Drugs

, Volume 64, Issue 15, pp 1715–1736 | Cite as

Aripiprazole

A Review of its Use in Schizophrenia and Schizoaffective Disorder
Adis Drug Evaluation

Summary

Abstract

Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia.

Aripiprazole 10 or 15mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (≥1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia.

Pharmacological Properties

Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1a, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole’s partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1a receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound.

Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours.

Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein.

Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased).

Therapeutic Efficacy

The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment.

The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients.

Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10–15 mg/day.

Tolerability

Aripiprazole 10–30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial).

In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%).

Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.

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© Adis data information BV 2004

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, AucklandNew Zealand

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