Bipolar affective disorder (BPAD) is “a debilitating psychiatric illness evidenced by cyclical episodes of mood elevation and depression.”1 Individuals with BPAD experience greater compromises in quality of life and higher rates of attempted or completed suicide, as compared to those with unipolar major depressive disorder (MDD).2,3 The majority of patient with BPAD spend a greater proportion of time in depressive versus manic episodes2

Bipolar and unipolar depression are “two distinct illnesses,” necessitating different treatment approaches. A recent article by Avery and Dayton reviews the management of BPAD, with particular emphasis on psychopharmacology.1

The primary goals of therapy in bipolar depression are to achieve complete remission, decrease the risk of suicidality, maintain and/or improve quality of life (QOL) and functioning, and prevent affective switches from depression to mania.4, There are currently three medications approved by the US Food and Drug Administration (FDA) specifically for the treatment of bipolar depression: olanzapine/fluoxetine combination (OFC), immediate- or extended-release quetiapine, and lurasidone) which is approved both as monotherapy and as an adjunct to lithium or valproate).1

Non-FDA Approved but Commonly Used Agents

There are several frequently used options for treatment of bipolar depression, including lithium or valproate monotherapy.4 Lamotrigine monotherapy is sometimes used as well, but the data regarding this approach are “conflicting and controversial.”1 A meta-analysis of five trials found lamotrigine to be superior to placebo in patients with severe depressive symptoms, but less effective in those with moderate symptom severity.5 For this reason, “lamotrigine should not be considered a first-line option for bipolar depression.” Findings regarding carbamazepine have been inconsistent; therefore monotherapy with this agent is not recommended.4

Monotherapy with aripiprazole, ziprasidone, and paroxetine is not recommended for treating bipolar depression, because these agents have been associated with negative outcomes.4 Antidepressants also cannot be recommended because they do not seem to be superior to placebo or other evidence-based treatment regimens.6,7 Moreover, antidepressants carry the risk of inducing conversion to mania.8 However, lithium monotherapy and valproate monotherapy—while not FDA-approved for this specific indication—are both evidence-based.2

FDA-Approved Agents for Treating Bipolar Depression

OFC: The FDA approved OFC for bipolar depression on the basis of an eight-week RCT9 that included patients with BPAD1 and a MADRS score of ≥20. Study participants were randomized to receive placebo (n=377), olanzapine (n=370) or OFC (n=86). Participants were allowed adjunctive benzodiazepines or anticholinergic agents. The olanzapine and OFC groups both experienced significant reductions in MADRS total score from baseline, as compared to placebo (P=0.002 and P<0.001 respectively). The incidence of treatment-emergent mania was similar across all groups. A 24-week open-label extension trial10 followed 376 study participants who completed the acute phase of the trial. After a one-week run-in phase, during which all participants receive olanzapine monotherapy, patients could elect to remain on olanzapine or begin OFC. Total score did not change significantly from baseline in either group for participants who entered the extension trial in remission (defined as a MADRS score of ≤12). However, those in the OFC group experienced higher rates of relapse, vs those in the olanzapine group. Total MADRS scores for participants who failed to achieve remission in the acute phase of the trial decreased significantly in both groups, and a majority achieved remission (66.7% in the OFC group and 64.7% in the olanzapine group).