Depression in Women

Chapter 37

Depression in Women Molly M. Hyer and Gretchen N. Neigh Department of Anatomy & Neurobiology, Virginia Commonwealth University, Richmond, VA, United States

INTRODUCTION Women are twice as likely as men to experience a major depressive episode in their lifetime [1,2]. The onset of this sex difference begins proximate to puberty, as girls experience increased symptoms of depression compared to boys around this time [2,3]. By the age of 12 years, the female bias for depression is evident and carries forward across the lifespan (CDC/ NCHS, National Health and Nutrition Examination Survey, 2009–2012; Fig. 1). As discussed in adjacent chapters, depression garners physical repercussions including increased prevalence of heart disease [4], stroke [5], and diabetes [6], as well as an increased risk of suicide [7]. Although these public health implications of depression are wellcharacterized, the etiology and underpinnings of the female bias in depression have not been fully elucidated. Historically, the gender gap in the prevalence of depression has been attributed to a wide variety of sources including gender roles, increased rumination in women, hormone fluctuations, and comorbidity with anxiety [8]. Although societal influences, impact of gender norms on symptom manifestation, and biases in diagnosis cannot be entirely ruled out [9,10], this chapter focuses on the potential biological roots of the female bias in the manifestation of depression. The influence of biology and society is difficult to tease apart in human studies; therefore, animal models can often be beneficial. Models of depressivelike behaviors [11–13] have been developed for use in rodents and, with the recent recognition of the need for representation of females in basic research [14,15], the underpinnings of the female bias in depression have been an increasing point of focus. In the sections below, we summarize a subset of the findings available from both human investigation and animal models to highlight potential mechanisms by which biology may predispose females to the manifestation of depression. The incidence of depression in women increases proximate to epochs of hormonal transitions, such as adolescence, pregnancy, and menopause [3]; therefore, hormones that are also sex steroids, such as estrogen and progesterone, have been proposed as key substrates in the female bias of depression. In addition to the influence of sex steroids directly, periods of vulnerability may derive from interactions between sex steroids and the hypothalamic-pituitary-adrenal (HPA) axis, one of the major stress response systems in the body [16] (Fig. 2). Often, the mechanisms by which depression becomes manifest are only partially dependent on acute biological events. Specifically, life experiences which may also be sexdependent can create biological alterations that predispose an individual to depression. Experiences such as stress [16,17] and disease states [18] can increase sex-specific vulnerability to depressive episodes. This may be due in part to the role of steroid receptors as nuclear receptors which act as transcription factors and can thereby have profound and long-lasting effects on physiology and behavior through manipulation of gene expression [16]. In addition, the impacts of steroids are both organizational, creating permanent alterations during critical developmental phases, and activational, facilitating transient effects of steroid exposure (Table 1). Alterations in hormones or function of the cognate receptors can alter neurotransmitter function, including serotonin and noradrenalin [19]. In women, it is plausible that ovarian hormones play a role in vulnerability to depressed states and potentially contribute to variations in efficacy of pharmaceutical treatment through developmental changes at the organizational level, changes in activation on an acute level, and via interactions with other steroid systems.

ORGANIZATIONAL EFFECTS: GENETICS AND GENOMICS Depression is a familial disorder with significant contributions from both genetic influences and environmental exposures [20]. The prevalence of depression is low during early childhood (<1%) [21]; the majority of studies find no differences in risk of depression in boys and girls during this stage [22,23]. Twin studies suggest that genetic factors contribute to Neurobiology of Depression. https://doi.org/10.1016/B978-0-12-813333-0.00037-8 Copyright © 2019 Elsevier Inc. All rights reserved.

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FIG. 1 Percentage of persons aged 12 and over with depression, by age and sex: United States, 2009–2012. (Adapted from CDC/NCHS, National Health and Nutrition Examination Survey, 2009–2012.)

incidence of depression equally in both sexes; however, it is likely that the genetic factors act in a sex-specific manner with other exposures to increase vulnerability to depression [18,24,25]. Interactions between genes and the environment begin to become apparent by adolescence when the prevalence of depression in girls exceeds that of boys [26], but the environmental exposures that influence genetic susceptibilities likely begin as early as during gestation. Sex-specific susceptibilities may be facilitated through epigenetic modifications of the genome. Although genes are inherited creating the genetics of an organism, the precise expression pattern of the inherited genetic code, referred to as genomics, is sculpted by epigenetic modifications catalyzed by physiological responses to both endogenous and exogenous environmental exposures. Highlighting this point, it has been demonstrated recently that the genomic patterns following chronic stress in the context of depression are sex-specific [27]. Before moving on to a more thorough examination of the mechanisms by which environmental exposures during development can impact depression in women, several examples of genetic susceptibilities to depression, with specific effects in women, are discussed. For more information on genetic influences in depression, multiple reviews on this topic exist [28–30] and advances in the field are frequent.

5-HTTLRP and MAOA Although not universally supported [31,32] or fully generalizable, since first reported in 2003 [33], much attention has been given to the possible role of a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) as a significant factor in the ability of stress to influence the onset of depression. In humans, being a carrier for one of the short forms of the allele positively influences the association between developing depression after childhood mistreatment [34]. Research in animal models has provided additional clarity on the possible interactions between 5-HTTLPR and developmental stress exposure. Offspring abuse in nonhuman primates spontaneously occurs, consisting of hitting, biting, or dragging of offspring. Although alterations in stress response biology are not evident at baseline in offspring exposed to developmental abuse, pharmacological stimulation of the stress system unmasks a hyperactivation of the system, most prominent in female offspring [35]. Furthermore, in the nonhuman primate, the magnitude of the behavioral and physiological impacts of abuse was associated with the 5-HTTLPR genotype [36].

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FIG. 2 The hypothalamic-pituitary-adrenal axis. External stressors cause initiation of the HPA axis by first stimulating CRF neurons in the hypothalamus. Corticotropes in the pituitary release ACTH that activates adrenal output of cortisol. Negative feedback inhibition loops return the system towards homeostasis. The hypothalamus also controls the pituitary-gonadal axis. In males, stress has been shown to activate androgen release that plays a direct or indirect role in negative feedback (left). Estrogens and progestogens in females may activate the HPA axis or disrupt negative feedback in females (right). (Adapted from Bourke CH, Harrell CS, Neigh GN. Stress-induced sex differences: adaptations mediated by the glucocorticoid receptor. Horm Behav 2012;62(3):210–8.)

TABLE 1 Modifications Driven by Organizational and Activational Effects Organizational

Activational

Relatively permanent

Transitory

Occurs prior to brain maturation

Occurs in adulthood

Restricted to a critical period

Not confined to a sensitive period

Genetic modifications

Biochemical modifications

Results in neurostructural changes

Can result in neurostructural changes

The inconsistent effects of polymorphisms in 5-HTTLPR within human studies [31,32] may be due to increased genetic heterogeneity in the human population. The manifestation of depression following early life adversity in adolescent girls with the 5-HTTLPR polymorphism has been demonstrated to be moderated by co-occurrence of a genetic abnormality in monoamine oxidase A (MAOA) [37]. Although these genetic factors may provide a combined contribution, it is also important to note that, in females, the presence of the tandem repeat that leads to a reduction of MAOA is sufficient to increase the likelihood of manifesting depression following early life adversity [38]. As studies of genetic influences on depression and other neuropsychiatric disease progress, there is growing recognition of the influence of polygenic risk in multiple disorders [29].

FKBP5 Interactions between sex and stress in the context of depression are, in part, influenced by interactions between the HPA axis and sex steroids (Fig. 2). These connections occur at multiple interaction points, with one of the prominent points being FKBP5. FKBP5 is a co-chaperone of heat shock protein 90 and is integral in the assembly of the glucocorticoid receptor (GR) complex. FKBP5 functions as a brake on the assembled GR complex; GR cannot translocate to the nucleus to act as a transcription factor until FKBP5 has dissociated from the complex [39]. In 2008, it was demonstrated that single nucleotide polymorphisms (SNPs) in FKBP5, which result in increased abundance of FKBP5, create susceptibility to both posttraumatic stress disorder (PTSD) [40] and depression [41–43] following exposure to early life trauma. Although initial studies

