Handbook of Clinical Gender Medicine. Группа авторов

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.

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.

      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.

Irrespective of their origin, these dimorphisms exist in neural systems of particular relevance for depression. For instance, gonadal steroids regulate the synthesis, metabolism, and receptor distribution of the neurotransmitters serotonin, GABA, and glutamate, as well as others implicated in affective regulation. Imaging data, which reveal both structural and functional dimorphisms, include different patterns of cortical maturation in adolescence (partially under the control of the androgen receptor) [8] and differences in amygdala projections (women display stronger connections between the amygdala and hypothalamus, cingulate, and subcallosum – all areas involved in mood mediation) [9]. Finally, even the nature of the affective valence of a stimulus to which the medial prefrontal cortex – a major regulator of affect – responds is determined by menstrual cycle-dependent variations in ovarian steroids [10].

      Psychosocial Factors

Because women have less power and status than men in most societies, they experience certain traumas more often than men do. Both physical and sexual abuses have been consistently linked to women’s high rates of depression, and childhood sexual assault appears to be a particularly powerful predictor of depression even into adulthood [11]. Emotional abuse, neglect, parental loss, and other childhood adversities are also risk factors for depression, particularly in girls and women. Furthermore, adults who live in poverty are twice as likely to suffer new incidences of depression, as are middle-and upper-class adults, and women are more likely than men to have incomes below the poverty line [12].

Even when women and men experience the same stressful life events, women may be more likely than men to develop depression because of sex differences in self-concepts or coping styles. Women are more likely than men to feel strong emotional ties with a wide range of people in their lives and to see their roles as caregivers and partners as central to their self-concepts. Developing strong social support networks can protect women against adversity; however, excessive concern over relationships may cause women to put aside their own wants and needs. Women’s greater interpersonal orientation may create more interpersonal stress in their lives and make them more vulnerable to stress when it occurs. Furthermore, men and women often use different coping styles in stressful situations. Women are more likely than men to ruminate in response to depressed or anxious moods, and researchers suggest that rumination contributes to the higher prevalence of depression in women [13].

      Genetics

There is strong evidence for familiality in major depression, and men and women appear to share most but not all genetic influences for the disorder [