The International Journal of Neuropsychopharmacology

Special Section

Recent placebo-controlled acute trials in bipolar depression: focus on methodology

David J. Muzina a1c1 and Joseph R. Calabrese a2
a1 Cleveland Clinic Foundation, Cleveland, Ohio, USA
a2 Department of Psychiatry, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio, USA

Article author query
muzina d   [PubMed][Google Scholar] 
calabrese j   [PubMed][Google Scholar] 


The completion of three recent large-scale, double-blind controlled acute trials in bipolar I depression has improved our understanding of the management of major depressive episodes associated with bipolar disorder. In contrast to the cross-over designs used in the early studies of lithium in bipolar depression, the designs utilized in these recent studies have employed random assignment to parallel arms including the use of placebo as a monotherapy in one study. The analyses of recent studies have all been conducted on intent-to-treat data, and included two types, change from baseline analyses and responder analyses. Lamotrigine monotherapy was shown to be superior to placebo with both types of analyses on the Montgomery–Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton Depression Rating Scale (HAMD) (n=195). The percentage of patients responding to placebo as a monotherapy were 29, 26 and 37%, respectively; there were no differences in switch rates (5% vs. 5%). Paroxetine augmentation was no better than placebo augmentation overall with both types analyses on the CGI and HAMD (n=117); the MADRS was not used. In patients with lithium levels [less-than-or-eq, slant]0.8 mequiv./l, the change from baseline analysis showed paroxetine to be superior to placebo, but responder analyses were negative; switch rates with paroxetine, imipramine, and placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in efficacy to imipramine (n=156), but had a lower rate of switching (4% vs. 11%).

(Received July 28 2002)
(Reviewed October 29 2002)
(Revised January 29 2003)
(Accepted February 9 2003)

Key Words: Bipolar depression; lamotrigine; placebo; paroxetine; tricyclic antidepressants.

c1 Dr D. J. Muzina, 9500 Euclid Avenue, P57, Cleveland, Ohio 44195, USA. Tel.: 216/444-5810 Fax: 216/445-7032 E-mail: