Contents List List o contri contribu buto tors rs Preace viii
page page vi vi
1.
Evidence-based pharmacotherapy pharmacotherapy of atten attentio tion n de�cit de�cit hyper hyperacti activit vity y disorder 1 Brigette S. Vaughan, John S. March, and Christopher J. Kratochvil
8.
Evidence-based pharmacotherapy pharmacotherapy of obsessive–co obsessive–compuls mpulsive ive disorder 128 Naomi A. Fineberg, Angus Brown, and Ilenia Pampaloni
2.
Evidence-based pharmacotherapy pharmacotherapy of schizophr schizophrenia enia 18 Stean Leucht, Stephan Heres, Werner Kissling, and John M. Davis D avis
9.
Evidence-based pharmacotherapy pharmacotherapy of post-t post-tra rauma umatic tic stress stress disorder 171 Jonathan Jonathan C. Ipser and Dan J. Stein
3.
Evidence-based pharmacotherapy pharmacotherapy of bipola bipolarr disord disorder er 39 Matthew J. aylor and John R. Geddes
4.
Evidence-based pharmacotherapy pharmacotherapy of major major depres depressiv sive e disor disorder der 53 Jamie M. Dupuy, Michael J. Ostacher, Jeffrey Huffman, Roy H. Perlis, and Andrew A. Nierenberg Nierenberg
10. Evidence-based pharmacotherapy pharmacotherapy of eating eating disor disorder derss 190 Martine F. Flament, Hany Bissada, and Wendy Spettigue 11. Evidence-based pharmacotherapy pharmacotherapy of nico nicoti tine ne and and alco alcoho holl dependence 214 Wim van den Brink
5.
Evidence-based pharmacotherapy pharmacotherapy of pani panicc diso disord rder er 73 Neeltje M. Batelaan, Anton J. L. M. Van Balkom, and Dan J. Stein
12. Evidence-based pharmacotherapy pharmacotherapy of illi illici citt substa substanc nce e use use disorders 235 Wim van den Brink
6.
Evidence-based pharmacotherapy pharmacotherapy of soci social al anxi anxiety ety diso disord rder er 90 Carlos Blanco, Laura B. Bragdon, Franklin R. Schneier, Schneier, and Michael R. Liebowitz
13. Evidence-based pharmacotherapy pharmacotherapy of Alzh Alzheimer eimer’’s disease disease 262 Darren Cotterell and Martin Brown
7.
Evidence-based pharmacotherapy pharmacotherapy of gener generali alize zed d anxiet anxiety y disorder 110 David S. Baldwin, Sarah Waldman, and Christer Allgulander
14. Evidence-based pharmacotherapy pharmacotherapy of person personali ality ty disord disorders ers 278 Luis H. Ripoll, Joseph riebwasser, and Larry J. Siever
Index 316
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Contributors Christer Christer Allgulander Allgulander Karolinska Karolinska Institutet, Institutet, Stockholm, Sweden Davi David d S. Ba Bald ldwi win n Clinical Neuroscience Division, School o Medicine, University o Southampton, UK Neeltj Neeltje e M. Bat Batela elaan an Department o Psychiatry and EMGO institute, institute, VU University University Medical Center and GGZ inGeest, Amsterdam, the Netherlands Hany Hany Bissad Bissada a Te Ottawa Hospital, Ottawa, ON, Canada Carlos Carlos Blanco Blanco Department o Psychiatry, Columbia College o Physicians Physicians and Surgeons, and the New York State Psychiatric Institute, New York, NY, USA Laur Laura a B. Brag Bragdo don n Department o Psychiatry, Columbia College o Physicians Physicians and Surgeons, and the New York State Psychiatric Institute, New York, NY, USA Angus Angus Brown Brown Hertordshire NHS rust, UK Martin Martin Brown Brown Hampshire Partnership NHS rust, Dunsbury Way Clinic, Havant, Hampshire, UK
Jami Jamie e M. Dupu Dupuy y Department o Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Naomi Naomi A. Fine Finebe berg rg University University o Hertordshire Hertordshire and Queen Elizabeth II Hospital, Hospital, Welwyn Welwyn Garden City, UK Mart Martin ine e F. Flam Flamen entt University o Ottawa Institute o Mental Health Research, Ottawa, ON, Canada John John R. Gedd Geddes es University Department o Psychiatry, Warneord Hospital, Oxord UK Stepha Stephan n Heres Heres Department o Psychiatry and Psychotherapy, Psychotherapy, echnische Universit¨ Universit at a¨t Munchen, u¨ nchen, Klinikum rechts der Isar, Munchen, u¨ nchen, Germany Jeffrey Jeffrey Huffman Huffman Department o Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Jona Jonath than an C. Ipse Ipserr Mailman School o Public Health, Department o Epidemiology, Epidemiology, Columbia University, New York, NY, USA
Darren Darren Cotterell Cotterell Solent Healthcare NHS rust, St James Hospital, Portsmouth, Hampshire, UK
Werner Werner Kissli Kissling ng Department o Psychiatry and Psychotherapy, Psychotherapy, echnische Universit¨ Universit at a¨t Munchen, u¨ nchen, Klinikum rechts der Isar, Munchen, u¨ nchen, Germany
John John M. Davi Daviss Department o Psychiatry, University o Illinois at Chicago, IL, USA
Christ Christoph opher er J. Kratoc Kratochvi hvill University o Nebraska Medical Center, Omaha, NE, USA
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List List of contri contribut butors ors
Stefan Stefan Leucht Leucht Department o Psychiatry and Psychotherapy, Psychotherapy, echnische Universit¨ Universit at a¨t Munchen, u¨ nchen, Klinikum rechts der Isar, Isar, Munchen, u¨ nchen, Germany Michae Michaell R. Liebow Liebowitz itz Department o Psychiatry Psychiatry,, Columbia College o Physicians Physicians and Surgeons, and the New York State Psychiatric Institute, New York, NY, USA John John S. Marc March h Duke University Medical Center C enter,, Durham, NC, USA Andrew Andrew A. Nieren Nierenber berg g Department o Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Micha Michael el J. Os Osta tach cher er Department o Psychiatry and Behavioral Sciences, Stanord University University School o Medicine, Stanord, Stanord, CA, USA Ilenia Pampaloni Pampaloni Surrey and Borders Partnership NHS rust, UK Roy Roy H. Perl Perlis is Department o Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Luis Luis H. Ripo Ripoll ll Mental Illness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, NY, USA Frankl Franklin in R. Schnei Schneier er Department o Psychiatry Psychiatry,, Columbia College o Physicians Physicians and Surgeons, and the New York State Psychiatric Institute, New York, NY, USA
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Larr Larry y J. Siev Siever er Mental Mental Illness Il lness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, NY, USA Wendy Spettigue Spettigue Children’s Children’s Hospital o Eastern E astern Ontario, Ottawa, ON, Canada Dan Dan J. Stei Stein n Department o Psychiatry, University o Cape own, Cape own, South Arica. Matt Matthe hew w J. Tayl Taylor or Institute o Psychiatry, King’s College London, UK Joseph Joseph Triebwasser Triebwasser Mental Mental Illness Il lness Research Education and Clinical Center, James J. Peters VA Medical Center, Bronx, NY, USA Ant Anton J. L. M. Van Van Balko alkom m Department o Psychiatry and EMGO Institute, VU University Medical Center and GGZ inGeest, Amsterdam, the Netherlands Wim va van n den den Brin Brink k Academic Medical Center o the University o Amsterdam, Department o Psychiatry, Psychiatry, Amsterdam Institute or Addiction Research (AIAR), Amsterdam, Te Netherlands Briget Brigette te S. Vaugha Vaughan n University o Nebraska Medical Center, Omaha, NE, USA Sarah Sarah Waldma Waldman n Mood and Anxiety Disorders Service, Hampshire Partnership NHS Foundation rust, UK
Preface Te pionee pioneers rs o modern modern psych psychop ophar harmamacology cology prided prided themse themselve lvess on the empi empirirical nature o their work, and the rigor o their their clinic clinical al data. data. Evide Evidence nce-bas -based ed medici medicine ne emph emphasi asizes zes the import importanc ancee o searc searchin hingg or relevant studies and making decisions in the the ligh lightt o the the data data,, an and d ther there eor oree has immediate appeal or psychopharmacology. cology. Tis volume attempts attempts to summarize recent advances in evidence-based medication treatment o psychiatric disorders. d isorders. Clin Clinic ical al deci decisi sion onss are are only only as good good as the the existing evidence, and critics have rightly pointed out the necessity or good clinical judgment and and or urther research when when the data is poor. Nevertheless, there has been a steady growth in methods or systematically reviewing the literature, assessing the clinical trials database, and optimizing clinical decision-making, as well as an ongoing expansion o the evidence-base. We there-
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ore elt that it was timely to update our pre vious collection o evidence-based e vidence-based chapters on psychopharmacology. Tis volume comprises chapters on each o the the majo majorr psyc psychi hiat atri ricc diso disord rder ers, s, an and d addresses questions such as (1) what is the best �rst-line psychopharmacological psychopharmacological interinter vention or a particular disorder; (2) how long should such an intervention be continued, and (3) what is the next best strategy should the �rst-line psychopharmacologic logical al agen agentt ail? ail? Tese Tese ques questi tion onss lie lie at the heart o clinical psychopharmacology, and we are hopeul that the volume will there thereo ore re appeal appeal to practi practicin cingg clinic clinician ians, s, whether they work in a primary or specialty setting. Dan J. Stein Beni Lerer Stephen Stahl
Chapter
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Evidence-bas Evidence-based ed pharmacoth pharmacotherap erapyy of atten ttenti tion on de de�c �cit it hyper yperact activ ivit ityy disorder Brigette S. Vaughan, John S. March, and Christopher J. Kratochvil
Introduction Attention Attention de�cit hyperactivity disorder (ADHD) is a neurobiological disorder, disorder, affecting signi�cant numbers o children, adolescents, and adults worldwide. Research throughout the past century has established a strong scienti�c oundation or our current understanding o the etiology, epidemiology, and treatment o ADHD. Te American Medical Association’s Council on Scienti�c Affairs in 1998 stated, “Overall, ADHD is one o the best-researched disorders in medicine, and the overall data on its validity are ar more compelling than or many medical conditions” (Goldman et al .,., 1998). Te American Academy o Child & Adolescent Psychiatry (AACAP), in their 2007 ADHD Practice Parameters concluded, “Although scientists and clinicians debate the best way to diagnose and treat ADHD, there is no debate among competent and well-inormed healthcare proessionals that ADHD is a valid neurobiological condition condition that causes signi�cant signi�cant impairment in those whom whom it afflicts” (Pliszka, 2007). Neuropsychological, neuroimaging, and genetic studies have demonstrated the biological underpinnings o ADHD. Tese studies have correlated de�cits in executive unctioning, response inhibition, delay aversion, vigilance, working memory, and planning with speci�c regio regions ns o the brain brain (Willcu (Willcutt tt et al .,., 2005 2005). ). Struct Structura urall imagin imagingg studi studies es have have demon demonstr strat ated ed that that children with ADHD have signi�cantly smaller brain volumes, on average, than same-aged comparison children (Castellanos & annock, 2002; Durston et al .,., 2004; Mostosky et et al .,., 2002), with smaller cerebellar and total cerebral volumes noted (Castellanos et al .,., 2002). In addition, unctional imaging has revealed discrete variations in brain activation, speci�cally in the rontal-striatal cerebellar circuits (Krain & Castellanos, 2006). Family, Family, twin, and more recently, recently, genotyping studies studies provide urther support or the biological basis o ADHD. Tere is considerable evidence that the principal cause o ADHD is genetic, with an estimated herheritability o 76% (Faraone et (Faraone et al .,., 2005). Parents o children with ADHD are 2–8 times more likely to have the disorder themselves, and the risk is similar or siblings o affected children (Faraone & Biederman, 2000). ADHD ADHD has has been been cons conserv ervat ativ ivel elyy esti estima mate ted d to occur occur in 3– 3–7% 7% o chil childr dren en (AP (APA, 20 2000 00), ), wi with th othe otherr esti estima mate tess as high high as 7– 7–12 12% % (CDC, (CDC, 20 2005 05;; Woodruff oodruff eet al ., ., 20 2004 04). ). Whil Whilee most most comm common only ly
Essential Evidence-Based Psychopharmacology, Psychopharmacology, Second Edition E dition,, ed. Dan J. Stein, Bernard Lerer, C Cambridge University Press. and Stephen M. Stahl. Published by Cambridge University Press.
