The Use of Aripiprazole for Bipolar Disorder

BIPOLAR UPDATE

Six years ago, I wrote about aripiprazole in Psychiatric Times. However, in my consulting work, I continue to see clinicians prescribing aripiprazole improperly, ie, not in accordance with the evidence base as to indications and dosage. I hope this update will have some impact on that confusion.

Aripiprazole was approved by the US Food and Drug Administration (FDA) as a treatment for acute mania. However, it is not one of the more robustly efficacious agents for mania; haloperidol, risperidone, olanzapine, and quetiapine, in that order, top the list in a meta-analysis by Cipriani et al.¹

Haloperidol is not recommended as a first-line agent because of the greater risk of tardive dyskinesia (TD) with first-generation antipsychotics.² Also, TD is more common in patients with mood disorders than in those with schizophrenia.³ Moreover, evidence indicates that it is the antimanic agent that is associated with the highest risk of the patient switching to a depressive episode after resolution of the mania.⁴

Aripiprazole had 2 early trials in which it did not differ from placebo in mania, which explains its lower effect size compared with other options.⁵ Efficacy has been found in some studies, using 15- to 30-mg doses. I see patients being prescribed much lower doses in the hope that they might treat or prevent mania, but there is no evidence supporting the use of those doses for mania.

Does aripiprazole have any role in treating or preventing bipolar depression? Many prescribers seem to think so, according to what I see when reviewing charts during consultations. However, it has not been found to be efficacious. Two large manufacturer-sponsored trials failed to show any difference from placebo after 8 weeks of treatment.³ It is not FDA approved for acute bipolar depression. What I think explains the prescribing of aripiprazole for bipolar depression is the fact that it is well known for its approval as an augmentation for antidepressants such as selective serotonin reuptake inhibitors in unipolar depression. It was heavily advertised for that purpose (at least, until it became generic, and now all the advertising is for its cousin brexpiprazole). 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. However, an expert consensus review recommended against antidepressant use in patients with bipolar depression and a history of rapid cycling (4 or more mood episodes per year), manias with mixed (depressive) symptoms (or a history of mixed manias), or a history of becoming manic after antidepressant treatment.6 The exception is the combination of olanzapine and fluoxetine, which is an FDA-approved treatment for bipolar depression. However, one usually wants to avoid that combination because olanzapine has severe metabolic adverse effects and induces insulin-resistance and abnormal inflammatory markers after even a single dose.⁷

In the two 8-week aripiprazole studies in bipolar depression, there was separation from placebo in some of the earlier weeks, but by week 8, there was no difference (number needed to treat = 44).⁸ The dosage at the end point reached a mean of 16.5 mg daily. Doses started at 2 to 5 mg daily, and the temporary improvement over placebo occurred during that early period. It has therefore been speculated that if study participants had stayed on the lower doses for the full 8 weeks, they might have had a sustained antidepressant effect. Maybe participants were having less akathisia at the lower doses and assumed the lower doses could have led to better results. This deserves further study, but with the drug becoming generic, potential funding sources for new studies have disappeared.

However, going against that hope, looking at the one maintenance study of aripiprazole in bipolar disorder (which resulted in its FDA approval as a maintenance agent in bipolar disorder), there was significant benefit in reducing manic episodes over 6 months compared with placebo, but no efficacy in preventing depressions or mixed states with depressive symptoms.⁹ Although the FDA generously gave aripiprazole approval for use in bipolar maintenance, it does not appear to have any maintenance efficacy for the depressions.

Other antipsychotics used as monotherapy have been found effective for bipolar depression. These include quetiapine, lurasidone, cariprazine, and lumateperone, all of which are FDA approved. Lamotrigine and lithium have efficacy and FDA approval as maintenance treatments in bipolar depression. Thus, for patients with bipolar depression, these 6 medications are preferable over aripiprazole.

Dr Osser is an associate professor of psychiatry at Harvard Medical School in Boston, Massachusetts; a psychiatrist at the Veterans Affairs (VA) Boston Healthcare System, Brockton Division; and codirector of the VA National Bipolar Disorders TeleHealth Program. He reports no conflicts of interest concerning the subject matter of this article.

References

1. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011; 378(9799):1306-1315.

2. Buchanan RW, Kreyenbuhl J, Kelly DL, et al; Schizophrenia Patient Outcomes Research Team (PORT). The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71-93.

3. Keck PE Jr, Mendlwicz J, Calabrese JR, et al. A review of randomized, controlled clinical trials in acute mania. J Affect Disord. 2000;59(suppl 1):S31-37.

4. 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(3):191-198.

5. Fountoulakis KN, Vieta E. Efficacy and safety of aripiprazole in the treatment of bipolar disorder: a systematic review. Ann Gen Psychiatry. 2009;8:16

6. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249-1262.

7. Hahn MK, Wolever TMS, Arenovich T, et al. Acute effects of single dose olanzapine on metabolic, endocrine, and inflammatory markers in healthy controls. J Clin Psychopharmacol. 2013;33(6):740-746.

8. Thase ME, Jonas A, Khan A, et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychopharmacol. 2008;28(1):13-20.

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