The placebo-controlled, double-blind trial of aripiprazole in acute bipolar manic and mixed patients was an outgrowth of previous randomized, controlled trials demonstrating the efficacy of other atypical antipsychotics in mania and of evidence of the efficacy of aripiprazole in the amelioration of positive and negative symptoms of psychosis in patients with schizophrenia. Because of aripiprazole’s unique mechanism as a partial D2 agonist, its effects on manic and mixed symptoms in patients with bipolar disorder were uncertain. This trial was one of two positive, placebo-controlled trials in inpatients hospitalized for manic or mixed episodes (with or without psychosis).

“The pharmacological options to treat various aspects of bipolar disorder have expanded substantially in the last 10-12 years.”

The results of this trial demonstrated that aripiprazole-treated patients displayed significantly greater overall mean improvement in manic symptoms from day 1-21 in this short-term, acute treatment trial. Aripiprazole was initiated at 30 mg/d, the highest dose previously studied in trials in patients with schizophrenia. This starting dose was chosen because of evidence in previous studies of generally good tolerability, but also because sedation is one of the few dose-related side effects of aripiprazole, and it was hoped that mild sedative side effects would be beneficial. Most patients tolerated this starting dose, with 86% remaining on this dose to study endpoint. Aripiprazole was generally well tolerated overall, with no significant differences in drop-outs due to adverse events between the aripiprazole and placebo groups. Some side effects occurred more commonly, however, in the aripiprazole group, including sedation, akathisia, and gastrointestinal complaints.

Although both ziprasidone and aripiprazole have been demonstrated to have antimanic efficacy each in placebo-controlled acute treatment trials, I know of no studies planned to compare them head to head. Both agents are considered among the first-line atypical antipsychotics for the treatment of bipolar I disorder, manic or mixed episodes, with or without psychotic symptoms. Neither agent has been studied in combination with lithium or divalproex in patients with acute mania.

The pharmacological options to treat various aspects of bipolar disorder have expanded substantially in the last 10-12 years. A number of agents now have US FDA indications for the treatment of the manic phase of bipolar I disorder: lithium, divalproex, the Equetro formulation of carbamazepine, and the atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. In 1994, only lithium and divalproex were among this list. Only one agent, the olanzapine-fluoxetine combination, currently has an indication for the acute treatment of bipolar I depression, but emerging data may also soon support the efficacy of quetiapine in this phase of the illness. Similarly, whereas only lithium had a claim for long-term relapse prevention in bipolar I disorder, now lamotrigine, olanzapine, and aripiprazole have similar indications.

Despite the availability of these agents, many if not most patients with bipolar I disorder require long-term treatment with more than one agent to optimize efficacy, prevent subsynromal symptoms and syndromal relapse, and optimize functioning. A number of important recent studies of operationalized forms of psychotherapy and psychoeducation have demonstrated the value of these modalities in reducing the risk of relapse in combination with medications. The genetic bases of bipolar disorder remain obscure, but breakthroughs in this area would dramatically alter our treatment approaches and open the door for targeted therapies.

View Dr. Paul Keck's record in ISIHighlyCited.com.