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diagnosed between ages 7 and 10 1 0 years, symptom presentation presentation and impairment can ofen be be seen in children as young as age 3 years (Lavigne et al .,., 1996). Epidemiological studies have shown that 2–6% o preschool children meet diagnostic criteria or ADHD (Angold et al .,., 2000; Lavigne et Lavigne et al .,., 1996). O those diagnosed with ADHD as children, 60–85% continue to meet criteria or the disorder as adolescents, and as many as 60% continue to experience et al .,., 1990, 2002; Biederman et symptoms symptoms as adults (Barkley et Biederman et al .,., 1996; Kessler et Kessler et al .,., 2005). A comprehensive differential diagnosis is essential or an accurate evaluation. Behaviors which are characteristic o normal childhood development may be misinterpreted as ADHD i not considered in an age-appropriate context. In addition, developmental disabilities, learning disorders, mental retardation, and hearing or vision impairments, as well as gener general al medical medical probl problems ems such such as hypert hyperthy hyro roidi idism, sm, partial partial comple complexx seizur seizures, es, or lead lead toxic toxicit ity y may mimic ADHD. Several aspects o the core symptoms o inattention, hyperactivity, and impulsivity, can also be indicative o depressive and anxiety disorders, substance abuse, or pediatric bipolar disorder. disorder. Te diagnostic criteria or ADHD require the presence o at least 6/9 inattentive symptoms, and/or 6/9 hyperactive-impulsive symptoms, with onset prior to age 7 years. Symptoms must be developmentally inappropriate and result in clinically signi�cant impairment in social, academic, and/or occupational unctioning (APA, 2000). Even preschool children with ADHD are at high risk or academic, social, behavioral, and amily dysunction due to the disorder disorder (DuPaul (DuPaul et al .,., 2001), and are are more likely likely to be placed placed in specialized specialized educa educationa tionall et al .,., 1998, 2004). Tese children also have increased rates o accidents and settings (Lahey et injuries (Lahey et et al .,., 1998), aggression (Connor et (Connor et al .,., 2003), and internalizing symptoms (Cunningham & Boyle, 2002). School-aged S chool-aged children with ADHD as a group have more difficulties with peer interactions, academic tasks, and con�icts with parents than do same-aged peers without ADHD. In addition to ongoing difficulties common to younger children, adolescents have elevated rates o substance use and abuse, motor vehicle accidents, academic and occupational impairments, teen pregnancy, and sexually transmitted diseases (Barkley, 2006). Nearly two-thirds o children diagnosed with ADHD also have at least one co-occurring psychiatric condition. Te Multimodal reatment Study o Children with ADHD (MA) consisted o one o the largest and best characterized ADHD populations to date ( n = 579 children aged 7–9.9 years), and demonstrated that only 31% o participants had ADHD alone, while 40% also met criteria or oppositional de�ant disorder, 38% or anxiety/mood disorders, 14% or conduct disorder, and 11% or tic disorders (MA Cooperative Group, 1999). Te National Initiative or Children’s Healthcare Quality (NICHQ) recommends that children with ADHD and their amilies receive individualized treatment with ongoing support and education (Bodenheimer et (Bodenheimer et al .,., 2002a 2002a, 2002b 2002b). Tey recommend that an effective ADHD management plan or children should generally include parent training, behavioral modi�cation and social-skills training, and school-based interventions. In preschool children, or those with mild symptoms, the AACAP (Pliszka, 2007) and American Academy o Pediatrics Pediatrics (AAP, (AAP, 2001) recommend a trial o behavioral interventions prior to starting medication. Unortunately, studies have shown that while behavioral therapies offer some bene�t, they may have limited effectiveness as a monotherapy or treating moderate to severe ADHD. In the majority o cases, behavioral interventions may be only one component o a more extensive treatment plan.
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Table 1.1. Treatment recommendations from the AACAP Practice Parameters for the assessment and treatment of attention deficit hyperactivity disorder (Pliszka, 2007).
Treatment Treatment
The treatment plan for f or the patient with ADHD should be well thought out and comprehensive. Pharmacological treatment should begin with an agent approved by the FDA for the treatment of ADHD. If a patient responds robustly to pharmacotherapy, medication treatment of their ADHD alone may be sufficient. If none of the FDA-approved medications result in satisfactory treatment, the clinician should review the diagnosis and consider behavioral therapy and/or the use of medications not approved by the FDA for the treatment of ADHD.
Monitoring
Patients receiving pharmacotherapy for ADHD should have their height and weight monitored throughout treatment. The patient should be monitored for treatment-emergent side-effects during pharmacotherapy. If a patient has a suboptimal response to medication, a comorbid diagnosis, or psychosocial stressors, adjunctive psychosocial intervention is often beneficial. Treatment should continue as long as symptoms remain present and cause impairment. The need for treatment should be periodically reassessed.
Te MA study randomized participants to intensive behavioral therapy, pharmacotherapy with systematically delivered methylphenidate, a combination o the two, or standard community care. Te pharmacotherapy and combined treatment groups demonstrated signi�cant improvement, and both were superior to behavioral therapy alone. Interestingly, howev however er,, the combin combined ed treat treatmen mentt group group’’s respo response nse was not signi� signi�can cantly tly bette betterr than than pharm pharmaacotherapy alone or the treatment treatment o core ADHD symptoms. Medication, thereore, thereore, appears to have the most signi�cant acute impact on the treatment o ADHD (MA Cooperative Group, 1999). Te addition o behavioral interventions to pharmacotherapy did, however, increase parent and teacher satisaction with treatment, improved children’s interpersonal relationships, and on average, children receiving behavioral interventions required lower medica medicatio tion n doses doses (MA (MA Cooperat Cooperative ive Group Group,, 199 1999). 9). A late laterr study study o childr children en aged aged 3–5 3–5.5 .5 years years with moderate to severe ADHD, the Preschool ADHD reatment Study (PAS), demonstrated limited response to behavioral therapy alone, resulting in the majority o children warrantin warrantingg the initiati initiation on o pharmacot pharmacothera herapy py ollowing ollowing treatmen treatmentt with only behavioral behavioral interinter vention (Greenhill et (Greenhill et al .,., 2006).
Practice Practice parameters parameters Te AACAP AACAP Practic Practicee Param Paramet eters ers or or ADHD ADHD publi publishe shed d in 200 20077 combin combinee shortshort- and long-t long-term erm empirical evidence with expert opinion rom pediatric mental health researchers and clinicians. Tey offer speci�c recommendations (able (able 1.1) or a comprehensive comprehensive treatment treatment plan, potentially consisting o pharmacological and behavioral interventions, and that i pharmacotherapy is indicated, the initial agent selected should be one with US Food and Drug Admin dminis istr trat atio ion n (FD (FDA) appr approv oval al or or ADHD ADHD.. Te AACA AACAP P urth urther er stat states es that that i the the resp respon onse se to an FDA-approved FDA-approved treatment is robust and normalizes the patient’s unctioning, medication alone may be sufficient (Pliszka, 2007). In their 2001 clinical practice guideline or treating ADHD in children, the AAP recommended mended that that the �rst �rst inte interven rventio tion n or or the youn youngg child child wi with th ADHD ADHD be behavi behaviora orall (AAP (AAP, 2001 2001). ).
Chapte Chapterr 1: Evide Evidence nce-ba -based sed pharma pharmacot cothe herap rapy y of ADHD ADHD
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Table 1.2. Treatment algorithm for preschool children with attention deficit deficit hyperactivity disorder (Gleason et al .,., 2007).
General principles Assessment and diagnosis should be comprehensive, developmentally appropriate and contextually sensitive. An adequate trial of psychotherapy should precede pharmacotherapy, and should continue even if medication is used. Pharmacotherapy should be considered in the context of the clinical diagnosis and degree of functional impairment. Referral of the parent for treatment may optimize family mental health. Medication discontinuation trials are recommended following 6 months of treatment. The use of additional medication to manage side-effects of medication is discouraged. dis couraged.
Stage 0: Diagnostic Diagnostic assessment and psychotherapeutic intervention. Stage 1: Methylphenidate Methylphenidate trial. Stage 2: Amphetamine Amphetamine trial. Stage 3: a-adrenergic a-adrenergic or atomoxetine trial.
Te 2007 AACAP (Pliszka, 2007) parameters indicate that behavioral therapy alone may be appropriate in mild cases o ADHD and should be considered or young children. Additionally, Gleason and colleagues made speci�c recommendations regarding treatment algorithms or pharmacotherapy in preschool-aged children (able 1.2) (Gleason et al .,., 2007). Gleason and colleagues went on to speci�cally address treatment o preschool-aged patients with wi th ADHD ADHD and ree reeren renced ced the PAS study study when when provi providin dingg guidan guidance ce or or treati treating ng youn youngg chilchildren dren wi with th a psych psychost ostim imula ulant nt.. Te AACAP AACAP does does note note that that subject subjectss in PAS were were only only random random-ized ized to pharm pharmaco acothe thera rapy py i they they did not demon demonstr strat atee signi� signi�can cantt or satis satisact actory ory impr improv oveme ement nt ollowing 10 weeks o parent training (Greenhill et (Greenhill et al .,., 2006).
Whaat is the Wh the �r �rst st-l -lin inee trea treatm tmen entt for AD ADHD HD?? Te role o pharmacotherapy (able 1.3) as a �rst-line treatment o ADHD is strongly supported in the literature (Biederman & Spencer, 2008). Te stimulant medications have decades o efficacy data rom hundreds o controlled trials, beginning as early as the 1930s, and were well-established as effective treatments or ADHD by the 1970s. Te pediatric saety and efficacy database on acute and long-term use o these agents has continued to grow and includes data not only on school-aged children, but more recently has expanded into preschool children and adolescents (AAP, 2001; Biederman & Spencer, 2008; Brown et al .,., 2005; Greenhill et al .,., 2002; Pliszka et Pliszka et al .,., 2007). Tere has also been a signi�cant incr increa ease se in data data supp suppor orti ting ng the the utili utility ty o nonnon-st stim imul ulan antt agen agents ts or or ADHD ADHD in the the past past 10 year yearss (AAP, 2001; Biederman & Spencer, 2008; Brown et Brown et al .,., 2005; Greenhill et Greenhill et al .,., 2002; Madaan et al .,., 2006; Pliszka et al .,., 2007). A meta-analysis o atomoxetine and stimulant studies revealed a robust effect size or atomoxetine and the stimulants, both o which are currently appr approv oved ed by the FDA FDA or or the treat treatmen mentt o ADHD ADHD.. Atomo tomoxet xetine ine demon demonstr strat ated ed an effect effect size size o 0.62, which would be considered a medium effect size, compared with 0.91 and 0.95, considered ered large large effect effect sizes, sizes, or or immedi immediat atee- and extend extendeded-rel releas easee stimu stimulan lants, ts, respe respecti ctivel velyy (Fara (Faraone one,, 2003). 200 3). A more more recen recentt FDA FDA-app -appro roved ved agent agent,, the a2 agonist agonist guanacine guanacine XR, demonstr demonstrate ated d effect sizes o 0.43–0.86 in two double-blind, placebo-controlled (DBPC) trials (Biederman et al .,., 2008b 2008 b; Sallee et Sallee et al .,., 2009b 2009b).
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Table 1.3. Medications with FDA approval for the treatment treatment of attention deficit hyperactivity disorder.
Name
Delivery system
Duration Duration of effect (Daughton & Kra Kratochvi chvill, 2009 2009))
Methylphenidate
Solution Chewable tablet Tablet Sustained release tablet Beaded capsule
4h 4h 4h Up to 8 h 7–8 h
Beaded capsule OROS capsule Transdermal patch
8–9 h Up to 12 h 12 h
Methylin Methylin Ritalin Ritalin SR Metadate ER, Methylin ER, Ritalin LA Metadate CD Concerta Daytrana
d-Methylphenidate
Tablet Beaded capsule
4h Up to 12 h
Focalin Focalin XR
Amphetamine
Tablet Beaded capsule
6h 10 h
Adderall Adderall XR
d-Amphetamine
Tablet Spansule capsule
4h 10 h
Dexedrine, Dextrostat Dexedrine Spansule
Lisdexamfetamine
Capsule
10 h
Vyvanse
Atomoxetine
Capsule
24 h
Strattera
Guanfacine extended-release
Tablet
8–12 h
Intuniv
Clonidine extended-release
Tablet
12 h
Kapvay
Trad rade name
Stimulants Stimulants Stimulants have historically been considered a �rst-line treatment treatment or ADHD, with approxiapproximately 75% o children responding to the �rst agent selected, and 80–90% eventually responding i two different stimulants are tried consecutively (Pliszka, 2003). Although the MA study examined the use o immediate-release methylphenidate, extended-release preparations are now commonly used to improve adherence to the treatment schedule, thus providing less opportunity or gaps in coverage. A combination o immediate- and extended-release preparations, selected and titrated according to tolerability and response, may ultimately be required to optimally manage the child’s individual pharmacotherapy needs. All stimulant medications currently approved approved or the treatment treatment o ADHD are derivatives o either methylphenidate or amphetamine, both o which act by enhancing the neurotransmission o dopamine, and to a lesser extent, norepinephrine (Biederman & Spencer, 2008). DBPC studies in children, adolescents, and adults have demonstrated demonstrated that 65–75% o subj subjec ects ts typi typical cally ly resp respon ond d to stim stimul ulan antt trea treatm tmen ent, t, com compare pared d wi with th 4– 4–30 30% % o those those on plac placeb ebo o (Greenhill et al .,., 2002; Pliszka, Pliszka, 2007). Recent Recent research research has ocused ocused on improvi improving ng the delivery delivery mechanisms o the stimulant medications in order to extend the duration o action. With multiple ormulations o these medications (short-, intermediate-, and long-acting) as well as a variety o administration options available (e.g. capsules, sprinkleable capsules, tablets, chewable tablets, oral solution, transdermal patches), treatment can be tailored to individual patient needs.
