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Aripiprazole

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Aripiprazole ELIZABETH WINANS

S

chizophrenia is a major mental illness that affects between 0.5% and 1% of the population.1 Typically, symptoms begin during the later teenage years to the mid-twenties, and men have an earlier onset than women. The symptoms are categorized as either positive (excess or distortion of normal function) or negative (diminution or loss of normal function).2 Characteristic symptoms include (1) delusions, (2) hallucinations, (3) disorganized speech, (4) grossly disorganized or catatonic behavior, and (5) negative symptoms (anhedonia, lack of motivation, speech deprivation). To meet the diagnostic criteria for schizophrenia, two or more of these five symptoms must be present for a significant amount of time over a one-month period1 and must also be present for at least six months. In addition, these symptoms are associated with marked social or occupational disturbances. Once a diagnosis has been made, it is further classified into the following subtypes: paranoid, disorganized, catatonic, undifferentiated, and residual. The diagnosis of a specific subtype is based on the most current clinical presentation. Further, since

Abstract: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of aripiprazole are discussed. Aripiprazole is a third-generation antipsychotic agent indicated for use in the treatment of schizophrenia. Unlike other antipsychotics, aripiprazole demonstrates mixed D2 and serotonin (5-HT1A) receptor agonist–antagonist activity that is hypothesized to improve schizophrenia’s positive and negative symptoms; the drug has been referred to as a dopamine–serotonin stabilizer. Aripiprazole is well absorbed, with peak plasma concentrations occurring within three to five hours after administration. The oral availability is 87%. The mean elimination half-life is about 75 hours for aripiprazole and 94 hours for its active metabolite. In controlled, randomized, multicenter trials, aripiprazole has demonstrated efficacy in the treatment of schizophrenia comparable to that of haloperidol and su-

symptom prominence may change over time, the specific schizophrenia subtype may change as well. Traditionally, patients with schizophrenia are treated with antipsychotics on a long-term basis. According to the Mount Sinai Conference consensus treatment guidelines for schizophrenia, patients experi-

ELIZABETH WINANS, PHARM.D., BCPP, is Clinical Associate Professor, Departments of Pharmacy Practice and Psychiatry, University of Illinois at Chicago. Address correspondence to Mary Ellen Bonk, Pharm.D., University HealthSystem Consortium, 2001 Spring Road, Suite 700, Oak Brook, IL 60523-1890 ([email protected]). The University HealthSystem Consortium acknowledges Danesh Alam, M.D., Gara L. Coffey, Pharm.D., Sondra May, Pharm.D., and Gerald A. Subar, Pharm.D., for their review of this monograph.

perior to placebo. In a single clinical trial, aripiprazole was superior to placebo in the treatment of acute mania. The most frequent adverse effects are headache, anxiety, insomnia, nausea, vomiting, and lightheadedness. Because aripiprazole is a substrate of both cytochrome P-450 isoenzymes 3A4 and 2D6, there is a potential for other drugs to affect its metabolism. The recommended starting dosage is 10 or 15 mg daily, preferably administered with meals. Aripiprazole offers an alternative to second-generation antipsychotic agents in the treatment of schizophrenia. Index terms: Absorption; Antipsychotic agents; Aripiprazole; Blood levels; Dosage; Drug administration; Drug interactions; Drugs, availability; Excretion; Half life; Mechanism of action; Metabolism; Pharmacokinetics; Schizophrenia; Toxicity Am J Health-Syst Pharm. 2003; 60:2437-45

encing their first psychotic episode should be treated for 12 to 24 months.3 For those with multiple episodes, lifetime antipsychotic treatment may be necessary. Positive symptoms such as hallucinations, delusions, and disorganized language or behavior are possibly related to a hyperdopaminergic activity within

Originally published as a drug monograph in April 2003 by the University HealthSystem Consortium. Reprinted with permission. Copyright © 2003, University HealthSystem Consortium. All rights reserved.

Am J Health-Syst Pharm—Vol 60 Dec 1, 2003

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The Formulary Review section contains monographs provided to AJHP by the Clinical Knowledge Service, Drug Monograph Group, of the University HealthSystem Consortium (UHC), Oak Brook, IL. The monographs are written by drug information specialists and pharmacotherapists from UHC member institutions and VHA institutions, undergo peer review by UHC and VHA pharmacists and physicians, and appear here some months after initial distribution. They have been edited by AJHP and contain new abstracts. For more information, see the initial installment in the December 1, 1997, issue or call Karl A. Matuszewski, M.S., Pharm.D., or Mary Ellen Bonk, Pharm.D., at UHC (630-954-1700).

the mesolimbic system. Conversely, negative symptoms are believed to derive from a hypodopaminergic state in the prefrontal and frontal cortex of the brain. Conventional antipsychotics work by antagonism of dopamine2 (D2) receptors throughout the brain. D2 receptor blockade in the mesolimbic area reduces dopamine, thus improving positive symptoms. Unfortunately, D2 receptor blockade in the prefrontal cortex/cortex area further decreases dopamine, resulting in no benefit and, at times, a worsening of negative symptoms.4 This has been a fundamental problem in the pharmacotherapy of schizophrenia. In general, antipsychotics are classified as either conventional (first-generation agents) or atypical (second-generation agents). Firstgeneration agents are further classified as either high- or low-potency agents based on their binding affinity to D2 receptors. Low-potency conventional agents strongly antagonize muscarinic, α1-adrenergic, and histamine receptors, leading to anticholinergic side effects, orthostatic hypotension, and sedation, respectively. Further, low-potency agents are associated with increased central nervous system depression. Highpotency agents are associated with increased extrapyramidal symptoms 2438

