A new study contributes to the growing body of evidence of gender-specific differences in both the efficacy and sideeffect profiles of antidepressant medications. Premenopausal women responded better to the SSRI sertraline, while men responded better to a tricyclic antidepressant (TCA), such as imipramine.

For some time researchers have observed that women do not respond as favorably to imipramine as do men. In addition, in studies comparing tricyclics with monoamine oxidase inhibitors (MAOIs) in treating atypical depression with associated panic attacks, women responded more favorably to MAOIs, while men responded better to TCAs.

However, Susan G. Kornstein, M.D., chair of the ambulatory care division in the psychiatry department at the Medical College of Virginia, and her colleagues point out in the September American Journal of Psychiatry that they were unable to find any research literature detailing gender-specific differences with the SSRIs.

Kornstein and her colleagues studied 235 men and 400 women who met DSM-III-R criteria for chronic major depression or double depression (acute major depression superimposed on dysthymia). Their multicenter, double-blind, parallel-group trial compared men and women who had a Hamilton Rating Scale (Ham-D) score of at least 18 and a Clinical Global Impression (CGI) severity-scale score of at least 3 after a one-week placebo washout. They randomly assigned subjects to one of two groups within each gender—women taking either sertraline or imipramine, and men taking either sertraline or imipramine.

Patients were observed weekly for six weeks, then biweekly for an additional six weeks. At each visit during the 12-week trial, patients were assessed with both the Ham-D and the CGI. A satisfactory clinical response at the conclusion of the trial was defined as a 50 percent reduction in the Ham-D score, with the Ham-D score being 15 or less, a CGI severity score of less than 3, and a CGI improvement scale score of 1 or 2.

The researchers found that their subjects’ treatment response significantly interacted with gender. Women were significantly more likely to respond to sertraline than to imipramine (57 percent versus 46 percent), and men were significantly more likely to respond to imipramine than to sertraline (62 percent versus 45 percent).

In addition, the team documented a statistically significant gender-versus-treatment interaction when they analyzed drop-out rates for the study. Women who were taking imipramine and men who were taking sertraline were much more likely to drop out of the study prior to its completion. The subjects overwhelmingly cited adverse reactions as the reason they discontinued their medication.

Among those taking sertraline, women were significantly more likely to report the side effects of nausea and dizziness, while men reported dyspepsia, increased urinary frequency, and sexual dysfunction. For those taking imipramine, women were significantly more likely to suffer from nausea, and men again reported increased urinary frequency and sexual dysfunction.

The time it took patients to respond also differed depending on medications and gender. Men who took imipramine responded significantly quicker than did women who were taking imipramine and who responded to it.

Kornstein and her colleagues are uncertain of the mechanism that is driving these gender differences. One possibility, they suggest, is that the serotonergic potency of sertraline is important for female physiology, whereas it is not as significant for males. Several studies have documented that estrogen enhances serotonergic activity, and preliminary work indicates that hormone-replacement therapy in postmenopausal women enhances SSRI efficacy.

Although the research provides evidence of gender-specific differences in the efficacy and side-effect profiles of SSRIs and TCAs in the treatment of chronic depression, Kornstein said, there are inherent limitations with the study.

A major limitation, according to the authors, is that the study lacked the control aspects of a placebo arm. The authors did not include a placebo arm in the study primarily out of ethical concerns; noting the tendency toward low placebo response in patients with chronic depression. In addition, they utilized stringent inclusion/exclusion criteria, and therefore, the generalizability of the findings could have been compromised.

The authors suggested that in clinical practice, both gender and menopausal status of women should be taken into consideration when physicians initiate antidepressant pharmacotherapy.