Clinical Updates From Bipolar Telehealth

Dec 31, 2019

There appears to be some confusion regarding the efficacy of aripiprazole in bipolar mania and depression and for preventing bipolar episodes.

Aripiprazole for Bipolar Disorder

There appears to be some confusion regarding the efficacy of aripiprazole in bipolar mania and depression and for preventing bipolar episodes. Aripiprazole is approved by the US Food and Drug Administration as a treatment for acute mania. It is not one of the more robustly efficacious agents for mania, however; haloperidol, risperidone, olanzapine, and quetiapine (in that order) top the list in a meta-analysis by Cipriani and collegues.1

Haloperidol is not recommended as a first-line agent because of the risk of tardive dyskinesia (more common in mood disorder patients versus schizophrenia). Moreover, evidence indicates that it is the antimanic agent associated with the highest risk switching to a depressive episode after resolution of the mania.2 Aripiprazole had two early trials in which it did not differ from placebo in mania, which lowered its effect size compared with other options. Efficacy was found in studies using 15 to 30 mg doses.

In bipolar depression, the situation is a little more complicated, but in short, aripiprazole has not been found to be effective. Two large manufacturer-sponsored trials failed to show any difference from placebo after eight weeks of treatment.3 It is not FDA-approved for bipolar depression. What is confusing for clinicians is that aripiprazole is well-known for its antidepressant effect as an augmenter of selective serotonin reuptake inhibitors in unipolar depression. It was heavily advertised for that purpose (at least, until it recently became generic). It has never been studied as an augmentation for antidepressants in bipolar depression.

The use of antidepressants (with or without augmenters) in bipolar depression remains controversial at best. The exception is the combination of olanzapine and fluoxetine, which is effective and FDA-approved for bipolar depression, although one usually wants to avoid it because olanzapine has severe metabolic adverse effects and induces insulin-resistance.

In the 8-week aripiprazole studies, there was separation from placebo in some of the earlier weeks, but by week 8 there was no difference (number needed to treat = 44).3 Dosage at endpoint reached a mean of 16.5 mg daily. Some have speculated that if they had used lower doses (eg, starting at 2 to 5 mg and titrating to 5 to 10 mg), the researchers might have found a more sustained antidepressant effect. The proposed mechanism is that at lower doses there could be less akathisia and it might have kept working on the depression over the full eight weeks. This is possible and deserves study.

However, in the one maintenance study of aripiprazole in bipolar disorder (which resulted in FDA-approval as a maintenance agent in bipolar disorder), there was significant benefit for reducing manic episodes over six months compared with placebo, but no efficacy in preventing depressions or mixed states with depressive symptoms.4

Other antipsychotics used as monotherapy have been found effective for bipolar depression. These include quetiapine, lurasidone, and cariprazine (all FDA-approved). Lamotrigine and lithium have efficacy and FDA-approval as maintenance treatments in bipolar depression. Thus, for many patients with bipolar depressions, these five medications would be preferred over aripiprazole.


Dr Osser is Associate Professor of Psychiatry, Harvard Medical School, and Consulting Psychiatrist, US Department of Veterans Affairs, National Telemental Health Center, Bipolar Disorders Telehealth Program, Brockton, Mass.


1. Cipriani A, Barbui C, Slanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple treatments meta-analysis. Lancet. 2011; 378:1306-1315.

2. Goikolea JM, Colom F, Torres I, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord. 2013;144:191-198.

3. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharm. 2008;28:13-20.

4. Keck PE Jr, Calabrese JR, McQuade RD, et al. A randomized, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67:626-637.❒