ReviewSex differences in stress-related psychiatric disorders: Neurobiological perspectives
Introduction
Stressor exposure initiates a complex set of neuronal, endocrine, and behavioral responses that prepare an organism to cope with this perturbation in homeostasis. Although initiation of these stress responses is typically adaptive, their persistent or inappropriate activation is linked to the pathophysiology of several medical and psychiatric disorders. Despite the fact that most people will experience a large number of stressful events during their lifetime, only a small percentage go on to develop the dysregulated stress responses that characterize these diseases. Thus, a major challenge of modern medicine is to determine what factors confer vulnerability or resilience to stress. Several of these factors already have been identified. For example, early life stress can increase the vulnerability to develop certain psychiatric disorders in adulthood (McCrory et al., 2012, Bremne and Vermetten, 2001, Heim and Binder, 2012). Additionally, coping strategy is a determinant of the development of certain diseases, such that a passive coping strategy is a risk factor for major depression, while a proactive coping strategy is a risk factor for cardiovascular disease (Koolhaas, 2008, Mao et al., 2003, Matheson and Anisman, 2003, Koolhaas et al., 1999, Manuck et al., 1983, Sgoifo et al., 1997). Another factor associated with stress vulnerability is biological sex. Although historically sex differences in medical and psychiatric disorders were largely ignored, more recent research has focused on the neurobiological underpinnings of sex differences in vulnerability and resilience to stress and its related disorders.
The interest in sex as a moderating factor of disease vulnerability comes, in part, from epidemiological data that reveal sex differences in the prevalence of many disorders that are exacerbated by stress (Table 1). For example, men are more likely to suffer from substance-related disorders, such as alcohol and drug abuse (Grant et al., 2004, Johnson et al., 2011). In contrast, women are roughly twice as likely to suffer from anxiety disorders, such as panic disorder, and trauma-related disorders, such as posttraumatic stress disorder (PTSD) (Kessler et al., 1995, Tolin and Foa, 2006, Breslau, 2002, Sheikh et al., 2002). Women also have higher rates of major depression than men (Kendler et al., 1995, Kessler et al., 1993, Kessler, 2003). Medical disorders that are often comorbid with depression and anxiety, such as migraines, insomnia, and irritable bowel syndrome, are reported more frequently in women, perhaps suggesting some common underlying pathology (Lydiard, 2001, Beghi et al., 2007, van Mill et al., 2010, Lipton et al., 2001, Singareddy et al., 2012, Drossman et al., 1990). These epidemiological data detail sex differences in many stress-related disorders, but population-based studies of disease prevalence can fail to capture nuances in presentation of these diseases. For instance, although fewer women experiment with drugs, when women are exposed to addictive drugs they develop substance abuse faster than men (Becker et al., 2012, Fattore et al., 2014). Additionally, a recent study on depression found that when additional symptoms related to the disorder, such as anger attacks/aggression, substance abuse, and risk taking, were included in the diagnosis, the sex disparities in disease prevalence were eliminated (Martin et al., 2013). Even while bearing these caveats in mind, the sex differences in the prevalence and presentation of stress-related disorders suggest sex differences in their underlying biology.
Given the diversity of psychiatric and medical disorders related to stress that have a sex bias, exploring the neurobiological mechanisms that contribute sex disparities in all of these disorders is beyond the scope of this review. Instead, we will focus on several disorders with a sex bias that share common pathophysiology as prototypical examples. These examples will illustrate how sex differences at the molecular and cellular level can contribute to sex differences in disease vulnerability and severity. The disorders that are the focus of the review include trauma-related disorders and major depression. Not only are these stress-related psychiatric disorders more prevalent in women, but they share three other features: dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, heightened reactivity to emotional stimuli with a negative valence, and hyperarousal. The goal is, when possible, to link sex differences in clinical features to sex differences in the circuitry that mediates these features (Fig.1). Additionally, preclinical studies that associate sex specific cellular and molecular alterations with sex differences in stress hormone levels, emotions, and arousal will be highlighted.
Section snippets
The HPA axis
One of the hallmarks of the stress response is activation of the HPA axis. Activation of this neuroendocrine response to stress results in the release of glucocorticoids. These hormones prepare the organism to deal with threatening stimuli by increasing energy though glucose metabolism, lipolysis, and proteolysis, while suppressing growth, reproduction, and the immune system (Munck et al., 1984, McEwen and Gianaros, 2011, McEwen and Seeman, 1999). There are several brain regions and endocrine
Sex differences in the circuitry activated by stimuli with a negative valence
Stressful events not only initiate hormonal responses but they also trigger negative emotions, such as fear and anxiety. Typically these emotions activate adaptive cognitive and behavioral responses aimed at coping with the stressor (Tooby and Cosmides, 1990, Moons et al., 2010). However, overactivation or dysregulation of these negative emotions increases susceptibility to stress-related psychiatric disorders (Cole et al., 1994, Critchley, 2003). Anecdotally, it is often remarked that women
Sex differences in the hyperarousal symptoms of depression and PTSD
A core feature of stress-related psychiatric disorders is hyperarousal, a maladaptive state that leads to agitation, restlessness, lack of concentration, and cognitive disruptions. Interestingly, sex differences in hyperarousal have been identified. For example, heightened arousal defines one of the symptom clusters of PTSD, and these hyperarousal symptoms are often more pronounced in women than men (Psychiatric Association and DSM-5 Task Force., 2013, Coker et al., 2005, Breslau et al., 1999).
Interactions between neuroendocrine, corticolimbic, and noradrenergic arousal systems
It is clear that PTSD and depression share a common pathophysiology which includes dysregulation of the HPA axis, corticolimbic circuits, and arousal centers. Sex differences from the molecular to the systems level that occur within these circuits can increase vulnerability to these disorders and exacerbate their presentation in females. It is possible that symptoms of stress-related psychiatric disorders in some women are attributable only to sex differences within one circuit. For example,
The role of gonadal hormones and sex chromosome compliment in PTSD and depression
Sex differences in the brain are typically established by activational effects of gonadal steroid hormones, organizational effects of gonadal steroids, or sex chromosome effects (Arnold, 2009, Juraska et al., 2013, Schulz et al., 2009, Phoenix et al., 1959). Activational effects of hormones occur when circulating gonadal hormones act on brain structures to alter behavior. These activational effects disappear when the circulating hormones are removed. In contrast, organizational effects of
Implications for treatment
Investigating sex differences in the mechanisms that contribute to the sex bias in stress-related psychiatric disease is not only important for understanding disease vulnerability, but it is also critical for developing better treatments for these disorders. Developing new treatments for PTSD and depression is vital, because a large portion of patients with these disorders are treatment-resistant (Rush et al., 2006, Foa et al., 2008). The preclinical data reviewed here reveal several potential
Conclusions
This review explored sex differences in the neurobiological bases of PTSD and depression as a way to illustrate how sex differences in stress response systems can contribute to sex biases in psychiatric disorders. Preclinical data demonstrates sex differences in several cellular and molecular mechanisms, including cell signaling, peptide expression, hormone release, receptor trafficking, synaptogenesis, and dendritic remodeling. What is remarkable is that at each level of analysis, sex
Acknowledgment
Supported by PHS grants MH092438 and MH040008.
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