Michael E Thase

Bipolar depression is more common, disabling, and difficult-to-treat than the manic and hypomanic phases that define bipolar disorder. Unlike the treatment of so-called "unipolar" depressions, antidepressants generally are not indicated as monotherapies for bipolar depressions and recent studies suggest that -even when used in combination with traditional mood stabilizers - antidepressants may have questionable value for bipolar depression. The current practice is that mood stabilizers are initiated first as monotherapies; however, the antidepressant efficacy of lithium and valproate is modest at best. Within this context the role of atypical antipsychotics is being evaluated. The combination of olanzapine and the antidepressant fluoxetine was the first treatment to receive regulatory approval in the US specifically for bipolar I depression. Quetiapine was the second medication to be approved for this indication, largely as the result of two pivotal trials known by the acronyms of BOLDER (BipOLar DEpRession) I and II. Both studies demonstrated that two doses of quetiapine (300 mg and 600 mg given once daily at bedtime) were significantly more effective than placebo, with no increased risk of patients switching into mania. Pooling the two studies, quetiapine was effective for both bipolar I and bipolar II depressions and for patients with (and without) a history of rapid cycling. The two doses were comparably effective in both studies. Although the efficacy of quetiapine monotherapy has been established, much additional research is necessary. Further studies are needed to more fully investigate dose-response relationships and comparing quetiapine monotherapy to other mood stabilizers (lithium, valproate, and lamotrigine) in bipolar depression, both singly and in combination. Head-to-head studies are needed comparing quetiapine to the olanzapine-fluoxetine combination. Longer-term studies are needed to confirm the persistence of response and to better gauge effects on metabolic profiles across months of therapy. A prospective study of patients specifically seeking treatment for rapid cycling and those with a history of treatment-emergent affective shifts also is needed. Despite the caveats, as treatment guidelines are revised to incorporate new data, the efficacy and tolerability of quetiapine monotherapy must be given serious consideration.