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did not extensively assess sex effects in the role of FKBP5 alterations, subsequent studies demonstrated female susceptibilities both in the likelihood of manifesting depression during pregnancy [44] and in the effects of oral contraceptives on stress physiology [45]. Female susceptibility to stress effects on FKBP5 have also been demonstrated in laboratory studies of rats such that exposure to chronic adolescent stress precipitates depressive-like behaviors [46], prolonged HPA axis activation [47], and elevated expression of FKBP5 in females, but not males [47]. Furthermore, the impacts of stress exposure on FKBP5 and the GR are modulated by estrogen [48]. These laboratory studies highlight that, in addition to potential genetic susceptibilities, female-specific sensitivity to genomic alterations in FKBP5 also exists. Importantly, FKPB5 is not the only component of the GR complex implicated in female susceptibility to stress effects and depression; genetic and epigenetic variation in GR have also been demonstrated to influence depression in women [49]. Although not currently a part of clinical practice, influence of polymorphisms in FKBP5 has been demonstrated to influence treatment response to antidepressant treatment [41,50].

PACAP Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide demonstrated to be profoundly influential in modulation of the stress response system [51]. Genetic and epigenetic modifications of PACAP have been implicated in the manifestation of PTSD; a SNP, specifically in the putative estrogen response element region of PACAP, increases the likelihood of PTSD diagnosis following trauma exposure in women only [52]. In a separate study, this SNP correlated with exposure to neighborhood violence; women with two copies of the risk allele were more likely to develop elevated symptoms of depression if they resided in high-crime neighborhoods [53]. Given that the PACAP SNP in theory alters PACAP presence in the brain facilitating its effects on behavior, a rodent study was conducted to determine whether administration of PACAP directly into the brain could alter depressive-like behaviors independent of other environmental exposures. Administration of PACAP into the lateral ventricles produced dose-dependent depressive-like behaviors, including reduced social interactions and a reduction in sucrose consumption [54]. However, it is not known if these effects differ between males and females, as the authors only assessed males in this particular study. Collectively, these three examples provide evidence of genetic influences in the manifestation of depression in women, suggesting that interactions between genetic susceptibilities and environmental exposures may be particularly salient in females.

ORGANIZATIONAL EFFECTS: EARLY LIFE ENVIRONMENT Prenatal The above examples of genetic and genomic susceptibilities to depression and depressive-like behaviors in females often require interaction with an adverse environment, as these adverse environments will frequently stimulate the stress response. Additionally, maternal depression is characterized as a neonatal stressor [55]. Stress-related biological substrates have been frequently studied and robust evidence implicates exposure to elevated concentrations of glucocorticoids, cortisol in humans, and corticosterone in rodents, in the manifestation of epigenetic alterations underpinning alterations in physiology and behavior [56]. Maternal stress can have a significant impact on the likelihood of offspring manifesting depression later in life; an influence that can be recapitulated in rodent models (reviewed in Ref. [57]). Salivary cortisol and salivary alpha amylase, stress metrics assessed during pregnancy in women, predict sex-specific outcomes for babies. At both 5 weeks [58] and 2 months of age, baby girls demonstrate a positive correlation between negative emotionality and the prenatal measures of both cortisol and salivary alpha amylase [59], suggesting that, even in utero, influences of adverse environments can be sexspecific. Assessment of fetal growth as a function of maternal stress metrics also demonstrates sex-specific effects, with baby girls showing greater compensation in the presence of maternal stress signals than baby boys [60]. This has been hypothesized to be mediated via greater placental variation in response to an adverse environment when the fetus is female [61]. Although beyond the scope of this chapter, the role of placental biology in programming of sex-specific resilience and susceptibility is a burgeoning area of study and has recently been reviewed [62]. Due to confounds inherent to human investigation, including genetic susceptibility and environmental variability, studies in rats and mice provide controlled and mechanistic insight into the sex-specific effects of developmental stress exposure. In addition, given the expedited life cycle of the rodent, life course studies can be completed in a truncated period of time, potentially decreasing the time to discovery. Rodent studies have demonstrated sex-specific effects of in utero stress exposure including increased corticosterone levels following exposure to a stressor in both sexes, but manifestation of depressive-like behaviors in female offspring only [63,64]. Furthermore, the impact of prenatal stress in rodents is