(EPSs) secondary to their high binding affinity to dopamine receptors but demonstrate less histamine blockade, fewer anticholinergic effects, and less α1-adrenergic blockade. Second-generation or atypical agents differ from conventional antipsychotics in that they are associated with fewer EPSs and possess serotonin2 (5-HT2) blockade in addition to D2 blockade.5,6 Product description Aripiprazole (Abilify, BristolMyers Squibb Company, Princeton, NJ, and Otsuka American Pharmaceutical Inc., Rockville, MD), an oral psychotropic, is a quinolinone derivative with a molecular weight of 448.38 (Figure 1). Unlike other antipsychotics, aripiprazole demonstrates mixed D2 and serotonin (5-HT 1A) receptor agonist–antagonist activity that is hypothesized to improve positive and negative symptoms of schizophrenia. On the basis of these unique antipsychotic pharmacologic properties, aripiprazole has been referred to as a third-generation antipsychotic and a dopamine–serotonin system stabilizer. The drug was approved by the Food and Drug Administration (FDA) on November 15, 2002, for the treatment of schizophrenia. Pharmacology The second-generation antipsychotics—risperidone, olanzapine, quetiapine, and ziprasidone—were introduced in the United States in the 1990s. These agents were developed in response to the inadequacies of the first-generation agents, including minimal or no efficacy in a number of patients with schizophrenia, lack of improvement in cognitive

functioning, a high incidence of tardive dyskinesia and other EPSs, and a lack of efficacy in the treatment of negative symptoms.7 Pharmacologic differences associated with secondgeneration as compared with firstgeneration agents include low D2 to D1 receptor occupancy, a high affinity for D4 receptors, a high ratio of 5-HT2 to D2 receptor blockade, and a selectivity for D2 receptors in the mesolimbic system.7 Thus, differences in dopaminergic activity, as well as greater 5-HT2 blockade, provide the atypicals with a unique approach to the treatment of psychotic symptoms. Aripiprazole, a third-generation antipsychotic agent, possesses a unique mechanism of action. It acts as a partial agonist at D2 receptors, while second-generation antipsychotics are antagonists at the D2 receptors.8 As a partial agonist, aripiprazole acts as a D2 antagonist in the presence of high levels of endogenous dopamine, and, conversely, when minimal endogenous dopamine is present, the drug has D2 receptor agonist activity. Aripiprazole has also demonstrated partial agonist activity at the 5-HT1A receptor,9 as well as antagonistic action at the 5-HT2A receptor.10 It has been postulated that partial agonist activity at the 5-HT1A receptor may contribute to improvement in anxiety, depression, negative symptoms, and fewer EPSs.9 To illustrate the concept of a partial agonist, Inoue et al.11 investigated aripiprazole’s effect on spontaneous prolactin release from isolated anterior pituitary slices in male rats. With the addition of talipexole, a D2 agonist, spontaneous prolactin release was decreased. The addition of haloperidol, a potent D2 antagonist, produced an eightfold increase in

Figure 1. Chemical structure of aripiprazole.


Cl

Cl N

NCH2CH2CH2CH2O

H I N

O

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prolactin release. By contrast, aripiprazole increased spontaneous prolactin release twofold. These results are consistent with aripiprazole’s partial D2 agonist–antagonist properties. Clinically, partial agonist activity at the D2 receptors may result in fewer prolactin-related adverse events, such as galactorrhea and amenorrhea. Bioavailability and pharmacokinetics Aripiprazole is well absorbed, with peak plasma concentrations occurring within three to five hours after administration.12 Its oral bioavailability is 87%. High-fat meals delay the time to maximum concentration (tmax) by three hours, although they do not affect the maximum concentration or the area under the curve (AUC). Aripiprazole is metabolized via three major hepatic routes: dehydrogenation, hydroxylation, and Ndealkylation.12 In vitro data suggest that aripiprazole is extensively metabolized via the hepatic cytochrome (CYP) P-450 3A4 and CYP2D6 isoenzyme pathways. Its major metabolite, dehydro-aripiprazole, has demonstrated similar affinities for D2 receptors and represents approximately 40% of aripiprazole’s AUC in the plasma.13 The mean elimination half-life (t½) is approximately 75 and 94 hours for aripiprazole and its active metabolite, respectively.12 Aripiprazole and dehydro-aripiprazole are more than 99% bound to serum proteins, primarily albumin. Mallikaarjun et al.14 reported the results from two randomized, placebocontrolled, double-blind studies that evaluated the safety, tolerability, and pharmacokinetic parameters of aripiprazole in normal healthy men. In the first study, subjects were randomized to receive placebo (n = 3) or one of four aripiprazole doses (5, 10, 15, or 20 mg daily). Six patients were assigned to each aripiprazole treatment group. In the second study, patients received either placebo or aripiprazole

titrated from 10 mg daily for days 1 and 2, to 20 mg daily for days 3 and 4, and then to 30 mg daily for days 5 to 14. Under steady-state conditions, on day 14, the mean peak plasma concentration of aripiprazole (Cmax) ranged from 77 to 302 µg/L, with a corresponding tmax of 3 and 5 hours, respectively. The terminal t½ ranged from 48 to 68 hours across all groups. Linear regression analysis of the Cmax and AUC versus dose demonstrated a linear pharmacokinetic profile for doses between 5 and 30 mg/day. There were no serious adverse events or deaths. However, one subject withdrew on day 1 because of nausea and postural hypotension. As a whole, nausea, postural dizziness, and somnolence were the most common adverse events and accounted for 46.9% of all such events. Their severity and frequency did not correlate with increasing concentrations of aripiprazole. Indications Aripiprazole is indicated for the treatment of schizophrenia, with efficacy established through trials lasting four to six weeks.12 In 2003, a supplemental new drug application for the long-term treatment of schizophrenia was submitted to FDA.15 In addition, aripiprazole is under investigation for the treatment of acute mania associated with bipolar disorder and Alzheimer’s disease.15,16 Clinical efficacy The efficacy of aripiprazole for the treatment of schizophrenia has been evaluated in several placebocontrolled, randomized, multicenter trials. Of these trials, three have included an active control of either haloperidol17,18 or risperidone.19 The drug has also been evaluated in subjects experiencing a mixed or manic episode of bipolar I disorder.16 Other than the published trial conducted by Kane et al.,17 all studies have been reported in abstract or poster form. Schizophrenia. Two long-term, multicenter, randomized, double-

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blind trials evaluating the safety and efficacy of aripiprazole compared with haloperidol were prospectively combined for analysis18 and will be collectively reported as one trial. In this 52-week trial, 1294 subjects were randomized to either 30 mg of aripiprazole daily (n = 861) or 10 mg of haloperidol daily (n = 433). Investigators were allowed a one-time dosage reduction to 20 mg/day of aripiprazole or 7 mg/day of haloperidol. All subjects were suffering from an acute relapse of schizophrenia. The primary efficacy measures were the Positive and Negative Syndrome Scale (PANSS) and Montgomery Asbury Depression Rating Scale (MADRS). The PANSS measures include positive and negative subscales, as well as the total score. On this scale, the individual symptom severity score ranges from 1 (symptomabsent) to 7 (symptom-severe). The Clinical Global Impression (CGI) scale comprises two 7-point scales: the Severity of Illness (CGI-S) and Global Improvement (CGI-I) scales. A score of 1 represents “not ill” on the CGI-S and a degree of change of “very much improved” on the CGI-I, while a score of 7 represents an “extreme” severity of illness on the CGI-S and “very much worse” on the CGI-I. Baseline demographics with respect to age, mean age at first episode, number of past hospitalizations, onset of recent relapse, weight, and mean PANSS scores were similar between groups. Failure to maintain a response was defined as a CGI score of ≥6 or an adverse event of worsening schizophrenia and a score of ≥5 on at least one of the following PANSS items: delusions, conceptual disorganization, hallucinations, or suspiciousness. Of the 861 subjects randomized to aripiprazole, 853 were analyzed for efficacy and 859 for safety. Similarly, of the 433 patients randomized to haloperidol, 430 were analyzed for efficacy and 431 for safety. The percentage of subjects discontinuing the study was


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57% for the aripiprazole group and 70% for the haloperidol group. Discontinuation secondary to symptom worsening was slightly higher in the aripiprazole group (17%) versus the haloperidol group (13%). A larger percentage of subjects in the haloperidol group discontinued secondary to adverse events. A 20% improvement in PANSS scores was achieved in 72% and 69% (p = 0.362) of the aripiprazole and haloperidol subjects, respectively. The weekly mean change from baseline on the total PANSS scores was similar between groups, reaching an approximate decrease of 21 and 23 points for haloperidol and aripiprazole, respectively. Further, 52% of the aripiprazole group and 44% of the haloperidol group achieved a ≥30% improvement on the PANSS measurement (p = 0.003), with significant differences favoring aripiprazole seen as early as week 12 (p ≤ 0.05) and continuing through week 52 (p ≤ 0.01). Using KaplanMeier estimates, the percentage of subjects maintaining a response of ≥30% improvement on the PANSS at week 52 was 85% for the aripiprazole group and 79% for the haloperidol group (risk ratio, 0.7; p = 0.098). At weeks 8, 26, and 52, the percentage of subjects receiving treatment and still responding was significantly greater in the aripiprazole group versus the haloperidol group. This study also used the MADRS to address depressive symptoms. At week 8, aripiprazole produced significant decreases in MADRS scores compared with haloperidol (p < 0.05). The incidence of the most common adverse events, including insomnia, anxiety, headache, agitation, and somnolence, was similar between treatment groups, although the incidence of akathisia and pseudoparkinsonian symptoms was significantly higher with haloperidol than with aripiprazole (25% versus 12%, p < 0.001). Similarly, any EPSrelated event was reported by ap-

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proximately 10% of the aripiprazole subjects versus 32% of the haloperidol subjects. At the study endpoint, subjects in the aripiprazole group demonstrated improvement from baseline on the following movement rating scales: the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating Scale (BARS), and the Abnormal Involuntary Movements (AIMS) rating scale. Those in the haloperidol group demonstrated a worsening of movement-related adverse effects on all scales. Overall, weight gain in both groups was minimal (≤1 kg), but in those subjects with a body mass index of less than 23 kg/m2, aripiprazole was associated with a significant weight gain compared with haloperidol (approximately 2.5 kg versus 1.5 kg, p < 0.05). Finally, there was no significant change from baseline in the QTc interval for either group. Another long-term trial comparing aripiprazole with placebo for the prevention of relapse in 310 patients with chronic, stable schizophrenia was conducted by Carson et al.20 Subjects were randomized to receive either 15 mg/day of aripiprazole (n = 155) or placebo (n = 155) for 26 weeks. The investigators defined “stable” as no significant improvement or worsening of symptoms during the previous three months. In this study, the primary outcome measure was the time to relapse, defined as a CGI improvement score of 5 (minimally worse) or a PANSS score of moderately severe on the hostility or uncooperative items for two consecutive days or a ≥20% increase in total PANSS score. Using Kaplan-Meier estimates, the probability of not experiencing a relapse before week 26 was 39% in the placebo group and 63% in the aripiprazole group. In the aripiprazole group, the total PANSS scores improved significantly (p < 0.05) versus placebo. However, the mean change from baseline at endpoint was approximately 5 points, which is of modest clinical significance. Significantly


