New research data, presented at APA’s annual meeting last month in Philadelphia, indicate that the long-anticipated "next generation" of antipsychotic medications could offer a significant new treatment option to patients with schizophrenia, bipolar disorder, and possibly severe or psychotic depression.
For patients and clinicians, aripiprazole, a next-generation atypical antipsychotic medication that is different from any other drug on the market, looks good. And Bristol-Myers Squibb Company (BMS) is ecstatic that the data strongly support both efficacy and safety. BMS could use some good news these days—the company has had a rough year with significant sales lost to generic competition, the FDA’s refusal to approve a new cancer drug in which the company had heavily invested, and rumors running rampant through the business community of an impending takeover by a larger, "healthier" pharmaceutical concern.
BMS submitted a new drug application for aripiprazole last October and hopes to receive marketing approval from the FDA late this year or during the first quarter of 2003.
The drug has a unique mechanism of action—different from anything else currently available.
"Aripiprazole is the first ‘atypical atypical,’ " said Jeffrey Lieberman, M.D., vice chair of psychiatry and a professor of psychiatry and pharmacology at the University of North Carolina at Chapel Hill. "It’s really a new generation of antipsychotic medications."
Lieberman was one of four schizophrenia experts participating in a BMS-sponsored press briefing covering several new research reports at APA’s annual meeting. All of the data presented were from company-sponsored clinical trials.
Aripiprazole is thought to be a dopamine D2 receptor "partial agonist"—that is, when dopamine levels are higher than normal, aripiprazole acts to block the D2 receptor; when dopamine levels fall below the normal range, the drug helps to boost the action of the dopamine that is present.
In addition, aripiprazole has a similar action at the serotonin 5HT1A receptor and exerts simple antagonism or blocking of the serotonin 5HT2A receptor. Pharmacologically, aripiprazole can be thought of as a "dopamine-serotonin system stabilizer."
Researchers have conducted four short-term (four to six weeks) fixed-dose, placebo-controlled trials of aripiprazole. More than 1,500 patients hospitalized for acute relapse of schizophrenia or schizoaffective disorder saw significant improvement in both their positive and negative symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS).
Two studies compared aripiprazole with haloperidol, while another study compared it with haloperidol and risperidone. Doses ranged from 2 mg to 30 mg of aripiprazole. Patients taking from 15 mg to 30 mg showed more improvement in the total PANSS score, as well as the positive and negative symptom subscales.
Patients in the trials were also evaluated with the Clinical Global Impression Improvement (CGI-I) and Severity of Illness (CGI-SI) scales. Again, those taking 15 mg and above achieved significant improvement on both scales. Patients who were taking aripiprazole had response rates that were consistently significantly higher than those taking placebo. The drug’s onset of action was rapid in all four studies, with a significant reduction in patients’ total PANSS score by week one.
In a 26-week study of patients with stable, chronic schizophrenia, significantly fewer patients relapsed while taking aripiprazole (34 percent versus 57 percent for placebo). Aripiprazole also doubled the time to relapse in this study.
Subjects in a 52-week maintenance study had significantly greater reductions in PANSS scores compared with haloperidol, particularly on the negative symptom subscale and on depressive symptoms (measured with the Montgomery-Asberg Depression Rating Scale).
Lieberman said, taken together, the results are very favorable that the drug will be an effective option.
A final efficacy study in schizophrenia involved switching patients from other antipsychotic therapy to aripiprazole. Three switching schemes were explored: abrupt discontinuation of the previous drug and initiation of aripiprazole at therapeutic doses, tapering off of the previous drug while titrating aripiprazole up to therapeutic doses, and tapering of the previous antipsychotic with abrupt initiation of aripiprazole at therapeutic doses.
For all three switching strategies, patients’ PANSS total, positive, and negative scores showed consistent progressive and significant improvement when switching from haloperidol, thioridazine, risperidone, or olanzapine. There were no differences between the three strategies.
In addition to its application in the treatment of schizophrenia, early data were also presented on the use of aripiprazole in treating patients with bipolar disorder. In a placebo-controlled study, aripiprazole was found to have a rapid onset of action, showing significant reduction in patients’ mania rating scale scores by day 4 of treatment.
Because of its serotonin receptor activity, researchers expect aripiprazole to be effective as well in treating depressive symptoms of bipolar disorder. Research is now being done in this area.
While Mary Kujawa, M.D., Ph.D., medical director for aripiprazole at BMS, cautioned that side-effect and adverse-event profiles inherently evolve following the introduction of any drug to the wider patient population following marketing approval, the profiles observed in all of the studies presented to date look relatively benign, particularly from a comparative point of view in the switching study.
Interestingly, in the switching study, significant weight loss (between four and seven pounds) occurred upon switching from another antipsychotic to aripiprazole. In patients starting aripiprazole but not switching from another drug, no weight differences have been observed that differ from placebo.
In addition, the switching study saw reductions in serum prolactin levels after aripiprazole initiation, in effect normalizing some patients’ previously elevated prolactin levels while on other antipsychotic medications. Aripiprazole also had no prolongation effect on the QTc interval, either in the short or long term.
The overall analysis of the extrapyramidal effects of aripiprazole showed no significant effects on patient ratings using the Simpson-Angus Scale, the Barnes Akathisia Rating Scale, or the Abnormal Involuntary Movement Scale (AIMS).
The overall incidence of side effects that emerged in the clinical trials is also low. Nausea, vomiting, insomnia, and tremor occurred more often in subjects on the ari-piprazole than on placebo. The subjects who were switched to aripiprazole from haloperidol or olanzapine, however, experienced fewer bothersome side effects than when they were taking haloperidol or olanzapine.
"There is a very high rate of switching medications among patients with schizophrenia, and in many instances the switching is driven by side effects," said Daniel Casey, M.D., chief of psychiatric research and psychopharmacology at the Portland VA Medical Center and a professor of psychiatry and neurology at Oregon Health Sciences University, who participated in the BMS briefing.
"In [the switching] study, patients were successfully switched to aripiprazole from commonly used antipsychotics, and in many cases there were distinct benefits," he said.
Researchers agreed that while they are optimistic that aripiprazole will provide a safe and effective treatment option for schizophrenia patients and possibly also for patients with bipolar disorder, the true picture remains to be seen as the drug is used in larger populations.
The FDA’s approval is expected by BMS to be the first worldwide for the drug. Applications are either pending or in preparation for submission to the European Medicines Control Agency, as well as Japanese, Australian, and South American regulators. ▪