Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study


  • G Sachs: Consultant for Abbott Laboratories, Janssen Pharmaceutica, Novartis, Eli Lilly and Company, Bristol-Myers Squibb, Glaxo SmithKline Pharmaceuticals, Elan, Sanofi, Sigma-Tau, AstraZeneca Pharmaceuticals; Grant Support from Abbott Laboratories, Janssen Pharmaceutica; Honoraria from Abbott Laboratories, Glaxo SmithKline Pharmaceuticals, Janssen Pharmaceutica, Eli Lilly and Company, Bristol-Myers Squibb, Solvay, Novartis, Sanofi, AstraZeneca Pharmaceuticals, Pfizer Inc; Stockholder – none. KNR Chengappa: has received grant/research support from Ortho McNeil and Janssen Pharmaceutica, and serves on the speakers bureau for AstraZeneca, Eli Lilly, Janssen, and Ortho McNeil. T Suppes: Sources of funding for clinical grants – Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Glaxo SmithKline Pharmaceuticals, Janssen Pharmaceutica, National Institute of Mental Health, Novartis, Robert Wood Johnson Pharmaceutical Research Institute, The Stanley Medical Research Institute; Consulting agreements/advisory boards – AstraZeneca, Bristol-Myers Squibb, Eli Lilly Research Laboratories, Glaxo SmithKline Pharmaceuticals, Janssen Pharmaceutica, Johnson & Johnson Pharmaceutical Research & Development, Pfizer, Pharmaceutical Research Institute (PRI), Ortho McNeil Pharmaceutical, UCB Pharma, Novartis Pharmaceuticals; Financial interests/stock ownership – none. JA Mullen, M Brecher, NA Devine, DE Sweitzer are all employees of AstraZeneca Pharmaceuticals.

Gary Sachs, MD, Harvard Bipolar Research Program, Massachusetts General Hospital, 50 Staniford St, 5th Floor, Boston, MA 02114, USA. Fax: 617-726-6768;
e-mail: sachsg@aol.com


Objective:  Evaluate the efficacy and tolerability of quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) in the treatment of acute mania.

Methods:  Patients were randomized to 21 days of double-blind treatment with QTP plus Li/DVP, or placebo (PBO) plus Li/DVP. QTP was rapidly dosed up to a maximum of 800 mg/day; Li was dosed to 0.7–1.0 mEq/L; or DVP to 50–100 μg/mL.

Results:  Fifty-six of 91 (61.5%) individuals in the QTP + Li/DVP group compared with 49 of 100 (49%) taking PBO + Li/DVP completed the study. A significantly greater mean reduction in total Young Mania Rating Scale (YMRS) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group (−13.76 versus −9.93; p = 0.021). The response rate (≥50% YMRS improvement) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients (54.3% versus 32.6%; p = 0.005), as was the proportion of patients achieving clinical remission (YMRS < 12) (45.7% versus 25.8%; p = 0.007). Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores (−1.38 versus −0.78; p = 0.001). The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria. Common adverse events (at least 10% and twice the rate of Li/DVP) in the QTP + Li/DVP group included somnolence, dry mouth, asthenia, and postural hypotension.

Conclusions:  Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania. Combination therapy was well-tolerated and most adverse events were mild, withdrawal because of adverse events being only 5% compared with 6% on Li or DVP monotherapy.