Are There Differences Between Women’s and Men’s Antidepressant Responses?

Data collected over a 20-year period in an outpatient depression research clinic were examined. A total of 1,746 patients took part in the nine different studies (12–19, unpublished 2002 manuscript of Stewart et al.) that provided data for this report. Because 59 patients who received placebo in a three-arm study (phenelzine versus imipramine versus placebo) were included in both the tricyclic antidepressant contrasts and the MAOI contrasts, summing the number of patients across all comparisons suggests that 1,805 patients were included in these studies.

Most of these data and the details of the individual studies’ design and outcomes have been previously published; one study is being prepared for publication (unpublished 2002 manuscript of Stewart et al.). Eight studies were double-blind, randomized 6-week trials with fixed, flexible dose schedules (12–18, unpublished 2002 manuscript of Stewart et al.). All but one study (12) was placebo controlled. The ninth study was a five-site, open-label fluoxetine treatment study, the purpose of which was to identify fluoxetine responders. Fluoxetine responders were randomly assigned to receive the drug or placebo in a subsequent discontinuation study (19). Because of the absence of a placebo arm and blind ratings in the acute phase, the results of this 12-week fluoxetine study must be interpreted with caution, and thus they are presented separately. The potential role of bias in this study is addressed later in the paper. The other eight studies investigated the effects of tricyclics (desipramine, imipramine) and MAOIs (phenelzine, tranylcypromine, L-deprenyl).

Outpatients, aged 18 to 65 years, who gave written informed consent were evaluated by using the Research Diagnostic Criteria (20) or the DSM-III or DSM-III-R criteria (depending on the year the study was conducted), the 21-item Hamilton Depression Rating Scale, the Clinical Global Impression (CGI) scale, and the SCL-90 (21). All studies were approved by the clinic’s institutional review board. In the fluoxetine study (19), the 17-item Hamilton depression scale was used.

Lacking data on menopausal status, we divided the female subjects into groups by using the arbitrary cutoff point of age 50. Obviously there is no fixed menopausal age. Stanford et al. (22) reported a median age of 51 years. In a study of 2,783 women, Cramer and Xu (23) found the mean age at menopause was 47.3 years (SD=3.5). They also noted that women with a history of depression go through menopause earlier. In the Results section, we demonstrate that there is no change in the study’s outcome if the female subjects were grouped with the cutoff point at age 52, 54, or 56, instead of age 50. Men were similarly grouped to assess the relevance of age for men’s response to antidepressants.

Since we were interested in the speed of onset of response to antidepressants, persistent improvement was most relevant. Fluctuating improvement would have less clinical relevance. Patients were judged to be responders at the point they received a score of 1 (very much improved) or 2 (much improved) on the change scale of the CGI and maintained that improvement for the duration of the study.

In organizing the data, we wished to have a large enough number of subjects and power to detect differences of 10%. At first, we combined data from the tricyclic antidepressant and MAOI studies (all were 6-week trials). A logistic regression analysis of the relationship between response and class of drug suggested that the outcome of the tricyclic antidepressant studies differed from that of the MAOI studies (χ²=13.91, df=1, p=0.002). Thus, separate examination of the data by drug class was required. The results of the tricyclic antidepressant studies are presented separately from those of the MAOI studies. Data from the fluoxetine study (a 12-week trial) are presented separately.

To determine if data from all studies within each drug class could be combined for analysis, the studies for each drug class were compared separately by using Cox proportional hazard analysis. When no differences in outcome by study by sex were found (i.e., similar to a finding of the absence of a site effect in a multisite study), data from studies utilizing antidepressants from the same class were combined. Cox proportional hazard analysis showed no differences in outcome in a five-by-two interaction examining the MAOI studies (χ²=5.42, df=4, p=0.25) and in a six-by-two interaction examining the tricyclic antidepressant studies (χ²=4.81, df=5, p=0.31). In all studies with a placebo control (13–18, unpublished 2002 manuscript of Stewart et al.), there were clear drug-placebo differences, indicating that some patients had drug-responsive disorders.

Kaplan-Meier estimates of time to response were computed and graphically presented to show potential sex differences. In these analyses, time to survival is equivalent to time to onset of response to medication. A shorter survival time, as shown by a steeper survival curve, indicates a greater response to the medication. Hazard ratios were used to contrast the speed of onset of the drug effect between sexes and age groups (24). The hazard estimate gives the conditional probability of becoming a responder during a time interval, provided that the individual has not responded at the beginning of the time interval. Thus, hazard is a function of survival time. The cumulative hazard at a given time is the hazard integrated over the whole time interval until the given time point. The cumulative hazard for a response estimate for men and women was calculated each week. If the difference between groups in hazard is statistically significant, one group is improving more rapidly than the other up to that point. With correction for multiple comparisons, p<0.008 was required for significance in the analyses for each of the 6 weeks in the MAOI and tricyclic antidepressant studies, and p<0.007 was required in the analysis of the fluoxetine study.

To determine if differences in response between women and men were attributable to a drug effect (e.g., whether the difference between drug and placebo effects for women is greater than that for men), Cox proportional hazards regression analysis was used. The parameter of interest was whether the sex-by-treatment interaction was significantly different from zero.

Despite the theoretical potential for differences between men’s and women’s response to antidepressants, we found few such differences. A higher proportion of women than men in this study group benefited from MAOIs. Women age 50 and older and those younger than age 50 had similar MAOI and fluoxetine response rates. Women age 50 and older had a superior response to tricyclic antidepressants.

Several studies have suggested that postmenopausal women are less likely to benefit from antidepressants and that hormone replacement therapy improves drug response (1, 5). The recent Women’s Health Initiative study reports increased risk of breast cancer, myocardial infraction, and stroke associated with replacement therapy (25). A 2002 editorial in JAMA concluded that even these small risks contraindicated long-term hormone therapy (26). Our data suggest that menopause, even in the absence of hormone replacement therapy, does not appear to affect antidepressants’ benefit. Depressed postmenopausal women should receive antidepressants regardless of whether they are also receiving hormone replacement therapy. It is unclear if adding hormone replacement therapy will be beneficial for women who are unresponsive to an antidepressant.

These findings appear to contradict those of Kornstein et al. (1), who found sex differences in response to antidepressants. We examined studies frequently cited as providing evidence for sex differences in antidepressant response and also did a MEDLINE literature review (1, 3–5, 11, 27–37). Hamilton (32) reviewed 205 imipramine studies published through 1991. In 35 studies (19%), a judgment about sex effect was possible. Six were reported to show a statistically significant difference favoring women. Six others suggested that men’s imipramine response was superior to women’s. Two of those six studies included schizophrenic patients (27, 28). In a third study, women with an adequate plasma level had a good response to imipramine (N=6 of 7) (33). In a fourth study, which included 13 men and 21 women and three treatment arms, the report that “interaction of sex and active treatment favored men” does not seem plausible, given the small number of subjects (35). We conclude that only two of these six studies supported an advantage of imipramine for men (34, 36).

Several other studies demonstrate a more favorable response to tricyclic antidepressants in men (1, 30, 31). One study of dothiepin maintenance suggests that time to relapse was longer for men than women (29). One study found that men had a better response to tricyclics than to MAOIs and that women had the reverse response, but the differences did not exceed chance because less than 50 comparisons were done (30). Two studies suggest superior imipramine response for men (1, 31).

When data for all patients included in the 35 studies reviewed by Hamilton were combined, 62% of the men and 51% of the women responded to imipramine. Many studies had a small number of subjects and were underpowered. Four studies clearly show an advantage of imipramine for men (1, 31, 34, 36), and none show such an advantage for women. Taken together, these data suggest a modest advantage of imipramine for men.

Kornstein et al. (1) suggested that women have a superior response to SSRIs compared to imipramine. Lewis-Hall et al. (4) analyzed data from several studies of women treated with fluoxetine and imipramine and found the drugs equally efficacious. Martenyi et al. (37) found women had a better response to fluoxetine than to maprotiline, and men had an equal response to the two drugs. However, men’s improvement while taking fluoxetine was equal to women’s. In a brief abstract, Steiner noted that women had equal benefit with imipramine and paroxetine (both superior to placebo) (3). In the fluoxetine study included in this analysis, men and women had an equivalent response in the acute open phase. Although this study had an open treatment design, equivalent relapse rates for men and women in the double-blind discontinuation phase suggest that ratings in the open phase favored neither men nor women (19). Thus, it is unclear if women’s response to SSRIs is superior to men’s; one study has suggested that it is (1) and two that it is not (37 and the current study). Whether women have a superior response to SSRIs compared to tricyclic antidepressants is also unclear; superior response to SSRIs is supported by one study (1) and not supported by two studies (3, 4).

What are the clinical and heuristic implications of these data? Men may have a slightly better outcome with imipramine, but it is unclear whether this small advantage is a result of pharmacokinetics, pharmacodynamics, or diagnostic differences. Perhaps men are more likely to have an imipramine-responsive subtype of depression with a distinctive neurophysiology that is as yet unidentified. Similar parameters should be considered in attempting to explain the slight advantage of MAOIs for women.

Even if we assume a real but small sex-related difference in tricyclic antidepressant and MAOI outcomes, the clinical relevance of the difference is minimal. SSRIs and other second-generation antidepressants have a more favorable side effect profile than the tricyclics and MAOIs, and most often clinicians choose to prescribe them first (38). MAOIs and tricyclic antidepressants have become second-line drugs, and the slight sex advantages (or disadvantages) should not alter their use. The current data do not allow a firm algorithm of choices, although a collaborative study may permit better informed decisions in the future (39).

One limitation of this study is that there were too few patients to be sure that 10% differences in outcome between the sexes exist. Given the large number of studies that have been done, relatively few data about female-male differences in outcome are available. To help clarify the extent of sex-specific differences in antidepressant response, we recommend testing for treatment-by-sex interactions in all studies of antidepressants and reporting both the positive and negative findings.

Received April 4, 2001; revisions received Dec. 5, 2001, and May 29, 2002; accepted June 6, 2002. From the Department of Therapeutics, New York State Psychiatric Institute; and Columbia University College of Physicians and Surgeons, New York. Address reprint requests to Dr. Quitkin, New York State Psychiatric Institute, 1051 Riverside Dr., New York, NY 10032; [email protected] (e-mail).