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Te MA study demonstrated the tolerability and efficacy o t.i.d. immediate-release methylphenidate in a randomized trial o 579 children aged 7–9.9 years with the combined subt subtyp ypee o ADHD ADHD.. Dose Dose titra titrati tion on wa wass ba based sed on effec effectt as repo report rted ed by pare parent nt an and d teac teache herr rati rating ng scales, and tolerability. Children in the manualized pharmacotherapy arm o the study had mean �nal doses o 32.1 ± 15.4 mg/day, mg/day, and those assigned to manualized pharmacotherapy plus plus behavioral behavioral interventi intervention on had mean �nal doses o 28.9 ± 13.7 mg/day. Te MA study allowed children weighing 25 kg to have methylphenidate doses o up to 35 mg/day, and allowed doses up to 50 mg/day or children who weighed more. Average Average doses in the smaller smal ler children were 0.95 ± 0.40 mg/kg, and 1.13 ± 0.55 mg/kg in those that were heavier (MA Cooperative Group, 1999). Prio Priorr to the the NIMH NIMH- -un unde ded d PAS ther theree were were ewe ewerr than than a doze dozen n small small plac placebo ebo-controlled trials o psychostimulants in preschool children, and all utilized immediaterelease methylphenidate (Kratochvil et al .,., 2004). Doses in these studies did not exceed 0.6 mg/kg, a narrower range than the 0.3–1.0 mg/kg used in older children (Kratochvil (Kratochvil et et al .,., 2004), and were administered q.i.d. or b.i.d., rather than the t.i.d. schedule s chedule ofen required or opti optima mall effec effect. t. Effica Efficacy cy o meth methyl ylph phen enid idat atee in the the pres presch chool ool age age grou group p vari varies es rom rom olde olderr chil chil-dren (Connor, 2002), as does the adverse effect pro�le (Firestone et al .,., 1998). PAS, which used a titration model similar to the MA’s, included 165 children aged 3.5–5 years initially rand random omiz ized ed to eith either er place placebo bo or imme immedi diat atee-re rele leas asee meth methyl ylph phen enid idat atee (1.2 (1.255 mg, mg, 2.5 2.5 mg, mg, 5 mg, mg, or 7.5 7.5 mg t.i. t.i.d. d.). ). Subj Subject ectss rece receiv ived ed a week week o trea treatm tmen entt wi with th each each dose dose duri during ng the the doub double le-b -bli lind nd cross-over titration phase. wenty-two percent o subjects were identi�ed as best responding to 7.5 mg t.i.d. Te mean �nal best dose in PAS was 14.22 ± 8.1 mg/day, or 0.7 ± 0.4 mg/kg.day (Greenhill et (Greenhill et al .,., 2006). When PAS data were compared with MA data, it was noted that the younger children had lower optimal doses, by weight, o immediate-release methylphenidate (0.7 mg/kg.day compared with 1.0 mg/kg.day). Pharmacokinetic data also demonstrated a slower clearance o a single dose o methylphenidate in 4- and 5-year-old children compared with schoolaged children (Wigal et al .,., 2007). olerability seems to have age-related variability, with younger children demonstrating more emotional adverse events (e.g. crabbiness, irritability, irritability, and an d prone pronenes nesss to crying) crying) than than schoolschool-age aged d childr children. en. Tus, Tus, slowe slowerr titra titratio tion, n, closer closer monit monitori oring ng and an d smaller smaller doses doses o stim stimula ulant ntss are advise advised d when when treat treating ing presc preschoo hooll childr children en (Plisz (Pliszka, ka, 200 2007). 7).
Adverse effects All ormulations o the stimulant medications medications have similar adverse-event pro�les (Greenhill et al .,., 2002). Delayed sleep-onset, decreased appetite, weight loss, headache, stomach upset and increased heart rate and blood blo od pressure are common. Emotional outbursts outbursts and irritability have also been requently reported in younger children (Wigal et al .,., 2006). Concerns with cardiovascular saety o ADHD pharmacotherapies have led to speci�c recommendations recommendations or pre-treatment pre-treatment evaluation, treatment selection, and monitoring. monitoring. Much scrutiny is given to the risks present or children with structural cardiac abnormalities, but potentially medication-related medication-related changes in heart rate and blood pressure are also observed obser ved in healthy children with ADHD. In a study o 10 years o Florida Medicaid claims, stimulant use in patients with ADHD was associated with 20% more emergency-room visits, and 21% more office visits or cardiac symptoms (Winterstein (Winterstein et et al .,., 2007). Gould et Gould et al . (2009) reported that the rate o sudden death in pediatric patients taking a psychostimulant psychostimulant was the same as that seen in the general population, with 11 sudden deaths
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reported between 1992 and 2005. However, in a matched case-control study, a signi�cant assoc associa iati tion on o stim stimul ulan antt use use wi with th sudd sudden en deat death h wa wass seen seen when when comp compar arin ingg data data or or 56 5644 repo reports rts o sudden death in 7- to 19-year-olds with the deaths o 564 same-aged patients who died in motor vehicle accidents accidents (odds ratio 7.4, 95% con�dence interval (CI) 1.4–74.9) (Gould et (Gould et al .,., 2009). Te AAP (Perrin et (Perrin et al .,., 2008) recommends that a targeted cardiac history and physical examination be part o the assessment o a child prior to initiating ADHD treatment. Questions regarding a prior patient history o heart disease, palpitations, syncope or seizures, or a amily history o sudden death in children or young adults, cardiomyopathy or long-Q syndrome should be asked. I these are present, an ECG and/or reerral to a cardiologist may be warranted prior to initiating treatment. Tese cardiovascular risks may become more o an issue in the treatment treatment o adults who may have concurrent hypertension hypertension and/or cardiovascular disease.
Atomoxetine Atomoxetine, which selectively blocks re-uptake at the noradrenergic neuron, was the �rst non-stimulant medication approved by the FDA or the treatment o ADHD. wo large, DBPC DBPC efficacy efficacy studi studies es demon demonstr strat ated ed signi� signi�can cantt impr improv oveme ement nt in ADHD ADHD sympt symptom omss with with atoatomoxe moxetin tinee compar compared ed wi with th placeb placebo, o, wi with th 64. 64.1% 1% and 58. 58.7% 7% o atom atomox oxeti etine ne subje subjects cts respo respondi nding ng (Spencer et (Spencer et al .,., 2002). More than a dozen DBPC trials have provided evidence supporting the saety and efficacy o atomoxetine dosed both once- and twice-daily or the treatment o ADHD in children, adolescents, and adults (Kelsey et et al .,., 2004; Michelson et Michelson et al .,., 2001, 2002, 2003; Spencer et Spencer et al .,., 2002; Weiss et Weiss et al .,., 2005). Te FDA-approved target therapeutic dose o 1.2 mg/kg.day was selected ollowing a dose-�nding study which observed a graded dose-response to atomoxetine 0.5 mg/kg.day and 1.2 mg/kg.day, but no signi�cant difference between 1.2 mg/kg.day and 1.8 mg/kg.day or reduction o core ADHD symptoms. Improvements in psychosocial unctioning, however, ever, were seen when the dose was increased to 1.8 mg/kg.day without without any signi�cant difference in adverse events (Michelson et (Michelson et al .,., 2001). Atomoxetine is not approved or use in children aged 6 years. However, there has been one DBPC trial (n trial (n = 101), examining the use o atomoxetine in 5- and 6-year-olds. Improvements were noted on parent and teacher ADHD–IV ratings or children assigned to atomoxetine compared with those on placebo ( p ( p 0.05). Tree subjects withdrew rom the study study due due to advers adversee event eventss (ato (atomo moxe xetin tinee = 0, placeb placebo o = 3). 3). Te mean ean �nal �nal dail dailyy dose dose o atomoxetine moxetine was 1.38 mg/kg.da mg/kg.dayy. Despite Despite statisti statistically cally signi�can signi�cantt improv improvemen ements ts in ADHD sympsymptoms toms,, an and d the the act act that that the the pare parent ntss rece receiv ived ed conc concom omit itan antt educ educat atio ion n on ADHD ADHD an and d beha behavi vior oral al inte interve rvent ntio ions ns as a part part o the the stud studyy, the the child childre ren n cont contin inue ued d to have have ADHD– ADHD–IV IV (pare (parent nt)) score scoress above the 86th percentile or age and gender at study completion (Kratochvil et al .,., 2008b 2008b).
Adverse effects Commo Common n acute acute advers adversee effects effects o atomo atomoxet xetine ine inclu include de sedatio sedation, n, loss loss o appet appetit ite, e, na nause usea, a, vomvomiting, irritability, irritability, and headaches. In an analysis o the efficacy and tolerability o atomoxetine atomoxetine in young vs young vs.. older children, no signi�cant differences differences were noted in the adverse event pro�le or response to atomoxetine atomoxetine (Kratochvil et (Kratochvil et al .,., 2008a 2008a). Atomoxetine Atomoxetine carries additional warnings or hepatotoxicity hepatotoxicity and suicidality risk. An analysis o laboratory data rom 7961 adult and pediatric subjects in atomoxetine clinical
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Chapte Chapterr 1: Evide Evidence nce-ba -based sed pharma pharmacot cothe herap rapy y of ADHD ADHD
trials trials reveale revealed d 41 instan instances ces o elevat elevation ionss in AS AS and AL AL. Tere Tere were were 351 spont spontane aneou ouss report reportss o hepatic events in the �rst 4 years atomoxetine was on the market. O these, three suggest gested ed atom atomox oxet etin inee as a proba probabl blee caus cause, e, an and d 1/3 1/3 had had a posit positiv ivee re-c re-cha halle lleng nge. e. In all thre threee case cases, s, symptoms resolved ollowing discontinuation o atomoxetine. Tese data resulted in recommenda mendatio tion n that that atomo atomoxet xetine ine be discon discontin tinued ued i jaund jaundice ice or eleva elevatio tions ns in hepat hepatic ic enzyme enzymess are a). A 20 present present (Bangs (Bangs et al ., ., 20 2008 08a 2008 08 an anal alys ysis is o data data rom rom 14 stud studie iess o atom atomox oxet etin inee by Ba Bang ngss and colleagues demonstrated that suicide ideation was more common in subjects receiving atom atomox oxeti etine ne (0.37% (0.37%,, 5/1357 5/1357 subje subjects cts)) compar compared ed wi with th those those receiv receiving ing placebo placebo (0%, 0/851 0/851 subsub jects). o place the risk o suicidality in context, the number needed to harm (NNH) was 227, whereas the number needed to treat (NN) to achieve remission o ADHD symptoms was �ve. No suicides occurred in any o the trials in the analysis (Bangs et al .,., 2008b 2008b).
Stimulant and atomoxetine comparator trials Atomo Atomoxe xetin tinee and osmoti osmoticc rel releas easee oral oral system system (OROS (OROS)) methy methylph lpheni enidat datee In a comparator trial in 516 children and adolescents aged 6–16 with ADHD, subjects were randomized to 6 weeks o treatment with either atomoxetine up to 1.8 mg/kg.day (n = 222), OROS methylphenidate up to 54 mg/day (n ( n = 220) or placebo (n (n = 74). Atomoxetine and OROS methylphenidate were both superior to placebo, with 45% ( p ( p 0.003) and 56% ( p ( p 0.001) responding, respectively. Effect sizes were 0.6 or atomoxetine and 0.8 or OROS methylphenidate. Decreased appetite was the only adverse event separating rom placebo or both active treatments ( p ( p 0.05). Subjects receiving OROS methylphenidate reported experiencing insomnia, while those assigned to atomoxetine had more requent comp complai laint ntss o somnol somnolenc ence. e. Weight eight loss loss and increa increased sed diasto diastolic lic blood blood pres pressur suree ( p 0.0 0.05) 5) were were note noted d to be sign signi� i�ca cant nt or or both both drugs drugs comp compar ared ed wi with th plac placeb ebo, o, an and d an incr increa ease sed d pulse pulse rate rate wa wass signi�cant in the atomoxetine group compared with OROS methylphenidate and placebo ( p 0.05) (Newcorn et (Newcorn et al .,., 2008). For the stimulant-naive patients (n ( n = 191) participating in this trial, response rates to atomoxetine (57%, p = 0.004) and methylphenidate (64%, p 0.001) were comparable ( p = 0.43), but those subjects with prior exposure to stimulants ( n = 301), had better responses to methylphenidate (51%, p = 0.002) than to atomoxetine (37%, p = 0.09) ( p = 0.03) (Newcorn et (Newcorn et al .,., 2008). Te effect size or atomoxetine was greater in stimulantnaive patients (0.9), compared with patients previously treated with stimulants (0.5), while the effect effect-si -sizes zes or or OROS OROS methy methylp lphen henida idate te in patien patients ts not previ previous ously ly treat treated ed wi with th a stimu stimulan lantt and with prior exposure were 1.0 and 0.8, respectively (Newcorn et al .,., 2008). Subjects initially assigned to OROS methylphenidate were then switched to atomoxetine at the end o the 6-week acute treatment phase o the study. Forty-two percent (29/69 sub jects) who did not respond to atomoxetine atomoxetine in the second s econd phase o the study had previously resp respon onde ded d to OROS OROS meth methyl ylph phen enid idat atee duri during ng acute acute trea treatm tmen ent, t, whil whilee 43 43% % o subj subject ectss who who did did not respond acutely to OROS methylphenidate (30/70 subjects) went on to respond to atomoxetine. Tis may indicate a differential response to treatment or some patients (Newcorn et al .,., 2008). Atomox Atomoxetine etine and mixed-am mixed-amphet phetamine amine salts In a 3-week laboratory school comparison o atomoxetine and extended-release mixed amphetamine salts in 6- to 12-year-olds with either combined or hyperactive-impulsive
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type ADHD, improved attention and academic perormance were noted with both treatment ments. s. Mi Mixed xed amph ampheta etamin minee saltssalts-tr trea eated ted subjec subjects ts had great greater er impr improv oveme ement ntss than than those those who received atomoxetine ( p ( p 0.001). Te difference at end-point was statistically and clinically sign signi� i�ca cant nt;; howe howeve verr, the the rela relati tive vely ly shor shortt 3-we 3-week ek dura durati tion on o the the stud studyy may may not not have have been been susu�cien �cientt to demon demonstr strat atee the ull ull effect effect o atom atomox oxeti etine ne trea treatme tment nt.. Te mixed mixed amph ampheta etamin minee salts salts group reported experiencing insomnia, decreased appetite, upper abdominal pain, anorexia and headache, while the most common adverse events reported in the atomoxetine group were somnolence, appetite decrease, upper abdominal pain, vomiting, and headache. Vital sign changes were similar or both groups and were not statistically signi�cant (Wigal et al .,., 2005).
