both groups. Confusion reached moderate intensity in symptoms (3 out of 5 points) even in a group of clients without any psychiatric burden. In a second assessed item - mood - a significant difference did not appear between both groups which would indicate more depressive experience even in clients located in OPH and NH who are not psychiatrically cured. The lack of motivation and anxious experience were the most distinct within this item in both groups of dwellers from OPH and NH. In the third assessed item – apathy - there was present a significant difference between both groups. In the fourth item - interpersonal relations - there was also significant difference between both groups. The listlessness to the surrounding was the most substantial in the group of clients without any psychiatric burden. In the fifth assessed item - physical dysfunctions - a significant difference between both groups was also present. The last scale which we used was the NOSGER scale (Nurse’s Observation Scale for Geriatric Patients). This assessment was interesting in a fact that according to assessments of nurses the clients without any psychiatric burden spoke more frequently that they are sad, useless, were anxious at night, they repeated the same thought in conversations more often, looked sad or weepy, they were irritable or argumentative more often when someone asked them something, they were more aggressive (verbally and in an action as well), they were stubborn, did not care about the instructions or rules compare to the patients with DAT. The nurses agreed on the fact that both groups “look clean and tidy”. The patients with DAT left their rooms inappropriately dressed more often, had difficulties to shave and comb themselves without any help, did not pay attention to their interest and hobbies, did not even watch TV programmes, they got into touch with the persons in their surroundings less often Age comparison p=0,255253
There is not any difference between the average age in the 1. and the 2. group so it is necessary to take into account the potential concurrent impact of the age.
Evaluating scales
ADL
IADL
CRI
SCAG-KF
SCAG-IV
SCAG-N
SCAG-A
SCAGTD
Average of the 1. group
5,52
5,00
19,64
2,32
1,80
2,12
1,80
1,96
Average of the 2. group
4,16
2,95
30,16
3,58
2,79
2,74
2,63
2,63
Difference among the averages
1,36
2,05
10,5
-1,26
-0,99
-0,62
-0,83
-0,67
0,003708
0,00313
0,087398
0,025471
0,03971
(Students t-test) p= 0,003658
0,005501 3,11 E-05
.
Discussion: It is rather important and at the same time a difficult task to assess the quality of life of the patients suffering from DAT living in OPH and NH. The research of the quality of life involves conceptual and methodological challenges (Brod, 2003). It is important to answer the questions what quality of life actually is in demented patients, by which variables it is defined and characterized, what we perceive the most on the patient’s behaviour and what impact it has on the interaction between the patient with DAT and care-givers. Behavioral management of behavioral disorders in Dementia of Alzheimer’s type represents the most frequent intervention in a clinical practice. Disturbing behaviour is also a result of an interaction between the specific behaviour of the patient and a reaction of the care-givers (Lovestone, Gauthier, 2001). Such behaviour has an impact on the quality of life not only of the patient with DAT but also on his care-giver. There is a great number of studies that deal with the meaning of cooperation between the patient with DAT and a care-giver (Stegaru, 2003; Purandare, 2003; Wettstein, 2003). Bonnin - Guillaume (2003) suggested
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in their work that nurses were considerably tolerant against the agitated behaviour, and it did not get worse even in demented patients. A significant fact is that a physical and also verbal aggressive behaviour was worse tolerated in both groups of demented and non-demented patients. Even the lower quality of life was related to behavioral disorders. Rodriguez et al. (2003) addressed psychological and social aspects in a management of patients with DAT in their work. They carried out the studies among the care-givers of 120 patients with the diagnosis of Dementia of Alzheimer’s type in a period of time from January 2001 until December 2002. All of the care-givers responded to a 50-item questionnaire related to social characteristics of the patient’s family, family relationships, private and public health care and a family psychological distress. Problems with the sleep, anxiety and depression depended on the quality of life of the patients with DAT. In another study by Novell et al.(2001), they compared the assessment of the quality of life in a sample of 76 patients with DAT, as it was assessed by themselves and their relatives though 17-item Duke profile of health. This study is an important source of information about the quality of life of the patient with DAT. Statistically significant differences were recorded in the main score in some dimensions where the patients and their relatives talked about lower quality of life which similarly came out in our studies, although we have used other evaluating scales for this assessment. Another works of Wimo, Winblad a Grafstrom (1999), referring to social consequences of DAT and a long term-care, show that dementia represents a future problem and that the average age is increasing along with the number of patients with DAT. Tereza González - Salvator et al. (2000) were engaged in the quality of life in demented patients in a long-term care, 32 nurses were asked about the quality of life of 120 patients in a long-term care who met with the diagnostic criteria of DSM-IV for dementia. Hospital physicians revealed better quality than they expected (assumed). Tereza González Salvator et al. (2000) report that interventions which could improve better orientation, physical capabilities just like cholinomirnetic treatment does, psychosocial intervention or behavioral strategies could also be in a future research on the quality of life. A rather interesting study was carried out in England where the authors focused on the quality of care provided for the patients with dementia. The aim of the study was to review the experience with a temporary care of the persons with dementia who lived in small groups in six Old peoples› homes run by two large voluntary organizations in England. The methodology of Dementia Care Mapping (DCM) was used for detection of the feeling of well-being, health in persons with dementia and for investigation of the range of their psychosocial needs dementia mapping included monitoring of the quality and also the quantity of behaviour (Innes, Surr, 2001). This work is inspiring also for other works in Slovakia, and it confirms that the behaviour of the demented patient significantly influences his quality of life and it significantly affects care-givers of the demented patients as well. Jason Karlawish et al. (2001) compared global quality of life of the patients with DAT in their work by using of the direct and substitute appraisal of the quality of life of the patients and their guardians. 20 patients with moderately severe and 11 patients with mild Dementia of Alzheimer’s type were included into the follow-up. Nearly half of the guardians of the patients with DAT reviewed the quality of life in a different way compare to the fact how it was expected among the patients. We have focused in our work on the assessment of the quality of life of the patients with DAT living in Old peoples’ homes and Nursing homes. We have used different scales. The NOSGER scale, the results of which we have already described, was among them. Validity and reliability of the NOSGER scale (Nurses Observation Scale for Geriatric Patients) were described by Wahle, Haller a Spiegel (1996) in their work. They portray the purpose of the NOSGER scale filled up by the nurses or care-givers. It works with daily behaviour of geriatric patients with the emphasis on 6 subsequent areas (dimensions): memory, instrumental activities of daily living (IADL), ordinary daily activities (activities of daily living - ADL), mood, social behaviour and intrusive behaviour. We have focused just on these areas in our study. Presented validity study comprises of 50 healthy elderly subjects, 25 patients with moderately severe dementia, 25 patients with progressing dementia and 25 elderly patients with depression. NOSGER was filled in by the persons living at home together with the patient, their guardians or a nurse in an institutionalized facility. The values between rtt=0.68 and rtt=0.89 (all p were smaller than 0.001) were found, detected in all six dimensions within NOSGER, the values were higher for cognitive dimension (memory, IADL, ADL) compare to non-cognitive dimensions (mood, social and intrusive behaviour). Retest reliability (stability) had a bit higher cognitive dimension NOSGER (memory rs=0.91, IADI, rs=0.92, ADL rs=0.88, p smaller 0.001) compare to noncognitive dimensions (mood rs=0.85, social behaviour rs=0.87, intrusive behaviour rs=0.84, p smaller 0.001). All of these values meet the degree rtt bigger or = 0.80, required in a deviation of psychomotoric standards (Whaled et at, 1996). Brunner and Spiegel (1996) show the NOSGER scale in their work, and also Calabresse, Essner, Forstl (2005) transparently present the NOSGER scale after 3 and 6 months of a treatment with memantine. The quality of life of the patients with DAT depends mainly on pharmacotherapeutical possibilities (Gauthier, 2001) but also on associated somatic illnesses, on a progression of DAT, intrusive behaviour and ordinary daily activities as well (Walker et al., 1998; Salek et al., 1998). The quality of life of the patients with DAT living in OPH and NH is affected mostly by us - medical doctors, nurses and care-givers who have to cope with the biggest burden of care and this care is based on deep moral and ethical principles, or as Stephen G. Post (2001) says – the quality of life is described as a basic principle of love and without it this work is not possible to carry out.
Conclusion: The quality of life of the patients with Dementia of Alzheimer’s type is lower compare to the clients without any psychiatric burden who live in Old peoples’ homes and Nursing homes.
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Cognitio, Behavior and Social Performance in the Elderby. 2004 Lovestone S, Gauthier S. Managment of Dementia. 2001; 161: 73-109 Michel JP, Gold G. Quality of the End of Life of Demented Patients Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Murnenthaler M, Mattle H. Neurologie. Grada Publishing, spol.s r.o. 2001; 625:67-74 Murphy GM. Inflammation and the Pathophysiology of Alzheimer’s disease. Dialogues in Clinical Neuroscience. 2000; Vol.2, No.3. 233-239 Newcomer JW, Farber NB, Olney JW. NMDA Receptor Function, Memory and Brain Aging. Dialogues in Clinical Neuroscience. 2000; Vol.2, No.3, 219-232 Novella JL, Jochum C, Jolly D, Morrone I, Ankri J, Bureau F, Blanchard F. Aggreement between patients’ and proxies’ reports of quality of life in Alzheimer’s disease. Quality of Life Researche 10; 2001 443-452 Papassotiropoulos NA. Cholesterol-Releted Genes and Risk for Alzheimer’s Disease. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Pidmen V, Bouček J, Latalová K. Léčba demence inhibitory cholinesteráz-bezpečnost a snášenlivost v praxi. Neurológia pre prax. 2003/5.254-257 Pietila S. Aging with One’s Native Language: A Study on Sweden - Finns Suffering from Dementia in a Nursing Home in Sweden. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Purandere NB, Ramchandran R, Hendry AM, Burns A. Positive Aspects of Caring for People with Dementia. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Ray 0. Aging, Getting Older, MCI, and Alzheimer’s disease: How Best to Measure? Europian Regional Meeting Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Rodrigez G, Leo D.Dc, Ginlre N, Vitali. P, Grossi E, Nobili F. Psychological and Social Aspects in Managment of Alzheimer’s patients: an inquiry among caregivers. Neurol Sci 2003; 24: 329-335 Ružička E. Diferenciálni diagnostika a léčba demencii. Príručla pro praxi. Galén, 2003; 173 Salek SS, Walker MD, Bayer AJ. A Review of Quality of life in Alzheimer’s Disease. Pharmacoeconomics 1998; 613-626 Stegaru AE, Dorenlot P, Henrard JC, Ankri J. Relationship Between Mood Condition, Cognitive Impairment and Problematic Behavior in Alzheimer’s Disease. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Tibaldi VM, Aimonimo N, Ponzetto M, Stasi MF Amati D, Raspo S, Fabris F. Patients with Advenced Dementia and Behavioral Problems. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby. 2004 Wahle M, Haller S, Spiegel R. Validation of the NOSGER (Nurses’ Observation Scale for Geriatric Patients): reliability and validity of a Caregiver rating Instrument. Int Psychogeriatr.1996 Winter;8 (4):525-547 Walker MD, Salek SS, Bayer AJ. A Review of Quality of Life in Alzheimer’s Disease. Pharmacoeconomics 1998; 499-530 Wimo A, Winblad B, Grafstorm M. The Scial Consequences for Families with Alzheimer’s disease patients: Potential Impact of New drug Treatment. International Journal of Geriatric Psychiatry. 1999;338-347 Wesnws KA. The Value of Assessing Cognitive Function in Drug Development. Dialogues in Clinical Neuroscience. 2000; Vol. 2, No.3, 183-197 Wettstein A, Konin’ g M. Willingness-to-Pay fer Dementia Therapy: Differences Between Patients and Caregivers. Europian Regional Meeting. Program and Abstract Book. Cognitio, Behavior and Social Performence in the Elderby 2004 Zanetti 0, Trabucchi M, Bosch G, Tonini G. Alzheimerova choroba. Ako žit› d›alej ? Nadácia Neuroimunologické centrum pre výskum Alzheimerovej choroby. Bratislava 1998. 107
COMPARISON OF GALANTAMINE AND RIVASTIGMIN EFFECTS 12-MONTH STUDY AUTHORS Dana Ignjatovičová, MD ,Milan Ignjatovic ,MD Non Governmental Psychiatric out Department,Jasenova 1, 974 01 Banská Bystrica, Slovak republic In our paper we concentrated on a 12-month monitoring of cognitive functions in patients with dementia of Alzheimer›s type, using a MMSE test /Mini Mental State Examination/. In a group A patients were selected who were receiving galantamine 8 mg two times a day /Female N1 = 9/ and an average age was 75.6 year and an average duration of disease 1.06 year. In a group B there were 16 pacients selected who received rivistigmine 6 mg two times a day /Female N2= 12/, an average age was 77.6 and an average duration of disease was 1.4 year. All the patients met all the ranking criterions for Alzheimer›s type of dementia. We recognized that the results of MMSE in the first month of dosage titration were co-equal /20.65 points in a group A and 20.125 points in a group B/; in the 3td month after finishing titration phase in both groups we experienced gentle decrease of MMSE /16,68 points/ in the group E patients receiving rivastigmine compared to the group A /22,56 pointst patents receiving galantamine. In the 12th month of monitoring there was no significant change in MMSE score, and we consider the status in both group as stabilized. No patient had the cholinesterase inhibitor discontinued due to any side effects of the drug /Pidrman, 2003; Svestka, 2001; Cummings, 2003/, however, there were some gastrointestinal difficulties /nausea, lack of appetite, „/ reported while receiving rivastigmine, what was solved by an extention of drug titration phase. In the group A: patients receiving galantamine, there were 8 patients having a caregiver and the same number was reported in the group B: patients receiving rivastigmine.
Study Goal To compare galantamine and rivastigmine effects in the treatment of mild to moderately severe Alzheimer›s type of dementia in a 12-month monitoring, using Mini Mental State Examination /MMSE/ to register possible undesirable drug effects that could cause the treatment stoppage, disease lasting before diagnosing and a caregiver presence in family /improvement or deterioration of patients self-containment/.
Conclusion: In our study we monitored and compared effects of galantamine and rivastigmine in 32 patents for 12 months. Both drugs appeared to be effective with a satisfactory degree of safeness and tolerability, though there were some deviations in MMSE tests during a long-term monitoring pro bono galantamine.
References: Andreasen NC. Brave New Brain, Conquering Mental Illness in the Era of the Genome, 2001, 345:253-314 Giacobini E: Management of Behavioral Symptoms with Cholinesterase Inhibitors, 12th International Psychogeriatric Association Congress, Geneva, 2003 Giannakopoulos P, Hof PR, Vallet FG, Giannakopoulos A-S, Charany Y, Bouras C: Quantitative analysis of neuropathologic changes in the cerebral cortex of centernarians, Prog. Neuro-Psychopharmacol. And Biol. Psychiatr. 1995, Vol.19, pp577-592 Hales RE, Yudifsky SC, Talbott JA: Textbook of Psychiatry, The American Psychiatric Press, 2nd Edition, 1994, 1608:327-347
Summary In last years Alzheimer’s dementia have changed from the ignored and hardly eligible part of neurology and psychiatry and became their key section /Lovestone, 2001/. In our paper we concentrated on a 12-month monitoring of cognitive functions in patients with dementia of Alzheimer’s type, using a MMSE test /Mini Mental State Examination/. In a group A patients were 16 patients selected who were receiving galantamine 8 mg two times a day /Female N1 = 9/ and an average age was 75.6 year and an average duration of disease 1.06 year. In a group B there were 16 patients selected who received rivistigmine 6 mg two times a day /Female N2 = 12/, an average age was 77.6 and an average duration of disease was 1.4 year. All the patients met all the ranking criterions for Alzheimer’s type of dementia. We recognized that the results of MMSE in the first month of dosage titration were co-equal /20.65 points in a group A and 20.125 points in a group B/; in the 3rd month after finishing titration phase in both groups we experienced gentle decrease of
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MMSE /16,68 points./ in the group B: patients receiving rivastigmine compared to the group A /22,56 points/: patients receiving galantamine. In the 12th month of monitoring there was no significant change in MMSE score, and we consider the status in both group as stabilized. No patient had the cholinesterase inhibitor discontinued due to any side effects of the drug /Pidrman, 2003; Svestka, 2001; Cummings, 2003/, however, there were some gastrointestinal difficulties /nausea, lack of appetite, .../ reported while receiving rivastigmine, what was solved by an extention of drug titration phase. In the group A: patients receiving galantamine, there were 8 patients having a caregiver and the same number was reported in the group B: patients receiving rivastigmine.
Introduction “Dementias are the aging problem. They are like a ticking time bomb” /Andreasen, 2001/ Gerontopsychiatry is a part of medicine centered on prevention, diagnostics and treatment of somatic and psychic disorders in elder age. It is the fastest growing area of psychiatry and in 1989 it was officially declared as a subspecialization in the USA - American Board of Psychiatry and Neurology /ABPN /Kaplan, 1991/. “Geriatric” comes from the Greek “geras” meaning an old age, sear and “iatros” meaning medicine, clinical, “geriatric” means a medical treatment or health in elder age /Kaplan, 1991/. Pathogenesis of Alzheimer’s disease is unclear and one of the risk factors of Alzheimer’s disease outset is age /Giannakopoulos, 1991/, gender, some researches expect higher prevalence of Alzheimer in women, lower education, and also neurotoxicity of some elements; for example aluminum and iron /Bouras, 1997/. Another risk factor is a familiar form of Alzheimer’s disease - changes on chromosome 14 and 21; risky is also middle age of people with Down’s syndrome, which manifests as a progressive dementia. Another further risk factors are head injuries /Cummings, 20031. Alzheimer’s disease is a characteristic example of a cortical dementia /Hales, 2002/. Gianakopoulos et al. looked for the neuroanatomical correlates of visual agnosia in Alzheimer’s The treatment of Alzheimer’s dementia consists of 4 main parts: Disease modifying treatment, that leads towards the progression of Alzheimer’s disease reduction / antioxidants: aipha-tocoferol and selegilin/. Cholinesterase inhibitors for improvement, stabilization and reduction of cognitive functions declination /Cummings, 2003; Pidrman, 2003/. There are 4 acetylcholinesterase inhibitors known - tacrin /Cognez/ - not used in Slovakia due to its hepathotoxicity, denepezil /Aricept/, galantamine /Reminyl/ and rivastigmine /Exelon/. While in Slovakia the cholinesterase inhibitors are registered for Alzheimer’s disease treatment only, according to some studies they could be used for other dementias with a cholinergic deficit as well - such as the dementia with Lewy’s bodies, Parkinson’s disease with dementia /Assal, 2003/. Alzheimer’s disease with a cerebrovascular illness and a vascular dementia /Cummings, 2003/. There is a new product on the market, memantin, which is registered in Slovakia from the 1st July, 2004 and does not belong to the cholinesterase inhibitors /Pidrman, 2003/. New possibility of Alzheimer’s disease treatment is a p-peptid immunization that is still in a research process. Paradoxically, this treatment is based on the immunization with pathological p-amyloid peptid /A beta/ with the scope to start the immunized response against the amyloid plaques in the brain /Schenk, 2000/. Psychotropic agents used for the treatment of behavioral disorder with neuropsychiatric symptoms /Finkel, 1996/, i.e. risperidon, olanzapin, …/Cummings, 2003; Katona, 1997; Svestka, 1998/. Treatment of depression is very important for Alzheimer’s disease /Verhey, 2000; Bums, 1991/. Work with the caregivers on their emotional needs saturation and on the alliance improvement of the care optimalisation for Alzheimer patients /Cummings, 2003/. Ginkgo Biloba plays an important role in cognitive functions improvement /Patocka, 2001/. Treatment based on cholinesterase inhibitors could be split up in stage of titration acute stage, the aim is to achieve a basic therapeutic dosage, with a 4-week basic titration interval; titration is necessary for both rivastigmine and galantamine. Second stage of Alzheimer’s dementia treatment is a long-term /therapeutic stage, achieved therapeutic dosage is applied for a long period /Pidrman, 2003/. Galantamine is a cholinesterase inhibitor with a dual effect mechanism, an inhibitor of acetylcholinesterase and alosteric modulation of nicotine receptors /Lovestone, 2001 1. Rivastigmine is a combined acetylcholinesterase and butyryleholinesterase inhibitor. Rivastigmine, unlike donepezil and galantamine, has no significant risk of metabolic interactions. Possible level oscillation consequent on the short half time is corrected by the pseudoireversible inhibition which takes 1012 hours /Pidrman, 2003/.
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Study Goal To compare galantamine and rivastigmine effects in the treatment of mild to moderately severe Alzheimer’s type ofdementia in a 12-month monitoring, using Mini Mental State Examination /MMSE/ to register possible undesirable drug effects that could cause the treatment stoppage, disease lasting before diagnosing and a caregiver presence in family /improvement or deterioration of patient’s self-containments/.
Study Design Galantamine and rivastigmine are registered for the treatment of mild to moderately severe Alzheimer’s type of dementia and both have a significant clinical effect as well as a good safety and tolerability attested in many long-term clinical studies and post-marketing studies.
Group and Methodology There were 32 patients that fulfill the criterions who were included into a 12-month study. Group A was formed from 16 patients receiving galantamine 8 mg twice a day and Group B was formed from 16 patients receiving rivastigmine 6 mg twice a day. We administered MMSE /Mini Mental State Examination/ with patients on the 1st day, after 1st month, after 3rd month, after 6th month and finally after 12th month of the galantamine or rivastigmine treatment. The overall clinical improvement was measured by CGI /Clinical Global Impression Test/.
Inclusion criterions ICD 10 and DSM-IV diagnostic criterions of diagnosis of mild to moderately severe Alzheimer’s type of dementia Age above 65 Presence of BPSD /Behavioral and Psychological Symptoms of Dementia/ No previous receiving of galantamine, rivastigmine and donepezil before joining our study
Exclusion criterions other neurodegenerative diseases multiinfarction dementia and clinically active cerebrovascular diseases delirium and other consciousness disturbances dependences schizophrenia and schizophrenic disorders serious somatic diseases of cardiovascular system, kidneys and liver
Results Our results are summarized in Figure 1 and Figure 2 Figure 1 Patients’ Profile Group Age
A /galantamine/ N1=16 75,6
Gender Duration of disease before
B /rivastigmine/ N2=16 77,6
Female = 9 1,06
Female = 12 1,4
diagnosing (in years) Caregiver presence in family /patients self- 8 containment/
8
Figure 2 Comparison of MMSE /Mini Mental State Examination/ during a 12-month monitoring MMSE /0/ 1st day
Group /Exami-nation Month/ A /gala-ntamine/ N1=16 17,18
B /rivasti-gmine/ N2=16 18,375
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MMSE /1/ After 1st month
MMSE /3/ After 3rd month
MMSE /6/ After 6th month
MMSE /12/ After 12th month
20,68
22,56
23,18
23,80
20,125
19,687
20,25
20,56
Discussion In Alzheimer’s disease there is a severely affected area of central acetylcholinergic system that is important for memory and a qualitative consciousness level. For dementia treatment the cognitives are stated, in Slovakia we have three acetylchotinesterase inhibitors available /rivastigmine, donepezil and galantamine/. Rivastigmine inhibits the brain acetylcholinesterases and also butyrylcholinesterases / Jirak, 2003/. In our study we concentrated on the comparison of galantamine and rivastigmine effects during a 12- month MMSE test monitoring. We decided upon the fact that there is a few researches of this type only and more attention was paid to the observation of donepezil and rivastigmine effects in patients with moderate Alzheimer’s type of dementia /Wilkinson, 2002/. In this 12-month study donepezil was tolerated better and both drugs /donepezil and rivastigmine/ showed similar effect on the cognitive functions improvement. At 41st Annual Meeting of ACNP /American College of Neuropsychopharmacology/ in Puerto Rico in December 2002 there were results of a donepezil and galantamine 52-week monitoring presented. The results were analyzed using MMSE and ADAS-cognition. The analysis showed that the patients receiving galantamine had better profile of cognitive functions improvement in comparison with those receiving donepezil, while the safeness and tolerability was similar for both groups /Bullock, 2002/. On the 6th Congress of European Federation of Neurological Institutes in October 2002, held in Austria, Tryen et al. presented preliminary analysis of higher galantamine effect on concentration and MMSE in comparison with donepezil during a 52-week monitoring. McKeith et al. presented a one-year comparative study of galantamine /24 mg/day/ and donepezil /10 mg/day/ and both drugs showed a significant clinical effect and a fair degree of safeness and tolerability /McKleith, 2003/. Most of the comparative studies we had available were realized with a participation of pharmaceutical companies producing acetyicholinesterase inhibitors and concerning this aspect it seemed to be necessary to verify the results on our own monitored patients group. Our group of patients was quite small /32 patients/ what we consider to be a deficiency of our study, but a long term monitoring in ambulatory conditions is rather difficult. Irrespective of studies supported by pharmaceutical companies we made certain of the good efficiency and tolerability of both galantamine and rivastigmine. For none patient we had to discontinue a drug due to side effects, however during rivastigmine receiving we noticed some gastrointestinal difficulties / nausea, lack of appetite.../, what we solved by extension of drug titration phase. Patients included into our study fulfill the criterions for an Alzheimer’s dementia diagnosis and had a comparable basic characteristic /age, gender, MMSE score of the lst day of monitoring/. After a one-month monitoring there was no difference in MMSE, in the 3rd month the MMSE score improved with patients receiving galantamine /from 17,18 points to 22,56 points/ and declined in a group of patients receiving rivastigmine 0,43 point what could be caused by a significant drop of MMSE score in a patient with aggravated somatic state with dehydration but without hospitalization and retirement from the study. There were no statistically significant differences between patients receiving galantantine and rivastigmine in neither 6th nor 12th month score, however more side effects were found in analysis of patient receiving rivastigmine. Both drugs appeared to be tolerated well and effective during a 12 months long-term monitoring.