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transgenerational [65] and sex-specific, with effects seen in the second generation as well. In addition to isolation of key variables, rodent studies have also facilitated advances in mechanistic understanding of sex differences in the effects of prenatal stress [66–68]. Finally, given that life course studies are often necessary to fully ascertain the influences of perinatal exposure, rodent studies have demonstrated that the influence of prenatal or early postnatal environment may result in delayed onset of alterations in affective-like behaviors in the offspring with manifestation in adolescence [69,70] or even adulthood [71]. Although robust literature exists demonstrating the implications of maternal depression during gestation on the offspring, fewer studies have investigated the impact of antidepressants during pregnancy. Work in rodent models is particularly advantageous in this context because, given the known risks of depression during pregnancy, withholding human treatment to facilitate experimental design would not be ethically sound. Alterations in the stress circuitry of female offspring exposed to in utero antidepressants [72] have been reported; however, these studies fail to recapitulate the neonatal environment of a depressed human mother, as antidepressants are administered to euthymic pregnant rodents, a circumstance that does not exist in the clinic. In fact, in rodent studies that pair stress exposure with antidepressant administration, either no impacts beyond the effects of stress are observed [71] or protective effects were observed [73]. In contrast, perinatal exposures may influence responsivity to antidepressants in adulthood. Effectiveness of the drug fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is dependent on the sexual differentiation process. In a repeated measures design, Gomez and colleagues [74] found that female rats during estrus (higher estrogen) required a lower dose of fluoxetine to display antidepressant-like effects in the forced swim task compared to males. Females who were neonatally masculinized with testosterone treatment prior to postnatal day 5 (a time point akin to the third trimester in humans) showed comparable depressive-like behavior to control females; however, they were resistant to fluoxetine. Following ovariectomy in adulthood, these masculinized females were entirely unresponsive to fluoxetine. These findings suggest that, in females, treatment with fluoxetine is dependent on organization of sex steroids [74].

Postpartum Maternal influences on programming that can lead to susceptibility to depression later in life continue in the postpartum period, primarily because the mother is such a prominent environmental influence in the early postpartum period. The risk factors for postpartum depression and the impact on the mother are discussed below, but here the focus is on the offspring. The bond that develops between a mother and her offspring alters the developmental trajectory of the child [75,76], and mothers who experience postpartum depression are more likely to have reduced engagement with their offspring [77]. It is difficult to isolate the impact of prenatal depression from postpartum depression, but several studies have made this distinction. In a group of both girls and boys, exposure to a postpartum depressed mother during their childhood significantly increased their morning cortisol levels at age 13 compared to controls. This increase was a positive predictor of clinical depression at age 16; however, sex was not a driving factor in this relationship [69]. Conversely, a more recent study demonstrated that postpartum depression sex-specifically impacted development of the amygdala in girls with a distinct pattern from the influence of prenatal depression [78]. Reduced levels of maternal care have been associated with a heightened stress response in adult offspring—both in humans and in rodent models [79,80], and this may be a means by which postpartum depression impacts the offspring. Rat mothers that show low licking and grooming as well as a less arched back while nursing raise pups with greater fearfulness and a higher corticosterone response to a stressor [79]. In addition, repeated, long-term separation of pups from their dam results in a similar response pattern [80]. Although initial studies were not differentiated by sex, more recent studies have recapitulated the behavioral effects of variations in maternal care in female rodents and have highlighted a mediating role of the progesterone metabolite allopregnanolone [81]. The literature on the specific effects of postpartum depression and adverse early postnatal environment, specifically on female offspring, is growing, but is currently underdeveloped as compared to other life phases. Important organizational effects of steroids and environmental exposures have the capacity to still be active during this period and additional research will provide further insight to sex-specific mechanisms of both risk and resilience during this period of development.

ADOLESCENCE: WHERE GENETICS AND ORGANIZATION MEET ACTIVATION The previous section considered several examples by which genetic influences can interact with the prenatal and early life environment in ways that can create a vulnerability to depression. Often, the evidence of this vulnerability does not manifest until adolescence. In fact, familial history and early life stress exposure are the primary predictive factors in the manifestation of adolescent depression [82]. For instance, prenatal maternal anxiety resulted in a flattened cortisol response in both

