Comprehensive Pharmacologic Management of Bipolar Depression

Although mania is the defining feature of bipolar disorder (BD), depressive episodes are more frequent, at least as impairing, and come at high individual and societal costs. Historically, BD depression (BDD) has been under-studied, but in the last 10–15 years data from numerous placebo-controlled trials of mood stabilizers, second-generation antipsychotics, and other agents have allowed for the formulation of evidence-based treatment recommendations (Table 1). Abundant evidence exists for the efficacy of lithium, lamotrigine, quetiapine, and lurasidone in treating acute BDD. Lithium, lamotrigine, and quetiapine are also robustly effective in preventing depression during maintenance treatment, while data for lurasidone is lacking. Other second generation antipsychotics besides quetiapine are of limited benefit, with the possible exception of olanzapine, particularly in combination with fluoxetine, although weight gain and other metabolic abnormalities limit its use for many patients. Antidepressants remain controversial in the treatment of BDD, and there is limited high-quality data to guide decision making. Nevertheless, the best available evidence suggests that SSRIs and bupropion, as adjuncts to mood stabilizers, are safe and effective in the treatment of acute BDD in patients with pure depression, no mixed symptoms, and no recent rapid cycling. However, they cannot be routinely recommended for maintenance therapy due to a lack of data regarding long-term efficacy and safety. Finally, a number of promising experimental agents with novel mechanisms of action deserve further study, including vigilance-promoting drugs such as modafinil and armodafinil; the dopamine agonist pramipexole; the glutathione donor N-acetylcysteine; fatty acid supplementation; and the NMDA-receptor-antagonist ketamine.