Conclusion: Alzheimer’s dementia represents a serious medical problem of latest years. It is not only a disease of individuals but it also affect the whole community /Koukolik, 1999/. In our study we monitored and compared effects of galantamine and rivastigmine in 32 patients for 12 months. Both drugs appeared to be effective with a satisfactory degree of safeness and tolerability, though there were some deviations in MMSE tests during a long-term monitoring pro bono galantamine.
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POUŽITIE MOBILNÉHO TELEFÓNU AKO POMOCKY PRI PANICKOM ZÁCHVATE (USE OF MOBILE TELEPHONE DURING PANIC ATTACK) AUTHORS MILAN IGNJATOVIC DANA IGNJATOVIC PSYCHIATRIC NON GOVERNMENTAL PSYCHIATRIC OUT CLINIC, CESTA K NEMOCNICI 1,97401 BANSKÁ BYSTRICA, SLOVAK REPUBLIC
SUMMARY Anxiety disorders together with depressive disorders are one of the most frequently diagnosed disorders. Very often mimicking somatic disorders, since the intensity of symptoms of cardiovascular, gastrointestinal, respiratory and vegetative systems is not insignificant and very often the psychiatric consult the very last one requested - frequently leading to demoralization of patients. In our research we have selected, from the group of patients with anxiety disorder, those meeting the criteria for panic disorder and agoraphobia with panic disorder, where panic attack represents acute phase of the disorders which must be addressed.. In the file of first-time examined 72 patients /51 females/, of average age 39 /females 41,5/ we have monitored and recorded number of all calls by patients to mobile phones of two physicians - psychiatrists, 24 hours a day, for 18 months. Most patients called in the first month of therapy /26 calls/ and in the second month 20 patients, while in the subsequent months only 2 patients called - in the third month of therapy. Patients with other disorders did not call at all. We have demonstrated that mobile phone can be a good panic tool, which enables remote management of acute anxiety disorders, without risk of addiction which could result in frequent and pointless phone calls to physicians.
KEY WORDS Panic attack, panic tool, mobile phone
INTRODUCTION Agoraphobia with panic disorder is one of the most frequent and relatively well defined anxiety disorders. Vegetative system manifestations include abdominal and chest discomfort and symptoms related to mental condition /dizziness, fainting, unrest, vertigo, derealization, depersonalization/ /Smolik, 1996/. In 1895 first detailed definition of panic attack was coined by Freud as “fear neurosis”. Later on - during the first world war Freud says the following about conflict and consciousness: “I think that philosophers think too philosophically and take little notice of primary motives. Therefore I would like to limit and correct the statement: ancient man triumphed over the enemy’s dead body without troubling himself about the mystery of life and death. Human thinking was not brought about by any intellectual mystery nor death, but by emotional conflict caused by death of beloved person who at the same time were foreign and hated. Concsciousness was born of this emotional conflict”/Freud, 2003/. The present article discusses conflicts that may exist in any one of us and especially in our patients with anxiety disorders. Through development of sciences, biological causes of anxiety disorders were sought in addition to psychological ones. At the beginning of the last century, an important role in origination of mental disorders was attributed to the axis - sympathetic system-adrenal glands (core) /Cannon, 1932/. Selye’s arrival on the scientific stage has brought further biological explanations to mental disorders and triggering factors, using the term “stress” for the first time. /Selye,1950/. Stress is defined as general psycho-biological response of an organism to the action of any extrinsic and/or intrinsic stressor, significantly affecting the homeostasis and causing general adaptive reaction. Individual components of this general adaptive reaction affect each other. Their complex interaction is realized through bidirectional processes and mechanisms between psycho-neural, endocrine and immune systems. New bio-psycho-social /Engel, 19801, later on holistic models /Goodman, 1991/, multidisciplinary and interdisciplinary approach to research of stress - psycho-neuro-endocrino-immunology /Ader, 1992/ bring better explanation to complex processes involving stress and mechanisms through which they are expressed. Selye divides stress into eustress and distress, discovering that general adaptation syndrome has three successive phases: alarm phase, resistance phase, and exhaustion phase. According to our experience, our patients present at our offices with mental difficulties in the second or third phase. Most of the patients are also defined by “learned helplessness” /Seligman, 1968/. Through animal experiments /Henry, 1977/ the authors attempted to find out which system becomes activated in aggressive and which in submissive subject. They have found that in aggressive subjects the sympathetic- adrenal (adrenal gland core) axis is activated and in submissive subjects - hypothalarnic-pituitary-adrenocortical axis is activated - with serious consequences brought about by high cortisol levels. For our practice it is very important to know how to help people suffering from anxiety disorders, based on bio-psychosocial model /Engel, 1980/. Therefore we have to know the other /psychosocial/ aspect, in addition to biology and basics of 112
neurophysiology and psycho-pharmacology - i.e. suppression of patient “demoralization” /which is usually neglected by standard medicine/, as well as social assistance and support. Various techniques were developed from psychotherapy through social assistance and support, such as “model of calm behavior which could be imitated”/Bandura, 1977/. In anxiety disorders, especially agoraphobia with panic attacks, it is necessary to know that that the patients have their panic partners and panic accessories /Erič, 1991/. Panic partner is one of the close relatives /spouse, children, parents../ and panic tool can be anything that enables the patient to better survive the panic attack and elusive agoraphobic behavior. Erič describes various accessories, including chewing guru, dark sunglasses, walking cane, dark clothing, even close proximity of one’s bed /Erič, 1991/. Current therapeutic modalities - in addition to modem psycho-pharmacotherapy such as by mirtazapine /Sarchiapone, 2003/ and psychotherapy - individual dynamic short-term psychotherapy, eclectic short-term psychotherapy according to Wolberg /Flegenheimer, 1982/, -include latest state-of-the art technology, which does not even resemble anything which could be used as panic tool. Opposite is the truth - as demonstrated by the present article, where mobile telephone was used as panic tool.
METHOD AND DESCRIPTION OF THE FILE This is a pilot study. The file consisted of 72 patients, who met the diagnostic criteria according to ICD-10 and DSM-IV for agoraphobia with panic disorder F.40.01 and panic disorder /episodic paroxysmal anxiety/ F.41.0. Each one of the primary patients received a private phone number to mobile phone of their attending physician - psychiatrist. We have assessed patient’s age, sex, education, social and financial status, family status API questionnaire was used /acute panic inventory test/ - not included in the Results. Over 18 months we assessed the number of phone calls in the first month, second month and during the remaining months of treatment. The presentation includes assessment of pharmacotherapy of the patients under survey.
Inclusion criteria: Age above 18 years Agoraphobia with panic disorder Panic disorders Patients examined at our offices for the first time - since July 1, 2002 Panic tool - patient’s own mobile phone
Exclusion criteria: Other psychiatric diagnoses Co-morbidity with other mental disorders Patients included in dispensary care
PURPOSE OF THE STUDY: to monitor the number of phone calls to mobile phone /panic too/ during first, second month of treatment and thereafter assess social-economical and matrimonial status of the patients list all medicines used to treat the disorder
ZERO HYPOTHESIS: Mobile phone cannot be used as panic tool
RESULTS: The results of our survey failed to confirm the zero hypothesis, mobile phone was shown as suitable and very effective panic tool used by patients suffering form panic disorder and agoraphobia with panic disorder. 72 patients were included in the survey - according to inclusion criteria for diagnosis of panic disorder and agoraphobia with panic disorder / males N=51 /average age 39 /females N=41,5 years/ see table 1. All patients were examined at our offices (2) since July 1, 2002. Overview of diagnoses - see table 2, whereas anxiety disorders were diagnosed in most patients examined at our offices for the first time /139 patients/. Education, social-economical and matrimonial status - see tables 3, 4, and 5. The more important finding is that mobile phone can be used as a very effective panic tool, as demonstrated by the finding that highest frequency of calls was during first month - 26 patients /females=14/ and during second month - 20 patients /females = 11/, then in the following month only two men called in the third month of monitoring. None of the patients with other diagnoses called /table 6/. 113
Medicine used most frequently to treat agoraphobia with panic disorder and panic disorder was paroxetine in average dose of 20 mg per day - in combination with anti-anxiety drug, sertraline in combination with anti- anxiety drug in 15 patients - dosage 100 mg per day and citalopram - 20 mg per day - in 12 patients. Overview of drug therapy - see table 7.
DISCUSSION: There is no life without stress /Kaličanin, 2001/. At the beginning of the last century Walter Cannon /1932/described the “fight or ran” reaction and found out that this reaction is controlled by sympathetic-adrenal axis /adrenal core/. Several decades later Hans Selye described stress as being caused by hyper-activity of the hypothalamic- pituitary-adrenocortical axis and hypertrophy of adrenal cortex, atrophy of thymus and peptic ulcers as a result of increased cortisol levels in experimental animal subjects /Selye, 1950/. Further research. focused on psycho-immunology /Gorman, 1986/, later on psycho-neuro-enclocrino-immunology /Ader, 1992/. In 1980s great development in medicine and research was brought about by bio-psycho-social model /Engel, 1980/ and holistic approach in 1990s /Goodman., 1991/. Based on the above theories, a lot of scientists and modem authors attempted to unify in their works the effects of psychosocial stress factors on bio-psycho-social changes in patients, including structural changes as well as emotional life and behavior of the patients. Unfortunately in our practice we often meet patients, who are demoralized by exhausting visits of specialists and due to poor condition of social institutions and lack of funds. Social support and assistance is at the minimum level. Therefore more emphasis is placed on psychiatric care which is becoming a social buffer (as demonstrated by management of psychiatric patients by general practitioners). All psycho-social stressors - beginning from leaving home, completion of school, birth of a child, divorce, through loss of employment - have negative effects on somatic as well as psychiatric patients. Selye himself maintained that genetic pre-disposition, stressing factor and personality structure have significant effect on further development of the disorder. Two cardiologists - Friedman and Rosenman attempted to define personality type A which is most often affected by cardiovascular disorders /Friedman, 1971/. Their efforts were not useless, and it helped other researchers to bring system to their work. Similar to situation in cardiology also in psychiatry we meet with genetic pre-dispositions, psycho-social stress and personality structure with mutual interactions. Very frequently the psycho-social stressor lies hidden in the patient’s history - related not only to the events of the previous day or year. Very often this involves death in the family, followed by fear of death, which is a part of the panic attack, partner’s infidelity followed by failure of adaptive capabilities of the organism. In relation to personality structure, this is dependent or anxiety personality disorder. An interesting model was proposed by Aron Antonovský /Antonovsky, 1995/ and his general resources of endurance, pointing out the fact that great majority of people will not be affected by a certain type of disorder, focusing on health and not on disease. One of his results is that people who are resistant to stress, say that it is worth living /Božin , 2001/. If we take into consideration everything that was written and our practical experience, we can say that most of our patients is «demoralized» - which is defined as a complex of destructive postures and emotions, as the condition of mind, accompanied by anxiety, depressive feelings, loss of sell-confidence, self-respect, feeling of hopelessness, isolation, inability to directly confront the new situation /Kaličanin, 2001/. In our practice we meet more and more of such first-time patients. The present article does not attempt to state all reasons why this is so, however one of the reasons is the lack of time devoted to patients by their physicians. For the first time I have encountered the term “moral” at Hopital Universitaire de Geneve, where I worked, and this is one of the reasons that inspired me to write this article. Another inspiration came from patients complaining of palpitation, breathing difficulties - attributed to mobile phones in their left breast pocket. Obviously we must not forget the effects of modern technology, but similar to computer tomography /CT/, magnetic nuclear resonance /MRI/, spectrophotometry /SPECT/, mobile phones are becoming a part of modern medicine. Many times they are used to save lives - for example to call for medical assistance after traffic accident, best way to describe this however, is in form of a case report - and we would find that mobile phone can be a good panic tool, enabling expedient and efficient management of acute anxiety attack, inform the patient and advise on how to manage the panic attack quickly and efficiently. It is also a method of social support, for which there is a permanent lack of funding in this country. All parties can save money in the end - including HMOs (medical insurance companies, since such interventions are of great benefit to patients - they don’t have to visit emergency room, they don’t have to be hospitalized. Our pilot study has shown that most patients called the mobile phone numbers of two physicians 24 hours a day for 18 months, most frequently in the first and second month of the treatment. Frequency after second month was significantly reduced or nil /only 2 patients in the third month of treatment/. This shows that psychological support and help is effective if its given when patient needs it - in acute phase of panic attack - leading to significant cost savings in indirect treatment costs..
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Within modem short-term dynamic individual psychotherapy Walberg supports the eclectic model, i.e. use hypnosis to get to deeper unconscious contents, as well as psycho-educational tools - video tapes and audio tapes fore relaxation. This model is very familiar to us, therefore if we want to really help the patient, 2-3 pills are not enough, we must attempt to prevent “Demoralization” of the patient, to develop major effort to ensure social support and assistance to patients. We opened the article by Freud’s words and we will conclude by his words as well: “… none of our instincts believes in death. Anxiety caused by fear of death which affects us more frequently than we think is, however, something secondary, usually arising from feeling of guilt...
CONCLUSION Mobile phone is a good panic tool, helping to remotely control acute anxiety attack, without risk of addiction which could be demonstrated by frequent and pointless calling of the physicians - as confirmed by minimum number of phone calls after second month of survey as well as no calls from other psychiatric patients.
REFERENCES Ader R/1992/:On the clinical relevance of psychoneuroeimmunology:Clinical immunology and immunopathology, 64, 1, 6 Antonovský A/1995 a/: The salutogenic Approach to Family System Health: Promise and Danger,Facta Universitatis/Series : Philosophy and Sociology/,1/2/,89-98 Bandura A/1977/:Self efficacy:Toward a unifying theory of behavioral change. Psychological review, 84, 191-215 Božin AA/20011:Ličnost i stres, 251:27,30 Cannon W13/1932/:The Wisdom of the Body, 2nd Edition, Norton, New York Engel GL /1980/:The clinical application of the biopsychosocial model.Am J.Psychiatry,137,535 Erič Lj/1991/:Panična stanja,II.dopunjeno i prošireno izdanje,Beograd-Zagreb, 331,12-22,105-156 Freud S/2003/:Podoby psychoanalýzy, preklad Krankus M,Bžoch z nemeckého originálu Sigmund Freud:gesarnmelte Werke,London, 1940-1952, 119 Flegenheimer WV/1982/: Techniques of Brief psychotherapy,199 :145-154 Friedman M,Rosenman RH/1971/: Type A behavior patterns association with coronary heart disease,Am.Clin.res., 3,300 Goodman A/1991/:Organic unity teory:the mind-body problem revisited,Am J.Psychiatry, 145:5,553-563 Gorman JM/1991/:Psychoimmunology:A Darwinian Approach In psychoimmunology Update Henry JP/1977/:Stress,Health and the Social Environment, Springer, New York-Heildelberg-Berlin Kaličanin P,Stožinic S,Paleev NR,Slijepčevic D/2001/: Stres-zdravlje-bolest,468,130-356,434,437 Kukumberg P,Ulč 1/2001/:Panická porucha,212 Sarchiapone M,Amore M,De Risio S,Carli V,Faia V,Poterzio F,Balista C,Camardese G,Ferrari G/2003/: Mirtazapine in the treatment of panic disorder: an opn-label trial, International Clinical Psychopharmacology, Vol.18, No1 Seligman M/1968/: The alleviation of learned helplessness in the dog.J. Anmorm Soc Psychol.73,256 Selye H/1950/:The Physiology and Pathology of Exposure to Stress,Acta,Montreal Smolik P/1996/:Duševni a behaviorálni poruchy, Pruvodce klasifikací,Nástin nozologie Diagnostika,504:243- 299Table l. Overview of patients
Females Males Total
Number of patients 51 21 72
Average age 41.5 31.6 29.4
Table 2: summery of diagnoses of examined first-time patients Diagnosis by ICD-1O Z.04 F.00-F.09 F.10-F.19 F.20-F.29
Number of patients 3 93 /F.06=58,F.07=5,F.01=8,F.00.1=4,F.00.2=18/ 35 /F.10=30,F.19=5/ 12 /F.20=2,F.23=10/
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F.30-F.38
36 /F.32=34,F.33=2/ 139 /F.40.01=29,F.41.0=43,F.41.2=13,F.43=49,F.45=5/ 12 /F.51=2,F.54=10/ 4 /F.63=4/ 8 /F.70=6,F.71=2/
F.40-F.48 F.50-F.55 F.60-F.69 F.70-F.73
Table 3: Education Completed level Basic (Grammar) school Vocational school without diploma Vocational school with diploma Gymnasium University Total
Females 3 10 19 8 11 51
Males 2 2 11 1 5 21
Table 4 – social - economical status
Student Employed Unemployed Retired-pensioner Total
Females 2 35 8 6 51
Males 2 16 3 0 21
Table 5: Matrimonial status
Single Married Divorced Widowed Registered partner Total
Females 10 27 8 5 1 51
Males 10 11 0 0 0 21
Table 6: overview of phone calls to mobile phones
Males Females Total *two calls in third month
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Calls during the first month 12 14 26
Calls during second month 9 11 20
Calls in the next 16 months 2* 0 2*
Table 7 : Overview of used medicines
Therapy No therapy Paroxetine + anxiolytic Citaloprame + anxiolytic Sertraline + anxiolytic
Number of patients /72/ 3 29 12 15
Fluvoxamine Fluoxetine Venlafaxine Mirtazapine Other anti-depressant
3 3 2 3 2
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TREATMENT OF SOMATOFORM AND PSYCHOSOMATIC DISORDERS AT OUTPATIENT PSYCHIATRIC CENTER AUTHORS Milan Ignjatovic, Dana Ignjatovic Non Governmental Psychiatric out Department, Banská Bystrica, Slovak republic
ABSTRACT Somatoform disorders (SFD) refer to a subgroup of mental disorders where physical symptoms are not conditioned by physical structural defect. (F45). Patients with somatoform disorders suffer a wide range of physical symptoms e.g. pain, nausea, fatigue, vegetative symptoms and repeatedly insist on physical examinations although previous examinations were negative (Smolik, 1996). Asthma, dermatitis, eczema, peptic ulcers, mucous colitis and ulcerative colitis belong to a group of psychosomatic disorders classified in psychiatry as mental and behavioral factors attributed to other diseases (F54), (Smolik, 1996). We studied cohort of 46 patients, 21 patients with diagnosis F45 (women N=14 total average age =49 years) and 25 patients with diagnosis F 54 (women N=17 total average age=53 years). In both groups we observed comorbidity with other mental disorders and made survey of applied theraphy. The most common line of theraphy in patients with somatoform disorders was combination of atypical neurolepticum (sulpirid) + SSRI and anxiolytic agent (8 patients). On the other hand patients with psychosomatic disorders were mostly treated with SSRI + anxiolytic agent (15 patients) or with combination of atypical neurolepticum (sulpirid) + SSRI and anxiolytic agent (8 patients). Patients with somatoform disorders suffered especially from gastrointestinal tract disturbances i.e. neurosis, dyspepsia and psychogenic aerophagia (F.45.31) 10 patients, cardiovascular disorders (F.45.30) 3 patients. 2 patients had unusual feelings of burning skin (F.45.38). Psychosomatic disorders most frequently occurring were asthma, migraine and peptic ulcer disease. All patients suffered from the symptoms for the average of 2 or more years. Key words: Somatoform disorders (F45), mental and behavioral factors attributed to other diseases- psychosomatic disorders (F54), sulpirid.
INTRODUCTION Patients with somatoform and psychosomatic disorders are the most frequent subjects visiting general practitioners. They can experience hypertension, asthma, diverse eczemas, gastrointestinal and urogenital problems. Moreover, physical symptoms can sometimes mask depressive symptoms (formerly known as larval or masked depression, today somatoform disorder) or the physical symptoms occur during depressive episode (somatic syndrome previously referred to as biological, vital, melancholic or endogenomorphous) (Smolik, 1996). Making the diagnosis we should not forget to omit mood disorders in somatic diseases (malign tumors, drug-induced depression, infection, etc.). They are very important in differencial diagnosis. Psychosomatic disorders together with psychosomatic medicine form interdisciplinary field that comprises collaboration of general practitioners, internists, cardiologists, gastroenterologists, surgeons, neurologists and psychiatrists. Sulpirid 2- methoxy benzamid in not only used in the treatment of psychotic and depressive disorders but also in somatoform and psychosomatic disorders. The mechanism of action of sulpirid in aforementioned disorders is not explicitly known. Although dopamine agonists (DA) have antidepressive effect, there are certain neuroleptics (DA receptor antagonists) that show antidepressive action, also (Schatzberg, Nemeroff, 2001, Janicak 2001). One of the possible explanations of this paradoxical effect (potency of sulpirid in therapy of depressive and somatoform disorders) is that neuroleptics, in small doses, can have antidepressive effect acting as DA autoreceptor antagonists thus increasing DA turnover (Floyd, 1995). Selective blockade of limbic DA receptors with sulpirid is associated with low incidence of neurologic adverse events. Sulpirid can antagonise DA receptors in blood vessels and gastrointestinal smooth muscles, as well (Turjanski, 1996). Using high doses of sulpirid (400-600mg per day) antipsychotic effect becomes dominant (Janicak, 2001). However, with low doses of sulpirid (150-300mg per day) we manage psychosomatic, neurotic and depressive disorders (Turjanski, 1996). Rimon states that sulpirid is efficacious in the treatment of various psychiatric disturbances. Given dose of 100-150mg per day is applicated in neurotic and depressive disorders. Gastrointestinal symptoms are the most common symptoms in subjects with somatoform disorders (Fraxinos, 1995). Therefore sulpirid represents new therapeutical modality in the management of those disorders where visceral hypersensitivity and somatoform component play crucial role (Fraxinos, 1996). Likewise sulpirid comes with new alternative for the treatment of psychosomatic disorders since psychoemotional background is very significant in the etiopathogenesis of above-mentioned disorders (Lemoine, 1996). Sulpirid does not decrease the amount of gastric acid in stomach, reduces postprandial serum gastrin levels, stimulates muconasal defence factors and basal or histamine-stimulated acid production stays unchanged during the course of long-term theraphy (Lemoine, 1996). Furthermore sulpirid is potent in controlling stress due to its well studied CNS effects (Crismer, 1972)
METHODS We studied cohort of 46 patients, 21 patients with main diagnosis of somatoform disorder and 25 patients with diagnosis of psychosoamtic disorder. To interpret comorbidity with other psychiatric diseases and to determine applicated therapy we retrospectively analysed patient’s files without using structural scale.
