A New Option for Treating Bipolar I Depression.

Characterized as the “black dog” by Winston Churchill and “the charnel house” by Kay Redfield Jamison, bipolar depression remains the scourge of those who struggle with the disorder. Although mania is the defining characteristic of bipolar I disorder, research shows that depression is the dominant pole of the illness.Thedepressivephase of bipolar I disorder typically lasts longer than mania (1), occurs more frequently (2), and drivesmuch of illness-related impairment (3). Relative to mania, bipolar depression is associated with a greater risk of suicide attempts (4) and longer time to remission (5). Those who suffer with bipolar I disorder come to fear the endless months of unremitting bleakness associatedwith depression, andmore importantly, despair in the knowledge that currently available treatments often fail to relieve these anguish-filled episodes. Despite the tremendous illness burden associated with bipolar depression, options for treating this phase of the disorder are extremely limited.Medications thatworkwell in the manic phase of bipolar I disorder often fail to treat the depressive phase of illness (6), and antidepressant medications, with the attendant risk of inducing a switch tomania or hypomania, have limited efficacy in bipolar I disorder (7). In the United States, only three medications are approved for acute treatment of depressive episodes in the context of bipolar disorder: olanzapine and fluoxetine in combination, quetiapine, and lurasidone. Although older medications such as lithium also have modest effects in acute bipolar depression, a recently conducted network meta-analysis incorporating data on both the efficacy and the tolerability of treatments for depression in the context of bipolar disorder concluded that the olanzapine-fluoxetine combination should be considered the first-line treatment, although the study authors acknowledged that this formulation is not available outside the United States and, indeed, is not commonly used evenwithin the United States (8). Notably, neither lurasidone nor the olanzapine-fluoxetine combination has been tested or approved for use in the manic phase, making it confusing to think about using these medications in an illness that almost invariably spans both types of moodepisodes. In short, efficaciouspharmacologic options for managing the most prevalent and most disabling phase of bipolar disorder are extremely limited, and treatments that work in both phases of the disorder are especially rare. New treatments are desperately needed. Against this backdrop of urgent need and dire lack of treatment options, patients and clinicians will welcome the news from Durgam and colleagues (9), who in this issue report thefinding that cariprazine is an efficacious treatment for bipolar I depression. Cariprazine, an atypical antipsychoticwith bothD3 andD2 receptor partial agonist activity as well as high affinity for 5-HT1A receptors, was previously shown to be efficacious in the manic phase of the illness (10). The present study provides evidence of cariprazine’s superiority to placebo as a treatment for depression, making it only the second atypical antipsychotic (the other is quetiapine) to have demonstrated efficacy in both phases of the disorder. In a multinational trial funded by Forest Laboratories, the manufacturer of cariprazine, participants (N5571) were randomlyassigned to receiveplaceboor cariprazine at 0.75 mg/day, 1.5 mg/day, or 3 mg/day for 8 weeks. The primary and secondary outcome measures were change frombaseline toweek6on the Montgomery-Asberg Depression Rating Scale (MADRS)andtheClinical Global Impressions severity subscale (CGI-S). Overall, the 1.5-mg/day dosage of cariprazine did best. Individuals in the 1.5-mg/day group showed significantly greater improvements on the MADRS and the CGI-S compared with the placebo group after 6 weeks, and improvements at 6 weeks were sustained at 8 weeks. Cariprazine at 0.75 mg/day was not significantly different from placebo. The 3-mg/day dosage did not fare any better than placebo either, after adjustment for multiple comparisons. Also, completion rates were higher in the 1.5-mg/day group (80%) compared with the 3-mg/day group (64%), suggesting that 1.5mg/daywas better tolerated than 3mg/day. Themost common adverse events were akathisia, insomnia, and nausea. The authors concluded that cariprazine at 1.5 mg/day is well tolerated and effective for the treatment of bipolar I depression. In the setting of limited options for managing bipolar I depression, cariprazine will be a welcome addition to the treatment armamentarium. Administered at 1.5 mg/day, it offers the potential for relatively rapid relief from symptoms and appears to be well tolerated. The large sample size and cross-national study design provide hope that findings from this phase II study will generalize to a larger population when moved forward into the next phase of Efficacious pharmacologic options for managing the most prevalent and most disabling phase of bipolar disorder are extremely limited, and treatments that work in both phases of the disorder are especially rare.