Women

Abstract

Studies have found (e.g., the Epidemiological Catchment Area study, the National Comorbidity Survey) higher rates of major depressive disorder in women than men. Clinicians need to be knowledgeable about potential sex differences in metabolism of antidepressants and treatment response. Data concerning such differences are limited, since Phase I and early Phase II clinical trials have historically excluded women of child bearing potential. However, the Food and Drug Administration is now encouraging inclusion of women at earlier stages of pharmaceutical research. A number of different factors may lead to sex-related differences in antidepressant response. Differences in brain structure and functioning (e.g., in the responsivity of the serotonin system) may lead to differences in antidepressant response. Sex differences in the pathophysiology of depression may also affect treatment response (e.g., women may be more likely to experience “atypical” depression). Research on mood disorders related to the female reproductive cycle, such as peripartum and perimenopausal depression, also suggests that unique gender-related pathophysiological processes may play a role in some depressive disorders in women and raises the question of the role of estrogen in treating these types of depression. Sex-related differences in the metabolism of antidepressants may also affect treatment response. Although pharmacokinetic data are still limited in this area, it appears that there are some sex-related differences in the activity of various CYP 450 enzymes, especially CYP 1A2, CYP 3A, possibly CYP 2D6, that may affect the metabolism of certain antidepressants and result in different blood levels and hence possible differences in response and side effects. Differences between women and men in the metabolism of the selective serotonin reuptake inhibitors (SSRIs) have been reported (e.g., plasma levels of sertraline have been round to be 27% lower in young men than in women of all ages; older women have been found to have higher plasma levels of nefazodone than younger patients of both sexes). Pharmacodynamic differences between men and women may also lead to differences in antidepressant treatment response. Studies have suggested that women may be more likely to respond to an SSRI than a tricyclic antidepressant (TCA), while men may be more likely to respond to a TCA. Studies have found that such differences in response did not occur in postmenopausal women who were not receiving estrogen replacement therapy, suggesting that estrogen may change blood levels, metabolism, or receptor characteristics in a way that improves the efficacy of the SSRIs in women. The increasing inclusion of women at earlier stages of clinical drug trials will hopefully provide answers to the many questions that remain to be answered regarding sex differences in antidepressant treatment response. Researchers need to consider adequate subgroup sizes and incorporate physiological factors unique to women (reproductive status, phase of menstrual cycle) into the parameters being studied. Such efforts will promote optimal treatment for depression in both women and men.