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Enrollment criteria: ICD-10 criteria for somatoform and psychosomatic disorder. Age 18 to 80 years. Treated more then 2 years in an outpatient psychiatric center.
Objectives: To find the most common somatoform and psychosomatic disorders at our outpatient center To map incidence of comorbitity with other psychical disturbances. To carry out a survey of the most frequently applied therapeuticals in somatoform and psychosomatic disorders at our outpatient clinic.
RESULTS We enrolled a cohort of 46 patients, 21 patients with main diagnosis F45 and 25 patients with diagnosis F54. Average age is given in Table 1 and Table lb. The most frequent somatoform and psychosomatic disorders were gastrointestinal disturbances (Tab.2) The comorbidity of somatoform disorders with other mental disorders appeared in the sample of 9 patients, 12 patients did not show evidence of comorbidity (Tab. 2). The most common psychosomatic disorders were asthma, migraine and peptic ulcer disease. 19 patients had comorbidity with other mental disorders, 6 patients were without comorbidity (Tab. 3). The most preferred therapy for somatoform disorders was a combination of atypical neurolepticum (sulpirid) + SSRI + anxiolytic agent (Tab. 4). An overview of SSRI used for this diagnosis is presented in Table 5. Psychosomatic disorders were treated with SSRI + anxiolytic agent (despite of high comorbidity with anxiety and depressive disorders) or with atypical neurolepticum + SSRI + anxiolytic agent (Tab 4b).
DISCUSSION Somatoform disorders present heavy therapeutical problem, not only for general practitioners but also for specialised clinicians during patient’s hospital stay , because patients’ symptoms vary widely (Lemoine, 1996). Described disorders cover a vast amount of psychiatric and other conslutation services (Ignjatič). Despite of many repeated examinations, the explanation that the disorder is not conditioned by structural defect, seems to be unsatisfactory and patients are finally placed in psychatric outpatient centers. Correct diagnosis and treatment prevents ongoing symptoms of chronic illness. Depressive symptoms may be evident and attributed to somatic or functional symptoms. On the other hand psychatric symptoms can be sometimes masked by somatic or functional symptoms (Lemoine, 1996). Low doses of sulpirid (100-200mg per day) may be effective in the treatment of various somatoform disorders. In one double blinded study, Nishida et al. (1974) compared efficiency of sulpirid (150-200mg per day) to oxazolam (30-60mg per day) in subjects with somatoform disorders. At the end of 3-week period patients on sulpirid showed significant improvement compared to oxazolam. Chent and Sttenhouver (1972) followed 30 patients with symptoms of tachycardia and dyspnoea. Results indicated reduction of symptoms while treated with low doses of sulpirid. Psychosomatic medicine is an interdisciplinary branch of medicine with „typical” psychosomatic disorders e.g. asthma, peptic ulcer disease, migraine and ulcerative colitis (Smolik, 1994). Because of participation of psychoemotional component in the etiopathogenesis, sulpirid has a significant role in modification and therapy of psychosomatic disorders (Lemoine, 1996). Migraine is also a very common symptom. Many authors tried to use sulpirid to reduce frequency of headaches and migraine (Aschoff, 1997, Barré, 1970). Hakkarainen and Vukari (1973) observed 30 subjects with migraine and 30 subjects with tension headaches, in both groups symptoms were associated with psychosomatic symptoms. Daily dose of sulpirid was 150mg. Compared to placebo the results in sulpirid group were much better and lead to alleviation of migraine and tension headaches (Lemoine, 1996). Application of sulpirid in 20 patients with asthma reduced the rate of attacks. According to Chevalier (1985), although sulpirid has no direct impact on pathophysiology of asthma, it is effective in the blockade of vicious circle of psychosomatic factors that contribute to pathophysiology of asthma. Several studies examined potential role of sulpirid (150-200mg per day) in sexual and urological disturbances (Mazeman,1975). The cons of studies that examined the efficiency of sulpirid in a variety of somatoform and psychosomatic disorders are : short period of examination, there are not double blinded, not placebo controlled and they focused on small number of patients. In spite of this fact, various studies support the application of sulpirid in somatoform and psychosomatic disorders treatment. Our survey did not evaluate efficiency of therapy for F45 and F54, but demonstrates the maximum possible use of combined therapy with atypical neurolepticum (sulpirid) + SSRI + anxiolytic agent is for discussed disorders. Average dose of sulpirid in our cohort was 100-150mg per day which is comparable to studies mentioned above. Given results suggest that therapeutical efficiency of sulpirid is indicated by its significant impact upon psycho-emotional component what might be common for miscellaneous somatoform disorders (Lemoine, 1996). Irritable bowel syndrome is another severe illness with prevalence of 15-30% in our population. It is characterised by abdominal pain, abdominal discomfort (symptoms for at least 3 months and several days in a week) and altered bowel habits. There are three major pathophysiological factors for irritable bowel disease: abnormal motility, sensitivity and a type of personality (Almy and Tulin, 1947). Those patients suffer from anxiety, depression and neurotic disturbances (Fraxinos) that corresponds with our data (high comorbidity with anxiety and depression). While the efficiency of sulpirid in the treatment of irritable bowel disease is under theoretical investigation, sulpirid may directly modify physiological processes of patients with peptic ulcer disease. Additional sulpirid’s quality is the capability to diminish stress factors. Sulpirid has dual function in reducing stress-induced ulcerations. The local activity normalizes 119
vascularization during pre-ulcerative and ulcerative period and it also indirectly modifies gastric secretion and psychological activity that contribute to formation of gastric ulcerations (Stein et al., 1994).
CONCLUSION Somatoform and psychosomatic disorders are very frequent in psychatric outpatient care centers. In differential diagnosis it is quite important to exclude depressive episodes since many patients suffering from depression do not present with any signs of depression. The term „somatization” applies to somatic symptoms that express emotional discomfort and may lead to misdiagnosis. A number of depressive subjects with somatic component really have somatic disease, but treatment is often insufficient. On the other hand many patients with inexplicable diffuse symptoms come to psychiatrist and are diagnosed with anxiety or depressive disorder (Stahl. ). Correct diagnosis of somatoform and psychosomatic disorder can help with the choice of pharmacological intervention relevently combined with psychotherapy. One such possibility is represented by combination of suipirid + SSRI + anxiolytic agent. However this modality needs further clinical studies.
LITERATURE Table 1 a Diagnose F.45 Male Female Total Table 1 b Diagnose F.54 Male Female Total
Number of patients
Age
Number of patients
Age
Table 2 Diagnose Number of patients F.45 somatoforrn disorder F.45.2 hypochondric disorder F.45.30 cardio and KVS system F.45.31 superior GIT F.45.32 inferior GIT F.45.33 respiratory system F.45.34 urogenital system F.45.38 other apparatus or system F.45.4 chronical somatoform painful disorder Total Table 3 a DG Without cormobidity Table 3 b DG Without cormobidity Table 4 a DG SSRI TCA anxiolytic agent SSRI + anxiolytic agent SSRI + typical neurolepticum Atypical neurolepticum Biston Atypical neurolepticum /sulpirid/ + SSRI + anxiolytic agent Total Table 4 b DG 120
SSRI SSRI + anxiolytic agent Atypical neurolepticum /sulpirid/ + SSRI + anxiolytic agent Other Total
CASUISTIC A 24-years old patient was examined at our outpatient psychiatric center in February 2003 for the first time. He had the first contact with psychiatric center /paediapsychiatric/ at the age of 13 - only psychotherapy ,without psychopharmacotherapy. At the age of 21 he was treated at outpatient psychiatric center with a diagnose of somatoform disorder, gastric neurosis F.45.31 with the following advised therapy : maprotilinum 150rng pro die, advised deep psychotherapy, maprotilinum gradually ex, a change for fluvoxamine. The patient travelled abroad for 2 months - without difficulties, he has ommited the therapy
RA: He had been brouht up by his parents until he was 13. Then his father died under unknown circumstances, his family refused the suspicion of suicide, he has an older sister, ocassional depressive episodes, t.b.: 0, DM: grandfather, ICHS: grandfather, IM: grandfather, NCMP: probably the great grandparents, ca: great grand father had bowels cancer, alcohol : 0, neuropsychiatric stress: grand mother was treated at psychiatric center, but he can not name her diagnose, his mother is under monitoring by outpatient neurology center, because of sclerosis multiplex
OA: He cameover usual children diseases, more serious diseases in childhood: at the age of 6 Months - coeliakia, operations: APE, TE, injuries: 0, fractures: 0, unconsciousness : 0, concussion of the brain: caused by downfall, there was only RTG done, allergy to medicine or to food not declared
SA: The patient has graduated on secondary industrial school, at this time unemployed, character: rather self-contained, introvert, pesimistic, with schizoid features, he does not go out very often, MS rejected, without seriuos relationship, only temporary occasional relationships
TO: He has been suffering from gastric neurosis from the time of his studies on secondary school, It was bearable till the age of 16, it has been getting worse since 2000. When he was abroad, he had no problems. Last year when he came back, his condition started to get worse, it is critical again, he tends to vomit, he is loosing his weight, aversion to food, he feels sick all the time, he has sleeeping problems, he thinks he is not able to go to meet people, only because he feels sick, not because of his anxiety about meeting people
Psychiatric objective: The patient comes to the psychiatric center alone, neat, he accepts social formalities, hygiene kept, mimicry and gesticulation appropriate, psychomotoric tempo is appropriate. Consciousness is clear, orientation by person, place, time, situation is right, mood subdepressive, without suicide tendencies, affectivity oscillates, his thoughts are strongly orientated to his somatic qualitative problems of his gatrointestinal tract, without false contents, perception without qualitative disorders, attention good, IMF appropriate to the age, education, surroundings, personality rather introvert, behaviour appropriate. DG: F.45 F.43.31 Advise: Paroxetin 20 mg pro die Clonazepam 2 mg pro die Sulprid 100 mg pro die
ETIOPATHOGENIC VIEW: Psychologically the patient’s self-confidence is lower, psychosocially his gatric problems could indicate the need of father’s love. Psychoanalytically somatic disorder is an expression of patient’s anger against unknown person who is responsibile for the pain caused by father’s death. Behaviouraly, somatic disorder would express an imitation of his mother’s disease (sclerosis multiplex, depressive episodes ) and strict upbringing by one of his parents (mother).
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BEGINNING AND DEVELOPMENT OF DISEASE The first symptoms of somatoform disorder occured at the age of 13, in the period of adolenscence, it means before the age of 30, it was in close relation with violent death of his father, which meant heavy stress for the young man. Due to the considerable somatic disorder, the patient was repeatedly examined although with negative diagnose. After 5 years of lasting physical problems without scructual defect, the patient was advised to see a mental specialist. His diagnose was somatoform disorder ( gastric neurosis ) with advised therapy. The patient was working abroad for 2 months, where he did not have any physical difficulties. After his return, his condition got worse : nauzei, vomiting, aversion to food, loosing weight, wind.... In differencial diagnoses, we have tried to eliminate these somatic diseases collagenoses, S.M.,myastenia gravis, AIDS, hypertyreosis, chronical infection diseases ...), whose physical symptoms can also be temporary and changeable. We eliminated heavy depressive disorder with somatic symptoms, as there are depressive episodes in the patient’s family anamnesis ( mother, sister ). We eliminated schizophrenia and other psychotic diseases. Concerning the comorbidity we considered stress and endurance situations. TH: Besides psychopharmacotherapy we have advised the patient for psychotherapy as well (cognito-behavioral psychotherapy)
1.CHECK UP After a month of treatment , the patient felt better, physical symptoms decreased , at this time the patient is looking for the job in Slovakia. IGNJATOVIĆ, B.
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MODITEN U LEČENJU SHIZOFRENIH PSIHOZA Medu savremenim neurolepticima Moditen zauzima dominantno mjesto u lečenju shizofrenih psihoza. Kao snažan antipsihotik brzo reducira shizofreni sadrIaj I stvara brojne ekstrapiramidne simptome. Apliciran u visokim dozama optimalni efekat ispoljava u dozi od 600 mg sedmično.
UVOD Medu mnogobrojnim neurolepticima, Moditen nesumnjivo Ina danas zavidno mesto u lečenju shizofrenih psihoza. Njegove glavne karakteristike su : brzo, efikasno i dugotrajno dejstvo. Proizvodi se u tabletama od 1 mg, 2,5 mg, 5 mg, 25 mg I 100 mg, kao i u injekcijama od 25 mg (Moditen - depo). Polivalentno dejstvo (umirujuće, anksiolitičko, sedativno i antipsihotično) svrstava ga u red neuroleptika sa široklm spektrom dejstva i omogućava mu manevrisanje u pogledu njegove pozologije. To je snažan neuroleptik, čije antipsihotično dejstvo varira u dozi od 5 do 1800 mg. Neki autori navode da su najbolji uspeh postigli primenom Moditena u dozi od 150 do 750 mg; drugi navode optimalne doze od 200 do 400 mg, a kod nekih se kreću čak do 1000. mg. Kao snažan antipsihotik pokazuje vanredne rezultate u kombinaciji sa sedativnim neurolepticima. Mnogi za neuspeh u lečenju navode neadekvatne doze, pa predlažu individualno doziranje za svakog bolesnika ako se želi dobiti optimalno reagovanje. Zbog njegove dobre podnošijivosti i male toksičnosti mnogi preporučuju upotrebu u visokim dozama.
CILJ ISPITIVANJA U toku ispitivanja pratili smo dejstvo Moditena, njegovo optimalno i minimalno doiziranje i trajanje medikacije, njegovu toleranciju i efikasnost u lečenju shizofrenih psihoza.
NAŠA ISKUSTVA U toku desetogodišnje primene Moditena u raznovrsnlm oblicima, kombinacijama sa drugim lekovima, kao i raznim dozama, imali smo mogućnosti da pratimo i zabeležimo neke od navedenih prednosti medu drugim neurolepticima. Zbog toga ćemo u jednom redosledu nabrajati naša iskustva i naše rezutate ispitivanja. Našim ispitivanjem obuhvaćeno je 47 shizoferenih bolesnika, muškog pola, od 18 do 51 godine starosti. Pre nego što smo ordinirali lek, obavili smo sve prethodno potrebne radnje predviđene za ispitivanje. Kontrolne pslhliatrijske preglede smo vršili na mesec dana. Ispitivanje je trajalo od 1 do 4 meseca. Doze niskodoznog Moditena su se kretale od 25 do 75 mg, a visokodoznog od 100 do 800 mg. Tablete smo administrirali samo ujutro i u podne, a optimalni efekat zabeležili smo na dozi od 600 mg kod 20 bolesnika, na 400 mg kod 4, na 300 mg kod 3, na 100 mg kod 5, na 75 mg kod 2, na 50 mg kod 3 1 na 25 mg kod 2 bolesnika. U toku ispitivanja zapazili smo poboljšanje raspoloženja, smanjenje anksioznosti, napetosti, a kod nekih poboljšanje aktivnosti, interesovanja, voije, autizma, pasivnosti, komunikativnosti, kritičnosti, uviđavnosti, te usklađivanje ponašanja. Na kraju lečenja sumiranjem rezultata zabeležili smo sledeći uspeh: znatno poboljšanje (+ + +) kod 23 bolesnika iii 48,9% delimično poboljšanje (+ + +) kod 16 bolesnika iii 34% neuspeh ... (0) kod 8 bolesnika iii 17,1% ukupno
47
100%
SPOREDNI EFEKTI ISPITIVANJA Nuzpojave smo zabeležili kod 40 bolesnika ili 85,1% a nije ih bilo kod 7 bolesnika lli 14,9%.. Kod bolesnika tretiranih niskodoznim Moditenom u tabletama od 25 mg zapazill smo pojavu istih kod svih, a same pojave su bile intenzivne i javljale su se prvog dana, a kod visokodoznog Moditena od 100 mg kod 7 ih nije bilo, a kod ostalih su se javljale češće na početku all ih je bilo i docnije. Povećanje broja leukocita od 8.800 do 17.500 zabeležili smo kod 13 bolesnika ili 27,7%. Broj leukocita se uglavnom povećavao kod povećanja doza, a smanjivao kod smanjenja doza. EEG je blo izmenjen kod 8 bolesnika. Jedina izmena osnovne trase sastajala se u nešto iregularnoj osnovnoj aktivnosti, a retko su zabeležene lakše dizritmične pojave uglavnom tokom hiperventilacije, a u jednom slučaju dizritmija je bila granična prema theta fokusu. Međutim, sve ove diskretne pojave povukle su se posle ukidanja Moditena. Visina doze nije bitno uticala na pojavu ovih nespecifičnih dizritmija. Ni u jednom slučaju nije došlo do aktivacije specifičnosti potencijala. Osim antiparkinsonika nismo apilcirall drugu dodatnu terapiju. Po završenom ispitivanju poste skidanja Moditena ponovo smo uvodili prethodnu terapiju, ali u znatno manjoj dozi. 2. Kod 89 shlzofrenih bolesnika, muškog pola, od 21 do 65 godina starosti, oridnirali smo Moditen u kombi- naciji sa sedativnim neurolepticima uz antiparkinsonik u vremenu od 3 do 7 meseci. Kombinacije su izgledale ovako: Nozinan (75 do 600 mg) + Moditen (7,5 do 15 mg) + Artane (6 do 15 mg). Iste takve kombinacije imali smo i sa hlorporomazinom i Mellerilom.
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Na kraju ispitivanja zabeležili smo sledeće rezultate: znatno poboljšanje ( + + +) kod 46 bolesnika ili 51,68% delimično poboljšanje(+ +) kod 35 bolesnika ili 39,34% neuspeh ... (0) kod 8 bolesnika ili 8,98% Ukupno 89 100% U toku ispitivanja nisu zabeleženi sporedni efekti ispitivanja. Najbolji uspjeh postignut je u toku lečenja u otklanjanju psihomotornog nemira, anksioznosti, napetosti, straha, autizma, pasivnosti i nezainteresovanosti. Kod 66 shizofrenih bolesnika, od 21 do 64 godine starosti, ordinirali smo Moditen - depo u ampulama od 25 mg na 25 dana, u vremenu od 2 do 14 meseci. Od 66 lečenih bolesnika 27 nije primalo dodatnu terapiju, a 39 je pored Moditena – depo dobijalo i jedan od sedativnih neuroleptika (75 do 300 mg) i Artane (6 do 15 mg), zbog egzacerbacije procesa. Rezultati lečenja na kraju bili su sledeći: Znatno poboljšanje (+ + + ) kod 35 bolesnika ili 53% delimično poboljšanje ( + +) kod 14 bolesnika ili 21,3% neuspeh ... (0) kod 17 bolesnika ili 25,7% Ukupno 66 100% Nuzpojava nije bilo kod 37 bolesnka iii 56,06 kod 29 ih je bilo ill 43,94% 4. Kod 20 shlzofrenih bolesnika, muškog pola, od 27 do 46 godina starosti ordinirali smo Moditen u tabletama ad 30 mg dnevno u vremenu od 3 meseca. Ekstrapiramidalne pojave smo zapazili kod svih u toku prva tri dana, a kod jednog samo 27-og dana i to kod jednih slabije, a kod drugih jače izražene. Kod 41 bolesnika, od 25 do 65 godina starosti, muškaraca, obolelih od shizofrenije ordinirali smo Leponex (100 do 600 mg) i Moditendepo u dozi od 25 mg na 25 dana u vremenskom razmaku od 3 do 7 meseci. Uspeh je bio mnogo bolji nego kod drugih kombinacija sa Moditenom, a sporedne efekte koje smo zabeležili primmenom samog Moditena nismo ovde zapazili. Rezultati lečenja izgledali su ovako: znatno poboljšanje (+ + + ) kod 32 bolesnika ili 78,0% delimično poboljšanje (+ +) kod 9 bolesnika ili 22,0% neuspeh (0) kod 0 bolesnika iIi 0,0% Ukupno 41 100%
ZAKLJUČAK Moditen među savremenim neurolepticima zauzima dominantno mesto u lečenju shizofrenih psihoza. Kao snažan antipsihotik reducira brzo shizofreni sadržaj stvara mnogobrojne ekstrapiramidalne pojave. Apliciran u visokim dozama optimalni efekat ispoljava u najvećem broju slučajeva na dozi od 600 mg. Ekstrapiramidalne pojave su češće kod niskodoznog Moditena nego kod visokodoznog. Otklanjaju se ili sprečavaju dodavanjem sedativnih neuroleptika li antiparkisonika. Niske doze Moditena II Moditenadepo uz sedativne neuroleptike daju bolji efekat u lečenju shizofrenih psihoza, a ne daju sporedne efekte. Moditen od 30 mg, kao i niskodozni od 25-75 daju kod svih bolesnikanuzpojave. Moditen-depo uz Leponex daje najbolje rezultate u lečenju bez ekstrapiramidnih pojava zapaženih primenom samog Moditena - depo.
LITERATURA 1) Bohčtek, N.: Principi prolongirane psiho farmakoterapije shizofrenih psihoza (značenje lečenja depo neurolepticima) u Novosti 1 Krka 1972, 85 - 88. 2) Fouks, L.: IVme Congres Mondi al de psychiatrie, Madrid, 1966. Edition squibb et sons. 3) Freeman, H.: Symposium on long - action phenotiazines. Dublin, 1969. 4) Frank, L.: International Drug Therapy Newsletter. Baltimore, 1970 Vol. 5. N. 4. 5) Flufenazine high dose protocol, E. R. Squibb and Sons LTD. 6) Imlah- N.:Symposium on ong - acting phenotiazines, Dubli, 1969. 7) Korbar, M., Belev, B , Pauković M : Lečenje visokim dozama flufenazin klorida, Neuropsih. 1976, 24, 115 — 119. 8) Lokar, L.: Upotreba flutenazin decanoata u socijalnim zavodima. u Novosti 1, Krka, 1972, 95— 98. 9) Milovanović, D : Klinička psihofarmakologija, Izdanje ‘’Lek’’, Ljubljana, 1972. 10) Medical references, High dosadage moditen (flufenazine) E. R. Squibb and Sons LTD 11) Nabney, J.: Symposium on long acting phenotiazines. Dublin, 1969. 12) Vitorovi’, M.: Naša iskustva naš stav u lečenju depo - flufenazinom, u Novosti 1, Krka, 1972, 89-93. 13) Vitorović M.: Psihofarmakologija, Zagreb, 1968, 129 132, 294 - 300. 14) Vitorović, M.: Psihijatrija, lzdanje ’’Lek’’ Ljubljana, 1969, 211 - 217
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THE MODITEN IN TREATING SCHIZOPHRENIC PSYCHOSES AUTHOR: IGNJATOVIĆ, B. BOŽIDAR IGNJATOVIĆ, neuropsihijatar NEUROPSIHIJATRIJSKA BOLNICA »DR SLAVOLJUB BAKALOVIĆ« VRSAC, PODVRŠANSKA, 7 The author expose the results of the treatment of schizophrenic psychoses after ten-year experience in the application of Moditen in all fashions of it production, as well as in the combination with other neuroleptics. High dosage Moditen administrated in doses from 100 to 800 mg gives an optimal effect at dose of 600 mg in the majority of cases. Low dosage Moditen administrated in doses from 25 to 25 to 75 mg provokes many and variable side effects; therefor it should be given together with antiparkinsonic at the very beginning of healing. The Moditen insmail doses from 7,5 to 15 mg, applicated with sedative neuroleptics (75 to 600 mg) and antiparkinsonic (6 to 15 mg) yielded good results in healing, but does not provoke extra-pyramidal disturbances. Moditen-depo, administrated alone or with sedative neuroleptics (75 to 300 mg) and antiparkinsonic (6 to 15 mg) yields good results in healing and side effects are minimal or none. The Moditen given in tablettes of 30 mg per day provokes in all patients extra-pyramidal effects, therefor in should be administrated with antiparkinsonics. Leponex /100 to 600 mg/ being administrated with Moditen-depo /25 mg/ yields the best results in curability, and side effects, that we meet at Moditen-depo, do not appear.