fewer subjects who were randomized to aripiprazole experienced a relapse or discontinuation secondary to lack of efficacy or an adverse event. In general, aripiprazole was well tolerated, with adverse events comparable to those seen in the placebo group. Further, subjects in both groups discontinued therapy because of adverse events at similar rates (aripiprazole, 11%; haloperidol, 8%). Kane et al.17 evaluated aripiprazole and haloperidol versus placebo in a four-week, double-blind, randomized study of 502 hospitalized patients suffering from an acute relapse of schizophrenia or other schizoaffective disorders. All subjects underwent a five-day washout period within one week of screening. At the end of the washout phase, 414 subjects were randomized to one of four treatment groups: aripiprazole 15 mg/day, aripiprazole 30 mg/day, haloperidol 10 mg/day, or placebo. Study drug doses were fixed throughout the four-week treatment period. All psychotropic agents were prohibited during the washout and double-blind treatment, except for lorazepam for anxiety or insomnia. The SAS, BARS, and AIMS scales were used to assess EPSs at baseline and then weekly throughout the study, and benztropine was allowed for treatment of EPS. The primary efficacy measure was the mean change from baseline at week 4 on the PANSS total and positive symptom subscales and CGI-S scores. Additional efficacy variables included mean change from baseline on the PANSS negative subscale, PANSS-derived Brief Psychiatric Rating Scale (BPRS), and mean CGII score. Efficacy data were collected at screening, at the end of the washout period (baseline), and on days 7, 14, 21, and 28. Baseline demographics were similar among the four treatment groups. At week 4, a total of 248 patients (60%) completed the trial. The most common reasons for discontinuation were withdrawal of con-

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sent (17%), adverse events (11%), and insufficient response (10%). Both dosage groups of aripiprazole and haloperidol produced significant improvements compared with placebo on the PANSS total score, PANSS positive subscale score, CGI-S and CGI-I scores, and BPRS core score. For the PANSS negative subscale, aripiprazole (15 mg) and haloperidol demonstrated significant improvement (p = 0.006 and p = 0.043, respectively), compared with placebo. Response, defined a priori, was either a CGI-I score of 1 or 2 or a ≥30% decrease from baseline on the PANSS total score. The aripiprazole groups receiving 15 and 30 mg produced significantly higher percentages of responders than the group receiving placebo (p = 0.002 and p = 0.050, respectively). Alternatively, the response rate for haloperidol did not differ significantly from that for placebo (p = 0.089). The onset of response was similar among all active treatment groups and was evident by week 2 of the study. In general, side effects were mild to moderate. Worsening of psychosis was the most common adverse event resulting in discontinuation. The most common treatment-emergent adverse effects (≥5%) were headache, anxiety, insomnia, nausea, vomiting, akathisia, somnolence, orthostatic hypotension, hypertonia, and blurred vision. Most cases of nausea and vomiting resolved within the first week of treatment. The overall incidence of EPSs was comparable between the placebo (21%) and the aripiprazole 15-mg (18%) and 30-mg (21%) groups. The 30-mg group was associated with a slight but not statistically significant increase (0.2) in SAS scores. On the BARS, the 15-mg dose was associated with a slight increase of 0.1 unit, which again was not statistically significant. Within the haloperidol group, 37% reported at least one EPS-related adverse effect. Haloperidol was associated with a significant worsening of scores on the SAS

(1.1, p < 0.001) and BARS (0.3, p < 0.05) compared with placebo, while aripiprazole when compared with placebo was not. Across all treatment groups, the mean change in body weight did not differ from that seen with placebo. With respect to increases from baseline in serum prolactin levels, haloperidol produced significantly greater increases than placebo (p < 0.001). Aripiprazole at both doses was associated with a slight but not statistically significant decrease in prolactin levels and was comparable to placebo. In all groups, changes from baseline in QTc intervals were not statistically significant. Yeung et al.19 assessed the efficacy and safety of aripiprazole versus risperidone in patients with schizophrenia or schizoaffective disorder. This four-week, multicenter, doubleblind, placebo-controlled trial involved 404 subjects who were experiencing an acute exacerbation of symptoms. Subjects were randomized to receive placebo (n = 103), aripiprazole 20 mg/day (n = 101), aripiprazole 30 mg/day (n = 101), or risperidone 6 mg/day (n = 99). Subjects randomized to risperidone were titrated to 6 mg/day over days 1 to 3. The primary outcome measures were the PANSS and CGI scales. At week 4, all three active treatment arms demonstrated significant improvement on the PANSS total, negative subscale, and PANSS-derived BPRS scores over placebo (p ≤ 0.05). Further, significant improvement was seen as early as week 1 for all active treatment groups. Discontinuation because of adverse events or lack of efficacy was similar among all three active treatments and less than the rate for placebo. All treatment groups demonstrated a slight decrease in mean SAS scores. When akathisia was assessed, all treatment groups demonstrated a slight increase in scores (approximately 0.18 for treatment and 0.11 for placebo). The mean weight change from base-

