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Depression continues to be the most difficult-to-treat phase of bipolar illness. Researchers in two large, related, manufacturer-sponsored, randomized, controlled trials compared the efficacy of quetiapine with that of placebo and active control. Patients had bipolar I or II disorder and no comorbid substance use disorder (Hamilton Rating Scale for Depression, >20; episode duration, 1–12 months).
Young and colleagues randomized 802 patients in a 2:2:1:1 ratio to quetiapine 300 mg, quetiapine 600 mg, lithium (600–1800 mg), or placebo. On the Montgomery-Asberg Depression Rating Scale (MADRS), quetiapine, but not lithium, was significantly superior to placebo at 8 weeks (response rates: quetiapine 300 mg, 69%; quetiapine 600 mg, 70%; lithium, 62%; placebo, 56%). Quetiapine 600 mg produced significantly greater improvement than lithium. Serum lithium level was unrelated to outcome. Rates of treatment-emergent mania were 4.2%, 2.2%, 2.2%, and 0.8%, respectively. Rates of clinically relevant (>7%) weight gain were 5%, 8%, 3%, and 2%, respectively.
McElroy and colleagues used a similar randomization ratio to compare quetiapine with paroxetine (20 mg) and placebo in 740 patients. On the MADRS, quetiapine, but not paroxetine, was significantly superior to placebo at 8 weeks (response rates: quetiapine 300 mg, 67%; quetiapine 600 mg, 67%; paroxetine, 55%; placebo, 53%). Both quetiapine doses had greater improvement than paroxetine. Treatment-emergent mania occurred somewhat more frequently than in the Young study (rates: 2.1%, 4.1%, 10.7%, and 8.9%, respectively). Rates of relevant weight gain were 9%, 11%, 3%, and 4%, respectively.
Young AH et al. A double blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry 2010 Feb; 71:150.
McElroy SL et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry 2010 Feb; 71:163.
Comment
In these acute-treatment studies, quetiapine compared more favorably to placebo than did lithium or paroxetine, although lithium's effects were intermediate. The high placebo response reflects the natural fluctuating course of illness; demonstrating short-term efficacy in these kinds of studies is difficult. The randomization ratio used in this study biases the findings toward quetiapine, although the numerical-rating-scale and response-rate differences suggest an edge with this drug. The increased risk for weight gain and the other known metabolic effects of quetiapine suggest that treatment selection for each patient requires an individual weighing of the drug's costs, both in price and adverse effects, against its benefit, which is likely to be significant for some patients. We await results from the extension phase of this study, involving a quetiapine–placebo comparison.