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EKSTRAPIRAMIDALNE POJAVE KOD PRIMENE NEUROLEPTIKA NJIHOV ZNAČAJ I LEČENJE Autor iznosi viastita iskustva vezana za pojavu i uklanjanje sporednlh efekata izazvanih aplikacijom flufenazina. Ekstrapiramidne pojave su češće i intenzivnije kod niskodoznog flufenazina (25 do 75 mg), a slabije i ređe kod visokodoznog flufenazina (100 do 800 mg). Flufenazin u dozi od 30 mg dnevno daje ekstrapiramidne pojave uglavnom u toku prva tri dana (u 100% slučajeva). Esktrapiramidni simptomi se ne javljaju ako se ovaj neurleptik aplikuje zajedno sa sedativnim neurolepticima i antiparkinsonskim medikamentom.
UVOD Nesumnjivo je, da neuroleptici zauzimaju dominantnu ulogu u lečenju shizofrenih psihoza, pa je zbog toga potrebno pored poznavanja njihovog psihofarmakološkog dejstva, da se nešto više zna i o ekstrapiramidalnim pojavama koje oni izazivaju. Danas je, ne samo poznato, već i dokazano, da se dejstvo neuroleptika odvija uglavnom u nivou retikularne formacije moždanog stabla, bilo direktno ili indirektno, zbog nekih releja sa svim ostalim centralnim nervnim strukturama. Zatim je dokazano, da snažni neuroleptici, kao što su flufenazini u visokim dozama stimulišu alfa i gama sisteme koji kontrolišu aktivnost motornih ćelija prednjih rogova i na taj način prouzrokuju ekstrapiramidalne pojave, a sedativni pak neuroleptici kao što su levomepromazin, hiorpromazin i tioridazin, deprimiraju ove sisteme, i tako sprečavaju pojavu istih. Odatle i potiče podela neuroleptika na snažne i sedativne. Prema tome, ekstrapiramidalne pojave izazvane snažnim neurolepticima mogu se predvideti, preduhitriti ili ublažiti dodavanjem nekog od sedativnih neuroleptika. Neurološke manifestacije koje izazivaju neuroleptici, treba shvatiti ozbiljno i uvrstiti in u urgentna stanja koje zahtevaju hitnu i adekvatnu medicinsku intervenciju. U literaturi su opisani mnogi smrtni slučajevi u toku terapije neurolepticima, pa je i zbog toga potrebna predostrožnost pri upotrebi istih. Procenat ekstrapiramidalnih pojava se razlikuje kod mnogih autora, kao i kod primene različitih neuroleptika. Steck je kod 300 bolesnika, lečenlh hiorpromazinom i rezerpinom, uočio pojavu ekstrapiramidalnih manifestacija kod više od jedne trećine. Rebeillard i saradnici kod 1933 boles- nika lečena tioproperazinom našli su ekstrapiramidne manifestacije u 50% slučajeva, a Maurel i Perrin kod 135 bolesnika u 40% slučajeva. Collard kod haloperldola nalazi ove pojave u 19% slučajeva. Sumirana učestalost nuzpojava kod vlšegodišnje primene neuroleptika po Milovanoviću je 17%, po Rosieru 51%, po, Aydu 23% I po Paugetu 28%. Kod udružene primene neuroleptika tioproperazina, flufenazina i tioridazina neki navode 7%.. Nema kriterijuma i pravila pomoću kojih bismo mogli da predvidimo pojavu ranih ekstrapiramidalnih manifestacija. Poznato je da snažni neuroleptici izazivaju ove pojave u većem procentu nego drugi neuroleptici. Isto tako se zna da aplicirani bez antiparkinsonika daju veći procenat, a u kombinaciji sa sedativnim neurolepticima manji procenat ekstrapiramidainih pojava, da su te pojave slabijeg intenziteta ili ih nema. Ekstrapiramidalne pojave najčešće se javljaju u toku prvih dana aplikacije, a češće su kod mlađih od 25 godina i starijih od 45 godina. Unošenje velikih dozna neuroleptika nema većeg značaja za učestalost ovih pojava. One su češće kod parenteralne primene neuroleptika. U psihijatrljskoj literature postoje dva suprotna stava u pogledu značaja ovih neurolotših pojava. Prema jednima, one poseduju odreden terapeutski efekat, a po drugima su nepoželjne, te ih treba sprečavati i otklanjati istovremenom primenom uz neuroleptike i antiparkinsonike u odgovarajućoj dozi. U prilog drugima ide i otkriće Clozapina, koji ne izaziva ekstrapiramidalne pojave a irna isti terapijski efekat kao i klasični neuroleptici koji izazivaju ove pojave. Po Milovanoviću (1972) terapijski efekat neuroleptika je jednak, bez obzira da li se primenjuju sami i zajedno sa antiparkinsonicima, all je pojava ekstrapiramidalnih simptoma onemogućena paralelnom primenom istih. Kod bolesnika lečenih neurolepticima ekstrapiramidalne pojave su bile registrovane u 24% slučajeva, a kod lečenih kombinovanom terapijom ih nije bilo.
CILJ Naš zadatak je bio, da na osnovu dugogodišnjeg ispitivanja neuroleptika u lečenju shizofrenih psihoza, iznesemo naša zapažanja i uporedimo natše nalaze sa onim što se do sada zna o neurolepticima i ekstrapiramidalnim pojavama koje oni izazivaju.
NAŠA ISKUSTVA 1. Flufenazin (Moditen) smo ispitivali kod 47 shizofrenih bolesnika od 18 do 51 godine starosti. Ispitivanje je trajalo od 1 do 4 meseca. Niskodozni flufenazin smo primeniii u dozi od 25 do 75 mg kod 9 bolesnika, a visokodozni flufenazin u dozi od 100 do 800 mg kod 38 bolesnika. Tablete smo ordinirall samo ujutru i u podne, a posmatranje bolesnika vršili u toku celog dana. Nuz pojave su se javljale najčešće u toku prepodnevnog rada, ređe i popodne, te nam nije bilo teško da ih zapazimo i registrujemo. Ekstrapiramidalne pojave smo zabeležili kod 40 bolesnika ili 85,1% a nije ih bilo kod 7 ili 14,9. Kod svih 9 bolesnika koji su primali niskodozni flufenazin zapažene su intenzivne ekstrapiramidalne pojave, a kod ostalih 38 bolesnika na visokodoznom flufenazinu kod 7 ih nije bilo, i to kod 4 na dozi ad 600 mg i kod 3 na dozi od 100 mg do 300 mg. Kod niskodoznog flufenazina E. P. su bile intenzivnije i javljale se odmah na početku, a kod visokodoznog su se javljale na početku a i docnije. Primenom antiparkinsonika u dovoljnoj količini sve ove pojave su brzo iščezavale. Ove sekundarne pojave mogle su da se jave kod jednog bolesnika po 1,2 ili 3 i to u isto vreme iii u dva različita vremena, na početku, sredini ili kraju. 126
2. Kod 89 shizofrenih bolesnika, muškaraca, od 21 do 65 godina starosti ordinirali smo Moditen u kombinaciji sa sedativnim neurolepticima uz antiparkinsonik u vremenu od 3 do 7 meseci. Kombinacije su izgledale ovako: Nozinan (75 do 600 mg) + Modizen (7,5 do 15 mg) + Artane (6 do 15 mg). lste takve kombinacije smo pravill sa hiorpromazinom i tioridazinom. U toku ispitivanja ekstrapiramidalne pojave se nisu ispoljile ni kod jednog bolesnika, pa ih nismo ni registrovali. 3. Kod 66 shizofrenih bolesnika, muškaraca, od 21 do 64 godine starosti, smo Moditenedepo u ampulama od 25 mg na 25 dana, u vremenu od 2 do 14 meseci. Od 66 lečenlh bolesnika, ekstrapiramidalnih pojava nije bilo kod 37 bolesnika ili 56,06%, a kod 29 smo ih registrovall ili 43,94%. Našlii smo nesanicu kod 25, akatiziju kod 4, tremor kod 2, rigor kod 2, hipersalivaciju kod 1, I okulogirne krize kod 1 slučaja. Kod jednog bolesnika javljale su se po 1 ill 2 ill 3 pojave u isto vreme ili u dva vremena. Otklanjali smo lh lako dodavanjem antiparkinsonika od 6 do 15 mg. 4, Kod 20 shizofrenih bolesnika, muškog poia, od 27 do 46 godina starosti, ordinirali smo Moditen u tabletama od 30 mg dnevno, u vremenu od 3 meseca. Ekstrapiramidalne pojave smo registrovali kod svih bolesnika iii 100%. Kod 6 se javilo prvog dana, kod 7 drugog, kod 6 trećeg i kod jednog 27-og dana. Dodavanjem antiparkinsonika od 6 - 15 mg lako smo ih i brzo otklanjali. Samo kod jednog bolesnika, gde su ove pojave bile vrlo teške, sa pojavom više formi paroksizmalnih diskinezija u isto vreme, morali smo da intervenišemo tri sata da bi ih otklonill i bolesnika povratili u prethodno stanje. Kao antidot smo aplicirali 2 amp. Ponalida, 2 tabl. Artane-a od po 5 mg, detoksikaciju i na kraju iednu ampulu Phenobarbitona od 0,10gr. 5. Kod 41 shizofrenog bolesnika, muškaraca od 25 do 65 godina starosti, ordinirali smo Leponex (100 do 600 mg) i Moditendepo u dozi od 25 mg na 25 dana u vremenu od 3 do 7 meseci. Ekstrapiramidalne pojave koje prate moditen-depo nismo registrovali jer ih nije ni bilo.
ZAKLJUČAK Ekstrapiramidalne pojave su češće i intenzivnije kod niskodoznog flufenazina (25 do 75 mg), a slabije i ređe kod visokodoznog flufenazina (100 do 800 mg). Flufenazin uz sedativne neuroleptike i antiparkinsonik ne daje ekstrapiramidalne manifestacije. Flufenazin-depo (25mg na 25 dana) izaziva ove sporedne pojave u 43,94% slučajeva. Flufenazin u dozi od 30 mg dnevno daje ekstrapiramidalne pojave uglavnom u toku prva tri dana u 100% slučajeva. Flufenazin-depo u kombinaciji sa Leponexom ne daje nuzpojave koje se manifestuju aplikacijom samo flufenazina-depo. Sve navedene pojave lako se otklanjaju uvođenjem antiparkinika od 6 do 15 mg. Kod težih i komplikovanijih slučajeva dati antiparkinsonik u ampulama i u većim dozama.
LITERATURA 1) Bohaček N.: Principi prolongirane psihofarmakoterapije shizofrenih psihoza, u Novosti 1, Krka, 1972, 85-88. 2) Fouks L.: 1Vme Congrec Mondial de psychiatrie, Madrid, 1966. Edition Squibb et Sons. 3) Flufenazine high dose protocol, E. R., Squibb and Sons LTD. 4) Korbar M., Belev B., Pauković M.: Lečenje visokim dozama flufenazin klorida, Neuropsih. 1976, 24, 115-119. 5) Milovanović D.: Klinička psihofarmakologija, lzdanje Lek, Ljubljana, 1972. 6) Vitorović M.: Naša iskustva i naš stav u lečenju depo-flufenazinom, u Novosti 1, Krka, 1972, 89-93. 7) Vitorović, M.: Psihofarmakologija, lzdanje Zagreb, 1968, 129-132, 294-300. 8) Vitorović, M.: Psihijatrija, lzdanje Lek, Ljubljana, 1969, 211-217.
EXTRAPYRAMIDAL PHENOMENA IN THE APPLICATION OF NEUROLEPTICS – THEIR IMPORTANCE AND HEALING IGNJATOVIĆ, B. The author exposes his experience in connection with the appearance or removing of side effects during ten-year administration of the fluphenazine. So high dosage of fluphenazine in doses from 100 to 800 mg in 40 patients provoked extrapyrarnidal phenomena or 85,1 %, in 7 patients these phenomena did not appear or 14,9 %. Low dosage fluphenazine, from the other side, administrated in doses from 25 to 75 mg provoke these phenomena 100 %. Fluphenazine in the dose of 7,5 to 15 mg in combination with sedative neuroleptic (75 to 600 mg) and antiparkinsonic (6 to 15 mg) does not give extra-pyramidal distrubances. Moditen-depo applicated in injections by 25 mg for 25 days provoked extra-pyramidal disturbances in 56,06 %. During the administration of fluphenazine in tablette of 30 mg daily, we noted extra-pyramidal disturbances 100%. By the application of Leponex (100 to 600 mg) together with Moditen-depo (25 mg) we did not find the extra-pyramidal symptoms that appear in the application moditen- depo only. Low dosage fluphenazines, consequently, in doses from 30 to 75 mg seem to give 100 % extra-pyramidal phenomena, therefor they should be given from the very beginning with antiparkinsonics or sedative neuroieptics preventing on that wy the undesirable action. Božidar Ignjatović, neuropsihijatar Neuropsihijatrijska bolnica Dr. Stavoijub Bakalović Vršac, Podvršanska, 7
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PENFLURIDOL U LEČENJU HRONIČNIH SHIZOFRENIH PSIHOZA Penfluridolom je tretirano 26 hroničnih shizofrenika; sedmična doza neuroleptika bila je između 20 i 60 mg. Ispitivanje je trajalo od 3 do 14 meseci. Autori referišu o rezultatlma koji su postignuti aplikacijom Penfluridola.
UVOD Penfluridol /R 16 341, zaštićeno ime Semap/ spada u neuroleptike novijeg datuma. Njegova neuroleptička aktivnost i slaba toksičnost dokazani su serijom eksperimenata vršenim na miševima, pacovima, psima, zečevima i zamorcima. Njegove najslablje efektivne doze su 8 do 16 puta manje od doza hlorprornazina, a približne dozama haloperldola i pimozida. Veliki broj kliničkih ispitivanja ukazuje na povoljno dejstvo Penfluridola u produženom tretmanu kod hroničnih psihoza, gde su dominirall deficitarni simptomi /autizam, apatija, pasivnost, sniženje afektiviteta, dezinteresovanost/, kao i ispoljeni simptomi sumanutosti i halucinacije. Međutim, manje je bio efikasan kod ispoljenog psihomotornog nemira i agitacije, te su uz Penfluridol bili dodavani i sedativni neuroleptici. Procenat poboljšanja u tretmanu Penfluridolom, prema nekim kliničarima, kretao se od 30 do 70%, a negde čak i do 85%. Po mišljenju mnogih kliničara, Penfluridol je oralni neuroleptik, koji ispoljava snažan antipsihotični efekat, all skoro nikakvo sedativno i hipnotičko dejstvo, sa pojavom minimainih sporednih efekata i prolongiranim delovanjem od 7 dana, te je pogodan za primenu u lečenju i održavanju hroničnih psihotičnih bolesnika iz shizofrene grupe, kojima je potreban produžen tretman. Najbolji terapeutski efekti se navode primenom pojedinačnih sedmičnih doza od 40 do 60 mg, a lek se nalazi u prometu od 20mg u tabletama.
CILJ ISPITIVANJA U toku ispitivanja pratill smo dejstvo Penfluridola, njegovo optimalno doziranje i trajanje madikacije, njegovu toleranciju.
NAŠA ISKUSTVA Našim ispitivanjem obuhvaćeno je 26 hroničnih shizofrenih bolesnika, muškog pola, od 30 do 54 godine starosti, sa trajanjem bolesti od 3 do 25 godina. Po dijagnostičkoi strukturi zastupljenost je bila sledeća: Sch.simplex /295.0/ 3 bolesnika ili 11,54%, Hebephrenia /295.1/ 9 bolesnika ili 34,62%, Catatonia /295,2/ 2 bolesnika ili 7,69%, Sch.paranoldes /295,3/ 12 bolesnika ili 46,15%. Neurološki i somatski nalazi pri pregiedu su bili uredni. Pre nego što smo ordinirali Penfluridol obustavili smo prethodnu terapiju samo za jedan dan i u toku tog dana napravili potrebne laboratorijske analize i kontrolne psihijatrijske preglede. Sledeće kontrolne psihijatrijske preglede kao i laboratorijske analize vršili smo na kraju prvog, drugog i trećeg meseca i zajedno sa prethodnim uneli u odgovarajuće test liste. Kod bolesnika koji su lečeni duže od 3 meseca kontrolne psihijatrijske preglede smo vršili i delje na mesec dana. Ispitivanje je trajalo od 3 do 14 meseci. Doze Penfluridola su se kretale od 20 do 60 mg /1 do 3 Tabl./ svakog sedmog dana.
REZULTATI LEČENJA Evaluaciju terapeutskog efekta vršili smo pre početka lečenja, a zatim u razmacima od po 4 nedelje, pomošću kratke psihijatrijske ocenske lestvice s 19 osobina i 4 stepena ocene simptoma: 0 odsutan, 1 = blago izražen, 2 = umeren, 3 = jako izražen. Na kraju lečenja sumiranjem rezultata zabeležili smo sledeći uspeh: znatno poboljšanje kod 11 bolesnika ili 42,30% delimiano poboljšanje kod 10 bolesnika ill 38,46% neuspeh kod 5 bolesnika ili 19,24% Kod svih bolesnika lečenje smo počeli u bolnici, all smo posle otpuštanja nekih bolesnika nastaviii tretman i daije primenom Penfluridola, uz uobičajene mesečne kontrole. U toku ispitivanja, kod 3 pacijenta je došlo do pogoršanja bolesti sa pojavom psihomotomog nemira, agitiranosti, napetosti i sumnjičavosti, te smo bili prinuđeni da uz Penfluridol ordiniramo i jedan od sedativnih neuroleptika /Leponex/ i tako otklonimo postojeći psihopatološki sadržaj. U toku lečenja zapazili smo najbolje poboljšanje u voljnoafektivnoj sferi, sa izraženom stimulacijom afektiviteta, a zatim vidno poboljšanje interesovanja, aktivnosti, komunikativnosti, inicijative, ponašanja i spoljašnjeg izgleda.
SPOREDNI EFEKTI ISPITIVANJA Sporedni efektiiIspitivanja bili su zapaženi u sledećem redosledu: nesanica kod 9, umor kod 6, mišićni nemir kod 6, hipnosedacija kod 4, nedostatak izražajnosti kod 3, akatizija kod 3, mišićni tremor kod 2, akazizija i tazikinetija kod 1, okulogirne krize kod 1, rigidnost mišića kod 1, protruzija jezika kod 1,i parkinsonizam kod 1 bolesnika. Sve ove gore navedene nuzpojave javljale su se najčešće na početku lečenja i nisu zavisile od doze leka. Nesanicu smo otklanjali uvođenjem Mogadona, a ostale nuzpojave ordiniranjem antiparkinsonika od 6 do 15 mg dnevno. Efekat je bio brz, a sve pojave blage. Interesantno je napomenuti, da je jedan bolesnik, za celo vreme dok je bio na Penfluridolu, to jest za vreme od 14 meseci, dok je primao po 20 mg sedmično, bio u dobroj remisiji, a nuzpojave nisu bile zabeležene.
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ZAKLJUČAK Penfluridol /R 16 341,Semap/ je neuroleptik sa protrahiranim dejstvom ali bez hipnosedativnog dejstva. U toku ispitivanja zapazili smo njegovu terapeutsku eflkasnost kod hroničnih shizofrenlh psihoza dužeg trajanja. Njegovo stimulativno i antiautističko delovanje, kao i oralna primena, daju mu prednost među psihofarmacima, a snažno antipsihotično dejstvo ga ubraja u red savremenih neuroleptika.
LITERATURA 1) Bobon J., Melon J„ Mormont., C., Dufrasne M., Pinchard A., Neuroleptique á longue duree d› action. III: Etude pilote du penfluridol. Acta Neurolog. Belg.70,523,1970. 2) Janssen Pharmaceutica: Basic medical information on Penfluridol Research Laboratories, 1973. 3) Mormont Ch.: Neuroleptiques álongue duree d› action. III. Etude pilote du penfluridol /R 16 341/: donées psychométriques, Acta Psychiat. Belg. 72, 595, 1972. 4)Roelofs G.: ”Penfluridol /R 16 341/ as a maintenance therapy in chronic psychotic patients: a double-blind clinical evaluation. Acta psychiat. scand. 1974, 50, 219-224.
SUMMARY
PENFLURIDOL IN TREATING THE SCHIZOPHRENIC CHRONIC PSYCHOSES Penfluridol /R 16 341/ was administrated by us in 26 chronic schizophrenic patients of male sex, 30 to 54 years old, with case history from 3 to 25 years. The investigation lasted from 3 to 14 months and doses varied from 20 to 60 mg /or 1 to 3 tabl./ per week. In the course of this investigation we reached the following results: notable amelioration / + + + / in 11 patients or 42,30% partial amelioration / + + / in 10 patients or 38,46% unsuccess /0/ in 5 patients or 19,24% Total 26 100% Side-effects were mild and negligible and we removed them by the administration an oral antiparkinsonian agent from 6 to 15 mg. Penfluridol, as a potent antipsychotic with prolonged duration of action and easy oral administration, has found its place among the modern neuroleptics in treating the schizophrenic chronic psychoses. Božidar Igniatović, neuropsihijatar Nouropalhijatrijska bolnica “Dr. Slavoijub Bakalović“ Vršac, Podvršanska, 7
IGNJATOVIĆ, B.
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ZNAČAJ VISOKIH I NISKIH DOZA NEUROLEPTIKA U LEČENJU SHIZOFRENIH PSIHOZA Autor opisuje iskustva pojedinih autora, kao vlastito iskustvo stečeno primjenom visokih, srednjlh i niskih doza neuroleptika.