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line was approximately 1.2 kg for the aripiprazole 20-mg dose, 0.7 kg for the 30-mg dose, 1.5 kg for risperidone, and –0.25 kg for placebo. Mean serum prolactin levels increased fivefold for risperidone over placebo, but aripiprazole showed no change in prolactin levels. Aripiprazole demonstrated changes in QTc prolongation that were similar to those seen with placebo, while risperidone was associated with a twofold increase in QTc intervals. Acute mania. Aripiprazole was compared with placebo in a threeweek multicenter, double-blind, randomized study of 262 subjects experiencing a mixed or mania episode of bipolar I disorder.16 The drug was initiated at 30 mg with an option to decrease to 15 mg if patients could not tolerate the higher dose. The primary efficacy measure was the change from baseline on the Young Mania Rating Scale (YMRS); secondary measures included CGI-Bipolar (CGI-BP) scores (for mania, depression, and overall bipolar illness) and the CGI-S. Lorazepam was allowed through day 10 on a fixed, tapered, milligram-per-day basis. Baseline subject demographics between the two groups were similar. Treatment was completed by 54 (42%) and 28 (21%) subjects in the aripiprazole and placebo groups, respectively. A total of 10% of those in the aripiprazole and 12% of those in the placebo groups discontinued treatment secondary to lack of efficacy. The percentage of discontinuations appears low, since subjects not doing well clinically were eligible to enter into open-label treatment. Other reasons for discontinuation included adverse events, withdrawal of consent, loss to follow-up, subjects deemed unreliable, and other known causes. The mean dose of aripiprazole at endpoint was 27.9 mg/day, with 86% of the subjects remaining on 30 mg/day of aripiprazole throughout the study. On day 21, YMRS changes from baseline were


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significantly greater in the aripiprazole group than in the placebo group (–8.15 versus –3.35, p = 0.002, respectively). In addition, aripiprazole was statistically superior to placebo (p < 0.005) beginning on day 4 and throughout the study endpoint. CGI-BP scores for aripiprazole were statistically superior to those for placebo from day 4 through day 21. Mean changes in CGI-BP scores were –1.0 versus 0.39 (p = 0.001) for the aripiprazole and placebo groups, respectively. Finally, the overall response rate, defined as a decrease of ≥50% in the YMRS total score at week 3, was significantly greater for the aripiprazole group than for the placebo group (40% versus 19%, p = 0.001). Safety data (EPSs, serum prolactin, and weight) were collected for all subjects who received at least one dose of double-blind medication using the last observations carried forward. Pseudoparkinsonian symptoms were assessed using the SAS, while akathisia was assessed with the BARS. The SAS change from baseline score was –0.01 for placebo versus 0.48 for aripiprazole. Similarly, the change in BARS scores at endpoint was –0.1 for placebo versus 0.33 for aripiprazole. Both groups experienced minimal weight loss: approximately 0.8 kg for placebo and 0.3 kg for aripiprazole. Adverse events that occurred at ≥5% and were twice those seen with placebo included accidental injury (12%), nausea (13%), somnolence (20%), and akathisia (11%). The total discontinuation rate resulting from adverse events was 11% for both groups. In the aripiprazole group, 2% of subjects discontinued therapy because of akathisia and nausea and 1% because of tremor. Adverse effects and toxicities Treatment-emergent adverse events occurring at an incidence of ≥5% and more frequently than placebo during short-term, placebocontrolled trials are summarized in

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Table 1. Data were collected on 926 subjects who received aripiprazole at doses of 2 mg or more for up to six weeks. Overall, aripiprazole appears to be well tolerated. Nausea and vomiting seem to be problematic with initial therapy. However, administration with a meal may help reduce these bothersome side effects. Further, the incidence of nausea, vomiting, and dyspepsia is greatly reduced after one week of therapy. A meta-analysis of the safety and tolerability of aripiprazole in patients with schizophrenia (n = 1648) was completed by Stock et al.21 Data from five double-blind, placebo-controlled trials lasting four to six weeks were pooled: Four of the trials used haloperidol (5 to 20 mg/day) as active controls and one used risperidone (6 mg/day). Four studies used fixed aripiprazole doses ranging from 2 to 30 mg/day, while another used ascending daily doses of aripiprazole 5 to 30 mg. Baseline demographics were similar for all five studies. The incidence of EPSs was similar with aripiprazole (21.1%) and placebo (19.4%) but significantly greater in the haloperidol group (43.5%) compared with placebo (p < 0.001). Baseline SAS scale scores for those randomized to aripiprazole did not change significantly, although patients randomized to haloperidol had significant increases of approximately 1.2 (p < 0.01) compared with placebo. A significant change of 0.4 point from baseline was seen on the BARS in the haloperidol group and 0.1 point for all aripiprazole groups compared with placebo (p < 0.01 and p < 0.05, respectively). No linear dose relationship between aripiprazole and the development of akathisia was apparent. In fact, 15 mg/day, as opposed to 30 mg/day, produced the greatest incidence of akathisia. Weight gain associated with shortterm treatment at all doses (10 to 30 mg/day) of aripiprazole produced a mean increase of 0.68 kg compared


Table 1.

