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Handbook of Clinical Gender Medicine


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alcohol and drug use and dependence. Furthermore, among those with chronic medical conditions such as diabetes and coronary heart disease, women are more likely than men to exhibit comorbid depressive symptoms.

      Treatment

      Sex-related physiological differences can potentially impact pharmacokinetics – the absorption, distribution, metabolism, and excretion of medication. Most antidepressants are weak bases that are most effectively absorbed under basic conditions. Since women secrete less gastric acid than men, the female stomach is a more basic environment that could lead to enhanced absorption. The bioavailability of antidepressants has not been found to be greater in women, however, perhaps due to slower gastric emptying resulting in increased degradation. Women have an increased fat-to-lean body mass ratio and show greater distribution of fat-soluble drugs, which could result in lower plasma concentrations and a prolonged half-life of drugs such as trazodone and bupropion. Because body fat tends to increase with age, especially in women, some sex-related differences in drug distribution may be exacerbated with age.

      There are no reported sex differences in the absorption of antidepressants after adjustment for body weight and surface area. Most agents do not exhibit sex-related differences in distribution although, as stated above, higher volumes of distribution for bupropion and trazodone have been reported in women. Current research suggests that women can exhibit higher plasma levels of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and sertraline, but sex differences in circulating levels of other antidepressants are small or nonexistent [3].

      Cumulative research indicates that a diagnosis of atypical depression, which is more common among women than men, merits special treatment considerations. Clinical trials have demonstrated the superiority of monoamine oxidase inhibitors (MAOIs), especially phenelzine and, to a lesser extent, SSRIs, when compared with TCAs in the treatment of atypical depression. As such, one can speculate that the reported superiority of SSRIs over TCAs in depressed women may in part reflect the increased prevalence of atypical depression in women.

      Until sex differences in the therapeutic response to antidepressants are clearly established and demonstrated to be independent of differences in pharmacokinetics, it will remain unclear whether there are indeed sex-dependent pharmacodynamic differences. Given the heterogeneity of depression, the influence of sex on the variance in treatment response may be difficult to determine.

      Pathogenesis

      Physiological Dimorphisms

      Sexual dimorphisms are found at all levels of the neuroaxis – from differences in intracellular organelles to the size of select brain nuclei to the pattern of synaptic development and pruning. Most of these dimorphisms reflect different levels of exposure to androgens and estrogen, leading to structural and functional differences that either require the continued presence of gonadal steroids (activational effects) or no longer require steroid presence after initial steroid exposure (organizational effects). These sexual dimorphisms may reflect gonadal steroid concentration-dependent effects, that is, the effect would be the same in both sexes if concentrations were similar, or alternatively may reflect sex-dependent differences in the response to gonadal steroids. Not surprisingly, evidence exists for both sources contributing to observed sex differences.

      Psychosocial Factors

      Genetics