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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.

On a metabolic level, sexual dimorphisms in cytochrome P450 enzymes could also underlie sex differences in plasma levels following a given dose of medication. CYP3A4, the most abundant hepatic CYP450 enzyme and metabolizer of half of all drugs, displays a 20–50% greater reactivity in women than in men. The activity of CYP2D6, which metabolizes most antidepressants, is also higher in women [as cited in 3].

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].

Subtle sex differences in pharmacokinetics notwithstanding, sex differences in the efficacy and tolerability of antidepressants – presumed pharmacodynamic effects – have been explored. A meta-analysis of 35 studies of response rates to the tricyclic antidepressant (TCA) imipramine reported that men responded more favorably than did women [4]. Kornstein et al. [5] later found that women were significantly more likely to show a favorable response to the SSRI sertraline than the TCA imipramine and reported that women taking the TCA and men taking the SSRI were more likely to withdraw from the study. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial evaluated more than 2,500 patients taking citalopram and also found that the SSRI was more effective in women than in men. In prospective and retrospective uncontrolled, naturalistic studies, however, Parker et al. [6] found no significant sex effects in TCA or SSRI effectiveness. Similarly, data of more than 1,700 patients from controlled studies of antidepressants failed to indicate sex effects on treatment response rates [7].

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.