Advances in the diagnosis and treatment of bipolar depression.

Bipolar depression is a common and costly condition. In this supplement, a group of experienced clinician-researchers review the substantial prevalence and burden as well as the diagnostic (especially differentiation from unipolar depression) and therapeutic (too few interventions with established efficacy, and those commonly have tolerability limitations) challenges of bipolar depression, in addition to describing the important advances in addressing these challenges. In the first article of this supplement, Dr. Shefali Miller of Stanford, California, and associates examine the prevalence and burden of bipolar depression, reviewing substantial data indicating that depressive symptoms are more pervasive than mood elevation or mixed symptoms and, consequently, impose more burden on patients, caregivers, and society. Dr. Miller and associates conclude that, in light of its prevalence, pervasiveness, and costs, more effective treatments for bipolar depression are needed to mitigate its profound impact upon individuals and society. In the next article, Dr. Robert Hirschfeld of Galveston, Texas, reviews the differential diagnosis of bipolar disorder and major depressive disorder, with these being particularly challenging to differentiate from one another, as patients with bipolar disorder spend most of their symptomatic time enduring depressive symptoms. Dr. Hirschfeld emphasizes that proper screening and comprehensive evaluation is necessary to avoid patients with bipolar disorder being misdiagnosed with unipolar major depressive disorder, and that accurate differentiation of these conditions has profound therapeutic implications. Dr. Hirschfeld also describes how several validated, easily administered screening instruments, as components of careful comprehensive evaluations, can help avoid patients with bipolar disorder being misdiagnosed with unipolar major depressive disorder, which can profoundly improve outcomes. In the third article, Dr. Mark Frye of Rochester, Minnesota, and associates review current therapeutic options for bipolar depression, focussing not only on approved agents, but also unapproved alternatives such as mood stabilizers and antidepressants. Dr. Frye and associates also describe the substantial unmet need for interventions that are efficacious, effective, and have a low side-effect burden, and the fact that future research needs to not only establish efficacy and tolerability but also advance personalized therapeutics through the development of response biomarkers. The next article, by Dr. Terence Ketter of Stanford, California, and associates describes use of number needed to treat and number needed to harm to quantify risks of benefits and harms for treatment selection in patients with bipolar depression. Dr. Ketter and associates demonstrate how efficacy and safety/ tolerability data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses can be used for benefit versus harm risk assessments for older and newer acute bipolar depression treatments. Whereas older (olanzapinefluoxetine combination and quetiapine monotherapy) approved treatments with adequate efficacy but tolerability limitations may have utility in high-urgency situations, older (lamotrigine and antidepressants) and newer unapproved treatments with adequate tolerability but efficacy limitations may have utility in low-urgency situations. In contrast, the newly approved agent lurasidone, which combines adequate efficacy and tolerability, may ultimately prove useful in diverse situations. Finally, Dr. David Kemp of Cleveland, Ohio, reviews management of side effects of commonly used treatments for bipolar depression. Dr. Kemp describes how weight gain, metabolic dysregulation, sedation/somnolence, and akathisia can negatively affect treatment adherence and clinical responses, and reviews management options including lifestyle modifications such as diet and exercise, switching to medications with more favorable sideeffect profiles, and use of adjunctive medications if these other efforts at side-effect mitigation yield inadequate outcomes. Although this supplement describes substantive advances in the diagnosis and treatment of bipolar depression, there clearly remain important unmet needs to enhance the management of this common and costly condition. Nevertheless, the important advances described in this supplement suggest that there is reason for optimism that ongoing research will yield additional diagnostic and therapeutic progress necessary to enhance outcomes for individuals struggling with bipolar depression.