Are there differences by gender in response to pharmacotherapy for depression?

BACKGROUND: Depression is common in primary care, but little is known about gender differences in response to medication. This randomized trial compared men and women in response to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

POPULATION STUDIED: A total of 235 men and 400 women between 21 and 65 years who meet Diagnostic and Statistical Manual of Mental Disorders, third edition, revised criteria for major depression with or without dysthymia were enrolled at 12 centers. The average age for men and women was 43 and 40 years, respectively. Of these, 91% were white; 64% had recurrent depression; 54% were also dysthymic; and 57% were previously treated with pharmacotherapy. Depressive symptoms were severe, averaging 25 on the Hamilton Depression (HAM-D) scale. The study population was probably similar to many patients seen by family physicians but with more severe depressive symptoms and more dysthymia. Caution should be exercised in extrapolating results to patients with mild depression, patients of color, or anyone older than 65 years.

STUDY DESIGN AND VALIDITY: This was a randomized controlled trial (allocation assignment concealed). Subjects were given imipramine or sertraline starting at 50 mg per day. Doses were increased until therapeutic results or intolerable side effects occurred, to an average of approximately 140 mg per day of sertraline and 200 mg per day for imipramine. Response to medication was measured by the HAM-D, Beck, and Clinical Global Severity and Improvement (CGI) scales. Analyses of baseline characteristics and end points were performed using the Mantel-Haenszel chi-square and analysis of variance, adjusted for site, baseline severity, and type of depression. Methodologic strengths include the randomized design, efforts to conceal allocation, and use of both intention-to-treat and efficacy-only analysis. Minor weaknesses included lack of information about treatment groups at baseline, absence of a true placebo, and the lack of control for potentially important confounding factors, such as concurrent psychotherapy, other treatments, and social support.

OUTCOMES MEASURED: Response was defined as a 50% decrease of HAM-D score, a HAM-D score of less than 15, a CGI severity score of less than or equal to 3, or a CGI improvement score of 1 or 2. Compliance, side effects, and withdrawals were also tracked. Outcomes important in primary care that were not addressed include other clinical outcomes (suicide attempts, hospitalization), the use of other modalities (additional medication, electroconvulsive therapy, therapy), functional status, patient satisfaction, and cost of care.

RESULTS: Men and women were somewhat different at baseline, although the authors did not report the characteristics of each treatment subgroup. Women were significantly more likely to have been treated for depression and to have a first-degree relative with depression, while men were more likely to be married and to have coexistent dysthymia. Follow-up was complete. Women responded better to sertraline than imipramine (57% improved vs 46%; P=.03; number needed to treat [NNT]=8), and men responded more to imipramine than to sertraline (62% vs 45%; P=.03; NNT=6). Women taking imipramine were more likely to withdraw from the study than those taking sertraline (26% vs 14%; P=.02; NNH=10), but women completing a course of imipramine still had a significantly poorer response than those taking sertraline. Men and women taking either drug showed no significant sex differences in overall frequency of treatment-emergent adverse events; however, more than 90% of all patients reported adverse effects, and adverse effects were the most common reason for withdrawal from the study. For men, imipramine caused significantly more dry mouth, dizziness, and constipation than sertralin, and a similarly high rate of sexual dysfunction and somnolence. For women, sertraline caused significantly more insomnia and diarrhea and less constipation and dry mouth than imipramine.