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boys and girls in adolescence; however, this altered hormone profile was associated with increased prevalence of depression in girls only [70]. This single finding illustrates a more global observation in that sex-dependent disparities in depression emerge in adolescence, with twice as many girls experiencing depressive episodes compared to boys [8]. The coincident occurrence of puberty and the divergence of depression rates between boys and girls suggest a prominent role for the activational effects of the endocrine system, more specifically sex steroids, in depression onset. Steroid receptors are present throughout the brain and activity of these receptors has been shown to modify functional and structural plasticity of brain regions involved in emotional regulation—specifically the hippocampus and the amygdala [83]. Hormone receptors can also interact with neurotransmitters to alter mood states. For instance, the primary neurotransmitters that estrogen can modulate include norepinephrine and serotonin which have established roles in the manifestation and treatment of mood disorders (reviewed in Ref. [84]). Estrogen can interact with these neurotransmitters by altering receptor expression, synthesis, firing rates [85], and turnover [86]. Of note, recently the dopamine system has also been implicated in female-specific effects of chronic stress in a rodent model, suggesting that, in the female, the dopamine system is more susceptible to the influence of chronic stress than in males [27]. Although this study was in adults, given the sensitivity of the dopaminergic system during adolescent development [87], future study in adolescent females is essential. In addition to the increased activational influences of hormones, important aspects of brain maturation culminate during adolescence [88]. Adolescents show increased activation of the amygdala, a brain region that mediates emotional responsivity, following exposure to emotional stimuli [89]. The maturation of this region, as well as innervation by the prefrontal cortex, does not occur until adulthood, making adolescents particularly vulnerable to depressed states [90]. Furthermore, aspects of neural structure take on sex-dependent characteristics in adolescence. For instance, functional magnetic resonance imaging data of boys and girls demonstrated increases in white matter throughout adolescence. However, this increase was much steeper in boys than in girls [91]. Other examples of structural changes specific to adolescence include increased synaptic pruning [92]. These changes, combined with the shifting hormone environment, may make females more susceptible to mood disturbances. Moreover, the timing of stress exposure during adolescence can be a defining feature in later development of psychopathology. For instance, women who experience trauma before the age of 12 are more likely to develop major depressive disorder, while women who experience trauma after age 12 are more likely to develop symptoms related to PTSD [93]. Another key event in determination of vulnerability to depression is the age of menarche. In a sample of girls, those with early-onset menarche, defined as prior to age 10, score significantly higher on a depression inventory compared to girls who experienced menarche at 12 or later. Despite this negative relationship, the early-onset girls employed fewer ineffective coping strategies, suggesting that their ability to cope with negative situations was more mature [94]. In addition, assessment of depressive symptoms from 7th through 12th grade male and female students demonstrated that the female bias in depressive symptoms was present by 7th grade, but that this bias was primarily driven by early maturing girls with a recent stressful life event [95]. However, the relationship between pubertal timing and stress and depression is multidirectional such that early life adversity is correlated with early menarche [96], making directional interpretation of these relationships tenuous. It is possible that ovarian hormones play a role in the manifestation of depression onset through initiating early puberty as well as restructuring neural circuitry and interacting with the HPA axis to increase depressed states in adolescent females, but additional mechanistic studies will be essential to delineate these relationships. One thing is for certain, manifestation of a first episode of depression during adolescence increases the risk for a lifetime of recurrent depression [97,98], highlighting the importance of early and effective intervention.

ADULTHOOD: EXPOSURE TO CYCLIC SEX STEROIDS AND STRESS While sex differences in depression first manifest during adolescence, they peak during adulthood. Adult women have the highest rates of depression compared to any other group [8]. Similar to depression at other life stages, the specific mechanisms of these mood disruptions are not fully characterized; however, evidence strongly suggests gene by environment interactions [99,100] and a particularly influential role of hormonal cyclicity.

Premenstrual Dysphoric Disorder Subtypes of mood disorders in adult women appear to be linked to dramatic reductions in ovarian hormones either over the menstrual cycle or with parturition [101]. While these variations are not depressogenic in the majority of women, a subset of women seem particularly sensitive to these naturally occurring hormonal shifts. In the case of premenstrual dysphoric disorder (PMDD), progesterone, or more specifically, allopregnanolone has been proposed as a key modulator of robust

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alterations in mood [102]. A recent clinical trial assessed the ability of inhibition of allopregnanolone, by treatment with the GABAA modulating steroid antagonist Sepranolone (UC1010), during the premenstrual phase to reduce symptoms of PMDD. The results of this study demonstrate similar efficacy of UC1010 to SSRI therapy in ability to modulate negative mood symptoms [103]. In addition, a separate study tested the possible role of allopregnanolone in PMDD through treatment with 5α-reductase inhibitor dutasteride, which blocks conversion of progesterone to its neurosteroid metabolite allopregnanolone. Treatment with dutasteride demonstrated a dose-dependent ability to block the symptoms of PMDD [104], further supporting the hypothesis that fluctuations in allopregnanolone can precipitate mood alterations in a subset of women.

