that women are twice as likely as men to meet criteria for lifetime major depressive disorder, a finding that has been confirmed across many countries, cultures, and ethnic groups [1]. Depression occurs at approximately the same rate in boys and girls; however, small sex differences emerge between the ages of 13 and 15. This gap further widens later in adolescence, and the depression rate in women remains elevated until midlife [2].
Although women are more prone to initially develop depression, there are no clear-cut sex differences in the duration or recurrence of the disorder [2]. Sex differences in rates of comorbid psychiatric disorders and prevalence of certain symptoms, however, have been identified. Women are two-to three-fold more likely than men to exhibit atypical depression. This condition is characterized by mood reactivity, appetite and weight increase, hypersomnia, and interpersonal sensitivity. Atypical depression is associated with higher rates of comorbid psychiatric illness and typically has an early onset and chronic course. Its greater prevalence in women may contribute to sex differences in presentation reported in some studies. Additionally, depression often occurs in tandem with other disorders that may complicate evaluation and treatment response in men and women. Common comorbidities that alter treatment response in depression include anxiety disorders, eating disorders, and substance abuse. While women with depression are more likely to endorse symptoms associated with general anxiety disorder and bulimia, depressed men are more likely to exhibit symptoms of 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