Adverse Events Occurring in ≥ 5% of Patients12 Adverse Event

Frequency (%)

Rash Asthenia Constipation Akathisia Somnolence Lightheadedness Vomiting Nausea Insomnia Anxiety Headache

6 7 10 10 11 11 12 14 24 25 32

with baseline (p < 0.001). Likewise, compared with placebo, risperidone produced a significant increase of approximately 1.4 kg from baseline (p < 0.001). Weight gain associated with haloperidol did not differ significantly from placebo. An open-label, 26-week trial (n = 255) comparing aripiprazole with olanzapine assessed changes in weight and cholesterol.22 At the study endpoint, subjects treated with olanzapine gained significantly more weight (3.6 kg), while those on aripiprazole lost 0.9 kg (p < 0.05). Further, when data across three bodymass-index groups were analyzed, aripiprazole resulted in weight loss in all three groups, while olanzapine was associated with weight gain in all groups. Further, median changes from baseline were reported for cholesterol. At weeks 4, 8, and 26, aripiprazole was associated with a decrease in median change from baseline for cholesterol (197 to 187 mg/dL). Conversely, olanzapine was associated with statistically significant (p < 0.001) increases (202 to 210 mg/dL), although these results are of marginal clinical significance. First-generation antipsychotics and risperidone are known to cause prolactin elevations. Hyperprolactinemia-related side effects such as sexual dysfunction and dysmenorrhea can be very problematic for patients. Pooled data demonstrated that ari-

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piprazole is not associated with an increase in serum prolactin.23 In fact, the drug was associated with a small decrease in prolactin levels compared with baseline. However, haloperidol and risperidone demonstrated significant elevations in prolactin of 120% and 60% (p < 0.01), respectively. A separate meta-analysis of the cardiac safety of aripiprazole was presented by Stock et al.24 This analysis includes both short- and long-term data with comparisons to haloperidol (up to 10 mg/day), risperidone (up to 6 mg/day), and olanzapine (dose not reported). In the short-term studies, mean QTc change from baseline was similar for aripiprazole and placebo, regardless of the patient’s age. In fact, there were small decreases in QTc intervals noted for all aripiprazole dosages (mean change, –4.4 msec). QTc changes associated with haloperidol and risperidone were –1.04 and 2.15 msec, respectively. At the study endpoint, 4.3% of aripiprazole subjects exhibited a 30-msec increase in QTc, similar to that for placebo patients (5.5%), compared with 7.8% and 10.5% of haloperidol and risperidone subjects, respectively. Longterm, 52-week data demonstrated that compared with haloperidol, aripiprazole was associated with a significant decrease in mean change in QTc from baseline (–7.4 msec versus –4.0 msec, p < 0.05, respectively). In a 26-week, open-label comparator study of olanzapine, aripiprazole demonstrated a significantly greater decrease in mean change in QTc from baseline than olanzapine (–4.61 msec versus 1.35 msec, p < 0.05). Thus, both long- and short-term data suggest that aripiprazole is not associated with QTc prolongation. The incidence of tardive dyskinesia associated with aripiprazole is not known. Postmarketing data and clinical experience will assist clinicians in determining this risk. Until such data are available, all patients should be monitored at least annually for the

development of abnormal involuntary movements.12 Two possible cases of neuroleptic malignant syndrome that occurred in patients being treated with aripiprazole were reported in the premarketing worldwide clinical database. While the diagnostic evaluation of patients with this syndrome is complicated, exclusion of serious medical illnesses should be considered before arriving at a diagnosis of this syndrome.12 Drug interactions Because aripiprazole is a substrate of both the CYP3A4 and CYP2D6 isoenzyme pathways, there is a potential for other drugs to affect its metabolism.12 Agents that are known to induce the CYP3A4 isoenzyme (such as carbamazepine and phenytoin) may induce aripiprazole metabolism, resulting in lowered blood levels.25 Conversely, inhibitors of the CYP3A4 isoenzyme (such as nefazodone and ketoconazole) or the CYP2D6 isoenzyme (such as quinidine, fluoxetine, and paroxetine) may inhibit aripiprazole metabolism and cause increased blood levels. Aripiprazole is unlikely to cause clinically significant changes in the metabolism of other drugs metabolized through the CYP3A4 (e.g., dextromethorphan), CYP2C9 (e.g., warfarin), or CYP2C19 (e.g., omeprazole) isoenzymes. Further, aripiprazole has not been shown to alter CYP1A2- and CYP3A4-mediated metabolism.12 Citrome et al.13 evaluated the pharmacokinetic profile and safety of aripiprazole in the presence of the mood stabilizers lithium and divalproex sodium. In this study, 12 subjects received lithium and 10 received divalproex in conjunction with aripiprazole in an open-label manner. Subjects received aripiprazole (30 mg/day) for the first 14 days, and a mood stabilizer was added on days 15 to 36. The lithium dose was titrated to achieve a serum concentration of 1 to 1.4 meq/L. The divalproex dose was titrated to

