(1)
Neuroleptics are the standard treatment for
schizophrenia. The first drugs of this class, such as
haloperidol, were marketed nearly 50 years ago, and
neuroleptics released over the past 15 last years have provided no major advance. (2)
Aripiprazole is a new
neuroleptic licensed for the treatment of
schizophrenia. (3) Five double-blind placebo-controlled trials lasting 4 to 6 weeks showed that
aripiprazole was a little more effective than placebo at daily doses of 10 mg to 30 mg, without a clear dose-response relationship. Based on the least demanding definition of "treatment response" (a 30% reduction in the PANSS global score), less than 50% of patients responded to
aripiprazole. (4) In a double-blind trial lasting 6 months,
aripiprazole 15 mg/day was more effective than placebo in preventing acute relapses of
schizophrenia (34% versus 57%), but the clinical relevance of the combined endpoint used to define relapse is unclear. (5) The only double-blind comparison versus another
neuroleptic (
haloperidol) involved two trials that were pooled for analysis.
Haloperidol was provided at a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose
aripiprazole (30 mg/day), but failed to do so. The proportion of patients who "responded" during an acute episode, based on the least stringent definition, was about 70% in both groups. In both groups, response persisted in approximately three-quarters of patients. (6)
Aripiprazole exhibits the adverse effects classically seen with
neuroleptics. In clinical trials, daily doses of
aripiprazole, ranging from 15 mg to 30 mg, provoked fewer
extrapyramidal disorders than
haloperidol 10 mg/day. In contrast, there was no difference in the frequency of
extrapyramidal disorders with
aripiprazole 20 or 30 mg/day and
risperidone (6 mg).
Aripiprazole has no proven advantage over
haloperidol in terms of the risk of
tardive dyskinesia. One trial showed no difference between
aripiprazole and
olanzapine in the risk of diabetes.
Weight gain appears to be comparable with
aripiprazole and
haloperidol.
Aripiprazole provoked
postural hypotension and
neuroleptic malignant syndrome, but the precise risk relative to other
neuroleptics has not been documented. Supra-therapeutic doses of
aripiprazole cause dose-dependent QT prolongation. (7) Increased mortality was seen in elderly patients treated with
aripiprazole. (8) Animal studies have shown
retinal degeneration in rats and biliary
lithiasis in monkeys. These adverse effects have not been observed in clinical trials, but they have not been specifically assessed in humans. (9) Animal studies raised the possibility of fetal toxicity and teratogenicity. (10) The
aripiprazole dose must be either halved or doubled during co-administration with inhibitors or inducers of
cytochrome P450 isoenzymes CYP 3A4 and
CYP 2D6. (11) In practice, there are too many unanswered questions to recommend
aripiprazole for patients with
schizophrenia.