Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials

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Abstract

Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson–Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p≤0.01). Haloperidol showed increased SAS and Barnes Akathisia scores over placebo (p≤0.01). There was minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56 kg), and a lack of QTc prolongation. Serum prolactin increased with haloperidol, but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and tolerability profile with low potential for EPS, weight gain, prolactin elevation, QTc prolongation, and sedation. Aripiprazole's safety profile may offer benefits in schizophrenia treatment.

Introduction

The introduction of typical (first-generation) antipsychotic agents, which have antagonist activity at dopamine D2 receptors, in the 1950s and 1960s was a major breakthrough in the treatment of schizophrenia, and these agents were the mainstay of therapy into the 1990s. The drawbacks of these agents are, however, well documented. Although effective in treating the positive symptoms of schizophrenia, they are usually less effective against the negative symptoms of the disorder. Furthermore, their antagonist activity at dopamine D2 receptors is associated with significant side effects, including extrapyramidal symptoms (EPS), tardive dyskinesia, and hyperprolactinemia. These factors are thought to contribute to noncompliance with these agents—one study reported that 46% of patients became noncompliant over a 1-year period with orally administered typical agents (Gaebel, 1997).

The “atypical” or second-generation antipsychotics, introduced in the 1990s, combine D2 antagonism with antagonist activity at serotonin 5-HT2A receptors and, in general, produce significantly less EPS and hyperprolactinemia (except risperidone) than the typical antipsychotics. However, unique side effects have been observed with individual atypical agents including weight gain, sedation, prolonged QTc interval, and abnormalities in glucose and lipid levels. These adverse events present health risks, and can decrease compliance and may lead to relapse Fleischhacker et al., 1994, Kurzthaler and Fleishhacker, 2001. Many patients with schizophrenia have preexisting risk factors for cardiovascular disease, such as obesity and smoking Allison and Casey, 2001, Brown et al., 1999. Adverse events that increase cardiovascular risk, such as weight gain, are therefore of particular relevance when treating certain individuals with schizophrenia. Similarly, the glucose and lipid dysregulation observed with some atypicals have long-term implications for patients with risk factors for cardiovascular disease and diabetes. Thus, there is still an unmet need for novel antipsychotic drugs that are safer and better tolerated than earlier typical agents or currently available atypical medications.

Aripiprazole is a novel antipsychotic with a unique combination of dopamine and serotonin receptor binding affinities and activities. Preclinical studies have shown that aripiprazole has partial agonist activity at dopamine D2 receptors Burris et al., 2002, Inoue et al., 1996, distinguishing it from all currently available antipsychotics, which are D2 antagonists. Preclinical studies have also shown that aripiprazole has D2 antagonist activity under hyperdopaminergic conditions, which is believed to be associated with control of psychotic or positive symptoms, and D2 agonist activity under hypodopaminergic conditions, which is thought to be associated with improvement of negative symptoms and cognition, and minimize EPS and prolactin changes. It has been suggested that partial agonist activity at D2 receptors stabilizes the dopamine system while avoiding the hypodopaminergia that may limit the tolerability of currently available antipsychotics Carlsson et al., 2000, Stahl, 2001a, Stahl, 2001b.

Aripiprazole is also a potent partial agonist at serotonin 5-HT1A receptors (Jordan et al., 2002), and an antagonist at 5-HT2A receptors (unpublished data). Partial agonist activity at 5-HT1A receptors has been linked to anxiolytic action (Glennon and Dukat, 1995), and may also be associated with improvement in depressive, cognitive, and negative symptoms in patients with schizophrenia (Millan, 2000). 5-HT2A receptor antagonist activity may be associated with favorable effects on negative symptoms of schizophrenia Leysen et al., 1993, Rao and Möller, 1994, improvements in cognition and control of agitation and aggression Kasper et al., 1999, Raheja et al., 1995, and with low liability for EPS (Richelson, 1999).

Studies comprising the clinical development program for aripiprazole have shown it to be effective for the treatment of patients with acute relapse of schizophrenia or schizoaffective disorder. Aripiprazole has been demonstrated to improve both the positive and negative symptoms of schizophrenia, and has shown a favorable safety and tolerability profile, with low liability for EPS, tardive dyskinesia, weight gain, sedation, hyperprolactinemia, or QTc prolongation, and a lack of adverse effects on glucose and lipid levels Yeung et al., 2001, Saha et al., 2001, Carson et al., 2001, Cornblatt et al., 2002.

The current analysis includes the safety and tolerability data from five short-term, placebo-controlled, phase II and phase III trials of the aripiprazole clinical development program in schizophrenia. This allows analysis of the experience with aripiprazole in a large patient population, and an assessment of the overall safety and tolerability of this novel atypical antipsychotic compared to placebo and haloperidol. The inclusion of haloperidol as an active control can provide assurance that the study is sensitive to meaningful differences among groups.

Section snippets

Trials

This analysis was conducted using safety and tolerability data from all five completed short-term (4- or 6-week), placebo-controlled, aripiprazole studies in patients hospitalized for acute relapse of schizophrenia and schizoaffective disorder (Table 1). All five studies (two phase II and three phase III) were in-patient studies. Three of these studies employed haloperidol as an active control.

Patients were screened for inclusion at the initial study visit and then underwent a placebo washout

Patient population

In all, 932 patients were randomized to aripiprazole treatment, 201 patients to haloperidol and 416 to placebo in the five studies. Of these, 10 patients did not receive study medication, and were not included in the safety analysis (aripiprazole, n=6; placebo, n=3; haloperidol, n=1). The baseline characteristics of the patients included in the safety analysis are shown in Table 2. A breakdown of aripiprazole treatment by dose level showed that 59 patients received 2 mg/day, 165 received 10

Discussion

The results of these analyses showed that aripiprazole, over a 4- to 6-week treatment period, was safe and well tolerated for the treatment of patients with acute relapse of schizophrenia or schizoaffective disorder. Aripiprazole had a low potential for EPS, and showed a low liability for other side effects including weight gain, sedation, hyperprolactinemia, QTc prolongation, and changes in glucose and cholesterol levels, which have been associated with treatment with other atypical agents. In

Acknowledgments

These studies were supported by Bristol-Myers Squibb and Otsuka Pharmaceutical.

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