Aripiprazole

achieve a serum concentration between 50 and 125 mg/L. Clinical symptomatology was assessed by the PANSS, and cognitive function was assessed by the Mini-Mental Status Examination (MMSE).13 Coadministering lithium and aripiprazole had no apparent effect on the steady-state pharmacokinetic parameters of aripiprazole or its active metabolite.13 There were small increases in the Cmax and AUC of aripiprazole, while clearance (CL) decreased by 15%. Overall, there were no consistent differences in Cmax, AUC, and CL in subjects receiving aripiprazole monotherapy or combination therapy. When the drug was administered with divalproex, moderate changes in pharmacokinetic parameters were observed. The AUC, Cmax, and minimal concentrations of aripiprazole were decreased by 24%, 26%, and 22%, respectively. In addition, the tmax and CL increased by two hours and 33%, respectively. There were similar effects on the pharmacokinetic parameters of the active metabolite. Overall, the combination of aripiprazole with either lithium or divalproex appears to be safe and well tolerated. In the lithium group, adverse events were mild to moderate in severity and resolved when therapy was discontinued. However, there was one serious adverse event of a confusional state, an event judged to be lithium-induced encephalopathy. In the divalproex group, four subjects withdrew: two withdrew consent and two discontinued therapy because of adverse events (i.e., inguinal hernia and hostile behavior). Again, adverse events were mild to moderate and generally resolved one day after therapy was discontinued. When the drug was used in combination with lithium and divalproex, there was no evidence of clinical deterioration, impaired cognition, or increase in EPSs. With respect to laboratory parameters, there were no significant changes observed with


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either combination. Finally, observed changes in aripiprazole’s pharmacokinetic profile secondary to lithium are minimal, and they are moderate for divalproex. Despite these moderate pharmacokinetic changes, they appear to be of little clinical significance. Dosage and administration The recommended starting dose of aripiprazole is 10 or 15 mg daily, preferably administered with meals. Aripiprazole has been shown to be effective at dosages up to 30 mg/ day12; however, doses higher than 10 to 15 mg/day have not been shown to be more effective.26 Dosage increases should be made no earlier than two weeks after therapy begins; this is the time needed to achieve a steady state. Dosage adjustments are not routinely indicated for patients with hepatic or renal impairment, and there are no recommendations for dosage adjustments based on gender, race, or smoking status. Data from single-dose (15mg) studies in patients 65 or older demonstrated a 20% decrease in CL compared with younger adults. However, after multiple doses, the pharmacokinetics of aripiprazole appeared similar to those observed in young, healthy subjects. Thus, no dosage adjustment is recommended for the elderly. Safety and effectiveness in pediatric and adolescent patients have not been established. Aripiprazole is classified as pregnancy category C, and it is recommended that women taking this medication not breastfeed.12 For patients who are taking aripiprazole in combination with agents known to inhibit the CYP3A4 or CYP2D6 isoenzymes, the dose of aripiprazole should be reduced to one half of the usual dose. Similarly, for patients taking CYP3A4 inducers such as carbamazepine, the aripiprazole dose should be doubled, with additional increases based on clinical evaluation.12 Following the discontinuation of an inhibitor or inducer, it will be necessary to adjust the aripiprazole

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dose accordingly to maintain clinical stability. Dosage forms Aripiprazole is available in tablet form in the following strengths: 10 g, 15 g, 20 g, and 30 mg.12 The product should be stored at 25 °C (77 °F). Safety issues To date, data on overdoses of aripiprazole are minimal.12 In premarketing studies involving more than 5500 patients, accidental or intentional overdoses were identified in seven patients. Of two patients who ingested 180 mg, the largest amount identified, one patient experienced somnolence and vomiting. For all patients who were assessed in the hospital, including these two, there were no adverse changes in vital signs, laboratory assessments, or electrocardiogram parameters. An 18-month-old child accidentally ingested 15 mg of aripiprazole and 2 mg of lorazepam; the episode was uneventful. Occasionally, some medications, both generic and brand, have similarsounding names, resulting in the potential for product name confusion. Table 2 lists various agents that sound similar to aripiprazole and have the potential for medication errors. Economic issues As an illness that affects approximately 0.5% to 1% of the population, schizophrenia accounts for a disproportionately large economic burden. In 1990, costs related to schizophrenia were estimated to be $65 billion per year7; the direct costs approached $18.6 billion, and the indirect costs, including lost productivity, totaled $46.5 billion.7 Although many assume that medications comprise a large percentage of the direct costs, in fact, prescription medications accounted for only 2.3% of direct costs, or about $397 million.27 While these data are somewhat dated and do not include all currently available secondgeneration antipsychotics, the in-


creased price of these agents compared with first-generation agents may not significantly increase the overall costs associated with schizophrenia. Table 3 compares the costs of the second-generation antipsychotics, which may be used as firstline treatment for schizophrenia. Similar agents under consideration Aripiprazole is a novel antipsychotic with a unique mechanism of action. No other agents in this class of drugs are under investigation. Recommendations and critical issues In clinical trials, aripiprazole has demonstrated efficacy comparable to that of haloperidol and superior to that of placebo. Generally, clinical practice acknowledges the secondgeneration antipsychotics as firstline treatment for patients suffering from schizophrenia; despite this, haloperidol continues to be the gold standard comparator in initial efficacy studies. Aripiprazole is well tolerated, with a low potential for EPSs, cardiovascular effects, and weight gain, so it can be used as a first-line treatment option for patients with an acute exacerbation of schizophrenia. The low potential for adverse events may help improve compliance in a patient population where this is a significant factor. For patients who are overweight or have diabetes, aripiprazole would be preferable to olanzapine and quetiapine. Aripiprazole’s ability to act as a partial agonist at the D2 and 5-HT1A receptors has led investigators to refer to it as a Table 2.

“Sound-Alike” Drugs That May Be Confused with Aripiprazole Drug

Available Dosage Strength (mg)

Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole

20, 40 15, 30 10, 20, 40 20, 40 40

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Table 3.