UVOD Danas je poznato, da neuroleptici kao psihotropne supstancije zauzimaju dominantno mesto među savremenim psihofarmacima. Njihova uloga i značaj u lečenju shizofrenlh psihoza imaju prioritet u terapijskom pristupu. Iskustva u primeni istih su mnogobrojna i raznovrsna, a postignuti rezultati veoma povoljni u otklanjanju psihopatološke simptomatologije. Međutim, postoje vidne razlike u doziranju. Dok jedni preporučuju niske i srednje doze drugi su za primenu visokih doza neuroleptika. Treća grupa kliničara daje prednost kombinaciji dva ili više neuroleptika. Sigurno je, da sva tri predloga imaju svoje opravdanje, te bi naš cilj bio da na osnovu naših ispitivanja i postignutih rezultata doprinesemo pravilnom usmeravanju primene neuroleptika, kao i upoznavanju sa njihovim pozitivnim i negativnim osobinama u okviru predlagane pozologije. Nesumnjivo je, da različite doze neuroleptika ispoijavaju i različita dejstva. Međutim, i jedan isti neuroleptik, može da ima različite efekte na postojeći shizofreni sadržaj, a sve to zavisno od doze, tolerancije i evolucije postojeće psihoze. Poznato je, da neuroleptici u malim dozama ispoljavaju samo psiholeptičko dejstvo, a u većim i hipnotičko. Isto tako se zna, da sedativni neuroleptici u većim dozama imaju antipsihotično dejstvo, a antipsihotični u većim dozama i sedativno dejstvo. Znači da svi neuroleptici istovremeno poseduju i sedativno i antipsihotično dejstvo, zavisno od doze koja bude primenjena u datom momentu. Tako se nameće pravilo, da bi za postizanje odgovarajućeg efekta bilo potrebno primeniti i odgovarajuću dozu. Levomepromazin (Nozinan) u manjim dozama ima umirujuće dejstvo i pojačava san, u srednjim je odličan anksiolitik, a u većim pored sedativnog ispoljava i antipsihotično dejstvo. Radi boije i što preglednije ilustracije pozologije i efekta neuroleptika, kao najbolji primer može da nam posluži flufenazin (Moditen) koji ispoljava polivalentno dejstvo: umirujuće u malim dozama od 0,5 do 5 mg; anksiolitičko od 100 do 200 mg; sedativno od 100 do 1500 mg i antipsihotično od 5 do 1800 mg dnevno. Dalje se zna, da flufenazin u dozi od 0,25 do 2 mg ima umirujuće dejstvo kod neuroze, a u srednjim dozama od 10 do 300 mg anksiolitičko i antidepresivno, Kod manijakodepresivnih psihoza, u maničnoj fazi, veće doze flufenazina mogu izazvati depresivno raspoloženje. Doziranje flufenazina je strogo individualno, pa je potrebno istraživati optimalnu pozologiju a ne mlnimalnu kao što se to radi sa drugim neurolepticima. Ako je doziranje neuroleptika nedovoljno, bolesnici se žale na brzo zamaranje, depresivne tendencije, afektivnu tupost, astenične smetnje, te postaju pasivni, anksiozni, mrgodni i mrzovoljni, a prethodno postojeći pslhopatološki sadržaj počinje da egzacerbira pa bolesnik izgleda kao da se muči, kao da mu nešto nedostaje. Svi ovi gore navedeni simptomi nestaju kad se doze neuroleptika povećaju. Kao efikasne doze flufenazina neki preporučuju 200 do 400 mg, a kod nekih se one kreću do 1000 mg. Kod predoziranja, bolesnik je obično usporen, inhibiran, pasivan, više ili manje nesvestan svojih poremećaja, somnolentan. lz tih razioga se ne žali na svoje tegobe već ih podnosi pasivno i ravnodušno. Po pravilu, njegova okolina upozorava na njegovu apatiju, usporenost i somnolenciju. Predoziranje može takođe održavati ili prouzrokovati pslhotične poremećaje, aktivirati ili pojačati halucinacije. Sve ove pojave nestaju nakon naglog smanjenja doze datog neuroleptika. Doziranje flufenazina je strogo individualno i to kako premo svakom bolesniku, tako i premo involutivnom vremenu bolesti svake osobe, a kreće se u granicama od 2 do 1800 mg. Taj njegov raspon u efektivnom doziranju, zahteva od terapeuta stalan i neprekidan nadzor, kao i najpažljiviju budnost. Uzrok mnogih smrtnih ishoda, koji se navode u literaturi, možda leži baš u odsustvu ovih mera predostrožnosti a ne u visokoj dozi neuroleptika. Gayral I Lambert (1966) su na 142 bolesnika ispitivall flufenazin u dozama između 100 do 1000 mg za vreme od tri godine. Lek su primenjivali uglavnom kod shizofrenih bolesnika i zabeležili značajno poboljšanje autizma, inertnostl i apragmatizma. Oni su vrlo često uz flufenazin ordinirali i visoke doze sedativnih neuroleptika od 100 do 500 mg radi postizanja boljeg sedativnog efekta. Korbar I sar. (1976) navode da su najbolje rezultate postigli primenom visokih doze flufenazina od 600 mg. Neki autorl navode optimalne doze od 150 do 7500 mg. Dalje se opisuje dobra podnošljivost flufenazina u dozi od 50 do 500 mg bez značajnih kardiovaskularnih promena. Mi smo na našem materijalu, kod ispitivanja flufenazina u dozi od 100 do 800 mg, postigli optimalan uspeh u lečenju shizofrenih psihoza na dozi od 600 mg u najvećem broju slučajeva. Međutim, osim ispoljenih sporednih etekata kod nekih bolesnika, drugih nepoželjnih sekundarnih pojava nismo imali. lz literature su poznata i dva smrtna slučaja (Henry, 1971) kod aplikacije Moditena-depo. Vitorović (1967) navodi 28 smrtnih slučajeva kao posledice neuroleptika kod starijih bolesnika, zatim lečenih od ateroskleroze, srčanih oboljenja i kod osoba sklonih ortostatskom kolapsu. Isti autor navodi i komplikaclje pri upotrebi niksih ambulantnih doza neuroleptika pa zbog toga preporučuje obazrivost kod starijih, ateroskleroze, hipertoničara, vegetativno labilnih i tamo gde je CNS lediran pre terapije.
NAŠA ISKUSTVA U toku desetogodišnjeg iskustva imali smo mogućnosti da primenjujemo flufenazin u svim oblicima prolzvodnje: tabletama od 1 mg, 2,5 mg, 5 mg, 25 mg, 100 mg i ampulama u depo obliku od 25 mg. Polivalentno dejstvo kao i različit uspeh u lečenju shizofrenih psihoza zavisio je uglavnom od doze i evolucije bolesti.
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Kod 47 shizofrenih bolesnika, muškaraca, od 18 do 51 godine starosti primenjivali smo niskodozni flufenazin (25 do 75 mg) i visokodozni flufenazin (100 do 800 mg) dnevno u vremenu od 1 do 4 meseca. Kod 11 bolesnika smo primenili niskodozni flufenazin, a kod 38 visokodozni. Optimalni efekat smo zabeležili kod 20 bolesnika na dozi od 600 mg, kod 4 na 400 mg, kod 3 na 300 mg, kod 5 na 100 mg, kod 2 na 75 mg, kod 3 na 50 mg i kod 2 na 25 mg. lz ovoga se vidi, da smo najbolji uspeh, kod najvećeg broja slučajeva, postigli na dozi od 600 mg, all se vidi i to da optimalne doze nisu iste kod svlh, te ih treba tražiti i na njima se duže zadežavati. Jedna ista doza kod jednog bolesnika može da bude optimalna, kod drugog nedovoljna, a kod trećeg da ukazuje na predoziranost i nepodnošljivost. Na kraju smo zabeležili sledeće rezultate: znatno poboljšanje kod 23 bolesnika ili 48,9% dellmično poboljšanje kod 16 ili 34 % i neuspeh kod 8 ili 17,1%. Nuzpojave smo zabeležili kod 40 slućajeva ili 85,1%. Kod 89 shizofrenih bolesnika, muškaraca, od 21 do 65 godina starosti, primenjivali smo flufenazin (7,5 do 15 mg) uz jedan od sedativnih neuroleptika (75 do 600 mg) i antoparkinsonik (6 do 15 mg) u vremenu od 3 do 7 meseci. Na kraju smo zabeležili sledeće rezultate: znatno poboljšanje kod 46 ili 51,68%, delimično poboljšanje kod 35 ili 39,34% i neuspeh kod 8 ili 8,98%. U toku ispitivanja nuzpojave nismo zabeležili. Bolji uspeh je zapažen primenom ove kombinovane terapije. Kod 66 shizofrenlh bolesnika, muškog pola, od 21 do 64 godine starosti, primenili smo Moditen-depo od 25 mg na 25 dana, u vremenu od 2 do 14 meseci i to kod 27 samo Moditen-depo a kod 39 pored njega dodali smo i 1 sedativnl neuroleptik (75 do 300 mg) i 1 antiparkinsonik (6 do 15 mg). Rezultati su bili sledeći: znatno poboljšanje kod 35 ili 53%, delimično poboljšanje kod 14 ili 21,3% i neuspeh kod 17 ili 25,7%. Upadijivo je da su rezultati približno kao kod primene visokodoznog i niskodoznog flufenazina. Nuzpojave su bile ispoljene kod 29 slučajeva ili 43,94%. Kod 20 shizofrenlh bolesnika, muškog pola, kod 27 do 46 godina starosti, ordinirali smo flufenazin u dozi od 30 mg dnevno. U toku lečenja morali smo da dodajemo kod nekih i po jedan od sedativnih neuroleptika (75 do 300 mg) da bi postigli bolji efekat u otklanjanju psihopatološkog sadržaja, kao i jedan antiparkinsonik (6-15 mg) radi otklanjanja ekstrapiramidalnih pojava kojih je bilo 100%.
ZAKLJUČAK Dejstvo neuroleptlka, prikazano na flufenazinu, može da bude polivalentno, to jest u različitim dozama različito. Efekat dejstva zavisi od doze, tolerancije i evolucije psihoze. Optimalni efekat se postiže kod flufenazina u najvećem broju slučajeva na dozi od 600 mg, kao i na nižim dozama ali uz davanje jednog od sedativnih neuroleptika. Doze od 30 mg su kod pojedinlh bolesnika nedovoljne za otklanjanje postojećeg shizofrenog sadržaja, te je potrebno administrirati i po jedan sedativnl neuroleptik. Nuzpojave su češće kod doze od 30 do 75 mg nego kod doza od 100 do 800 mg, te za boiji uspeh dodavati i antiparkinsonik.
LITERATURA 1 ) Males medico-psychologiques, 1965, 5, 821-824. 2) Congres international de neuropsychopharmacologie, Washington, 1966, 3) Fouks, L.: IVme Congres Modial de psychiatrie, Madrid, 1966. 4) Flufenazine high dose protocol, E.R. Squibb and Sons LTD. 5) Korbar, M. , Belev, B., Pauković, M.: Lečenje visokim dozama flufenazin klorida, Neuropsihijatrija, lzdanje Zagreb, 1976, 24, 115119. 6) La Presse Medicale, 1971, 51 1757. 7) Milovanović, D.: Klinička psihofarrnakologija, Izdanje Lek, Ljubljanja, 1972. 8) Medical references, High dosage moditen/flufenazine/ E.R. Squibb and Sons LTD. 9) Petrović, D., Sedmak, T.: Psihofarmakoterapija dugo lečenih psihoza shizofrenog tipa, u Anali zavoda za mentalno zdravlje, Beograd, 1974. 10) Vitorović, M.: Psihofarmakologija, lzdanje Zagreb, 1968, 129-132, 294-300. 11) Vitorović, M.: Psihijatrija, Izdanje Lek, Ljubljana, 1969, 211-217.
THE IMPORTANCE OF HIGH AND LOW DOSES OF NEUROLEPTICS IN TREATMENT SCHIZOPHRENIC PSYCHOSES IGNJATOVIĆ, B. The author describes the experience of the other reseachers as well as his own in the appliance of high, midle and low doses of neuroleptics, on the bases of the administration of fluphenazine (Moditen) being alone and in combination with sedative neuroleptics. Polyvalent action of Moditen depends on the doses, but the optimal effect was reached at dose of 600 mg in the bigest number of schizophrenic patients; some workers give doses from 100 to 750 mg. By the application of low doses of fluphenazine, as well as in the case of unsufficient dosage - better results in the reduction of schizophrenic content were noted by the increase of the doses of moditen or by the addition of the sedative neuroleptics. By product symptoms appeared sooner at the low-dose moditen than at the high-dose one. These symptome were removed by the addition of anti-parkinsonics. Božidar Igniatović, neuropsihijatar Neuropsihijatrijska bolnica Dr Slavoljub Bakalović 131
RACIONALNA UPOTREBA PSIHOFARMAKA (Izvodi iz predavanja održanih u okviru Sedmog seminara za stručno poslediplomsko usavršavanje lekara dana 7. maja 1977. godine u Vršcu)
Predavači: Prof. Dr Dimitrije Milovanović, Neuropsihijatrijska klinika Medicinskog fakulteta, Beograd; Prof. Dr Vladislav Varagić, Farmakološki institut Medicinskog fakulteta, Beograd; Prof. Dr Stojan Vučković, Institut za neuropsihijatriju i mentalno zdravlje, Medicinski fakultet, Novi Sad; Dr Božidar ignjatović, neuropsihijatar, Neuropsihijatrijska bolnica, Vršsac, u koautorstvu s dr Brankom Vučkovićem, dr Draganom Jevdićem, dr Dragoljubom Jovanovićem i dr Svetozarom Bokorovom, neuropsihijatrima Neuropsihijatrijske bolnice, Vršsac. Psihofarmaka su za nepune tri decenije svoga postojanja zauzela čvrsto mesto u savremenoj medicini. Ova grupa lekova izlazi daleko izvan područja rada neuropsihijatra. Pored upotrebe od strane specijalista svih grana kliničke medicine, ova sredstav ulaze u svakodnevni terapijski arsenal lekara opšte prakse. Prema nedavno sprovedenim istraživanjima Zavoda za farmakologiju i toksikologiju medicinskog fakulteta u Novom Sadu, u kojima se korišćenje lekova izrazilo kroz broj doza izdatih za pojedine farmakoterapijske skupine lekova, zastupljenost psihofarmaka čini čak 11% svih propisanih doza u ambulatnim uslovima (receptura SIZ Novi Sad) i 17% od svih primenjenih doza na klinikama Medicinskog fakulteta u Novom sadu. Slični podaci kao na klinikama Medicinskog fakulteta u Novom Sadu su i podaci dobijeni istom metodologijom u Medicinskom centru „Dr Radivoj Simonović“ u Somboru. Pri tome je nađeno da sve klinike i sva odeljenja ove dve ustanove koriste psihofarmaka u značajnoj meri. Ovi podaci stoga jasno govore o potrebi stalne edukacije lekara o racionalnoj upotrebi ove relativno nove skupine lekova. „Medicinski pregled“ je u svome dvo-broju 9/10 (volumen 30), 1977, str. 509-512 već objavio tekst profesora Stojana Vučkovića pos naslovom „O psihijatrijskoj dijagnozi danas“. Taj tekst sadrži deo materije koju je prof.Vučković izneo, pa se čitalac upućuje tamo. U istom broju ovoga časopisa (str.513-515) objavljen je članak doc.dr Milana Stanulovića, doc.dr Nile Kapor-Stanulović i doc.dr Branka Baniča pod naslovom „Problemi u kliničkoj oceni efekata psihofarmaka“, i na koji takođe upućujemo zainteresovanog čitaoca.
PREGLED KLINIČKE UPOTREBE SAVREMENIH PSIHOFARMAKA D. Milovanović Dosadašnja iskustva sa psihotropnim supstancama opravdala su njihovu primenu ne samo u psihijatriji, već i u nizu drugih medicinskih disciplina. Za četvrt veka svog postojanja i razvitka ova nova oblast, interdisciplinarno postavljena – psihofarmakoterapija – sakupila je veliki broj novih saznanja, uočila aktuelne probleme i odredila puteve daljih istraživanja. Niz nerešenih pitanja ipak ne umanjuje svu ekstenzivnu i intenzivnu racionalnu upotrebu različitih vrsta psihofarmakoloških sredstava. U svetlu kliničkeprakse pitanje njihovog klasifikovanja nije do kraja usaglašeno. Ovome ne protivureču činjenica da su ovde mogući različiti pristupi, kao: biohemijski, farmakološki i drugi, ali se u najvećem broju slučajeva ima u vidu njihovo delovanje na ponašanje čoveka i ovaj aspekt postaje vodeći prilikom izrade svake vrste klasifikacija. U tom smislu psihofarmaci se dele u tri velike grupe: psiholeptike, psihoanaleptike i psihodizleptike. Najviše upotrebljavani u medicini su danas preparati iz grupe psiholeptika. Ovim imenom se označavaju svi oni lekovi koji, ispoljavajući svoje dejstvo u oblasti moždanog stabla, redukuju stanja povišene psihičke aktivnosti mozga i time oduzimaju snagu centralnom nervnom sistemu. Dalja njihova diferencijacija dovodi ih do podele na: hipnotike, ataraksike i neuroleptike. Hipnoticima se nazivaju takva sredstva koja izazivaju veštački san, a mogu biti barbiturnog i nebarbiturnog porekla. Veoma se mnogo koriste u medicini ne samo u psihijatrijskoj, već i u bolesnika iz svih ostalih grana medicine. Njihova nekontrolisana upotreba veoma je široka i u pripadnika tzv.zdrave populacije. U naše vreme ova sredstva se najčešće koriste namerno u samoubilačke svrhe, ili kao zadesna prilikom intoksikacija u dece. Ataraksicima ili anksioliticima se naivaju oni medikamenti koji ublažavaju stanja straha, psihičke napetosti i uznemirenosti, a uz to deluju blago antikonvulzivno, dok na periferiji izazivaju smanjivanje mišićne napetosti. Veruje se da je potrošnja ovih lekova enormna u celome svetu. Međutim, nema sumnje da se i pri stogo racionalnom doziranju javlja opravdana potreba za visokim konzumiranjem ataraksičnih preparata. Rizici koji prate upotrebu ataraksika su mogućnost navikavanja i pojava zavisnosti od ovih medikamenata (tabletomanije). Neuroleptici deluju sedativno, nenarkotički u terapijskim dozama, obuzdavajući psihomotorni nemir, u prvom redu psihoza, i utičući pozitivno na shizofrene i manične sindrome. Antipsihotični efekt ovih preparata ogleda se, pre svega, u kupiranju produktivnih psihotičnih fenomena (halucinacije i sumanute ideje), a u nešto blažem obimu i deficitarnih i regresivnih psihopatoloških pojava. Lekovi iz ove grupe (tzv.bazični, sedativni i snažni neuroleptici) doveli su do radikalnih promena u psihijatriji i olakšali humanizaciju postupanja sa psihijatrijskim bolesnicima. Nasuprot pozitivnom sedativnom i antipsihotičnom efektu, neuroleptici iz različitih grupa raspolažu i nepoželjnim motornim fenomenima ekstrapiramidnog tipa i vegetativnim pojavama. Mogućnost pojave paroksizmalnih i tardivnih diskinezija, kao i hipotenzivnih kriza nalaze korektivnu medikaciju sa antiparkinsonicima i analepticima. Prvim dvema generacijama sada se pridružuje treća, a na pomolu je i četvrta generacija neuroleptika s manje nuzefekata, a s dinamizirajućim i sve više selektivnim delovanjem. Osim ovih osobenosti, danas postoje sintetizovani neuroleptici s brzim, prolongiranim (retard-oblici) i dugotrajnim dejstvom (depo.oblici).
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Psihoanaleptici se dele na timoleptike i timeretike. Zajednički pojam označava sposobnost određenih supstanci da podižu nivo psihičkog života, u prvom redu podsticanjem raspoloženja i voljno-nagonskih dinamizama. Osim ovih dveju podgrupa, ovde se ubrajaju i psihostimulansi ili energizeri koji jednim dejstvom na opšte stanje organizma takođe deluju analeptičkim efektom. Dugo vremena u medikamentoznoj terapiji depresija vodeće mesto pripadalo je inhibitorima monoaminooksidaze. Oni su odigrali važnu ulogu, jer je uz njihovu pomoć došlo do uspostavljanja kateholaminske teorije o nastanku depresija. Upravo dejstvo MAO inhibitora zasnivalo se na njihovoj osobini da povećaju sadržaj monoamina u mozgu uz istovremeno kočenje njihove intracelularne metaboličke razgradnje. Primena MAO inhibitora je bila praćena brojnim nuzefektima, posebno od strane kardiovaskularnog, renalnog, hepatičnog, retikuloendotelijalnog i autonomnog nervnog sistema, pa je vremenom napuštena. Posle napuštanja MAO inhibitora u terapiju depresija uvedeni su triciklični antidepresivi s reprezentantom imipraminom. Ovaj preparat, posle izvanrednih rezultata, sve manje je imao mesta u terapiji depresija, ali je značajan po nešto drugačijem mehanizmu dejstva. On ne deluje na enzimatske procese razgradnje i sinteze moanamina, već koči aktivni transport noradrenalina i 5-hidroksitriptamina u sinaptozome. Danas su drugi preparati iz grupe antidepresiva – triciklični i tetraciklični – zauzeli vodeće mesto u lečenju depresivnih sindroma. Psihodizleptici kao supstance sposobne da menjaju aktivnost centralnog nervnog sistema nisu našli svoje mesto u medicinskoj praksi i njihova upotreba nosi mnogo veće rizike nego koristi.
MEHANIZAM DELOVANJA PSIHOTROPNIH LEKOVA V.M. Varagić Razumevanje mehanizma delovanja psihotropnih lekova intimno je povezano s boljim razumevanjem metabolizma biološki aktivnih supstancija u velikom mozgu, pre svega biogenih amina (kateholamini, 5-hidroksitriptamin, histamine). Per analogiam se može pretpostaviti da će i u centralnom nervnom sistemu, baš kao i na periferiji, najosetljiviji prema dejstvu lekova biti procesi neurohumoralne transmisije nadražaja. U centralnom nervnom sistemu postoji veći broj biološki aktivnih supstancija koje vrše ulogu transmitera nadražaja, ili su pak sposobne da deluju kao modulatori te transmisije. Ipak, daleko najveći značaj ima sposobnost psihofarmaka da promene metabolizam kateholamina (dopamine, noradrenalina, adrenalina) u velikom mozgu. Poseban značaj imaju novija saznanja o sistemu cikličnog adenozin monofosfata u mozgu, o delovanju lekova na adrenalinu ciklazu, o identičnosti dopaminskog receptora i adenilne ciklaze u nekim strukturama mozga. Veliki broj psihofarmaka upravo deluje na ovaj osetljivi system, što podrazumeva da se na ovaj način menja ne samo receptorna aktivnost, već i metaboličke karakteristike neurona.