a2 agonists Te a2 adrenergic agents, clonidine (Catapres) and immediate-release guanacine (enex), have been used relatively commonly over the past decade as second-line or adjunctive treatments in the USA. International International comparisons (Winterstein (Winterstein et et al .,., 2008), however, however, show very differe different nt co-med co-medica icatio tion n patt pattern ernss betwee between n the USA and Euro Europea pean n count countrie riess where where a 2 adrenergic agents are rarely used. Clonidine C lonidine has been shown to reduce ADHD symptoms in patients with comorbid tics, aggression and conduct disorder. Immediate-release clonidine is shortacting and requires multiple divided doses throughout the day (Brown et al .,., 2005). In the USA clonid clonidine ine is also avail availabl ablee as a transd transderm ermal al patch, patch, allowin allowingg or or onceonce-wee weekly kly appli applica catio tion. n. M An extended-release ormulation ormulation (Kapvay ) was approved approved by the FDA in September 2010, or the treatment o ADHD in children and adolescents aged 6–17 years. Kapvay received approval approval as both monotherapy and in combination combination with a stimulant. stimulant. Guan Guana aci cine ne is a more more sele selecti ctive ve a2 -adr -adren ener ergi gicc agon agonis istt wi with th less less seda sedati tion on an and d a long longer er dura dura-tion o action (Biederman & Spencer, 2008). A small open-label study o immediate-release guanacine showed improvements in hyperactivity and inattention, with transient sedation as the most common adverse event (Hunt et al .,., 1995), and additional studies have demonstrated its utility and good tolerability in treating ADHD with co-occurring tic disorders and ourette’s ourette’s (Chappell ( Chappell et et al .,., 1995; Scahill et Scahill et al .,., 2001). An extended-release orm o guanacine was given FDA approval in 2009 as monotherapy or pediatric ADHD ollowing two controlled trials (study 1: n = 345, ages 6–17 years; study 2: n = 324, ages 6–17 years). Adverse events were largely dose-dependent. Both studies had similar tolerability data, with the most common treatment-emergent treatment-emergent adverse events being headache, somnolence, atigue, sedation, and upper abdominal pain. No clinically signi�cant vital sign or ECG changes were seen (Biederman et al .,., 2008b 2008b; Sallee et al .,., 2009b 2009b). Dose-based effect sizes ranged rom 0.43 to 0.86, and response rates were 43% or the 3-mg dose and 62% or the 4-mg dose. Guanacine’s most common acute adverse effects include somnolence, headache, atigue, upper upper abdomi abdominal nal pain, pain, and sedatio sedation. n. Bradyc Bradycar ardia dia was report reported ed in long-t long-term erm studi studies es (Biederman et iederman et al .,., 2008a 2008a; Sallee et Sallee et al .,., 2009a 2009a).
Whaat is the Wh the im impa pact ct of AD ADHD HD ph phar arma maco coth ther erap apy? y? Te bene�ts o pharmacotherapy are most evident in reduction o the core symptoms o ADHD. By reducing inattention, hyperactivity, and impulsivity, patients with ADHD are are bette betterr able able to perorm perorm academi academicall callyy and socially socially.. Studi Studies es have have demon demonstr strat ated ed that that
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Chapte Chapterr 1: Evide Evidence nce-ba -based sed pharma pharmacot cothe herap rapy y of ADHD ADHD
children treated with stimulants have improved attention attention to school work, decreased disruptive behaviors, and decreased non-compliance. Short-term data also show improvements in academic perormance and productivity (Barkley, 1998). Some data suggest that children with ADHD treated with psychostimulants demonstrate better academic outcomes as evidenced by WIA-II subtests and high school grade point average (GPA) than children with ADHD ADHD who who were were not not trea treate ted. d. Ho Howe weve verr, the the trea treate ted d child childre ren n did did not not do as well well as nonnon-AD ADHD HD controls. It is unclear i pharmacotherapy alone translates to long-term academic success (Powers et (Powers et al .,., 2008). Social interactions between affected children and their parents, teachers, and peers are signi�cantly improved with stimulant treatment. reated children are more compliant with commands and more appropriately responsive to interactions with others, with less negative and off-task behavior. As a result, adult redirections and supervision needs decrease, and praise and positive attention to the child increase. ADHD children treated with stimulants also appear to be better accepted by peers, probably as a result o reduced negative and aggres aggressiv sivee behav behavior ior (Barkle (Barkleyy, 199 1998). 8). He Healt alth-r h-rela elate ted d quali qualityty-oo-li liee outco outcomes mes measu measured red by the Child Health Questionnaire (CHQ) were improved along with ADHD symptoms in children treated with atomoxetine in a DBPC dosimetry study in children and adolescents aged 8–18 years (Michelson et (Michelson et al .,., 2001). Early treatment with methylphenidate does not appear to increase risk or negative outcomes, and may have bene�cial long-term effects (Mannuzza et al .,., 2008). However, longterm data rom the MA MA study notes that bene�ts o pharmacotherapy pharmacotherapy are sustainable up to 2 years or the majority o subjects ollowed, but by the third year o ollow-up, only about one third o subjects demonstrated ongoing bene�t with medication treatment (Swanson et al .,., 2008). Despite decreases in ADHD symptoms, the MA subjects as a group still had relatively poorer ratings o behavior, academic, and overall unctioning compared with normal controls at 6- and 8-year ollow-ups.
How long long shou should ld trea treatm tmen entt last last?? Epidemiological surveys o community samples indicate that 2–6% o preschool children meet diagnostic criteria or ADHD (Angold et (Angold et al .,., 2000; Lavigne et Lavigne et al .,., 1996), with prevalenc lencee rate ratess in schoo schooll-ag aged ed chil childr dren en cons conserv ervat ativ ivel elyy esti estima mate ted d to be betwe between en 3% an and d 7% (AP (APA, 2000) 200 0).. As chil childr dren en grow grow into into adol adoles esce cenc ncee an and d adul adulth thood ood the the prev preval alen ence ce o ADHD ADHD decr decrea ease ses, s, yet still persists in signi�cant numbers, estimated at approximately 3–4% in adults (Fayyad et al .,., 2007). Even though the presentation may vary rom early childhood to adulthood, the impairment there is no less signi�cant (Kessler et al .,., 2006). A multitude o studies have demonstrated a correlation between ADHD in adults and global impairment in unctioning, including: smoking and substance abuse, diminished rates o college graduation, occupational/vocational difficulties, motor vehicle accidents, legal problems, unplanned pregnancies, and relationship problems (Barkley, 2006). In a 10-year case-controlled ollow-up study o 112 male adults with ADHD, potential protective actors o stimulant treatment or ADHD were assessed. Biederman et al . (2008c (2008c, 20 2009) 09) oun ound d no evid eviden ence ce that that stim stimula ulant nt trea treatm tmen entt in child childhoo hood d or adol adoles esce cenc ncee eith either er increased or decreased the risk or development o substance use disorders in young adulthood, but that ADHD patients treated treated with stimulants were at signi�cantly less risk o developing depressive depressive and anxiety disorders, disruptive behavior, behavior, and repeating a grade in school
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than the ADHD patients who were not treated. Daviss et al . also demonstrated a similar �nding o ADHD pharmacotherapy reducing the risk o later major depression (Daviss et al .,., 2008). With the longit longitudi udinal nal course course o ADHD ADHD docume document nted, ed, the AACAP AACAP Practi Practice ce Param Paramet eter er recrecomme ommend ndat atio ions ns serve serve as a remi remind nder er to peri periodi odica call llyy eval evalua uate te the the need need or or ongo ongoin ingg trea treatm tmen entt o ADHD ADHD wi with th pharma pharmacot cothe herap rapyy. Follo Follow-u w-up p clinic clinic visits visits ensur ensuree that that medica medicatio tion n remain remainss effect effect-ive, dosing is optimal, and adverse events are minimized. Te AACAP recommends that ADHD treatment be individualized, and that the duration o treatment should continue as long as impairing symptoms are present (Pliszka, 2007). Considerable evidence demonstrating the efficacy o psychostimulants psychostimulants in treating adults with ADHD (Asherson, 2005) led to FDA approval o both methylphenidate (extendedrelease release methylph methylphenida enidate te and d-methyl d-methylphen phenidat idate) e) and ampheta amphetamine mine (extended-r (extended-release elease mixed amphetamine salts). Atomoxetine has also received FDA approval or adults with ADHD based on two DBPC studies (Buitelaar et al .,., 2007).
Adverse effects A speci�c concern with long-term pharmacotherapy is impact on growth, so much so that the AACAP Practice Parameter or ADHD treatment includes a speci�c recommendation regarding regular height and weight monitoring, including serial plotting o growth parameters. Te AACAP advises that a change in height or weight crossing two percentile lines is suggestive o abnormal growth and warrants a medication holiday, dose adjustment, or change. Reductions in growth must be balanced with bene�ts o treatment (Pliszka, 2007). Swanson et al . (2005) demonstrated that children treated with stimulants grew more slowly and appeared to gain less weight than expected; however, they also theorized that, in general, children with ADHD may have different growth trajectories than their ‘normal’ peer peers. s. Stat Statis isti tical cally ly sign signi� i�ca cant nt dela delays ys in heig height ht an and d weigh weightt were were also also seen seen wi with th stim stimul ulan antt trea treattment in a meta-analysis o 22 studies by Faraone et al . (2008). Te pooled data showed that the the weig weight ht de�c de�cit itss were were more more signi signi�c �can antt than than the the de�c de�cit itss seen seen in heigh heightt ( p = 0.002), 0.002), although although both appeared to normalize over time (Faraone et al .,., 2008). Based Based upon upon a quali qualita tativ tivee meta-a meta-anal nalysi ysis, s, Farao Faraone ne et al . sugg sugges este ted d that that the the effect effectss on weig weight ht and heigh heightt may may be dose-de dose-depen penden dent. t. Tere Tere was no appar apparen entt differ differenc ence, e, howev however er,, in the growth growth effects between methylphenidate and amphetamine, and cessation o treatment appeared to normalize growth (Faraone et (Faraone et al .,., 2008). Tis normalization o growth with breaks over the summer or with drug discontinuation has been demonstrated in additional studies (Gittelman et al .,., 1988; Kaffman et Kaffman et al .,., 1979; Klein & Mannuzza, 1988; Saer et Saer et al .,., 1975); although analysis o data rom the MA study (MA Cooperative Group, 2004) showed that while discontinuation o methylphenidate treatment did not reverse losses in expected height, it did have a bene�cial effect on weight gain. Atomoxetine has also been clearly linked with changes in height and weight trajectories, which or the group appeared to dissipate over time, despite continued treatment (Spencer et al ., ., 20 2005, 05, 20 2007 07). ). Tese Tese data data appea appearr to indi indica cate te that that or or most most child childre ren n grow growth th supp suppre ress ssio ion, n, i prese present nt,, will be transi transien entt and not clinic clinically ally signi� signi�can cantt over over time. time. Nonet Nonethel heless ess,, there there is clearl clearly y an effect o these medications on growth. Tereore, Tereore, while group averages over time may not be overly concerning, close monitoring o individual children taking ADHD medication is clearly indicated.
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Chapte Chapterr 1: Evide Evidence nce-ba -based sed pharma pharmacot cothe herap rapy y of ADHD ADHD
What Wh at is the the mana manage geme ment nt of trea treatm tmen entt-re resi sist stan antt cases cases?? Te vast majority o patients with ADHD will respond to one o the FDA-approved pharmacotherapies or the treatment o ADHD. I a patient does not respond adequately to appropriate trials (adequate duration and optimal dose) o these agents, a re-assessment o the diagnosis is warranted both to con�rm the diagnosis o ADHD and to re-examine or missed co-occurring disorders (AACAP recommendation). Co-occurrence o learning disorders, developmental disorders, and other psychiatric conditions can affect response to treatment and/or complicate treatment planning, and the addition o behavioral therapy to a medication medication regimen regimen may be require required. d. Non-FD Non-FDA A-appro -approved ved pharmacot pharmacothera herapie piess (e.g. buprobupropion or tricyclic antidepressants) may be tried i interventions with a greater evidence base are either ineffective or contraindicated. Finally, combination therapy with FDA-approved agents and/or non-approved agents might be clinically indicated. Use o medications not approved approved or the treatment o ADHD, and treatment with more than one medication simultaneously elevates poten potential tial risks, however, and these risks as well as other treatment treatment options must be discussed with the patient and caregivers, and i employed monitored closely (Pliszka, 2007).
Conclusion ADHD is one o the best-studied disorders in psychiatry. Reliable diagnosis at a young age is possible, and recognition o ADHD as a potentially lie-long impairing disorder is increa increasin sing. g. As data data emerge emerge which which descri describe be the physi physiolo ologic gical al eviden evidence ce behind behind the histo historica rically lly “beha “behavio vioral ral”” diagno diagnosis sis,, accep acceptan tance ce o the role role o pharm pharmaco acothe thera rapy py has increa increased sed or or preschool children through adults. Guidelines such as those rom the AACAP provide clear recom recommen menda datio tions ns to the practi practisin singg clinic clinician ian or or diagno diagnosin sing, g, treat treatin ingg and monit monitori oring ng patie patient ntss with ADHD, in a manner which maximizes effectiveness, tolerability, and ultimately, unctionality o the patient. As improvements are made in the delivery systems and durations o effect o the various psychostimulant agents, clinicians and patients will still be aced with what to do or those who do not respond. Research is expanding into non-stimulant agents, and the speci�c role these may have. Further examination o a potential “differential response,” as suggested in the comparator trial o atomoxetine and OROS methylphenidate, methylphenidate, may may ulti ultima mate tely ly bett better er ino inorm rm clin clinic icia ians ns as to the the sele selecti ction on o a spec speci� i�cc phar pharma maco coth ther erap apyy or or a speci� speci�cc indivi individu dual. al. In the inter interim, im, appr approp opria riate te diagno diagnosis sis,, inorm inormed ed presc prescrib ribing ing,, clinic clinical al monmonitoring, and collaborative treatment planning can all help to optimize outcomes in ADHD management.