Comparative Cost of Second-Generation Antipsychotic Medications Drug Aripiprazole (Abilify) Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Risperidone (Risperdal)

Ziprasidone (Geodon)

Strength (mg) 10, 15 20, 30 2.5 5 7.5 10 15 20 25 100 200 300 0.25 0.5 1 2 3 4 20, 40, 60, 80

dopamine–serotonin stabilizer. 10 These pharmacologic actions make aripiprazole unique. Despite these pharmacologic differences, clinical evidence suggests that aripiprazole and haloperidol are equally efficacious. Studies comparing the efficacy of aripiprazole with that of secondgeneration antipsychotics such as risperidone and olanzapine have not been conducted. Its once-a-day dosing may make it more acceptable to patients than the twice-daily dosing required for ziprasidone, quetiapine, and risperidone. References 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 2. Lawler CP, Prioleau C, Lewis MM et al. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology. 1999; 20:612-27. 3. Marder SR, Essock SM, Miller AL et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophr Bull. 2002; 28:5-16. 4. Heritch AJ. Evidence for reduced and dysregulated turnover of dopamine in schizophrenia. Schizophr Bull. 1990; 16:605-15. 5. Inoue A, Miki S, Seto M et al. Aripiprazole, a novel antipsychotic drug, inhibits quinpirole-evoked GTPase activity but does not up-regulate dopamine D2 receptor following repeated treatment in the rat striatum. Eur J Pharmacol. 1997; 321(1):105-11.

Average Wholesale Price per Tablet or Capsule ($)28 10.14 14.34 5.36 6.34 7.26 9.63 14.45 19.25 1.60 2.90 5.48 7.22 2.96 3.07 3.17 5.10 6.17 8.13 4.47

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6. Tamminga CA, Lahti AC. The new generation of antipsychotic drugs. Int Clin Psychopharmacol. 1996; 11(suppl 2):73-6. 7. Worrel JA, Marken PA, Beckman SE et al. Atypical antipsychotic agents: a critical review. Am J Health-Syst Pharm. 2000; 57:238-55. 8. Burris KD, Molski TF, Xu C et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther. 2002; 302:381-9. 9. Jordan S, Koprivica V, Chen R et al. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur J Pharmacol. 2002; 441(3): 137-40. 10. McQuade RD, Burris KD, Jordan S et al. Aripiprazole: a dopamine-serotonin system stabilizer. Paper presented at 2002 Collegium Internationale NeuroPsychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. 11. Inoue T, Domae M, Yamada K et al. Effects of the novel antipsychotic agent 7-(4-[4-(2,3-dichlorophenyl)-1piperazinyl]butyloxy)-3,4-dihydro-2 (1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther. 1996; 277(1):137-43. 12. Abilify (aripiprazole) tablets package insert. Princeton, NJ: Bristol-Myers Squibb; 2002. 13. Citrome L, Josiassen R, Bark N et al. Pharmacokinetics and safety of aripiprazole and concomitant mood stabilizers. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. 14. Mallikaarjun S, Salazar DE, Bramer SL. The pharmacokinetics, tolerability and safety of aripiprazole following single and multiple oral dose administration in nor-

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mal volunteers. Paper presented at 2000 Collegium Internationale NeuroPsychopharmacologium Congress. Brussels, Belgium; 2000 Jul 9–13. FDC Reports. NDA pipeline. Aripiprazole. www.ndapipeline.com/c3/pipeline/ display.plex/did=36821/ (accessed 2003 Feb 28). Jody D, Marcus R, Keck P et al. Aripiprazole vs placebo in acute mania. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Kane JM, Carson WH, Saha AR et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2002; 63:763-71. Kujawa M, Saha A, Ingenito GG et al. Aripiprazole for long-term maintenance treatment of schizophrenia. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Yeung PP, Carson WH, Saha A et al. Efficacy of aripiprazole, a novel antipsychotic, in schizophrenia and schizoaffective disorder: results of a placebo-controlled trial with risperidone. Eur Neuropsychopharmacol. 2001; 11(suppl 3):S259-60. Abstract. Carson W, Pigott T, Saha A et al. Aripiprazole vs. placebo in the treatment of stable, chronic schizophrenia. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Stock E, Marder SR, Saha AR et al. Safety and tolerability meta-analysis of aripiprazole in schizophrenia. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Cornblatt B, Carson WH, Ali M et al. Neurocognitive effects of aripiprazole vs. olanzapine in stable psychosis. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Carson W, Saha A, Iwamoto T et al. Meta-analysis of prolactin effects with aripiprazole. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Stock E, Saha A, Brunell R et al. Metaanalysis of cardiac safety with aripiprazole. Paper presented at 2002 Collegium Internationale Neuro-Psychopharmacologium Congress. Montreal, Canada; 2002 Jun 23–27. Winans EA, Cohen LJ. Assessing the clinical significance of drug interactions in psychiatry. Psychiatr Ann. 1998; 28:399-405. Auby P, Saha A, Ali M et al. Safety and tolerability of aripiprazole at doses higher than 30 mg. Eur Neuropsychopharmacol. 2002; 12(suppl 3):288. Abstract. Rice DP. The economic impact of schizophrenia. J Clin Psychiatry. 1999; 60(suppl 1):4-6. Cohen HE, ed. Drug topics red book. Montvale, NJ: Thompson PDR; 2003.


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