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Lithium Augmentation in Treatment-Resistant Depression: Meta-Analysis of Placebo-Controlled Studies

Bauer, Michael MD, PhD*; Döpfmer, Susanne MD

Journal of Clinical Psychopharmacology: October 1999 - Volume 19 - Issue 5 - p 427-434

The addition of lithium to the treatment regimens of previously nonresponding depressed patients has been repeatedly investigated in controlled studies. The authors undertook this meta-analysis to investigate the efficacy of lithium augmentation of conventional antidepressants. An attempt was made to identify all placebo-controlled trials of lithium augmentation in refractory depression. Only double-blind studies that involved participants who had been treated with lithium or placebo addition after not responding to conventional antidepressants were to be included in the meta-analysis. Further inclusion criteria were the use of accepted diagnostic criteria for depression and the use of response criteria based on the acceptable measurement of depression as an outcome variable. Studies were located by a search of the MEDLINE database, a search in the Cochrane Library, and an intensive search by hand of reviews on lithium augmentation. Nine of 11 placebo-controlled, double-blind studies were included in this meta-analysis. Aggregating three studies with a total of 110 patients that used a minimum lithium dose of 800 mg/day, or a dose sufficient to reach lithium serum levels of ≥0.5 mEq/L, and a minimum treatment duration of 2 weeks, the authors found that the pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31 (95% confidence interval, 1.46-7.53). The corresponding relative response rate was 2.14 (95% confidence interval, 1.23-3.70), the absolute improvement in response rate was 27% (95% confidence interval, 9.8%-44.2%), and the number of patients needed to be treated to obtain one more responder was 3.7. Inclusion of six more studies that fulfilled inclusion criteria but which treated subjects with additional lithium for less than 2 weeks or with a lower lithium dose (total, 234 patients) resulted in even higher estimates. Lithium augmentation seems to be the treatment strategy in refractory depression that has been investigated most frequently in placebo-controlled, double-blind studies. The authors conclude from this meta-analysis that with respect to efficacy, lithium augmentation is the first-choice treatment procedure for depressed patients who fail to respond to antidepressant monotherapy.

*Department of Psychiatry and †Institute of Medical Statistics, Epidemiology and Informatics, Klinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany

Received May 26, 1998; accepted after revision September 23, 1998.

Address requests for reprints to: Michael Bauer, MD, PhD, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles (UCLA), 300 UCLA Medical Plaza, Suite 2330, Los Angeles, CA 90095-6968. Address e-mail to:

© 1999 Lippincott Williams & Wilkins, Inc.