Statem Statement ent of intere interest st Dr. Kratochvil was supported by NIMH Grant 5K23MH06612701; received grant support rom Eli Lilly, McNeil, Shire, Abbott, Somerset and Cephalon; was a consultant or Eli Lilly, AstraZeneca, Abbott Quintiles Seaside, and P�zer. He is Editor o the Brown University Child & Adolescent Psychopharmacology Update, Update, member o the REACH Institute Primary Pediatric Psychopharmacology Steering Committee, member o the American Proessional Society or ADHD & Related Disorders Board o Directors, and received study drug or a NIMH-u NIMH-unde nded d study study rom rom Eli Lilly Lilly and Abbott. bbott. Dr. Dr. Kratoc Kratochv hvil il recei receives ves royal royaltie tiess rom rom Oxor Oxord d University Press. Ms. Vaugha aughan n has receiv received ed salary salary suppo support rt rom rom NIMH NIMH Grant Grant 5K2 5K23MH 3MH066 0661270 12701, 1, Eli Lilly Lilly, and Bristol-Myers Squibb.
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Dr. Dr. Ma Marc rch h has has serve served d as a cons consul ulta tant nt or scien scienti ti�c �c advi adviso sorr to P�ze P�zerr, Eli Lilly Lilly,, Wyeth yeth,, Glax GlaxooSmithKline, BMS, Johnson and Johnson, Psymetrix, Scion, ransition Terapeutics and MedAvante; MedAvante; has received research support rom Eli Lilly and P�zer; has received study drug or a NIMH-unded study rom Eli Lilly and rom P�zer; is an equity holder in MedAvante; recei receives ves royal royaltie tiess rom rom Guil Guilor ord d Press Press,, Oxor Oxord d Univers niversit ityy Press Press and MultiH ultiHeal ealth th Syste Systems ms;; and receives research support rom NARSAD, NARSAD, NIMH, and NIDA.
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treatment on inhibitory control in children with attention-de�cit/hyperactivity attention-de�cit/hyperactivity disorder. disorder. Journal o Child and Adolescent 17 , 356–366. Psychopharmacology 17 Powers Powers RL, Marks DJ, Miller CJ et al. (2008). al. (2008). Stimulant treatment in children with attention-de�cit/hyperactivity attention-de�cit/hyperactivity disorder moderates adolescent academic outcome. Journal o Child and Adolescent 18 , 449–459. Psychopharmacology 18 Saer D, Allen R, Barr E (1975). Growth rebound afer termination o stimulant drugs. Pediatrics drugs. Pediatrics 86 , 113–116. Sallee FR, Lyne A, Wigal , McGough JJ (2009a (2009a). Long-term saety and efficacy o guanacine extended release in children and adolescents with attention-de�cit/ attention-de�cit/ hyperactivity disorder. disorder. Journal o Child and 19 , 215–226. Adolescent Adolescent Psychopharmacology 19 Sallee FR, McGough J, Wigal et et al. (2009 al. (2009b b). Guanacine extended release in children and adolescents with attention de�cit/ hyperactivity disorder: a placebo-controlled trial. Journal trial. Journal o the American Academy Academy o 48 , 155–165. Child and Adolescent Adolescent Psychiatry 48 Scahill L, Chappell PB, Kim YS et YS et al. (2001). al. (2001). A placebo-controlled study o guanacine in the treatment o children with tic disorders and attention de�cit hyperactivity disorder. disorder. 158 , American Journal Journal o Psychiatry Psychiatry 158 1067–1074. Spencer , Heiligenstein JH, Biederman J et J et al. (2002). Results rom two proo-o-concept, placebo-controlled placebo-controlled studies o atomoxetine in children with attention-de�cit/hyperactivity attention-de�cit/hyperactivity 63 , disorder. Journal disorder. Journal o Clinical Psychiatry 63 1140–1147. Spencer J, Kratochvil CJ, Sangal RB et RB et al. (2007). Effects o atomoxetine on growth in children with attention-de�cit/hyperactivity attention-de�cit/hyperactivity disorder ollowing up to �ve years o treatment. Journal treatment. Journal o Child C hild and Adolescent 17 , 689–700. Psychopharmacology 17 Spencer J, Newcorn JH, Kratochvil CJ et CJ et al. (2005). Effects o atomoxetine on growth afer 2-year treatment among pediatric patients with attention-de�cit/hyperactivity attention-de�cit/hyperactivity disorder. Pediatrics disorder. Pediatrics 116 , e74–e80. Swanson J, Arnold LE, Kraemer H et H et al. (2008). al. (2008). Evidence, interpretation, and quali�cation rom multiple reports o long-term outcomes in the multimodal treatment study o children with ADHD (MA): (MA): Part II:
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Chapter
2
Evidence-bas Evidence-based ed pharmacoth pharmacotherap erapyy of schi schizo zoph phre reni niaa Stean Leucht, Stephan Heres, Werner Kissling, and John M. Davis
Introduction Enormo Enormous us scien scienti� ti�cc efforts efforts have have been been made made since since the develo developme pment nt o chlorp chlorprom romazi azine ne in 195 19533 to impr improv ovee the the drug drug trea treatm tmen entt o schi schizo zoph phre reni niaa leadi leading ng to more more than than 10 00 0000 cont contro rolle lled d trial trialss currently summarized in the Cochrane Schizophrenia Group’s Group’s register (Adams et (Adams et al .,., 2008). In this context, the current article presents our personal interpretation o the core evidence about the pharmacological treatment o schizophrenia. Other interpretations exist and the article cannot compete with national treatment guidelines that have been methodologically developed (e.g. Lehman et Lehman et al .,., 2004). But what makes our article different is that it attempts to ollow the logical steps o clinical care. Arranged as a simple algorithm it starts rom the choi choice ce o an an anti tips psyc ycho hoti ticc or or acute acutely ly ill pati patien ents ts an and d ends ends wi with th the the most most impo importa rtant nt ques questi tion onss about maintenance maintenance treatment. treatment.
Method Te report is based on published systematic systematic reviews or relevant key articles on topics not yet covered by a systematic review. We did not perorm a literature search or this review but the �rst author (S.L.) regularly runs MEDLINE searches with the key words ‘antipsychotic ∗ OR schizophreni∗ ’.
Treatment of an acute episode epi sode (see Fig. 2.1 for outline) outli ne) Choice Choice of antipsy antipsycho chotic tic drug drug and what what is the �rst-l �rst-line ine pharma pharmacot cother herapy apy More than 50 years o psychopharmacological research on antipsychotics have yielded little evid eviden ence ce-ba -base sed d data data or or the the choi choice ce amon amongg the the at leas leastt 50 an anti tips psyc ycho hoti ticc drugs drugs avai availa labl blee wo world rld-wide wi de (Gae (Gaebe bell & Awa wad, d, 1994). 1994). Much uch hope hope has has been been plac placed ed in phar pharma maco coge gene neti tics cs,, but but this this �eld �eld is still in its inancy (Stone et al .,., 2010). As all drugs have advantages and disadvantages, it is impossible to de�ne a single �rst-line compound. In this context we brie�y summarize our interpretation o the discussion about second-generation antipsychotics (SGAs) vs. vs. �rst-generation antipsychotics (FGAs), and which is the best SGA, mainly based on recent systematic reviews (Leucht et al .,., 2008b 2008b, 2009a 2009a, 2009b 2009b) and effectiveness studies CAIE (Lieberman et al ., . , 20 2005 05)) an and d EUFE EUFES S (Kah (Kahn n et al ., . , 20 2008 08). ). We did did not not incl includ udee the the most most rece recen nt
Essential Evidence-Based Psychopharmacology, Psychopharmacology, Second Edition, Edition, ed. Dan J. Stein, Bernard Lerer, C Cambridge University Press. and Stephen M. Stahl. Published by Cambridge University Press.
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
A Pragmatic criteria criteria for selection of of drug: • Evidence of prior response to the same drug • Avoid side-effects experienced with a drug in the past • Small differences in antipsychotic efficacy • General side-effect profile and patient characteristics • Patient's preference for a specific drug • Planned mode of administration
Insufficient clinical effect
B Before assuming non-response, non-response, check: • Is the underlying diagnosis correct? correct? • Do side-effects mask a response (e.g. akathisia)? • Sufficient dose? • Adequate duration (no major change if not complete lack of response response despite at least 2–4 weeks with full dose)? • Compliance? Optimize compliance-tra compliance-transparency nsparency by depot, liquids or rapidly-dissolving rapidly-dissolving tablets, tablets, plasma-level • Adequate plasma level reached? Check for cytochrome P450 polymorphism polymorphism or drug–drug drug–drug interaction
C Alternatives
Switch the antipsychot antipsychotic: ic: Preferably choose an antipsychotic antipsychot ic with a receptor-binding profile that is in contrast with the previously chosen drug and take into account A
Dose increase: E.g. for another 2 weeks if side-effects allow. Note: almost no evidence supporting this procedure beyond therapeutic dose ranges
Insufficient clinical effect: go to
19
Special situations
Agitated patients: • Parenteral administration brings about little gain in time and and is often only only necessary in patients patients unable to accept accept oral treatment • Among the many available options haloperidol + promethazine is best examined by appropriate RCTs RCTs • If a Iater treatment with a SGA is planned, using the i.m. SGA facilitates facilitates the transition
Negative symptoms: • Best evidence for low-dose amisulpride (50–300 mg/d) in patients patients with predominant predominant negative symptoms • Only amisulpride, clozapine, olanzapine and risperidone risperidone have been shown to be more efficacious efficacious than first-generation first-generation antipsychotics antipsychot ics for general general negative symptoms • Adding an antidepressant seems to be effective
Depressive symptoms: • Effect of antipsychotic treatment on affective symptoms symptoms should be be waited for • In case of persistent depressive symptoms or post-psychotic depression antidepressants antidepressant s may be added added • Risk of worsening of psychosis through antidepressant drug appears to to be low
B and C, consider clozapine (guidelines suggest at least two adequate trials with other antipsychotic antipsychot ic drugs)
Chronic persistent aggressive behavior • Best evidence for clozapine
Augmentation strategies: Augmentation • Currently no augmentation strategy can be generally recommended • If used at all, choice should be directed by target symptoms (e.g. benzodiazepines benzodiazepines – sedation, sedation, moodstabilizers – manic symptoms, symptoms, lamotrigine – possibly possibly for positive symptoms) • Complementary drugs should be chosen for antipsychotic antipsychot ic combinations (e.g. (e.g. multi-receptor antagonist and selective selective dopamine antagonist/partial antagonist/partial dopamine dopa mine agonist) • ECT has a role as a last resort
Fig. Fig. 2.1. 2.1. Treatment of an acute episode of schizophrenia.
antipsychotic drugs (paliperidone, asenapine, iloperidone) except or listing their optimum dose ranges as comparative data are still sparse. We interpret the meta-analyses such that overall clozapine, amisulpride, olanzapine and risperi risperidon donee may may be somewh somewhat at more more efficacio efficacious us than than FGAs FGAs an and d other other SGAs SGAs (Davis (Davis etal ., ., 20 2003; 03; Geddes et Geddes et al .,., 2000; Leucht et Leucht et al .,., 2009a 2009a, 2009b 2009b). Te magnitude o the efficacy superiority
20
Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
was small, and certainly smaller than differences in the most requent side-effects. Te use o clozapine is restricted to reractory patients due to the increased risk o agranulocytosis (Alvir, (Alvir, 1994). However However, careul monitoring monitoring o changes in the blood count has almost eliminated agranuloctyosis-induced death (Lieberman, 1998). Haloperidol produced more extrapyramidal side-effects (EPS) and tardive dyskinesia than SGAs, even when it was used at doses 7.5 mg/day (Leucht et (Leucht et al .,., 2009a 2009a). Prophylactic antiparkinson antiparkinson medication reduces haloperidol’s haloperidol’s EPS (Rosenheck et et al .,., 2003). Low-potency FGAs FGAs prod produc ucee ewe ewerr EPS EPS than than halo haloper perid idol ol,, an and d not not more more than than all SG SGAs As (Leuc (Leucht ht et al ., . , 20 2003 03b b, 2009a 2009 a). Te risk o mid-potency FGAs such as perphenazine, is between that o high- and low-potency FGAs (Klein & Davis, 1969), and it was similar to risperidone according to Hoyberg & Fensbo (1993). Among the SGAs a meta-analysis suggested that clozapine and quetiapine probably have the lowest and risperidone the highest EPS risk (Rummel-Kluge et al .,., 2010). In contrast to this partial amelioration o EPS with SGAs there is also a shif in the sideeffect pro�le with most SGAs increasing the risk o metabolic abnormalities (de Hert et al .,., 2009;; Newco 2009 Newcomer mer,, 200 2005). 5). Clozap Clozapine ine an and d olanza olanzapi pine ne produ produced ced most most weigh weightt gain gain and metabo metabolic lic problems (Allison et (Allison et al .,., 1999) (the POR guideline recommends against using them �rstline in �rst-episode patients; Buchanan et al .,., 2010), while ziprasidone and haloperidol cause caused d the least least ollo ollowed wed by aripi aripipra prazol zole, e, amisul amisulpri pride, de, and proba probably bly mid-po mid-pote tency ncy FGAs FGAs such such as perphen perphenazi azine ne.. Low-po Low-pote tency ncy FGAs, FGAs, zotep zotepine ine,, sertind sertindole ole,, queti quetiap apine ine,, and risperi risperidon donee probprobably lie somewhere in the middle (Leucht et (Leucht et al .,., 2009a). Tioridazine, ziprasidone, sertindole, and pimozide are probably associated with most Qc prolongation (Buchanan et (Buchanan et al .,., 2010). Risperidone and amisulpride seem to produce the greatest prolactin increase, even more so than haloperidol (Bushe et (Bushe et al .,., 2008; Kleinberg et Kleinberg et al .,., 1999). Aripiprazole, clozapine, and quetiapine may be associated with the smallest prolactin increase. Any creation o a clear hierarchy is difficult. Ideally, studies studies including all agents would be necessary, but or obvious reasons such studies are not available. Many drugs have not been compared head-to-head and methodologically sound dose-�nding studies have not been conducted or almost all �rst-generation compounds (Davis, 1974). For example, the evidence on sulpiride and perphenazine – drugs that did well in the CAIE (Lieberman et al .,., 2005) and CUtLASS studies (Jones et al .,., 2006) – is scarce and their optimum doses have not been establ establish ished ed in appr approp opria riate te �xed-d �xed-dose ose design designss (H (Hart artun ungg et al ., . , 20 2005 05;; Omor Omorii & Wan ang, g, 2009 20 09). ). Furth Further ermo more re,, it is diffic difficul ultt to weigh weigh all thes thesee diffe differe renc nces es in effica efficacy cy an and d side side-e -effe ffect cts. s. For For many patients patients weight gain may be unacceptable, while or other patient p atientss EPS are undesired. Again other patients may want to receive the most efficacious drug regardless o side-effects. Recommendation: Drug Recommendation: Drug choice needs to be primarily based on pragmatic criteria:
Prior response to an antipsychotic assuming that previous efficacy predicts efficacy in the current episode. Te avoidance o an antipsychotic that produced side-effects in an earlier episode. General side-effect pro�le o the substances (see above) and patient characteristics (e.g. in a patient with diabetes, substances causing weight gain should be avoided). Slight differences in efficacy. efficacy. Te intended long-term administration. I it is clear that a depot substance is to be administered or maintenance therapy, therapy, the choice o an oral antipsychotic antipsychotic that is available as a depot can acilitate the later change.
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
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I possible, patients’ preerences should be taken into account in a shared decision-making process. Tis may improve compliance and in the end it is the patient who must take the medication. Tereore patients patients should be involved (Hamann et al .,., 2003).
Sedati Sedation on strate strategie giess in agitat agitated ed patien patients ts Tere are many strategies or the treatment o agitated patients such as monotherapy with an antipsychotic (high or low potency, oral or parenteral), monotherapy with a benzodiazepine, combining both, adding a sedating low-potency FGA, rapidly dissolving tablets, liqu liquid id orm ormul ulat atio ions ns,, etc. etc. Due Due to a lack lack o RC RCs a de�n de�nit itee reco recomm mmen enda dati tion on is not not possi possibl blee an and d probably most options work in some way. Liquid and rapidly dissolving tablets are options or saeguarding drug intake. Parenteral administrations do not lead to a much aster onset o action (Moller et (Moller et al .,., 1982). A review ound no signi�cant difference between intramuscular ormulations o haloperidol and chlorpromazine (Leucht et al .,., 2008a 2008a). Te combination o haloperidol and lorazepam seems to be more efficacious than their monotherapy (Alexander et al .,., 200 2004; 4; Battagl Battaglia ia et al .,., 199 1997). 7). Te SGAs SGAs aripi aripipra prazol zole, e, olanza olanzapi pine ne and ziprasi ziprasi-done are available as intramuscular ormulations ormulations (Citrome, 2007). Teir advantage includes ewer EPS than haloperidol. A general problem is that the SGA studies were conducted or registrational purposes and all participants had to give inormed consent. Tese are not the patients or whom intramuscular medication is indicated (ofen violent patients who are not willing to take medication). From a methodological perspective our large (200–300 participants), real-world pragmatic trials with intramuscular medication need to be highlighted (Alexander et (Alexander et al .,., 2004; Hu et et al .,., 2003, 2007; Raveendran Raveendran et et al .,., 2007). In these the combination o haloperidol and promethazine produced more rapid tranquillization with ewer dysto dystonic nic reacti reaction onss than than haloperi haloperidol dol alone alone (H (Hu u eet al ., . , 20 2007 07)) an and d no more more EPS EPS than than lora loraze zepa pam m alone (Alexander et (Alexander et al .,., 2004). It did outperorm olanzapine in secondary outcomes (number o additional injections) with no difference in EPS, probably due to the anticholinergic properties o promethazine (Raveendran, 2007). Only intramuscular midazolam, a highly sedating benzodiazepine, was more efficacious than haloperidol plus promethazine (Hu et al .,., 2003) but the mean dose o haloperidol in this study was lower compared with the other listed trials and so a dosing effect leading to the avorable outcome or the benzodiazepine compound cannot be completely ruled out. In the case o chronic, persistent aggressive behavior clozapine was superior to haloperidol and olanzapine (Krakowski et (Krakowski et al .,., 2006). Te evidence or other SGAs or mood stabilizers is indirect at best (e.g. derived rom nonschizophrenic populations), because RCs in this speci�c group o patients have not been conducted. Recommendation: Paren Parente teral ral admini administr strat ation ion should should usual usually ly only only be appli applied ed in emerg emergency ency situations situations when patients reuse medication. Among the many available options the best evidence is available or haloperidol combined with promethazine. promethazine. I the subsequent subsequent oral treatment is planned to be an SGA it can be reasonable to choose its intramuscular ormulation or sedation. Treatme reatment nt of patien patients ts with with depres depressiv sivee sympto symptoms ms Depressi Depressive ve symptom symptomss are requen requently tly present present in acutely acutely ill patients patients with schizophrenia schizophrenia (Barnes & McPhillips, 1995) and may �rst improve with antipsychotics alone. Based on limit limited ed data data some some SGAs SGAs have have shown shown super superior ior an antid tidep epre ressa ssant nt prope properti rties es (Leuch (Leuchtt etal .,2009a .,2009a). A Cochran Cochranee review review ound ound some some eviden evidence ce that that an antid tidep epre ressa ssant ntss are effect effective ive or or post-p post-psy sycho chotic tic
22
Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
depression (Whitehead et (Whitehead et al .,., 2003). Te risk that an adjunctive antidepressant antidepressant may provoke psychosis has been judged to be small (Siris, 1991; Whitehead et al .,., 2003). Recommendation: Depressive symptoms associated with an acute episode should not be automatically automatically treated with an antidepressant. antidepressant. Neuroleptic-induced Neuroleptic-induced depressive symptoms might be ruled out by anti-parkinson medication or switching to a drug with ewer EPS. Post-psychotic Post-psychotic depression may b bee treated with an antidepressant.
Treatme reatment nt of patien patients ts with with neg negati ative ve sympto symptoms ms All SGAs and haloperidol improved negative symptoms more than placebo (Leucht et al .,., 2008b 2008 b). In Leuc Leuch ht et al . (200 (20099a), only our our SGAs SGAs (amisulp (amisulpride, ride, clozapine clozapine,, olanzap olanzapine, ine, risperirisperidone) were more efficacious than FGAs or negative symptoms. However, almost all relevant studi studies es were were condu conducte cted d in patien patients ts sufferi suffering ng predo predomin minan antly tly rom rom positi positive ve sympt symptom oms. s. In such such patients patients it is unclear whether it is a superiority or negative symptoms symptoms related to primary, or only to secondary, negative symptoms which can stem rom positive symptoms, depression or EPS. Only studies in patients with primary/predominant negative symptoms could clariy whether SGAs are truly more efficacious. Here, the best evidence is available or low-dose amisu amisulp lpride ride (50–300 (50–300 mg/da mg/day) y) which which prove proved d superi superior or compar compared ed wi with th placebo placebo in severa severall trials trials (Leucht et (Leucht et al .,., 2002b 2002b). However, However, comparing SGAs to FGAs only a ew RCs RCs in predominant predominant negative symptoms are available and among these only a single small trial showed superiority ity o olanza olanzapi pine ne compar compared ed with with halope haloperido ridoll (Linden (Lindenma maye yerr etal .,., 2007 2007). ). Tree Tree meta-a meta-anal nalyse ysess showed that adding an antidepressant can be effective or predominant negative symptoms (Rummel et (Rummel et al .,., 2006) or in chronic patients with schizophrenia (Sepehry et (Sepehry et al .,., 2007; Singh et al .,., 2010). Recommendation: Secondary Recommendation: Secondary negative symptoms due to EPS should be ruled out (e.g. by antiparkinson antiparkinson medication or changing the antipsychotic). Low-dose amisulpride is the bestexamined drug in patients with predominant predominant negative symptoms. Adding an antidepressant antidepressant can be tried. Factor actorss that that ne need ed to be rule ruledd out out be befo fore re nonnon-re resp spon onse se is assum assumed ed Beore assuming non-response and introducing a major change in treatment, a number o items need to be ruled out. Is the diagnosis o schizophrenia correct? A psychotic A psychotic depression/mania depression/mania or severe personality disturbances can be difficult to distinguish rom schizophrenia. Do side-effects mask a response? Akathisia Akathisia can resemble psychotic agitation and parkinsonism can mimic negative symptoms. Sufficient dose? Tere Tere is better inormation about the therapeutic dose ranges o SGAs than FGAs because dose-�nding studies have been conducted during their registration processes. Tere is some s ome variability between guidelines, but we present the recommendations o the POR guideline (Buchanan et (Buchanan et al .,., 2010), supplemented supplemented by Falkai et Falkai et al . (2005) or our own evaluation i necessary: amisulpride 400–800 mg/day or predominant positive symptoms and 50–300 mg/day or predominant negative symptoms, aripiprazole 10–30 mg/day, asenapine 10–20 mg/day, clozapine 300–800 mg/day (in treatment-resistant patients), iloperidone 12–24 mg/day, olanzapine 10–20 mg/day, quetiapine 300–800 mg/day, paliperidone 3–15 mg/day, risperidone 2–8 mg/day, sertindole 12–20(24) mg/day, ziprasidone 80–160 mg/day, zotepine 150–250 mg/day. Regarding FGAs, an in�uential review concluded that very high doses (700 mg/day chlorpromazine) are generally no more efficacious than
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
23
moderate doses (Baldessarini et (Baldessarini et al .,., 1988). A Cochrane review suggested that in uncomplicated patients higher doses than 7.5 mg/day haloperidol do not bring about more efficacy (Waraich et (Waraich et al .,., 2002) and in single RCs, 4 mg/day (Zimbroff et (Zimbroff et al .,., 1997) or neuroleptic threshold doses (average 3.3 mg/day) were as effective as higher doses (McEvoy et et al .,., 1991). Much uch less less is know known n ab abou outt the the dose dosess o othe otherr FGAs FGAs and dose dose-e -equ quiv ival alen ence ce tabl tables es are are prob proble lemmatic among others since they assume linear relationships. We orient the interested reader to recent publications publications on dose equivalence (Andreasen et al .,., 2010; Davis & Chen, 2004; Gardner et ner et al .,., 2010; Kane et Kane et al .,., 2003). First-episode and elderly patients ofen need lower doses. Te latter are also more sensitive to side-effects due to reduced metabolism and one-third o the dose in younger patients has been suggested as a rule o thumb (Jeste et al .,., 1993). Was the patient compliant? Compliance Compliance problems are so requen requentt that they should always be addressed by switching switching to liquid medication or rapidly dissolving tablets in inpatients; inpatients; or considering depot medication in outpatients (Leucht & Heres, 2006). Plasma levels and the determination determination o a patient’s patient’s cytochrome c ytochrome P450 status can also a lso be useul. Sufficient plasma level? Tere level? Tere is not sufficient evidence to allow the exact titration o antipsychotics guided by therapeutic drug monitoring except or clozapine, where it can be useul. Tereore, plasma-level measurements are only indicated in the ollowing situations (or review o therapeutic ranges see Baumann et al .,., 2004):
Suspicion o non-compliance. Lack o response in spite o taking usually sufficient doses to rule out ultra-rapid excessive metabolization o the antipsychotic due to a polymorphism o the cytochrome P450 enzyme system. Pronounced side-effects despite the administration o a usual dose to rule out ‘poor metabolizers’ due to too little production o cytochrome P450 enzymes. Medication interactions, smoking, etc., which can also lead to elevated or lowered plasma levels via effects on the cytochrome P450 system.