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ZNAČAJ EKSTRAPIRAMIDALNIH POJAVA KOD PRIMENE PSIHOFARMAKA B.Ignjatović, D.Jevdić, B.Vučković, D.Jovanović i D.Milovanović Složenost mehanizma dejstva psihotropnih droga u današnje vreme nesumnjivo izaziva veliko interesovanje. Pored sposobnosti da modifikuju mentalnu aktivnost oveka, da utiču na ponašanje, preko metabolizma mozga, one izazivaju i iznenadne sekundarne pojave, često intezivne i ponekad alarmantne, akoje su grupisane pod opštim nazivom ‘sindrom impregnacije’. Ove supstancije su, dakle, podjednako sposobne da vrše svoje dejstvo na izvesne nervne strukture, kortikalne i supkortikalne, koje neprekidno kontolišu motorne, tonične, posturalne ili refleksne aktivnosti, ili tačnije rečeno, aktivnost efektornog sistema. Danas ne samo da je to prihvaćeno, već je i dokazano da se dejstvo neuroleptika odvija uglavnom u nivou retikularne formacije moždanog stabla, bilo direktno ili indirektno, zvog njenih releja sa svim ostalim centralnim nervnim strukturama. Tako, od donje bulbarne regije do hipotalamusa izvesni delovi su stvarno u tesnoj vezi s malim mozgom, drugi predstavljaju anatomski supstrat aktivatornih i inhibitornih sistema, ulaznih i silaznih, koji su međusobno povezani i u vezi s korteksom, talamusom, hipotalamusom, sivim jedrom i rinencefalonom. Ova retikularna formacija predstavlja strukturu u isto vreme dinamogenu i inhibitornu, koja istovremeno reguliše kortikalnu i medularnu aktivnost, a osobito kontroliše monosinaptičke reflekse. Retikularna aktivnost je na taj način potčinjena jednom intracerebalnom kruženju retikulo-kortiko-retikularnoj retroakciji, inhibitarnom dejstvu, koje se može priključiti klasični fronto-retikularni put, čija aktivnost pojačava dejstvo bulbarne inhibitorne mrežaste formacije. Polazeći od ovih podataka, može se osmotriti mehanizam neurofiziološkog dejstva neuroleptika u determinizmu sindroma impregnacije. Proučavajući dejstvo psihotropnih droga J. Rigal i sar. su obelodanili njihovo dejstvo na sisteme alfa i gama koji kontrolišu aktivnost motornih ćelija prednjeg roga. Dokazano je da flufenazin u visokim dozama stimuliše, ahloropromazin deprimira sisteme alfa i gama, te otuda podela neuroleptika na snažne (oštre) i sedativne. Snažni neuroleptici, kao što su flufenazini, stimulišući alfa i gama sisteme, prouzorkuju ekstrapiramidalne pojave, a sedativni, kao što su hlorpromazin, deprimirajući ove sisteme, sprečavaju pojavu istih. Prema tome, ekstrapiramidalne pojave izazvane snažnim neurolepticima mogu se predvideti, preduhitriti, ili ublažiti dodavanjem nekog drugog sedativnog neuroleptika. Mi smo na našem materijalu, u 84 shizofrenih psihoza, ordinirali kombinovanu terapiju sedativnih neuroleptika (levomepromazin, tioridazin i hlorpromazin) pojedinačno uzetih, uz flufenazin (moditen) i jedan antiparkinsonik (artane) postigli sledeće rezultate: znatno poboljšanje u 41, delimično poboljšanje u 35 i neuspeh u 8 bolesnika. Ekstrapiramidalne pojave nismo očekivali, pa se iste nisu ni pojavile. U literaturi postoje dva suprotna stava o terapijskom značaju neurološkij sindroma izazvanih neurolepticima. Dok jedni smatraju da neurološke pojave poseduju određen terapijski efekt, te ih treba provocirati, dotle drugi misle da su one suvišne i nepoželjne. Pristalice prvog shvatanja navode korisnot ekstrapiramidalnih pojava za ishod lečenja, pa smatraju da postoji i korelacija itmeđu intenziteta ekstrapiramidalnih simptoma i stepena poboljšanja mentalnih oboljenja. Oni su protiv sprečavanja ekstrapiramidalnih pojava uvođenjem antiparkisonika koji, po njima, remete procenu dejstva neuroleptika. Pobornici suprotnog stava predlažu paralelnu primenu neuroleptika i antiparkisonika, jer smatraju da je nehumano i protivno lekarskoj etici namerno izazivati ekstrapiramidalne pojave koje bolesnici mučno doživljavaju, a pored toga postoje i hipoteze da bi mogle preći u hronične. D. Milovanović u svojoj knjizi „Klinička psihofarmakoterapija“ navodi da su u bolesnika lečenih neurolepticima paroksizmalne diskinezije registrovane u 24% slučajeva, a u bolesnika lečenih kombinovanom terapijom nije bilo zapaženo ispoljavanje paroksizmalnih diskinezija i ostalih neuroloških sindroma neuroleptičkog porekla. U prvih su postigli znatno poboljšanje u 77% slučajeva, a u drugih u 80% slučajeva. Prema gore navedenim rezultatima, a takav je i naš stav, terapijski efekat neuroleptika je jednak, bez obzira na to da li se oni primenjuju sami ili zajedno sa antiparkinsonicima. S druge strane, paralelna primena neuroleptika i antiparkinsonika onemogućuje pojavu ekstrapiramidalnih siptoma. Prema kliničkim rezultatima NPK u Beogradu, negira se terapijska vrednost paroksizmalnih diskinezija, pa samim time i potreba za namernim provociranjem. U novije vreme otkrićem slozapin-a (leponex-a) došlo je do novog zaokreta u mišljenjima i stavovima. Tako, dok su ranije novosintetizovana jedinjenja bila klinički proučavana samo ako su već ispoljila značajnu kateleptičku aktivnost u eksperimentima na životinjama, danas to više nije pravilo. Clozapin ima isti terapeutski efekat kao i „klasični neuroleptici“, ali se razlikuje od njih u tome što ne utiče na ekstrapiramidalne pojave pri eksperimentu na životinjama, niti pri aplikaciji na ljudima. Po hemijskom sastavu clozapin je blizak „klasičnim neurolepticima“. Gross i Langer su potvrdili nalaze Bente-a (1966 g.) i Berzewsky-a (1969 g.) da je terapeutska efikasnost tricikličnih neuroleptika nezavisna od njihovog efekta na ekstrapiramidalne funkcije. Biohemijskim istraživanjima je dokazano da clozepin, kao i „klasični neuroleptici“, utiče na metabolizam dopamina, tj.u shizofrenih bolesnika dovodi do porasta kocentracije HVA (homo vanilinske kiseline) u mozgu, ali suprotno „klasičnim neurolepticima“, utiče i na metabolizam norepinefrina.
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Primenjujući i ispitiujući clozapin u shizofrenih psihoza, odnosno u 61 bolesnika, postigli smo sledeće rezultate: znatno poboljšanje u 35 ili 57,4%, delimično poboljšanje u 21 ili 34,5% i neuspeh u 5 ili 8,1%. Ekstrapiramidnih pojava nije bilo, te ih nismo mogli ni da registrujemo.
ZAKLJUČAK Ekstrapiramidalne pojave koje daju snažni neuroleptici stimulišući alfa i gama sisteme nisu vuše dokaz terapijske vresnosti. Sedativni neuroleptici u kombinaciji sa snažnim neurolepticima smanjuju pojave ekstrapiramidalnih siptoma, a dodavanjem atiparkinsonika ih sprečavaju. Iz tih razloga ekstrapiramidalne pojave ne treba provocirati, već suzbijati. Neuroleptici koji ne utiču na ekstrapiramidni sistem, te na taj način i ne daju ekstrapiramidalne pojave (clozapine) mogu da ispoljavaju snažno antipsihotično dejstvo kao i “klasični neuroleptici”.
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KLINIČKI ASPEKTI HRONIČNIH NEUROLEPTIČKIH POJAVA B. Vučković, B. Ignjatović. D. Jevdić i D. Jovanović Da bi se mogla pratiti problematika koja nastaje u vezi sa sporednim efektima i komplikacijama primene neuroleptičke terapije, neophodno je poznavanje kliničke slike, načina lečenja i profilakse. Ove pojave su veoma raznolike, one zavise od individualne osetljivosti organizma, ali i niza drugih faktora, a javljaju se kao rezultat direktnog dejstva preparata na organizam. S terapijskog aspekta važna je diferencijacija ovih pojava koje u najopštijem smislu možemo razdvojiti na povratne ili funkcionalne i nepovratne odnosno organske. Pri ovakvoj orijentaciji nećemo se zadržavati na pojavama kratkotrajne primene, niti pak na akutnim pojavama koje prate dugotrajnu primenu. Zadovoljićemo se time da ih samo spomenemo. Dugotrajnu primenu neuroleptika, kao i ukidanje istih, prati niz izraženih komplikacija koje se mogu obuhvatiti u jedinstvenu pojmovnu celinu hroničnog ekstrapiramidnog sindroma. Ovaj sindrom se javlja prilikom primene svih psihotropnih lekova (trankvilizeri, antidepresivi), ali daleko najčešće uz primenu neuroleptika. Ove komplikacije perzistiraju mesecima i godinama i ne pokazuju tendenciju regrediranja. Pojam i značaj ovog sindroma najbolje se može sagledati iz kliničke slike koju smo iz didaktičkih razloga pratili kroz tri sledeće komponente: Ekstrapiramidni znaci: oralne diskinezije, atetoidno-horeiformne hiperkinezije, mioklonije, tremor, hipertoničko-akinetički sindromi i akinetički sindrom. Psihički znaci: psihička pasivnost, aspontanost, redukcija motivacija i sumanutih ideja, emocionalna nepostojanost sa psihičkim hiperestezijama, anksioznost. Vegetativni znaci: poremećaj rada srca, vaskularnog tonusa, motorike i sekrecije digestivnog trakta, znojnih i lojnih žlezda. Ove znake prate poremećaji metabolizma masti, vode i soli, hipovitaminoze. Uz ove javljaju se i poremećaji endocrine regulacije. Ova trijada znakova čini suštinu hroničnog ekstrapiramidnog sindroma. Biohemijski aspekti: ovde je naročito važno zadržati se na pojavama koje nastaju posle ukidanja neuroleptičke terapije. Ukidanje izaziva, ili jako potencira pojavu hiperkinetičkog poremećaja. Činjeni su pokušaji da se ova pojava objasni, oslanjajući se na hipotezu Pletcher-a, prigušenjem biogenih amina: kao kompenzatorna pojava u tkivima mozga stvara se višak monoamina – koji, pak, uzrokuje sindrom lišavanja. Ovu teoretsku postavku neki autori su pokušali da iskoriste za postavljanje hipoteze o narkomanskom privikavanju na neuroleptike. U prilog ovome spomenimo da Prokudin (1912) smatra da se pri ovome formira kompulsivna zavisnost od neuroleptika, koju prati i psihička, što se manifestuje pojavom straha i neurotskih smetnji pri lišavanju. Battegay – koji daje najiscrpnije opise ovih zavisnosti – smatra da postoji mogućnost nastajanja fizičke zavisnosti, bez pojava psihičke zavisnosti, povišenja tolerancije i samim time apstinencijalnih kriza. Terapijske specifičnosti: Hronični ekstrapiramidni sindrom je gotovo rezistentan prema antiparkinsonskim lekovima. Ovde se postiže olakšanje detoksikacionom terapijom: glikoze s vitaminima, male doze insulina, fiziološki rastvor NaCl supkutano; takođe preparati broma i trankvilizeri – oralno. Lokalne diskinetičke smetnje mogu se olakšati uvodjenjem kokaina ili sedativnih doza largaktila. Pojedina stanja (akatizija, tazikinezija, hiperkineza tipa hodanja, tahikinezija i sl.) uglavnom se kupiraju, pored antiparkinsonika, i meprobamatom. U zaključku ovoga rada pokušaćemo da damo odgovor na neka od suštinskih pitanja problema o kome raspravljamo. Problem optimalne dužine primene neuroleptičke terapije svakako je jedan od osnovnih. Odgovor na ovo pitanje može da pruži provera biohemijskih nalaza, kao što je patološki nalaz holesterola, transaminaza, elektorforeze serumskih proteina, timola, bilirubina, u tom smislu što bi njihovi određeni pokazatelji bili indikator za prekid neuroleptičke terapije. Kao drugo, nameće se pitanje koji od ovih poremećaja ostaju kao aktivno nepovratni neurološki, u tom smislu i psihički poremećaji. U odgovoru na ovo pitanje, napominjemo da se naša iskustva baziraju na praćenju grupe bolesnika tokom dugotrajne neuroleptičke terapije i posle njenog ukidanja. Zapazili smo da u približno jedne polovine slučajeva nema nikakvih kliničkih znakova sporednih efekata i komplikacija. U ostalog dela bolesnika zapažene su manifestacije apstinencijalnih znakova i kriza (kompulsivnost). Ipak, u većine ovog, drugog dela posmatrane grupe zabeležene su komplikacije ekstrapiramidne simptomatologije. Ovde je interesantno spomenuti da se ove komplikacije i efekti češće javljaju u žena. Na završetku želimo da istaknemo da smo duboko svesni činjenice da ovo nisu ni pravi ni potpuni odgovori. Bili bismo veoma zadovoljni ako bi naš rad, makar i u neznatnoj meri, uneo izvesnu svetlost u zamršenost ove problematike. Pitanja kojih smo se dotakli ostaju i dalje otvorena, odgovor na njih, nadajmo se, jeste delo budućnosti.
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DILEME PRI UPOTREBI PSIHOFARMAKA B. Ignjatović, B. Vučković, D. Jevdić, D. Jovanović i S. Bokorov Mesto i uloga psihofarmaka u današnjim uslovima su veoma značajni, i to ne samo u psihijatriji, već i u drugim granama medicine. Danas se zaista dosta zna o primeni psihofarmaka u neurologiji, internoj medicini, pedijatriji, hirurgiji, infektologiji, ginekologiji i akušerstvu. Posebno bi možda moglo da se govori o uslovima i potrebama da se proučavanjem psihofarmaka, odnosno psihofarmakoterapijom pozabave i bolje upoznaju ne samo specijalisti gore navedenih grana, već i lekari opšte medicine. Najveći broj bolesnika s funkcionalnim smetnjama različitih organa po pravilu se najpre obraća za pomoć lekaru opšte medicine ili specijalisti interne medicine. Ukoliko ne upute bolesnika psihijatru, ili iz bilo kojih razloga nemaju mogućnosti i vremena za to, oni su, hteli ili ne, u situaciji da prepišu neko od sredstava sa psihotropnim delovanjem. Neurovegetativne cistonije, psihosomatska oboljenja, hipertenzije granična su indikaciona područja interniste i psihijatra. Iz tih razloga internista je upućen ne samo na saradnju sa psihijatrom. Već mu je za kliničku praksu potrebno da poznaje osnove psihofarmakoterapije. Specifičnosti dečjeg doba opravdano nalažu posebnu obazrivost pri upotrebi psihofarmaka. Kao što je već poznato, deca pokazuju izuzetnu osetljivost prema psihofarmacima, a psihofarmaci se pak odlikuju mnogobrojnim nuspojavama dramatičnog izgleda, te se mora voditi računa o racionalnoj i kontrolisanoj upotrebi psihofarmaka u pedijatriji. Od ne manjeg značaja je upotreba psihofarmaka u hirurgiji. Kod izbijanja operativnih i postoperativnih konfuzno-delirantnih stanja hirurg nema vremena da se razmislja i da čeka, već mora odmah da se odluči koji psihofarmak i u kojoj dozi da primeni. Prilikom predoziranja butirofenona može da se kao znak intoksikacije javi dramatična klinička slika akutnog abdomena, a bolovi mogu biti izmenjeni, potisnuti ili provocirani pod uticajem psihofarmaka, te i o tome treba voditi računa. Shizofreni bolesnik često puta zbog gubitka afekta, osnosno emocionalne tuposti koja se ispoljava u apatiji i ravnodušnosti, kao i zbog nesklada draži i afekta (paratimija), nesklada između afekta i mimike (paramimija) ne daje adekvatne podatke, daje suprotne ili nikakve, tj.ponaša se suprotno od onoga što se u njemu zbiva. Iz ličnog iskustva znamo da su se neki naši bolesnici ponašali neadekvatno u stanjima postojećeg ileusa, te smo pored povraćanja, bledila i napetog trbuha zapazili potpunu ravnodušnost prema postojećim tegobama, a u nekih čak i osmeh na licu. Zbog svega ovoga se javljaju poteškoće u dijagnostici ileusa u nekih shizofrenih bolesnika, pa se samim time nameće i potreba za većom i uzajamnom saradnjom hirurga i psihijatra. Infektivne bolesti predstavljaju posebno mesto za saradnju infektiologa i psihijatra. Sigurno je da i ovde psihofarmaci imaju značajnu ulogu u suzbijanju psihomotornog nemira i insomnije u akutnih afekcija CNS izazvanih raličitim noksama, kao i pri upotrebi diazepama u terapiji tetaunusa. Sindrom menopauze, usled brojnih polimorfnih psihičkih somatskih tegoba za najbolji pristup u terapiji, zahteva upravo saradnju psihijatra, ginekologa i endokrinologa. Kod trudnica za vreme porođaja savremeni psihofarmaci mogu da ublaže strah i otklone afektivnu napetost. Eklamptična stanja, takođe, zahtevaju pravilan pristup lečenju. Sigurno je da ne treba biti u dilemi prilikom intervencije i odlučivanja koji psihofarmak dati i u kojoj dozi. Da li će to biti fenobarbiton, litički koktel, hlorpromazin ili diazepam, zavisiće od našeg poznavanja, iskustva i poverenja u odgovarajući psihofarmak. Posebno mesto u zajedničkom tretmanu imaju psihijatar i lekar opšte medicine pri primeni psihofarmaka kod neurotičnih sindroma, alkoholozma, akutne alkoholisanosti, apstinencijalnog sindroma u alkoholičara, patološkog napitog stanja, toksikomanije, epilepsije i dr. Iz gore navedenih činjenica može se izvesti kratak zaključak da se primenom psihofarmaka i u ostalim granama medicine oseća sve veća potreba za saradnjom, kao i većim poznavanjem uloge i dejstva psihofarmaka, a sve to radi pravilne i racionalne primene, radi postizanja što boljeg afekta i uspeha u lečenju. Posle ovoga, nameće se potreba da nešto kažemo o psihofarmacima, kao i o psihofarmakoterapiji u domenu psihijatrije. Psihofarmakoterapija je vrlo jednostavan i praktičan metod lečenja, pa je pogodna kako u hospitalnim tako i u ekstrahospitalnim uslovima. Pojavom prvih psihofarmaka psihofarmakoterapija počinje da probija sebi put postižući sve bolje rezultate u lečenju psihijatrijskih bolesnika, a sledstvenim povećanjem broja psihofarmaka postiže zavidan uspeh u psihijatriji, kakav ranije nije postigao nijedan drugi metod lečenja (piretoterapija, insulinoterapija, elektokonvulzivna terapija i psihoterapija). Psihofarmaci su aktivne hemijske supstance koje se vezuju za pojedine strukture mozga i na taj način otklanjaju, ublažavaju ili izazivaju mentalne poremećaje. Oni mogu da modifikuju aktivnost CNS, da utiču na ponašanje čoveka, da ga menjaju, te ih po tome Delay i Deniker dele na: psiholeptike koji deluju deprimirajuće, sedativno na normalne ili pojačane funkcije CNS; psihoanaleptike koji deluju stimulativno, ekscitativno na normalnu ili sniženu funkciju CNS; i psihodisleptike koji ispoljavaju perturbantno dejstvo na normalnu psihičku aktivnost. Među psihofarmacima osnosno psiholepticima najvažnije mesto zauzimaju neuroleptici koji imaju sposobnost da smanjuju psihomotornu hiperaktivnost, redukuju pojavu akutnih, hroničnih i eksperimentalnih psihoza, a dejstvom preko hipotalamičnoretikularne oblasti da stvaraju i značajne neurovegetativne i ekstrapiramidne manifestacije. Njihova je zasluga što su psihijatrijske bolnice izmenile svoj lik, a psihijatri svoj odnos prema psihijatrijskom bolesniku. Radi bolje pregledanosti i celishodnije primene u psihijatriji Lambert i Revol su ih 1960.godine podelili na derivate s leve strane, kao najsedativnije, čiji je predstavnik levomepromazin, derivate s desne strane, kao najsnažnije anipsihotike, čiji je predstavnik tioproperazin, i derivate sa intermedijarnom pozicijom koji poseduju sedativno i antipsihotično dejstvo, a čiji su predstavnici hlorpromazin, rezerpin i tioridazin. Važno je napomenuti da neuroleptici u manjim dozama imaju samo psiholeptičko dejstvo, a u većim i hipnotičko. Sedativni pak neuroleptici u većim dozama ispoljavaju i antipsihotično, a antipsihotični u većim dozama imaju i sedativno dejstvo. 137
Samim tim se nameće i pravilo: za postizanje odgovarajućeg efekta potrebna je odgovarajuća doza. Na primeru flufenazina može se mnogo naučiti kad su u pitanju doze i različiti efekti ispoljavanja. Tako, flufenazin u malim dozama do 2 mg dnevno je koristan za tretiranje stanja anksioznosti i napetosti. U dozi od 2,5 do 30 mg dnevno ispoljava antipsihotično, ali ne i sedativno dejstvo. Neki autori ovako opisuju polivalentno dejstvo flufenazina: umirujuće dejstvo 0,5-5 mg; anksiolitičko 100-200 mg; sedativno 100-1.200 mg; antipsihotično 5-1.800 mg dnevno. Amerikanci i Francuzi su upotrebljavali mnogo veće doze flufenazina, jer su zapazili da se ekstrapiramidne pojave smanjuju ako se doze flufenazina progresivno povećavaju. Najbolje rezultate su postigli aplikacijom flufenazina u opsegu od 150-750 mg dnevno. Ne treba zaboraviti da je flufenazin 20 puta jači od hlorpromazina, te se ne savetuje upotreba visokih doza ako se poželjni efekti postignu manjim dozama. Često se za neuspeh od nekih autora okrivljuje neadekvatna doza. Kad se postigne terapeutski efekt, savetuje se postepeno smanjivanje leka do doze održavanja. Naglo i suviše brzo smanjenje može da dovede do relapsa (pogoršanja bolesti), te i o tome voditi računa. Važno je voditi računa o predoziranju, a isto toliko i o nedovoljnom doziranju. I u jednom i u drugom slučaju treba poštovati ličnost bolesnika. Kod predoziranja bolesnik je obično usporen, inhibiran, pasivan, više ili manje nesvestan svojih poremećaja, somnolentan. Zato se ne žali na svoje tegobe i podnosi ih pasivno i ravnodušno. Po pravilu, bolesnikova okolina upozorava na njegovu apatiju, usporenost i somnolenciju. Predoziranje može takođe održavati ili prouzorkovati psihotične poremećaje, aktivirati ili pojačati halucinacije. Ove pojave nestaju nakon naglog smanjenja doze. Kod nedovoljnog doziranja bolesnici su mrzovoljni, pasivni, mrgodni, žale se na brzo zamaranje, depresivne tendencije, a posebno su opterećeni postojećim psihopatološkim sadržajem. Svi ovi simptomi nestaju kad se povećaju doze. Na primeru flufenazina mogli bismo da izvučemo neka korisna iskustva i pri primeni drugih neuroleptika. Smatramo da bi naše izlaganje bilo nepotpuno ako ne bismo nešto rekli i o pitanju terapijskog pristupa. Klasičan stav u terapijskom pristupu je nozološki, ali u hitnim slučajevima da etiološki određujemo morbidnu kategoriju nemamo vremena, te se primenjuje sindromološki pristup, gde se daje ciljani psihofarmak na ciljane postojeće siptome i sindrome. Za ciljani pristup, pored dobrog poznavanja simptoma, potrebno je i dobro poznavanje osobina jednog leka. U okviru ove ciljane psihofarmakoterapije ponikao je i pojam „target“ ciljanih simptoma. „Target“ simptomi bi bili oni na koje pojedini psihofarmaci uspešno deluju. Hertrich je 1965.godine proširio prvu listu „target“ siptoma od 5 na 9 sindroma, a koja danas izgleda ovako: Sindrom psihomotornog nemira; Sindrom akutnog straha i anksioznosti; Sindrom stupora; Sindrom autizma; Paranoidni sindrom; Manični sindrom; Depresivni sindrom; Halucinatorni sindrom; i Sindrom mentalne konfuzije. D. Milovanović je u svojoj knjizi „Klinička psihofarmakoterapija“ iznosi da nema oštre granice između sindromološkog i nozološkog pristupa, da su oba celishodna i da se u toku celokupnog lečenja skladno dopunjuju. Zatim kaže da na početku lečenja najpre treba primeniti sedativne neuroleptike, a posle suzbijanja psihomotornog nemira primeniti pravu ciljanu antipsihotičnu terapiju.
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DIHYDROERGOTAMIN- METANSULFONAT (DITAMIN) U LEČENJU GLAVOBOLJA Postignuti su dobri rezultati aplikacijom Dihydroergotamine-methanesulfonatae (Ditamin) kod onih pacijenata koji su imali glavobolju praćenu ortostatskom hipotenzijom. Medikament je primjenjivan ambulantno, u dozi od 25 kapi ujutro i 50 kapi uveče.
UVOD Danas se glavobolja veoma često pojavljuje u ambulanti lekara opšte medicine. Mogućnosti za njeno lečenje, pri prvom susretu sa bolesnikom, su nedovoljne i nezahvalne, pogotovu ako bismo hteli da postignemo neki zadovoljavajući uspeh. Uzroci glavobolja su raznovrsni i mnogobrojni, te je za efikasna tretman, potrebno postaviti pravilnu dijagnozu. Iz tih i drugih razloga takvi pacijenti se najčešće upućuju neuropsihijatru. U današnje vreme se mnogo vise zna o etiologiji i patofiziologiji glavobolja, pa shodno tome postoje i mnogobrojne klasifikacije. Moderno lečenje vaskularnih glavobolja, što je predmet našeg izučavanja, počinje otkrićem ergotamina 1918 (Stoll), kao i primenom istog kod migrene 1926 (Mayer). U lečenju glavobolja prednost ima kauzalna terapija, ali je nesumnjivo od značaja i simptomatska terapija. Da bi se postigao što bolji uspeh u lečenju, važno je da se zna, da dejstvo jednog leka ne zavisi samo od njegovog farmakodinamskog svojstva, već i od pravilne i blagovremene primene, količine i oblika leka, kao i mogućnosti resorpcije. Smatra se da su dilatacija, distenzija, dislokacija i trakcija bolno osetljivih arterija mozga najčešći uzrok glavobolja intrakranijalnog porekla, a zapalenje, pritisak i istezanje pak uzroci glavobolja ekstrakranijalnog porekla. Većina glavobolja počinje kratkotrajnom vazokonstrikcijom, koja izaziva prodromske simptome, posle čega usledi dugotrajne vazodilatacija i distenzija s konsekutivnim edemom u zidu i oko arterija, a takođe i sniženim pragom nadražaja za bol. Bol iz intrakranijalnog prostora se prenosi iradijacijom preko moždanog stabla, talamusa i kičmene moždine u tipične segmente, kao kod angine pektoris, i tako izaziva glavobolju. Sve je ovo veoma značajno, radi blagovremene i pravilne primene leka, jer je poznato da dihidroergotamin-metansulfenat (Ditamin) izaziva vazokonstrikciju ili vazodilataciju, zavisno od postojećeg tonusa krvnih sudova, pa se sledstveno tome može primenjivati u profilaksi i terapiji glavobolja.
CILJ RADA U radu je praćen efekat leka dihidroergotamin~metansulfonata (Ditamin) kod pacijenata koji su po našem nalazu bolovali od „klasične” migrene, „atipične” migrene i neurotične glavobolje. Posmatranjem smo nastojali da pomoću uobičajenih para-metara prikažemo mehanizam dejstva ovog leka na postojeće simptome navedenih glavobolja.
METODOLOGIJA U našoj grupi pacijenata sa simptomima glavobolja, od kojih su mnoge praćene i ortostatskim smetnjama, uzeti su potrebni anamnestički podaci i izvršeni neurološki i somatski pregledi, te tako isključena organska obolenja. Dihidroergotamin-metansulfonat (Ditamin) smo ordinirali oralno u dozi od 25 kapi ujutru i 50 kapi uveče u vremenu od 30 dana, zatim pauza 30 dana, a zatim ponovo primena leka 30 dana. Kod tri pacijenta smo uveli dodatnu terapiju zbog postojećih neprijatnih neurotskih smetnji. Kod jedne pacijentkinje smo morali da prekinemo lek zbog upornih povraćanja. Kontrolne preglede i razgovore sa pacijentima smo vršili na 7, 14, 30 i 60 dana od početka uzimanja leka.
REZULTATI U ispitivanje je bilo uključeno 30 bolesnika i to 24 žena i 6 muškaraca od 22 do 55 godina starosti. Po dijagnostičkoj strukturi zastupljenost je bila sledeća: „klasična” migrena 11, „atipična” migrena 7 i cephalea neurotica 12 pacijenata. Na kraju ispitivanja sumiranjem rezultata zabeležili smo sledeći uspeh: znatno poboljšanje (+++) kod 10 pacijenata ili 33,33%, delimično poboljšanje (++) kod 16 pacijenata ili 53,34 + i neuspeh (o) kod 4 pacijenta ili 13,33 %. Uspeh raspoređen po dijagnozama izgledao bi ovako: „klasična” migrena +++ kod 7, ++ kod 4 i çþ kod O pacijenata „atipična” migrena +++ kod 2, ++ kod 3 i çþ kod 2 pacijenta, cephalea neurotica +++ kod 1, ++ kod 9 i çþ kod 2 pacijenta. U toku ispitivanja primetili smo da je na lek reagovalo sa poboljšanjem glavobolja i drugih pratećih simptoma određeni broj pacijenata u sledećoj zastupljenosti: odmah nastalo poboljšanje kod 8, trećeg dana kod 9, sedmog dana kod 4, desetog dana kod 2, četrnaestog dana kod 5, i bez poboljšanja kod jednog pacijenta. Kod osam pacijenta čija je glavobolja bila praćena ortostatskom hipotenzijom, pored poboljšanja simptoma glavobolje došlo je i do popravljanja hipotenzije od 100/70 na 120/80 u toku prvih nekoliko dana.
SPOREDNI EFEKTI ISPITIVANJA Samo jedna pacijentkinja se žalila u toku prvih 9 dana na uporna povraćanja posle uzimanja leka, te smo isti morali da prekinemo, a nju isključimo iz daljeg ispitivanja.
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ZAKLJUČAK Dihidroergotamin- metansulfonat (Ditamin) se pokazao efikasnim lekom kod neurotičnih glavobolja, „klasičnih” i „atipičnih” migrena, kao i glavobolja praćenih ortostatskom hipotenzijom. subjektivno se dobro podnosi i praktično je bez toksičnih i drugih sekundarnih neželjenih pojava. U toku ispitivanja nismo zapazili neke izmene u laboratorijskim, biohemijskim, rentgenskim i EEG nalazima. Preparate smo primenjivali ambulantski, pa smatramo da se može ordinirati sa uspehom kod navedenih glavobolja i to kako ambulántski tako i stacionirano.
LITERATURA 1) Anthony M.: „The Management of Migraine”. New Ethicals and Medical Progress, 1974. 2) Ivanković D., Savić S., Misirlić T., Tubin M., i Dimitrijević, l.: Terapija ortostatske disregulacije i nekih hipotenzivnih stanja dihidroergotamin-metansulfonatom. Praxis medioi, vol. X, 1979. 3) Medicinska enciklopedija. Zagreb, MM LXVll. 4} Neurologija, „Simpozij o neurologiji i psihijatriji”, Lek, Ljubljana, 1969. 5) Radojičić B.: Klinička neurologija, Medicinska knjiga, Beograd-Zagreb. 1965. 6) Volans G.: „Research Review Migraine and Drug Absorption Clinical Pharmacokinetics 3:313-318, Adis Press, 1978.
DIHYDROERGOTAMINE-METHA-NESULFONATE (DITAMIN) IN TREATING HEADACHE Ignjatović, B. We applied Dihydroergotamine-methanesulfonate (Ditamin) and followed its effect in 30, patients, who had symptom of headache. ln 8 patients these headaches were followed by Orthostatic Hypotension. The testing was done out of hospital; the drug was given oralv 25 drops in the morning and 50 drops in the evening. Efficacy in removing the existing symptoms of headache and the associated Ortohostatic Hypotension were noted by us in the greatest number of cases in the course of ñrst days. Only one patient-girl had complication in the form of, constant vomiting and we were forsed to stop that treatment. Due to the efficacy of the Ditamine, as well as its good tolerance, poor toxicity, and due to the fact that by effects are negligible, this drug may be recommended in healing the headaches, especially those followed by Orthostatic l-lypotension. BOŽIDAR IGNJATOVIĆ, neuropsihijatar Neuropsihijatrijska bolnica „Dr Slavoljub Bakalović” Vršac, Podvršanska, 7
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VEGETATIVNI POREMEĆAJI PRI UPOTREBI PSIHOTROPNIH LEKOVA AUTORI B. Vučković, B. Ignjatović, D. Jovanović i D. Jevdić Psihofarmaci, psihotropne supstancije. ispoljavaju psihoaktivno dejstvo u otklanjanju psihopatološkog sadržaja, u potiskivanju postojećih simptoma i sindroma i na taj način zauzimaju vidno mesto u psihíjatriji, odnosno, u savremenom pristupu lečenja psihoza i psihotičnih ispoljavanja, ali pored tih svojih pozitivnih osobina oni ispoljavaju i neka neželjene dejstva u toku njihove aplikacije. Tako, pored već poznatih ekstrapiramidalnih pojava, neki od njih izazivaju i mnogobrojne vegetativne smetnje na koje mi u našem referatu želimo da skrenemo pažnju, ne samo zbog značaja istih, već i zbog opasnosti koje mogu da prate ove pojave, a koje se mogu preduhitriti razumnim vođenjem terapije. Ovi prolazni poremećaji funkcije autonomnog nervnog sistema uočavaju se najčešće pri lečenju neurolepticima i antidepresivima. Međutim, najkarakterističnije neurovegetativne pojave su kod primene antidepresiva. One su povezane, uglavnom, sa holinergičnim efektom preparata, ali je teško reći šta uslovljava poremećaj vegetativne ravnoteže – prigušenje funkcije ili povećanje suprotnog uticaja. Selbach (1957) izdvaja u dejstvu antidepresiva dve faze: početnu, sa prevagom trofotropnog i narednu, sa prevagom erogotropnog uticaja. Najizrazitije adrenolitičke osobine poseduju proizvodi fenotijazína (Largactil Nozínan). a, takođe, i tioksanteni. Largactil snižava TA od 10 - 40 a ponekad i do 70 mm Hg stuba. Neznatne hipotenzive osobine poseduju piperazinski proizvodi fentotijazina (Lyogen, Terfluzine.Frenolon]. Rezerpin koji poseduje parasimpatično dejstvo, može, takode, izazvati izrazitu hipotoniju. Hipotoniia se može uočiti već u prvim satima posle početka lečenja, pri malim dozama preparata. U isto vreme se pojavljuje opasnost od nastanka ortostatskog kolapsa. Hipotenzivni efekat se ispoljava skoro kod svih osoba pri primeni neuroleptika, naravno kod nekih ređe, a kod nekih češće i intenzivnije. Takođe ie zapaženo da je pad krvnog pritiska veći kod starijih osoba, arteriosklerotičara, hipertoničara i vegetativno labilnih. U literaturi je opisano nekoliko slučajeva smrtnog kolapsa, naročito kod prelaska iz ležećeg u stojeći stav. Smanjenje arterijskoq pritiska pojavljuje se pri intravenskoi aplikaciji preparata i to srazmerno povećanju doze. Opasnost ortostratskon kolapsa veća je u bolesnika starijeg uzrasta. Kod primene hlopromazina i rezerpina, u cilju sprečavanja ortostatskog kolapsa, preporučuje se ležanje u postelji od 1 do 2 časa posle svakog uzimanja preparata. Neki preporučuju u oslabljenih bolesnika, kao i onih sa labilnim i smanjenim vaskulariim tonusom, u prvim danima terapije neurolepticima profilaktičnu primenu Carnigena, Sympatola i drugo. Takođe se smatra da je za otklanjanje ortostatskog kolapsa dovoljno postaviti bolesnika u horizontalni položaj podignutih nogu uvis, uz aplikaciju Sympatola. Pri teškom kolapsu, pokazali su se efikasnim: adrenalin, noradrenalin, i efedrin. U slučaju neophodnosti ovi se preparati uvode nekoliko puta na dan. peros ili intravenski sa fiziološkim rastvorom. Kao drugi propratni, neugodan vegetativni poremećaj navodi se tahikardija za koju se ne preporučuje specijalno lečenje jer se smatra da je ona sama po sebi prolazna pojava. Međutim, ubrzanje pulsa ponekad može da pređe granice koje se tolerišu od 90-100 udara u minuti i dostigne od 100-130, a, po nekima, i preko 180 udara u minuti, pa se takvim slučajevima preporučuje rezerpin, smanjenje ili ukidanje ordinirane psihotropne supstancije. Piperazinski proizvodi fenotijazina i butirofenona ne izazivaju primetne tahikardije. Ponekad se javlja tahikardija i pri lečenju antidepresivima (Tofranil, Anafralin). U literaturi se opisuju i pravi infarkti, a neki od njih su se i fatalno završili. To nam skreće pažnju da neuroleptici mogu da budu i opasni prilikom primene, a naročito u starijih osoba, srčanih bolesnika, arteriosklerotičara, te ih treba davati oprezno i u manjim dozama. Sigurno je da srce mlađih osoba može da izdrži i veće opterećenje kod primene visokih doza kao i dugotrajne upotrebe leka. Bradikardija je uočena ponekad pri lečenju haloperidolom, rezerpinom i litijumom. Često je praćena i ekstrasistolama, bolom u srcu. otežanim disanjem i cijanozom. Dobri rezultati u otklanjanju ovih pojava postignuti su ordiniranjem korektora (atropin, artane] i kardiotonika. Važno je istaći efekat neuroleptika i na unutar-srčanu sprovodljivost. Demidova (1956) je zapazila umereni poremećaj unutar predkomorne sprovodljivosti pri lečenju Largactilom. Uticaj neuroleptika na promene elektrokardiograma zapažen je od strane nekih autora, a najčešće se opisuje aplatiran, odnosno, izmenjen zubac T, koji po svoj verovatnoći nema nekog kliničkog značaja. Promene na elektrokardiogramu češće su bile izražene pri lečenju Mellerilom i Largactilom. Zapaženi su i teški poremećaji srčane sprovodljivosti sve do atrioventrikularne blokade sa smrtnim ishodom (Kelly sa sard. 1965). Roy i Scherrer (1972) ukazuju na komplikacije od strane kardiovaskularnog sistema koje se javljaju pri lečenju antidepresivima, najčešće Tofranilom (poremećaj ritma, ishemij, infarkt) itd. Mada su ove pojave retke, ipak se skreće pažnja na postojanje istih. Druge vegetativne pojave, kao što su hiperhidroza, hipersalivacija, poremećaj akodomacije, često se pojavljuju zajedno sa ekstrapiramidalnim manifestacijama, i, u isto vreme, nestaju sa njima primenom antiparkisonih medikamenata. Suvoća sluzokože usne duplje i usnica je česta pojava kod primene neuroleptika i antidepresiva. Ove promene nastaju usled antiholinergičnog efekta preparata, koji smanjuje sekreciju pljuvačnih žlezda. Oticanje sluzokože nosa sa otežanim disanjem na nos, česta je pojava na početku terapije neurolepticima.
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Pri lečenju neurolepticima, pored gore navedenih pojava, zapažena je i hipovitaminoza, (suv, presvučen skramom ili crven jezik. ispucale usne, izmene ukusa, smanjenje apetita, ponekad odbijanje hrane), te se u tim slučajevima preporučuje davanje vitamina kao i obrada usne duplje. Poremećaj sekrecije i motiliteta želudačno-crevnog trakta česte su pojave kod primene neuroleptika. Smanjenje apetita, gađenje, bol u stomaku, povremeno povraćanje, dijareja, ponekad se javljaju pri lečenju rezerpinom, koji prema podacima nekih autora povećava želudačnu sekreciju. Neki opisuju želudačna krvavljenja i perforacije čira na želucu kod primene rezerpina. Mi smo, takođe, imali dva slučaja s perforacijom čira na želucu posle izvesnog vremena tretiranih rezerpinom. Poznato je da Largactil smanjuje želudačnu sekreciju i deluje nadražajno na sluzokožu želuca, te na taj način smanjuje apetit, izaziva promenu i gubitak ukusa kao i pečenje u epigastriumu. Profilaktično se preporučuje uzimanje svih ovih preparata posle jela, kao i uzimanje većih količina mleka posle toga. Ako ove dispeptične pojave imaju stalan karakter, radi smanjenja gađenja i bola u stomaku preporučuje se Extractum Belladonae. Jak bol u stomaku, povraćanje i dijareja dovoljni su pokazatelji za prekid terapije i prelaz na parenteralni način uvođenja preparata. Neki lekovi (Nozinan) stvaraju sklonost prema opstipaciji, te se preporučuju laksantivna sredstva i klizme po potrebi. Pri lečenju antidepresivima kod pojedinih bolesnika se smanjuje želudačna kiselina, što se može odraziti na varenje hrane kao i na resopciju leka. Kao retka komplikacija javlja se poremećaj ispuštanja mokraće, koja je uslovljena spazmom sfinktera i atonijom mokraćne bešike. Preporučuju se termoior, kateterizacija i neka holinergična sredstva (acetilholin hlorid), kao i analeptici (cofein i dr). Izuzetno retko uočava se komplikacija u vidu paralitičnog ileusa, koji je u vezi sa lokalnim spazmom glatko muskulature (Rumore, 1962). U takvim slučajevima preporučuje se ukidanje neuroleptika i primena napred navedenih holinergičnih sredstava, klistir i drugo. U nekim slučajevima javlja se poremećaj ejakulacije izazvane blokadom adrenergičnih mehanizama. Neki navode u vegetativne pojave i poremećaj menstruacije, laktacije, kao i pojavu impotencije kod primene neuroleptika. Sve ove vegetativne pojave su uglavnom kratkotrajne i, u većem broju slučajeva, ne predstavljaju opasnost. Ponekad je psihoterapija dovoljna mera lečenja.
NAŠA ISKUSTVA Primenjujući visokodozni i niskodozni flufenazin (Moditen) u 47 psihotičnih bolesnika, zapazili smo vegetativne poremećaje u 16 bolesnika ili 34%. Brojčano zastupljenost je bila sledeća: hipersalivacija 7, smetnje akomodacije 2, hipotenzija 2, tahikardija 2, muka i povraćanje 1, suva usta 1 i alergični erítem 1. lspitivanjem Leponexa u 61 shizofrenog bolesnika, zabeležili smo vegetativne pojave u sledećem obliku i broju: hipersalivacija 14, opstipacija 5, tahikardija 7, hipotenzija 3. U jednog mlađeg bolesnika s ispoljenim maničnim sindromom, ordinirali smo drugog dana od prijema 600 mg Leponexa i postigli zadovoljavajući uspeh u otklanjanju postojećeg psihopatološkog sadržaja. Međutim, u istog bolesnika zapazili smo pojavu ortostatske hipotenzije, koju smo uspeli da otklonimo zadržavanjem bolesnika u postelji, aplikacijom Sympatola i smanjenjem Leponexa na 300 mg. U jednog drugog bolesnika na dozi od 300 mg, Leponexa, pojavila se tahikardija (120 do 140 udara u minuti), te smo morali da prekinemo lek i zamenimo ga drugim. Kombinacijom Leponexa i Moditena-depo našli smo u 41 shizofrenog bolesnika sledeće vegetativne pojave: hipersalivacija 9, opstipacija 5. Primenom kombinovane terapije sedativnih neuroleptika (levomepromazin, hlorpromazin, tioridazin). sa flufenazinom (Moditen) i antiparkinsonskim preparatom (Artane), u 89 hroničnih i akutnih psihoza nismo zapazili nlikakve sekundarne pojave i to, kako vegetativne, tako ni ekstrapiramidalne. Primenom drugih neuroleptika zapazili smo česte pojave hipotenzije, a naročito primenom Nozinana i Largactila, koje smo otklanjali Sympatolom u kapljicama ili ampulama, zavisno od jačine iste. Dalje smo zapazili da se ove vegetativne pojave mogu da jave u svako doba tretmana, ali najčešće na početku. Kod jednog bolesnika može da se javi samo jedna ili više vegetativnih pojava u isto vreme. Tako smo kod jednog pacijenta lečenog Leponexom zapazili u isto vreme pojavu tahikardije, hipersalivacije i opstipacije. Intenzitet vegetativnih pojava je različit kako kod bolesnika, tako i kod raznih neuroleptiika. Negde su one slabije a negde jače izražene. Sve zabeležene vegetativne pojave otklanjali smo smanjenjem ili ukidanjem leka, dodatnom terapijom ili izmenom postojeće terapije.
Sažetak Neuroleptici i antidepresivi kao aktivne hemijske supstancije, pored otklanjanja psihopatološkog sadržaja, izazivaju i sporedne efekte u obliku vegetativnih pojava. One mogu da budu zastupljene u lakšem iil težem obliku, mogu da predstavljaju opasnost po život bolesnika, te je poželjno poznavanje istih. Neke od njih su prolazne i beznačajne, za neke je potrebna dodatna terapija a kod nekih izmena postojeće terapije, smanjenje ili prekid ordinirane psihotropne supstancije. Sigurno je da neki psihotropni lekovi daju veći a neki manji broj vegetativnih pojava.
Summary 142
Neuroleptics and antidepressive therapy as well as active chemical supstances, besides removing the psychopathological contents, provoke subordinate effects in the form of vegetative appearances. They could be represented in the easier or heavier form, they might be dangerous for a patient. so it is desirable that one should know them. Some of them are passable and of no importance. For some, there is a need of additional therapy, and for some there is a need of changing the therapy, reduction or cutting of the prescribred psychothropic supstances.
Literatura 1. Avruckij G. i sarad. »Farmakoterapija psihičesnih zabolevanij«, Moskva. 1974. str. 154-294. 2. Vitorović M. »Ptsihofarmakoterapija shizofrenih psihoza« - Psihijatrija - Simpozij o neurologiji i psihijatriji, Ljubljana 1989. 3. Ignjatović B., Zbornik V Kongresa Nevrologov in Psihiatrov Jugoslavije - Ljubljana 1976. str. 143-146 i str. 147-150. 4. Milovanović D. »Klinička psihofarmakoterapija«, Ljubljana 1972. 5. Mihovilović M. »Psihofarmakoterapija depresisvnih stanja« Psihijatrija - Simpozij o neurologiji i psihijatriji, Ljubljana 1969. 8. Raevskij K., »Farmakologija neuroleptikov«, Moskva 1976, str. 207-245.
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UDRUŽENO DEJSTVO LEPONEXA I MODITENA DEPO U LEČENJU SHIZOFRENIH PSIHOZA Božidar Ignjatović Na kombinaciju Leponexa i Moditena depo odlučili smo se posle dužeg proučavanja ova dva leka. Smatrali smo da bi mogli da postignemo bolji efekat onda gde oni pojedinačno nisu bili dovoljni. Znali smo da Moditen depo nije dovoljno efikasan kod shizofrenih psihoza praćenih nesanicom, agitacijom, psihomotornim nemirom, agresivnošću i razdražljivošću. Leponex je, pak, u ovim slučajevima bio veoma zahvalan i brzo otklanjao gore navedene simptome, ali je njegov antipsihotički efekat bio nešto slabiji. Leponex, kao jedan novi neuroleptik, u ovim slučajevima gde smo ranije dodavali sedativno neuroleptike /nozinan, lar,
Naša iskustva Kombinaciju Leponexa i Noditena depo primenjivali smo i vršili ispitivanja kod 41 pacijenta, od 22 do 65 godina starosti i sa trajanjem bolesti od 1 do 25 godina. 2 bolesnika su ispoljavala akutan, a 39 hroničan tok bolesti. Ispitivanje smo obavljali na odeljenju gde se pretežno leče hronično shizofrene psihoze. Po starosnoj strukturi od 20 do 29 godina lečeno je 8, od 30-39 godina 8, od 40-49 21, od 50-59 3, i od 60-69 1 bolesnik. Po trajanju bolesti zastupljenost je bila: do 1 godine 2, od 2-10 godina 13, od 11 do 20 godina 16, i preko 20 godina 10 bolesnika. Po dijagnostičkoj strukturi lečenje se kretalo: 295.0/Sch.simplex/ 5, 295.1 / Heberhronia/ 18, 295.2 /Katatonia/ 1. 295.3 /Sch. Paranoides/ 11, 295.7 /Mešana Sch. Alika/ 1, i 295.9 /neodređena forma Sch/ 5 bolesnika, Po dužini trajanja lučenja do 3 meseca je bilo 5, do 5 meseci 22, do 7 meseci 9 i preko 7 meseci 5 bolesnika. Optimalne doze Leponexa, koje su se kretale od 100-600 mgr zastupljene su bile u ovom odnosu: na 100 mgr 1, na 150 mrg 3, na 200 mgr. 2, na 300 mgr 26, na 450 mgr 1, na 500 mgr 2 i na 600 mgr 6 bolesnika. Svi ovi pacijenti su bili pre toga na Moditenu depo, a naknadno smo uveli i Leponex ili je pak najpre uveden Leponex a posle i Moditen depo. U toku lečenja smo otpustili 13 a zadržali na bolničko lečenje 28 bolesnika.
