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Acute Worsening of Chronic Depression During a Double-Blind, Randomized Clinical Trial of Antidepressant Efficacy: Differences by Sex and Menopausal Status

Anne T. Harvey, Ph.D.; Beryl S. Silkey, Sc.M.; Susan G. Kornstein, M.D.; and Cathryn M. Clary, M.D.

Objective: Acute worsening of depression can negatively impact the outcomes of clinical trials of antidepressants and patient compliance to treatment. We hypothesized that acute worsenings would be more frequent in premenopausal women, relative to men or postmenopausal women, and in women who had demonstrated premenstrual symptom exacerbations (PMEs) prior to treatment, relative to those who had demonstrated no PMEs.

Method: Subjects diagnosed with DSM-III-R chronic major depressive disorder or double depression (dysthymia with concurrent major depressive episode) were randomly assigned between February 1993 and December 1994 to 12 weeks of double-blind treatment with flexibly-dosed sertraline or imipramine, with crossover to the alternate drug in the absence of response. A 6-point or more increase in the 17-item Hamilton Rating Scale for Depression relative to the (7-14 day) previous visit defined worsening. PME was assessed through daily diaries prior to treatment.

Results: There were 3582 evaluable visits attended by 554 subjects. Premenopausal women had a deteriorating depressive presentation at a greater proportion of their visits (8.6%) than did postmenopausal women (4.5%, p < .01) or men (5.9%, p < .01). The presence of PME at baseline was associated with more worsenings than the absence of PME (12.0% vs. 7.3%, p < .05). Results were similar whether the subject was treated with sertraline or imipramine. Nonresponse at treatment completion was more likely among subjects with worsening (p < .01). Dropouts were more likely than completers to have had an exacerbation at their terminal visit (p < .05).

Conclusion: Acute worsening of depression was associated with reproductive variables and negatively affected clinical trial outcomes including early treatment discontinuation and nonresponse.

(J Clin Psychiatry 2007;68:951-958)

Received April 11, 2006; accepted Nov. 22, 2006. From Via Christi Research, Inc., Wichita, Kan. (Dr. Harvey and Ms. Silkey); the Department of Psychiatry, Virginia Commonwealth University, Richmond, Va. (Dr. Kornstein); and Pfizer Inc., New York, N.Y. (Dr. Clary).

This research was supported by Pfizer Inc., New York, N.Y.

A preliminary report of this study was presented in poster format at the 45th annual meeting of the New Clinical Drug Evaluation Unit, June 6-9, 2005; Boca Raton, Fla.

Dr. Kornstein has received grant/research support from Pfizer, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Mitsubishi-Tokyo, Pharmacia and Upjohn, Merck, Biovail Laboratories, Wyeth, Berlex Laboratories, Novartis, Sepracor, Boehringer-Ingelheim, Sanofi-Synthelabo, and AstraZeneca and has been a member of advisory boards for Pfizer, Wyeth, Eli Lilly, Bristol-Myers Squibb, Warner-Chilcott, Biovail Laboratories, Berlex Laboratories, and Forest Laboratories. Dr. Clary is a stock shareholder of Pfizer, and her spouse is a consultant for Pfizer. Dr. Harvey and Ms. Silkey report no additional financial or other relationships relevant to the subject of this article.

Corresponding author and reprints: Anne T. Harvey, Ph.D., Via Christi Research, Inc., 1100 N. St. Francis, Suite 200, Wichita, KS 67214 (e-mail: