ReviewSex differences in anxiety and depression clinical perspectives
Introduction
The onset of anxiety and depressive disorders peaks during adolescence and early adulthood, with females being at significantly greater risk than males. Women have twice the lifetime rates of depression and most anxiety disorders (Kessler et al., 1994, Kessler et al., 1995, Weissman et al., 1994, Weissman et al., 1996, Gater et al., 1998). The exceptions in term of sex ratio are obsessive–compulsive disorder and bipolar disorder, which have similar prevalence in men and women. However, even for these disorders, men and women have differences in disease presentation and course. In addition to higher rates of affective disorders that meet full diagnostic criteria, subclinical anxiety and depression symptoms are also more common in women (Nolen-Hoeksema et al., 1999, Hankin, 2009).
Understanding the biological and cultural underpinnings of sex differences in affective disorders is likely to be a useful window into mechanisms of illness in both men and women (Rutter et al., 2003). Sex differences in brain structure and function are abundant and fluctuate across development (Courchesne et al., 2000, Lampl and Jeanty, 2003, Patton et al., 2004, Lenroot et al., 2007, Raznahana et al., 2013, Ingalhalikar et al., 2014). The challenge is to discern which sex differences in brain are relevant to sex differences in the epidemiology, phenomenology, and pathophysiology of affective disorders (DeVries and Sodersten, 2009). Some sex differences that promote reproductive success also likely increase vulnerability of women to mood and anxiety disorders. For example, adaptive behavioral differences in terms of childrearing seem to include, in females, superior social cognition and capacity for attunement with others, important for cognitive and social development of offspring (Halpern, 2007, Grey et al., 2012, Thompson and Voyer, 2014). However, these sex differences are also thought to result in women experiencing more sensitivity to rejection, criticism and separation, key features of depression and anxiety disorders (Cyranowski et al., 2000, Taylor et al., 2000, Zahn-Waxler et al., 2008, Martel, 2013). It is important to recognize that sex differences in behaviors and coping styles are not absolute, only more common in one sex than the other. In most instances, the magnitude of these sex differences are small. Although environmental influences, particularly cultural gender stereotypes, contribute to sex differences in human behavior and risk for psychiatric disorders, it is difficult to disentangle to what degree sex-specific cultural stereotypes are based on biologically determined sex-specific traits (Carter, 2011). Moreover, sex differences in life experiences and cultural expectations in turn may alter gene expression and contribute to development of sex differences in brain and physiology throughout the lifespan (Curley et al., 2011, Springer et al., 2012). For these reasons, we do not distinguish between sex and gender differences in this review.
In addition, the fluctuations in gonadal steroids and HPA axis regulation across the menstrual cycle and pregnancy are necessary for conception and gestation, but also expose women to more intense perturbation of gonadal steroid and glucocorticoid responsive brain systems. It is important to note that there are large individual differences in the activational effects of reproductive hormones on behavior. Although almost all women undergo the hormonal fluctuations related to menstruation, pregnancy and menopause, only a small minority of women (3–5%) experience the intense perimenstrual negative affect that occurs in women with premenstrual dysphoric disorder (Epperson et al., 2012) and similarly small subgroups of women experience perimenopausal or post-partum major depression (Gaynes et al., 2005, Freeman et al., 2014). The bulk of research indicates that these subgroups of women experience typical levels of reproductive hormone changes, but a sub-optimal central nervous system response that leads to negative affect and maladaptive behaviors (Schmidt et al., 1998, Bloch et al., 2000).
After a brief discussion of developmental events that have impact across mood and anxiety disorders, this review will summarize sex differences in the epidemiology, phenomenology and course of specific affective disorders across the lifespan, with a particular focus on periods of dynamic hormonal flux including puberty, pregnancy and reproductive senescence. Behavioral animal models are included where appropriate to illustrate potential biological mechanisms for sex differences in affective illness.
Section snippets
Developmental considerations
Biologically-determined sex differences can arise from effects of sex chromosome genes (Arnold et al., 2012, Lee and Harley, 2012, Raznahan et al., 2013, Seney et al., 2013), organizational effects of gonadal steroid exposure during development, and activational effects of reproductive hormone exposure throughout the lifespan (Arnold, 2009, McCarthy et al., 2012). In addition, recent animal studies suggest that maternal and paternal stress that occurs even prior to conception can have
Major depression
Prior to puberty, depression is difficult to diagnose, but estimated prevalence of 5% and the symptom profile are similar in boys and girls. Longitudinal studies have identified Tanner Stage III, the start of ovarian cycling, when estrogen levels rise significantly, as the onset of increased rates of major depression in girls (Angold et al., 1998). The increased risk of depression was evident only in girls with a family history of depression, suggesting that onset of puberty may activate a
Sex differences: anxiety disorders
In contrast to major depression which has an increased prevalence in girls beginning in mid-puberty, the increased risk of anxiety and anxiety disorders in girls begins in middle childhood (Lewinsohn et al., 1998). In addition, the increased tendency to ruminate, a risk factor for major depression, emerges in girls by age 9, also prior to puberty (Nolen-Hoeksema and Girgus, 1994).
Summary
Although there is higher prevalence of affective disorders in women and some sex differences in symptom pattern and course of illness, it is difficult to identify the biological and cultural factors that contribute to the generation of these sex differences. Mood and anxiety disorders are highly comorbid and have shared symptoms and familial risk (Angold et al., 1999, Kotov et al., 2011, Kravitz et al., 2014), suggesting that some of the same mechanisms are likely contributing to increased
Acknowledgments
The authors would like to recognize the following for their financial support: National Institute of Mental Health and NIH Office of Research on Women’s Health (P50 MH099910; CNE); National Institute on Drug Abuse (K24 DA03031; CNE)
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