Sporedni efekti ispitivanja Pospanost smo zapazili kod 9 bolesnika i to odmah na početku lečenja na dozi od 300 mgr, ali je kratko trajala, od 1 do 3 dana. Hiper-salivaciju takođe kod 9 bolesnika na dozi od 300 mgr, ali je nije bilo na 150 mgr. Kod 4 bolesnika zabeležili smo lak zamor i malaksalost i kod 5 opstipaciju. Ekstrapiramidne pojave, kao i druge uporedne efekte koje smo ranije zabeležili primenom Moditena depo od 25 mgr na 25-30 dana /nesanica 25, akatizija 4, tremor ruku 2, rigor 2 i okulogirne krize 1/ sada nismo našli iako je doza Moditena depo i u ovom slučaju uz Leponex bila ista i u istom razmaku ordinirana. Božidar Ignjatović, neuropsihijatar, šef odeljenja „F“ u Neuropsihijatrijskoj bolnici, Vršac
Rezultati lečenja Rezultati Tabela 1. Rezultati +++ ++
lečenja lečenja
Leponexa
i
Moditenom
depo
Broj
prikazačemo
pacijenata
na
sledećoj
tabeli:
Procenat
32 78,o% 9 22,0% 0 0% UKUPNO 41 100 % Radi boljeg pregleda i upoređenja prikazaćemo naše rezultate u sva tri slučaja: Rezultati lečenja shizofrenih psihoza samo Moditenom depo izraženi u procentima znatno poboljšanje 53%, delimično poboljšanje 21,3%, neuspeh 25,7% Rezultati lečenja shizofrenih psihoza samo Leponexom: znatno poboljšanje 57,4%, delimično poboljšanje 34,5%, neupseh 8,1% Rezultati lečenja shizofrenih psihoza kombinacijom Leponexa i Moditena depo i znatno poboljšanje 78,0%, delimično poboljšanje 22,0% i neuspeh 0%. Iz gore navedenih rezultata jasno se vidi da smo najbolje uspehe postigli primenom kombinacije Leponexa i Moditena depo. Najbolji uspeh smo i ovde postigli u najvećem broju slučajeva na dozi od 300 mgr Leponexa, a kod nekih tek na dozi od 600 mgr. Mnogi bolesnici koji su ranije lečeni i pokazivali neuspeh na prethodnoj terapiji sada su se nekako ponovo vratili u život, čak smo neke i otpustili kući i sa uspehom nastavili i vanbolničko lečenje. Brzo i sigurno smo pri prijemu novih bolesnika ili pri posmatranju psihičkog stanja hospitalnih bolesnika, otklanjali nesanicu, psihomotorni nemir, agitaciju, agresivnost i paranoidno-halucinatorni sadržaj. Zamenom Leponexa nekim od sedativnih neuroleptika često je dolazilo do pogoršanja kliničke slike. Na sledećoj tabeli ćemo prikazati i rezultate lečenja po dijagnostičkoj strukturi:
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Tabela 2.
Šifra bolesti 295.0 295.1 295.2 295.3 295.7 295.3 Svega:
Dijagnoza Sch.simplex Hebephrenia Katatonia Sch.paranoides Mešana Sch.slika Neodređena forma Sch
+++ 3 14 1 9 1 4 32
++ 2 4 2 1 9
Æ 0
Naše objašnjenje: +++ = znatno poboljšanje ++ = delimično poboljšanje Æ = neuspeh.
Zaključak 1. 2. 3. 4. 5.
Kombinovanom terapijom Leponexa i Moditena depo postigli smo bolje rezultate nego pojedinačnom upotrebom. Pored odličnog sedativnog i umerenog hipnotičkog pojačali smo antipsihotično dejstvo Leponexa dodavanjem Moditena depo. Postigli smo uspeh ne samo u otklanjanju nesanice, poihomotornog nemira, agitacije, napetosti, agresivnosti već i u boljem i bržem otklanjanju paranoidno~halucínatornog sadržaja, kao i poboljšanju volje, interesovanja i raspoloženja. Tamo gde nismo postigli željene rezultate na dozi Leponexa od 300 mgr uz Moditen depo, uspeli smo da to popravimo povećanjem doze od 600 mgr. Ekstrapiramidne pojave koje smo zapazili primenom Moditena depo bez kombinacije sa Leponexom, sada se nisu pojavile ni u jednom obliku.
Rezime •
•
• • •
Autor je ispitivao kombinovano dejstvo Leponexa i Moditena depo kod akutníh /2/ 1 hroničníh /39/ shizofrenih psihoza u vremenu od 3 do 8 meseci. Leponex je ordiniran u dozi od 100 do 600 nage dnevno, a Moditen depo od 25 mgr na 2530 dana parenteralno. Pojačavanjem antípsihotíčkog uz odlično sedativno i umereno hipnotičko dejstvo postigli smo bolje rezultate u otklanjanju paranoidno halucinatornog sadržaja, nesanice, psihomotornog nemira agitacije, napetosti, agresivnosti, kao i poboljšanje volje, interesovanja i raspoloženja. Rezultati lečenja su bolji nego kod pojedinačne primene Leponexa ili Moditena depo, a u procentima izgledaju ovako: +++ = 78,0% ++ = 22,0% i Æ = 0. Za razliku od ekstrapiramidnih pojava koje smo registrovali primenom samo Moditena depo ovde ih nismo zapazili. Zbog toga kombinaciju Leponexa i Moditena depo preporučujemo u lečenju svih formi shizofrenija.
Heuropsychiatric Hospital, Vršac, Yugoslavia
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THE COMBINED ACTION OF LEPOHEX AND MODITLEN DEPO IN TREATING SCHIZOPHREHIC PSYCHOSES Božidar Ignjatović Summary The author investigated the combineđ action of Leponex and Moditen depo in acute /2/ and Chronic /39/ schizophrenic psychoses during 3 to 8 months. Leponex was administered in dosages from 100 to 600 mg per day, and Moditen depo of 25 mg parenterally per 25 to 30 days. We reached much better results by amplification of the antipsychotic action in the same time when we had excellent sedntive and moderate hypnotic affects in removing psychopatological content as they are in: insomnia, agitation, routessness, tension, aggressive behavior, paranoid-hallucinatory change, with improvement of the will, interesting and the mood. The results of the treatment are much better than in the case of the single application of Leponex or Moditen depo. These results presented in percents look like this: +++ = 78,0%, ++ 22.0% and Æ =0. The registered extrapyramidal phenomena, with application of Moditen depo only, we did riot notice. Because of the above mentioned results we recommend the combination of Leponex and Moditen depo in treating all forms of a schizophrenia.
Literatura 1. Angst J.; Methodology for the Clinical Testing of Psychotropic Agents, Sumposium on the methodology of the pharmacological and trials of psychotropic drugs, Moscow, 1974.23-35.- 2. Avrutky G. Y., Zaitsev S.G., Magalif A.Y., Hofman D. Y. :Criteria for Comparative Evaluation of Neuroleptic Drugs as Appied in a Study of the effect of Leponex in Schizophrenic Patients, “Symposium”, Moscow, 1974, 49-63. 3. Bukowczyk A. Clinical Invesitigations of Clozapine in Schizophrenia, “Symposium”, Moscow, 1974, 115-127. 4. Bohaček, N., Principi prolongirane psihofarmakoterapije shizofrenih psihoza /znečenje lečenja depo neurolepticima/ u Novosti 1, Krka, 1972:str.85-88.-5. Fouks L. , IV me Congres Mondial de psychiatrie, Madrid 5-11 Septembra 1966. Edition squibb et cons. 6. Freeman H., Symposium on long-acting phenotiazines, Dublin, 1969. 7. Frank L. ,International Drug therapy, Newsletter, Baltimore, 1970. Volume V.Number4. 8.Hippius H. Matussek N.: Clinical and Biochemical Findings with Clozapine,”Symposium”, Moscow, 1974,65-70.-9. Imlah N., Symposium on long-acting phenotinzines, Dublin, 1969.- 10.Lange E., Konig L., Kuhne G.,Liefke T.; Experience with Leponex in Clinical Practice, “Symposium”, Moscow,1974,109-113.- 11.Lokar L. Upotreba Flufenazin decanoata u socijalnim zavodima, u Novosti 1, Krka, 1972.str.95-98.- 12. Milovanović D. Klinička psihofarmakologija. Izdanje “Lek”, Ljubljana, 1972.-13, Nevgorova T.A. Galperina L. E. , Obrachevskaya V.D., Verhovskaya T.V. :The Trentmant of Schizophrenic Patients with Leponex, “Symposium”, Moscow, 1974,101-108.-14. Nabney J., Symposium on long-acting phenotiazines, Dublin, 1969.-15. Petrović D., Sedmak T.:Psihofarmakoterapija dugo 1ečenih psihoza shizofrenog tipa, u Anali zavoda za mentalno zdravlje, Beograd, 1974, god.6, br.1,29-39.-16 Vencovsky E., Fischer-Cornelseen K.: Results of a Double-blind Clinical Study Comparing the efficacy of Clozapine and Chlorpromazine, “Symposium” Moscow, 1974, 93-100. -17. Vitorović, M., Naša iskustva i naš stav u leečenju depo-flufenazinom, u Novosti 1, Krka, 1972.str.89-93.
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NAŠA ZAPAŽANJA U LEČENJU SHIZOPHRENIA LEPONEXOM Božidar Ignjatović Kao najefikasniji lekovi u lečenju shizofrenije u zadnjih deset godina među psihofarmacima bili su neuroleptici, a njihov antipsihotički efekat je bio zasnovan na definiciji izraza “neuroleptički”, Tako su kliničari skretali pažnju i dokazivali da bi neki lek mogao da bude efikasniji samo onda ako bi prouzrokovao i ekstrapiramidne sporedne efekte. Međutim, situacij se menja sa otkrićem Leponexa. Leponex ima isti terapeutski efekat kao i “klasični neuroleptici” pri kliničkoj upotrebi, a razlikuje se od njih samo u tome što ne utiče na ekstrapiramidni sistem, odnosno ne daje ekstrapiramidne pojave u eksperimentu na životinjama ili primenom na ljudima. Po hemijskoj strukturi Leponex je blizak “klasičnim neurolepticima”. Klasični neuroleptici koji pripadaju grupama fanotijazina i butirofenona imaju blokirajući efekat na receptore dopamine u CNS. Leponex takođe utiče na dopaminergične neurone u CNS na taj način što dovodi do porasta homovanilske kiseline /HVA/ u mozgu tj. Utiče kao i klasični neuroleptici na metabolizam dopamine, ali u isto vreme suprotno njima učestvuje i na metabolizam norepinefrina. Blagodareći ovim biohemijskim, farmakološkim i neurofiziološkim istraživanjima na životinjama i ljudima danas ne zna da domaminergični neuroni ne samo da postoje u ekstrapiramidnom sistemu nego takođe u limbičkom i čeonom režnju CNS, što bi moglo biti razlogom za antipsihotično delovanje.
Naša iskustva Leponex smo ispitivali kod 61 shizofrenog bolesnika od 17 do 69 godina starosti i sa trajanjem bolesti od 1 do 30 godina. Kod 2 bolesnika tok je bio akutan, a kod 59 hroničan. Lek smo primenjivali kod hospitalnih i ekstrahospitalnih bolesnika. Broj bolesnika lečenih po dijagnostičkoj strukturi izgledao je ovako: 295.0/Sch. Simplex/ 6.295.1/Hebephrenia/21.295.3/Sch.paranoides/18.295.9/Neodređena forma Sch./ 16. Na prethodnoj terapiji ovi bolesnici nisu pokazivali neki naročiti uspeh. Leponex smo ordinirali odmah, neposredno posle prekida prethodne terapije, tako da nismo pravili pauzu od 7 dana koju prave neki autori zbog “ispiranja”. Po dužini trajanja Leponexa smo primenjivali kod 26 do 3 meseca, kod 23 do 5 meseci, kod 7 do 7 meseci i kod 5 bolesnika preko 7 meseca. Od ukupnih broja 61 lečenih, otpustili smo 24, a u bolnici nastavili lečenje kod ostalih 37 bolesnika. Optimalne doze su se kretale od 75 mgr do 600 mgr dnevno, a u odnosu prema broju bolesnika i izgledale su ovako: 2 bolesnika po 75 mgr, 4 bolesnika po 150 mgr, 40 bolesnika po 300 mgr, 7 bolesnika po 450 mgr i 8 bolesnika po 600 mgr dnevno. Visina optimalne doze kretala se u zavisnosti od prethodne terapije, stanja remisije ili egzacerbacije procesa, somatskog zdravlja kao i odgovarajućeg uspeha pri primeni iste. U toku tretmana nismo zapazili da se paranteralna primena pokazala efikasnijom od oralne. Sporedni efekti ispitivanja Nuspojave koje smo primetili izgledale su po obliku i broju ovako: hipersalivacija 14, pospanost 7, opstipacija 5, lak zamor 3, tahikardija 2, hipotenzija 3 i tremor 1. Ovi sporedni efekti imaju i neke svoje posebne karakteristike koje smo mi u toku ispitivanja zapazili. Mogu da se jave u svako vreme tretmana, ali najčešće na početku. Kod jednog istog bolesnika može da se javi samo jedna od gore navedenih nuspojava ili više njih u isto vreme ili u različito vreme tretmana. Kod dva bolesnika smo morali da prekinemo započetu terapiju Leponexom zbog nagle pojave više nuspojava odmah na početku lečenja / tahikardija 120/140, hipersalivacija, pospanost, lak zamor i opstipacija/. Postoje razlike i u intezitetu nuspojava, tako što su kod nekih bolesnika jače, a kod drugih slabije izražene. Isto tako i doza leka ima nekog značaja u pojavi istih. Na dozi od 300 mgr bilo je najviše zabeleženih sporednih efekata, a od njih je najbrojnija bila hipersalivacija koja je ne samo iščezavala smanjenjem leka već negde čak i povećanjem na 600 mgr. Kod drugih, pak, na dozi od 600 mgr nije bilo nikakvih nuspojava. Sve gore navedene sporedne efekte uspevali smo da otklonimo bilo smanjenjem, bilo ukidanjem leka. Rezultati lečenja Prateći tok lečenja i sumirajući rezultate na osnovu naše subjektivne procenemogli smo da konstatujemo da je povlačenja psihopatološkog sadržaja došlo na različite načine. Najbojle rezultate kod najvećeg broja bolesnika postigli smo na dozi od 300 mgr dnevno. Delimičan uspeh na 75 odnosno 150 mgr, a povećanjem doze do 600 mgr dnevno čak i znatno poboljšanje. Kod hroničnih bolesnika koji su dugo bili rezistentni na svu prethodnu terapiju i nisu pokazivali nade za neko poboljšanje ili izlečenje postigli smo dobre rezultate kod nekih na 300 mgr, ali još bolje uspeh kod više njih na 600 mgr dnevno. Odmah na početku lečenja zapazili smo brzo i efektno dejstvo u otklanjanju nesanice, napetosti, psihomotornog nemira i agresivnosti, a nešto sporije u potiskivanju paranoidno halucinatornog sadržaja, razdražljivosti, anksioznosti, emocionalne tuposti, autizma i odbojnosti prema radu. Zamena Leponexa prethodnom ili nekom drugom terapijom dovodila je često do izmene kliničke slike u smislu pogoršanja bolesti. Radi boljeg pregleda na sledećoj tabeli prikazaćemo lečenja Leponexom.
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Tabela 1.
Rezultati lečenja +++ ++ Æ Ukupno
Broj pacijenata 35 21 5 61
Procenat 57,4% 34,5% 8,1% 100%
Rezultate lečenja po dijagnostičkoj strukturi prikazujemo na sledećoj tabeli: Tabela 2.
Sifra bolesti 295.0 295.1 295.3 295.9
Dijagnoza Sch.simplex hebephrenia Sch.paranoides Neodređena forma Sch.
Svega
Æ
+++ 4 11 12 8
++ 3 8 3 7
2 2 1
35
21
5
Zaključak Leponex ili Clozapin /generičko ime/ moglo bi se reći da je opravdao naše poverenje u lečenju shizofrenih psihoza. Njegovo snažno antipsihotično, odlično sedativno i sa povećanjem doze negde manje negde više ispoljeno hipnotičko dejstvo stavljaju ga u red moglo bi se reći isperd Nozinana i Largnactila. S obzirom da ne daje skoro nikakve ili vrlo retko blage ekstrapiramidne pojave pogodan je za lečenje bolničkih i vanbolničkih pacijenata. Naročito je pogodan za lečenje onih bolesnika koji pri prijemu ili za vreme egzacerbacije procesa ispoljavaju nesanicu, psihomotrni nemir, napetost, agresivnost i paranoidno-halucinatorni sadržaj. Vegetativne smetnje koje izaziva ređe se javljaju, kratkog su trajanja i brzo nestaju smanjenjem doze leka. Delimično poboljšanje ili neuspeh koji se ponekad ispoljavaju kod malih doza leka, mogu se poboljšati povećanjem iste. Rezime Leponex smo primenjivali kod aakutnih /2/ i hroničnih /59/ shizofrenih psihoza u vremenu od 3 do 8 meseci i to kako kod hospitalnih tako i kod vanhospitalnih pacijenata. Ordinirali smo ga oralno i parenteralno u dozi od 75 do 600 mgr dnevno. U toku ispitivanja zabeleželi smo sledeće rezultate: znatno poboljšanje kod 35 ili 57,4%, delimično poboljšanje kod 21 ili 34,5% i neuspeh kod 5 pacijenata ili 8,1%. Kod dva bolesnika morali smo da prekinemo lečenje zbog pojave tahikardije /120-140/ i nekih drugih vegetativnih smetnji kod istog bolesnika. Naše objašnjenje: +++ = znatno poboljšanje ++ = delimično poboljšanje Æ = neuspeh. S obzirom da poseduje brzo i dugotrajno sedativno, snažno antipsihotično i slabije ili hipnotičko dejstvo naročito sa povećanjem doze, smatramo ga pogodnim u otklanjanju nesanice, psihomotornog nemira, napetosti, agresivnosti i paranoidno-halucinatornog sadržaja. Sporedni efekti ispitivanja a naročito ekstrapiramidne pojave ako se pojave, mada ređe, lako se otklanjaju smanjenjem doze, a ponekad i ukidanjem leka. Neuropsychiatric hospital, Vršac, Yugoslavia
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OUR OBSERVATIONS IN TREATING SCHIZOPHRENIC BY LEPONEX Božidar Ignjatović We were applyinc Leponex in acute /2/ and chronic /39/ acidzophronic psychoses during 3 to 8 months. Both inpatients and outopatients were treated. Leponex was administrared orally and parenterally in dosages from 75 to 600 mg per day. In the course of investigations we noted the following results: notable improvement in 35 patients or 57 percent, partial improvement in 21 or 34,5% and unsuccess in 5 patients or 8,15. In cases of 2 patients only-the treatment was interrupted due to the appearance of tachicardia /120-140/. Having in view thet Leponcx has quick and long-acting sedative effects, strong antipsychtic action and weaker or stronger hypnotic properties, especially with higher doseges - we consider that Leponex is favourable for healing incomnia, restlessness, tension, aggressive behavior and paranoid-hallucinatory contents. Side effects in this study, and especially oxtrapyramidal effects, are rare and if they appear they to be removed by lowering the dosages or sometimes by stopping the administration of Leponex. Literatura 1.Angst J.: Methodology for the Clinical Testing of Psychotropic Agents, Symposium on the methodology of the pharmacological and trials of psychotropic drugs, Moscow, 1974,23-35.2.Avrutky G.Y. Zaitsev S.G., Magalif A.Y., Holman D.Y. :Criteria for Comparative Evaluation of Neuroloptic Drugs as Appied in a Study of the Effect of Leponec in Schizpphrenic Patients, “Symposium”, Moscow, 1974,49-63. 3.Bukowczyk A.Clinical Investigations of Clozapine in Schizophrenia, “Symposium”, Moscow, 1974,115-127.-4 Hippius 11.,Matussek N.:Clinical and Biochemical Findings with Clozapine, “Symposium”, Moscow, 1974, 65-70. 5 Lange E.,Konig L.,Kuhne.G.,Liefke T.; Experience with Leponex in Clinical Practice, “Symposium”, Moscow, 1974.109-113.-6 Milovanović D.: Klinička psihofarmakologija. Izdanje “Lek”,Ljubljana,1972. 7.Nevsorova T. A. Galperina L. E. ,Obrachevskaua V. D. Verhovskaya. T. V. : The Treatment of Schizophrenic Patients with Leponex, “Symposium”, Moscow, 1974,101-108.-8 Petrović D. Sedmak T.: Psihofarmakoterapija dugo lečenih psihoza shizofrenog tips, u Anali zavoda za mentalno zdravlje -Beograd, 1974 god.6,br.1, 29-39.-9 Vencovsky E.,Fischer-Cornelssen K.: Results of a Double-blind Clinical Study Comparing the Efficacu of Clozapine and Chlorpromazine, “Symposium” Moscow, 1974, 93-100.
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Sadržaj / Table of Contents 5 10 16
Agoraphobia with panic disorder - family psychopharmacotherapy by paroxetin Acamprosate for out-patient alcohol dependence treatment
Outpatient psychiatrist activities of consultations in diagnosting process and treatment of psychosomatic disorders
23
Possible adverse effects in the treatment of agoraphobia with valproic acid and natrium valproateour one year experiences
27 35
The efficacy of depression treatment with milnacipran (a six- month experience)
Rivastigmine efficacy on behavioral and psychological symptoms of alzheimer’s disease- findings from a 12-months out- patients’ study.
41
Chronificated agoraphobia with panic disorder monitoring during one year interval and assumption of comorbidity with depression uprise
47 53
Psychopharmacotherapy or psychotherapy of anxiety disorders- one year results
Differential diagnostics of panic disorder and following treatment at the psychiatric clinic - our 1 years’ experience
63
Is combination of psychopharmacotherapy and psychotherapy effective at treatment of agoraphobia wiht a panic disorder?
66 Pharmacoeconomics of the treatment of agoraphobia with panic disorder 67 The efficacy of depression treatment with M1lnacipran (a six- month experience) 70 Crises periods in the treatment of alcoholism addiction syndrom in psychiatric medical office 75 Agoraphobia with panic disorder – family psychopharmacotherapy by paroxetin 79 Treatment of somatoform and psychosomatic disorders at outpatient psychiatric center 84 Cognitive and behavioral psychotherapy of specific phobia- casuistic 86 Pharmacoeconomics of the treatment of agoraphobia with panic disorder 87 Pharmacological treatment of late-life depression 93 The efficacy of depression treatment with milnacipran 98 The risk of suicide in the geriatric patients’ community 103 The quality of life in patients with dementia of Alzheimer’s type living in old people’s homes and nursing homes
108 Comparison of galantamine and rivastigmin effects - 12-month study 112 Použitie mobilného telefónu ako pomocky pri panickom záchvate (use of mobile telephone during panic attack) 150
118 Treatment of somatoform and psychosomatic disorders at outpatient psychiatric center 123 Moditen u lečenju shizofrenih psihoza 125 The Moditen in treating schizophrenic psychoses 126 Ekstrapiramidalne pojave kod primene neuroleptika njihov značaj i lečenje 127 Extrapyramidal phenomena in the application of neuroleptics – their importance and healing 128 Penfluridol u lečenju hroničnih shizofrenih psihoza 129 Penfluridol in treating the schizophrenic chronic psychoses 130 Značaj visokih i niskih doza neuroleptika u lečenju shizofrenih psihoza 131 The importance of high and low doses of neuroleptics in treatment schizophrenic psychoses 132 racionalna upotreba psihofarmaka 134 Značaj ekstrapiramidalnih pojava kod primene psihofarmaka 136 Klinički aspekti hroničnih neuroleptičkih pojava 137 Dileme pri upotrebi psihofarmaka 139 Dihydroergotamin- metansulfonat (ditamin) u lečenju glavobolja 140 Dihydroergotamine-metha-nesulfonate (ditamin) in treating headache 141 Vegetativni poremećaji pri upotrebi psihotropnih lekova 144 Udruženo dejstvo leponexa i moditena depo u lečenju shizofrenih psihoza 146 The combined action of lepohex and moditlen depo in treating schizophrehic psychoses 147 Naša zapažanja u lečenju shizophrenia leponexom 149 Our observations in treating schizophrenic by leponex
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Ignjatovići - 40 godina u psihijatriji Autor Dr Milan Ignjatović Prelom Zorica Mujković Dizajn Aleksandar Pasku www.freakinc.rs Obrada skenova Kristina Ilić Tehnička podrška Bratislava Cvetković Ilić Štampa Gama Studio, Beograd Tiraž 100 komada
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