Has the patient been treated sufficiently long? Te Te onset o response to treatment o individual patients is highly variable and recent analyses attempted to resolve some o the heterogeneity by identiying different trajectories (Levine & Leucht, 2010; Levine & Rabinowitz, 2010). Nevertheless, recent meta-analyses rejected the long-held hypothesis that there is a general ‘delay o onset o action’ o several weeks or antipsychotic drugs. Te largest part o the drug effect occurred in the �rst week and became consistently smaller thereafer (Agid et (Agid et al .,., 2003; Leucht et Leucht et al .,., 2005a 2005a). wo urther studies demonstrated that the antipsychotic drug effect can be disentangled rom placebo as early as 24 h (Agid et al .,., 2008; Kapur et Kapur et al .,., 2005). Tese Tese �ndi �nding ngss call call into into ques questi tion on guid guidel elin ines es that that a drug drug shou should ld not not be cons consid ider ered ed ineff ineffect ect-ive and switched beore 3–6 weeks (Gaebel et al .,., 2006; Lehman et Lehman et al .,., 2004; McGorry, 2005; NICE, NICE, 2003 2003). ). Indeed Indeed,, severa severall studi studies es have have now sugge suggest sted ed that that non-re non-respo sponde nders rs might might be idenidenti�e ti�ed d as soon soon as af afer er 2 week weeks. s. Very roug roughl hlyy, thos thosee pati patien ents ts who who did did not not have have an impr improv ovem emen entt o at leas leastt 20 20–2 –25% 5% in PANSS ANSS or BPRS BPRS total total scor scoree redu reduct ctio ion n (cor (corre resp spon ondi ding ng to less less than than miniminimally mally impr improv oved ed on the Clinic Clinical al Global Global Impr Impress ession ionss Scale; Scale; Leuch Leuchtt etal ., ., 20 2005 05b b,2005c ,2005c,2006)at 2 weeks weeks were were unlike unlikely ly to respon respond d later later (Asch (Ascher er-S -Svan vanum um etal ., ., 20 2008 08;; Chan Changg etal .,., 2006 2006;; Correll Correll et al .,., 2003; Jager et Jager et al .,., 2009; Kinon et Kinon et al .,., 2008a 2008a, Leucht et Leucht et al .,., 2007a 2007a, 2008c 2008c; Lin et Lin et al .,., 2007). In one analysis, however, only improvement at 4 weeks but not at 2 weeks predicted later response (Lambert et (Lambert et al .,., 2009). Although only little evidence is available that early switching o medication is effective (see below), keeping the patient on the original drug is likely
24
Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
to lead to a poor outcome. Tereore, changing treatment earlier than the usually proposed 4–6 weeks could be justi�ed. Recommendation: Recommendation : Beore non-response is assumed, the diagnosis should be con�rmed, and side-effects masking response, non-compliance, insufficient dose, and too-ast drug metabolism should be ruled out (e.g. by plasma levels). Any major change in treatment should not be considered beore absolute non-response to at least 2–4 weeks o treatment with a ull antipsychotic dose.
Swit Switch chin ingg the the drug drug or incr increa easi sing ng the the dose dose in init initia iall nonnon-re resp spon onde ders rs Surp Surpri risi sing ngly ly ew ew RC RCs have have exam examin ined ed the the effec effecti tive vene ness ss o swit switch chin ingg medi medica cati tion on or o a majo majorr dose increase. (a) Switching to a different antipsychotic. antipsychotic. o date only one trial examined switching afer only 2 weeks o virtually no improvement. improvement. It ound that switching switching rom risperidone to olanzapi zapine ne wa wass more more effect effectiv ivee than than keep keepin ingg pati patien ents ts on risp risper erid idon one, e, but but the the supe superi rior orit ityy wa wass small small (Kinon et (Kinon et al .,., 2010). Kinon et al . (1993 (1993)) trea treate ted d 11 1155 parti partici cipa pant ntss wi with th 20 mg/d mg/day ay �uph �uphen enaz azin inee or or 4 week weeks. s. Te 47 non-responders were randomized to double-blind treatment with ( a) continuation with 20 mg/day �uphenazine (control group), (b ( b) 80 mg/day �uphenazine (dose increase group) or 20 mg/day haloperidol (switching group). Regardless o the strategy, only our (9%) o these patients responded. Shalev et et al . (1993) randomized 60 patients with acute schizophrenia schizophrenia to haloperidol, perphenazine, or chlorpromazine. Non-responders Non-responders afer 4 weeks o treatment were randomized twice to open treatment with one o the other two antipsychotics. At the end o the study, the majority o the participants had responded with an overall higher number o patients responding to perphenazine or chlorpromazine than to haloperidol. Suzuki et al . (2007) (2007) random randomize ized d 78 patien patients ts with with schizo schizoph phren renia ia to olanza olanzapi pine, ne, queti quetiap apine ine or risp risper erid idon one. e. Afer Afer up to 8 week weekss trea treatm tmen ent, t, the the nonnon-re resp spon onde ders rs were were tw twic icee re-ra re-rand ndom omiz ized ed to the remaining compounds. Only 16 patients did not respond to any o the three antipsychotic drugs with olanzapine and risperidone showing comparable efficacy while quetiapine was less effective. As in Shalev et Shalev et al . (1993) the major limitation o the study was the lack o a control group o patients who stayed on the initial drug to rule out that the improvement was not simply an effect o time. Stroup et Stroup et al . (2007) post-hoc analyzed those 114 participants who had received perphenazine in CAIE phase I, but discontinued it. Tose participants who were randomized to quetiapine or olanzapine in phase II did better than those randomized to risperidone. Tis was explained by the similar pro�le o perphenazine and risperidone. Tus, i the antipsychotic drug is changed, it is reasonable to choose a compound with a different receptor-binding receptor-binding pro�le. (b) Substantially increasing the dose. dose . Te aorementioned study by Kinon et al . (1993) showed no incremental efficacy o increasing �uphenazine rom 20 mg/day to 80 mg/day. McEvoy et et al . (1991) randomized patients who did not respond to neuroleptic threshold dose dosess o halo halope peri rido doll (mea (mean n 2.3 2.3 mg/d mg/day ay)) to eith either er cont contin inua uati tion on o thre thresh shol old d dose dosess or dose dosess up to 10 times greater. Te dose increase was not associated with better efficacy. In Kinon et al . (2008b (2008b) ther theree wa wass no effica efficacy cy diffe differe renc ncee betw betwee een n 10 mg/da g/dayy, 20 mg/d mg/day ay,, an and d 40 mg/d mg/day ay olan olan-zapine in patients with suboptimal response to previous treatment. Olanzapine (40 mg/day) was, however, however, slightly better b etter in a severely ill subgroup. subgroup.
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
25
Recommendation: More ore evide evidenc ncee may may be avai availa labl blee or or swit switch chin ingg a drug drug rath rather er than than a masmassive dose increase beyond the official ranges, although even or the ormer strategy the evidenc dencee is scar scarce ce.. Indi Indivi vidu dual al pati patien ents ts resp respon ond d only only to very very high high dose dosess an and d such such a hist history ory shou should ld be considered, but we would not recommend this as a general strategy. I a dose increase beyond the optimum doses was not effective, the dose should be reduced to previous levels. An antipsychotic with a different receptor-binding pro�le should be chosen in case o a switch. Tere is no randomized evidence whether patients should be started on a loading dose, a medium dose, or titrated slowly upwards. Tis decision needs to be adapted to the situation (e.g. the acuteness o the symptoms) and the antipsychotic (some require titration or have clearly dose-related side-effects).
Clozap Clozapine ine and other other SGAs SGAs for treatm treatment ent resist resistanc ancee Clozapine had been continuously prescribed in several European countries in the 1970s and 1980s (Naber & Hippius, 1990). It was reintroduced reintroduced in the USA and other countries afer the landmark study o Kane et Kane et al . (1988) reporting clozapine to be superior to chlorpromazine in reractory patients. Tis �nding was con�rmed by subsequent studies (Kane et al .,., 2001; Rosenheck et et al .,., 1997) and meta-analyses (Chakos et (Chakos et al .,., 2001; Essali et Essali et al .,., 2009; Wahlbeck et al .,., 1999). Clozapine was superior to other SGAs in CAIE phase II but it was the only open-label arm (McEvoy et et al .,., 2006). In the CUtLASS study clozapine was more effective than other SGAs as a group (Lewis et (Lewis et al .,., 2006). A meta-analysis o 28 blinded RCs did not �nd signi� signi�can cantt superi superiori ority ty o cloza clozapin pinee compar compared ed with with other other SGAs SGAs (Leuch (Leuchtt et al ., ., 20 2009 09b b). We suggested that too-low clozapine doses explained this unexpected �nding. Nevertheless, we believe that a conclusive conclusive clozapine vs clozapine vs.. other SGAs trial is still needed. Concerning the efficacy o other SGAs compared to FGAs in treatment-resistant treatment-resistant patients patients a meta-analysis published in 2001 concluded that in contrast to clozapine none was con vincingly superior (Chakos et (Chakos et al .,., 2001). Te evidence base has not substantially changed since. We brie�y summarize the studies in treatment-resistant participants in Leucht et al . (2009a (2009a). Tere was no RC comparing amisulpride, sertindole, or zotepine with FGAs in treatment-resistan treatment-resistantt schizophrenia. Kane et Kane et al . (2007) ound no difference between aripiprazole and perphenazine in 300 participants who had not responded to olanzapine or risperidone. Olanzapine was superior to haloperidol in a post-hoc analysis o treatment-resistant pati patien ents ts rom rom a larg largee pivo pivota tall tria triall (Bre (Breie ierr & Hamil amilto ton, n, 19 1999 99;; olle olleso son n et al ., . , 19 1997 97). ). It was also also ound superior to haloperidol in patients having poorly responded to FGAs in Volavka et olavka et al . (2002). Four smaller studies did not �nd olanzapine clearly superior (Altamura et al .,., 2002; et al .,., 1998; Smith et et al . (2005) ound no Buchanan et Buchanan et al .,., 2005; Conley et Smith et al .,., 2001). Conley et difference between quetiapine, risperidone and �uphenazine, while in Emsley et Emsley et al . (2000) partial non-responders to �uphenazine did better when they were randomized to quetiapine quetiapine instead o haloperidol. Wirshing et al . (1999) ound a superiority o risperidone compared with haloperidol in the �rst 4 weeks o an 8-week study, while Conley et Conley et al . (2005), See et See et al . (1999) and Volavka Volavka et et al . (2002) did not �nd any clear superiority. Kane et al . (2006) ound superi superiori ority ty o zipra ziprasid sidone one compar compared ed with with chlorp chlorprom romazi azine ne in terms terms o negat negative ive sympt symptom omss but but not overall symptoms. In our opinion none o these �ndings are robust enough to generally recommend another SGA than clozapine or reractory patients. Recommendation: Recommendation : Clozapine remains the gold standard or treatment-reractory treatment-reractory patients while or none o the other SGAs is there sufficient evidence available. By most guidelines clozapine is recommended afer at least two adequate trials with different antipsychotic drugs.
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Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
Augmentation strategies Among the many augmentation augmentation strategies that have been examined, there was no clear effect o benzodiazepines (apart rom sedation; Volz et al .,., 2007), beta-blockers (Cheine et al .,., 2001), lithium (Leucht et al .,., 2007b 2007b), carbamazepine (Leucht et (Leucht et al .,., 2002a 2002a) and valproate (Basan et al ., ., 200 2004) 4).. Te larg larges estt valpr valproa oate te stud studyy (249 (249 parti partici cipa pant nts) s) show showed ed a more more rapi rapid d onse onsett o improvement in the augmentation group at 2 weeks (Casey et (Casey et al .,., 2003), but even this effect was not replicated in a recent trial with 402 participants (Casey et (Casey et al .,., 2009). Lamotrigine trigine is a promisin promisingg adjunct adjunct according according to a Cochrane Cochrane review review (Premkum (Premkumar ar & Pick, Pick, 2006) and a meta-analysis ocusing on clozapine non-responders (iihonen et al .,., 2009). However, ever, the latter meta-analyses were relatively small and possibly not robust (rikalinos (rikalinos et al .,., 2004). Attempts to add acetylcholinesterase inhibitors to improve cognitive de�cits have not proven effective (Stip et al .,., 2007). Te effects o other augmentation strategies such as polyunsaturated atty acids (omega-3 and omega-6 atty acids; Joy et Joy et al .,., 2006), glutamatergic agents (uominen (uominen et et al .,., 2006), estrogens (Chua et al .,., 2005), dehydroepiandrosterone (DHEA; Elias & Kumar, 2007), amphetamines (Nolte et al .,., 2004), cyclooxygenase2 (COX-2) inhibitors such as celecoxib (Akhondzadeh et al .,., 2007; Muller et al .,., 2002), and erythropoietin (Ehrenreich et al .,., 2007) are either still in the experimental stage or inconclusive. Recommendation: Recommendation : Monothe onotherap rapyy should should be the aim, aim, because because combin combinat atio ions ns o medica medicatio tions ns increase the risk o side-effects and drug–drug interactions. In drug combinations it is ofen not not clea clearr whic which h comp compou ound nd has has led led to succ succes esss an and d whic which h shou should ld be disco discont ntin inue ued. d. Comp Compli lian ance ce with several agents is difficult. Most importantly, there is no convincing evidence or any combination combination strategy. strategy. It might at best b est be tried or target symptoms symptoms (e.g. benzodiazepines benzo diazepines or anxiety) and quickly discontinued i ineffective. Combinat Combinations ions of antipsych antipsychotic otic drugs Altho Although ugh an antip tipsyc sychot hotic ic drugs drugs are are requ requen ently tly combin combined ed in clinic clinical al practi practice, ce, several several recen recentt syssystematic reviews did not show a clear bene�t. Correll et al . (2009) suggested a better response in the the comb combin inat atio ion n grou group p comp compar ared ed wi with th mono monoth ther erap apyy, but but it rema remain ined ed uncl unclea earr whic which h o the the many combinations combinations were effective, the positive p ositive results were mainly based on Chinese studies in which antipsychotics were combined right rom the start rather than afer non-response (which is current practice), i clozapine was part o the combination treatment, and i the trials lasted 10 weeks (con�rmed by Paton et Paton et al .,., 2007; but not by aylor & Smith, 2009). Furthermore, there was a possibility o publication bias. Barbui et al . (2009) included only studies in clozapine non-responders and ound a positive effect only in randomized open studies, but not in double-blind studies. Recent RCs suggested some bene�ts o adding aripiprazole to risperidone or reducing prolactin (Kane et (Kane et al .,., 2009) and to clozapine or reducing weight (Fleischhacker et al .,., 2008). Another study suggested possible efficacy or aripiprazole augmentation augmentation or negative symptoms symptoms (Chang (C hang et et al .,., 2008). Recommendation: Due to lack o convincing evidence, combining antipsychotic drugs cannot be generally recommended (Goodwin et al .,., 2009). I used, drugs with different receptor-binding pro�les should be combined. For example, clozapine, which has relatively ew an antid tidopa opamin minerg ergic ic prope properti rties, es, may may be combin combined ed with with select selective ive dopami dopamine ne recep recepto torr an antag tag-onists such as amisulpride, sulpiride, aripiprazole, aripiprazole, or low-dose haloperidol, while, or example, combining olanzapine and quetiapine makes less sense.
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
27
Electro Electrocon convul vulsiv sivee therap therapyy (ECT) and repeti repetitiv tivee transc transcran ranial ial magnet magnetic ic stimul stimulati ation on (rTMS) (rTMS) In a Cochr Cochran anee revi review ew,, EC EC mono monoth ther erap apyy wa wass more more effect effectiv ivee than than sham sham EC EC, but but less less effect effectiv ivee than anti-psychotic drugs (Taryan & Adams, 2005). Very limited evidence supported the combin combinat ation ion o EC wi with th an antip tipsyc sychot hotics ics.. Me Metata-ana analys lyses es ound ound mediu medium m effect effect sizes sizes or or rMS rMS or or positiv positivee sympt symptom omss (Alema (Aleman n etal .,., 200 2007; 7; ranuli ranuliss et al ., ., 200 2008) 8).. Fewe Fewerr stud studie iess exam examin ined ed the the effect o rMS applied over rontal areas in order to in�uence negative symptoms symptoms with more equivocal results (Hajak et et al .,., 2004; Klein et Klein et al .,., 1999). Guidelines consider rMS to be still in the experimental stage (Gaebel et (Gaebel et al .,., 2006; Lehman et Lehman et al .,., 2004). Recommendation: EC is recommended only as a last resort (except or special indications such as severe catatonia), but advantageously compared with the other augmentation strategies, it is effective as monotherapy and has a different mechanism o action than antipsychotics.
Maintenance treatment (see Fig. 2.2 for outline) Indication In naturalistic studies, only ∼20% o patients with a �rst episode did not experience another episode within 5 years (Robinson et al .,., 1999; Shepherd et al .,., 1989). We assume that in multiple-episode patients this proportion is even smaller. Maintenance treatment with anti an tipsy psycho chotic tic drugs drugs clearl clearlyy reduce reduced d relap relapse se rate ratess rom rom 53% to 16% wi withi thin n 9.7 month monthss (Gilbe (Gilbert rt et al .,., 1995). Intermittent treatment (tapering medication once a patient is in remission and only re-starting it when there are early warning signs) was less efficacious than continuous treatment (Carpenter et al .,., 1990; Herz et Herz et al .,., 1991; Jolley & Hirsch, 1990; Pietzcker et al .,., 1993; Schooler et Schooler et al .,., 1997), even in �rst-episode patients (Gaebel et al .,., 2010). Recommendation: As ther theree are are no vali valid d indi indica cato tors rs that that coul could d pred predict ict who who wi will ll not not rela relaps pse, e, we ollow an early guideline (Kissling et al .,., 1991) that suggested continuous maintenance treatment with antipsychotic drugs or all patients, except or those in whom side-effects outweigh the bene�ts, those with very mild episodes, and unclear diagnoses. Choice Choice of the antips antipsyc ychot hotic ic drug drug in mainte maintenan nance ce treatm treatment ent In Leucht et Leucht et al . (2003a (2003a), SGAs as a group reduced relapse rates compared with FGAs rom 23% to 15%. In an update the various SGAs were not pooled because we elt that they were too too diffe differe rent nt to orm orm a clas class. s. Amon Amongg the the sing single le SG SGAs As,, only only olan olanza zapi pine ne,, risp risper erid idon onee an and, d, based based on a single trial, sertindole were superior to FGAs (Leucht et (Leucht et al .,., 2009a 2009a). A clearer advantage includes lower incidence o tardive dyskinesia, which occurred with an annual incidence o 3.0% in SGAs vs SGAs vs.. 7.7% with FGAs (see Correll & Schenk, 2008, an update o Correll et al .,., 2004). Recommendation: Recommendation : For pragmatic pragmatic reason reasons, s, maintena maintenance nce treatme treatment nt can be carried out out with the the an anti tips psyc ycho hoti ticc drug drug to whic which h the the pati patien entt resp respon onde ded d in the the acute acute epis episode ode as long long as ther theree are are no important side-effects. However, However, the higher risk o FGAs or tardive dyskinesia or weight gain-related risks associated with several SGAs should be considered. Depot medication medication Depot ormulations are not more efficacious per se, but they could have advantages in terms o improved compliance, although the randomized evidence is limited. A summary o Cochrane reviews ound little supportive evidence but included short-term studies and
28
Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
Indication: As there is only a small proportion of individuals who will not have a second episode (~20% of first-episode patients, probably fewer among multiple-episode patients) and as it is impossible to predict who will not relapse maintenance treatment is recommended for all patients unless episodes were brief and mild, the diagnosis was questionable or side-effects outweigh the benefits
Fig. Fig. 2.2. 2.2. Maintenanc Maintenance e treatment treatment of schizophreni schizophrenia. a.
Choice of drug: • Choose the drug which was effective in the acute phase if it was well tolerated. tolerated. Advise about higher higher risk for tardive dyskinesia dyskinesia in case case of first-generation first-generation antipsychotic and and the long-term consequences consequences of weight gain in case case of relevant second-generation second-generation antipsychotics. • Otherwise selection criteria are similar to those of the acute phase • Depot treatment has obvious advantages in terms of compliance, but the randomized randomized evidence demonstrating superiority superiority compared compared to oral treatment treatment is limited
Dose: • As it is unclear whether it is possible to use lower doses in maintenance maintenance treatment than than standard acute acute doses, dose should should not be automatically automatically reduced unless there are important important side-effects, but excessive excessive doses applied in the the acute phase should now now be reduced • Any dose reduction or drug withdrawal should be made slowly
Duration: First-episode patients: at least 1–2 years Multiple-episode Multiple-epis ode patients: at least 5 years
studies in inpatients – both actors that may have limited the compliance-improving effect (Adams et al .,., 200 2000). 0). Indeed Indeed,, a recen recentt meta-a meta-anal nalysi ysiss inclu includin dingg only only long-t long-term erm RC RCs in outpa outpa-tients ound a superiority o depot compared with oral treatment, but there were limitation l imitationss (Leucht et (Leucht et al .,., 2011). Interested readers might reer to a comprehensive supplement on treatment with depot in the British Journal o Psychiatry Psychiatry (Patel et (Patel et al .,., 2009). Recommendation: Despite Recommendation: Despite the currently limited evidence, we believe that depot medication has obvious advantages such as assured medication and the awareness o when a patient stopped treatment (Kane et (Kane et al .,., 2003).
Durati Duration on of rel relaps apsee preven preventio tion n with with antips antipsych ychoti oticc drugs drugs Tere is little evidence to guide us about the ideal duration o antipsychotic relapse prevention. tion. An early early consen consensus sus cone conere rence nce sugges suggested ted keepin keepingg �rst-e �rst-epi pisode sode patie patient ntss on maint maintena enance nce
Chapter Chapter 2: Evidence Evidence-base -based d pharmaco pharmacothera therapy py of schizophr schizophrenia enia
29
medication or at least 1–2 years and multiple-episode patients or at least 5 years. In severe cases the prophylaxis might even be inde�nite (Kissling et al .,., 1991). Tis recommendation was based on a ew, small, controlled (but not all randomized), withdrawal trials. Multipleepisode patients who had been stable or up to 5 years had signi�cantly higher relapse rates when when their their medica medicatio tion n was withdr withdraw awn n compar compared ed with with those those stayin stayingg on drugs drugs (Cheun (Cheung, g, 198 1981; 1; Johnson, 1976, 1979; Odejide & Aderounmu, 1982). A later study ound the same result in patients who had been stable or 6 years (Sampath et al .,., 1992). In �rst-episode patients the duration was restricted to 2 years, because this was the longest study duration here (Chen etal ., ., 20 2010 10,, Crow Crow etal e tal ., ., 19 1986 86;; Hogart ogartyy & Ulri Ulrich ch,, 19 1998 98;; Ka Kane ne,, 19 1982 82). ). In the the last last 20 year yearss we have have gain gained ed litt little le new new evide evidenc ncee an and d this this rema remain inss a gap gap. But But even even a gradu gradual al symp sympto tomm-gu guid ided ed tape taperring (and discontinuation i easible) o antipsychotic treatment afer 6 months o symptom absence led to doubled relapse rates compared with maintenance treatment in �rst-episode patie patient ntss in a recen recentt trial trial (Wund (Wunderi erink nk etal etal ., . , 20 2007 07). ). It shou should ld also also be note noted d that that lack lack o evid eviden ence ce beyond 6 years (or 2 years or �rst-episode patients) does not mean that the risk or relapse goes goes down. down. Empi Empirica rically lly,, multi multiple ple-ep -episod isodee patie patient ntss stable stable or or 2 years years rela relapsed psed at the same same rates rates as pati patien ents ts newl newlyy ente entere red d into into a rela relaps psee stud studyy (H (Hog ogart arty y eet al .,., 197 1976). 6). Ma Many ny na natio tional nal guidel guideline iness have adopted the early suggestions. Teir recommendations range between 1 and 2 years or �rst-episode patients, and between 2 and 5 years or multiple-episode multiple-episode patients (Gaebel et al .,., 2005). Recommendation: Recommendation : First-episode patients should usually be kept on maintenance medication or at least 1–2 years and multiple-episode patients or at least 5 years.
The optima optimall dosage dosage in maint maintena enance nce treatm treatment ent It is unclear whether lower doses than those usually applied in the acute phase are sufficient or maintenance treatment. Studies in the 1980s and 1990s attempted to identiy doses o depot FGAs that were high enough to prevent relapses, but low enough to minimize sideeffects. Unortunately, the de�nition o an ideal dose was not clear-cut and the lowest doses led to the highest relapse rates, although the differences were not always statistically signiicant (Hogarty & McEvoy, 1988; Johnson et Johnson et al .,., 1987; Kane et Kane et al .,., 1983, 2002; Marder et Marder et al .,., 1984; Schooler et Schooler et al .,., 1997). In a systematic review, higher dosages o conventional antipsychoti chotics cs than than 375 mg/day mg/day chlorp chlorpro romaz mazine ine equiva equivalen lentt did not produ produce ce addit addition ional al effecti effectiven veness ess in maintenance therapy (Bollini, 1994). In another review, dosages between 50 mg/day and 100 mg/day chlorpromazine equivalents led to more relapses than doses between 200 and 500 chlorpromazine equivalents (Barbui et al .,., 1996). Only a ew dose-�nding studies on relapse prevention with SGAs are available. Arato et Arato et al . (2002) ound no difference between 40 mg/day ziprasidone and higher doses. Simpson et al . (2006) reported a trend superiority o risperi risperidon donee 50 mg bi-we bi-weekl eklyy compar compared ed wi with th 25 mg bi-we bi-weekl eklyy, and Wan angg etal . (201 (2010) 0) oun ound d the lowest relapse rate when the risperidone dose that was effective in the acute phase was maintained compared compared with 50% and 25% reductions. In a systematic review including SGAs and FGAs, standard doses were clearly more effective than “very low” doses, while the comparisons o relapses with “low” doses was only o borderline statistical signi�cance (Uchida et al .,., 2009). On the other hand, it may not be so important to lower the dose o SGAs, since within their official dose ranges many side-effects are not very dose related. Recommendation: Recommendation : Given the uncertainty whether lower doses are as effective as standard doses, we recommend keeping the dose o the acute phase as long as there are no important side-e side-effec ffects. ts. Never Neverthe theles less, s, due to variou variouss press pressur ures, es, psychi psychiat atris rists ts someti sometimes mes tend tend to give give very
30
Chapter Chapter 2: Evidence Evidence-base -based d pharmacot pharmacothera herapy py of schizophr schizophrenia enia
high high dose dosess or comb combin inat atio ion n trea treatm tmen ents ts in the the acute acute phas phase. e. Te main mainte tena nanc ncee phas phasee shou should ld dedeinitely be used or reducing such excessive dosing. Any dose reduction should be perormed very slowly to avoid withdrawal effects and rebound psychoses.
Statem Statement ent of Intere Interest st Stean Leucht has received speaker/consultancy/advisory board honoraria rom Sano�Aventis, Bristol-Myers Squibb, Eli Lilly, Essex Pharma, GlaxoSmithKline, Janssen/Johnson and Johnson, Lundbeck and P�zer including the ees and travel expenses or attending these unctions; he has received unding or research projects rom Eli Lilly and Sano�Aventis. ventis. Stephan Stephan Heres Heres has received received honoraria honoraria rom Jansse Janssen-Cilag n-Cilag,, Sano�-A Sano�-Aven ventis, tis, PharmasPharmastar, and Johnson & Johnson; he has accepted travel or hospitality payment rom JanssenCilag, Sano�-A Sano�-Aven ventis, tis, Johnson Johnson & Johnson Johnson,, P�zer, P�zer, Bristol-M Bristol-Myers yers Squibb, Squibb, AstraZene AstraZeneca, ca, Lundb Lundbeck eck,, Novart Novartis, is, and Eli Lilly Lilly and Compan Companyy. Werner erner Kissl Kissling ing has recei received ved speake speakerr and/or and/or advisory board/consultancy honoraria rom Janssen, Sano�-Aventis, Johnson & Johnson, P�zer, P�zer, Bayer B ayer,, Bristol-Myers Bristol-Myers Squibb, AstraZeneca, Lundbeck, Novartis, and Eli Lilly. Lilly.
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