Postpartum Depression Women with a history of PMDD are at increased risk for postpartum depression [105]. Up to 15% of women will report some form of postpartum depression [106], and it is likely that the frequency of depression in the prenatal and postpartum period is actually much higher, making prenatal and postpartum depression one of the most undertreated disease conditions [107]. Similar to the role of progesterone in PMDD, the ovarian steroid withdrawal hypothesis proposes that sex steroids, specifically estrogen, precipitate postpartum depression [108,109]. Just prior to birth, estrogen levels are at their highest. With the expulsion of the placenta following parturition, estrogen levels drop significantly and rapidly [110]. The hypothesis proposes the expeditious drop in estrogen concentrations precipitates depression in a subset of women with increased susceptibility to the alterations or perhaps a reduced or delayed ability of their system to compensate for the change. Women who are already vulnerable, due to previous life history [100] or genetic factors, may transition from just the postpartum blues to full onset postpartum depression with the decline in sex steroids. For instance, in a large epidemiological study of Danish women, incidence of adverse childhood events increased the likelihood of postpartum psychiatric episodes. Importantly, the authors observed a dose-response curve in that as the frequency of adverse childhood events increased, so did the likelihood of postpartum disruptions [111]. Given the potential risks to the child [112], covered earlier in the chapter, and the risks of depression for the mother directly, fast and efficacious treatment of postpartum depression is essential. Pharmacological therapies for postpartum depression traditionally focus on antidepressants similar to those used for depression in other contexts and a well-developed literature exists that is focused on the relative benefits and risks of traditional pharmacological interventions for depression during the perinatal period [113]. However, given the prominent role of hormones in the manifestation of postpartum depression, recent studies have begun to assess hormone manipulations for the treatment of postpartum depression. Intervention at the level of estrogen has been attempted through administration of transdermal estradiol; however, the study design failed to generate sufficiently elevated serum concentrations of estradiol and was stopped early [114]; therefore, the efficacy of this treatment approach is not yet known. Similar to the discussion of PMDD above, manipulation of allopregnanolone has been assessed as an intervention for postpartum depression. Brexanolone (USAN; formerly SAGE-547 Injection), a proprietary injectable allopregnanolone formulation, has been evaluated in cases of severe postpartum depression in both a proof-of-concept, open-label study [115] and a randomized controlled clinical trial [116]. Brexanolone was well-tolerated and efficacious in both studies and appears to be a promising treatment option for women that develop severe postpartum depression. In addition, these studies act as proof of concept for the assertion that hormonal changes, and more specifically, allopregnanolone, are key variables in the manifestation of postpartum depression. In addition to traditional pharmacological interventions and more novel hormone-based therapies, holistic approaches to the treatment of postpartum depression have also been assessed with modest levels of efficacy. Mother-child contact and bond formation has been suggested to alleviate negative mood in women such that mothers who engage in more contact with their infants show increased gray matter in areas of the brain associated with emotional regulation [75]. However, it is important to note that, given the complexity of these relationships, conclusions beyond correlation are not feasible. Exercise has also been proposed as a possible intervention mechanism for postpartum depression. Although the benefits of exercise are multifaceted, the efficacy and utility in the context of postpartum depression have not yet been comprehensively assessed [117] in humans. Limited data exist from a rodent model of postpartum depression which suggest that SSRI treatment and exercise have distinct effects on the behavioral and physiological implications in a rodent model of postpartum depression [118]. Finally, a single randomized placebo-controlled double-blind study has been conducted assessing the efficacy of a probiotic started during pregnancy and continued for 6 months postpartum. Women on the probiotic had lower depression scores during the postpartum period [119]. Although this study suggests a possible preventative effect of probiotic intervention, it does not support the conclusion that probiotics started after the onset of postpartum depression can

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be an effective therapeutic option. The findings do suggest that gut-brain interactions may play a role in the development of postpartum depression as they have been documented to do in other subtypes of depression [120].

Major Depressive Disorder While postpartum depression comprises the largest portion of depression in adult women, a depressed state frequently occurs independent of extreme hormonal changes. Earlier life exposures are a risk factor and women who experienced depression during childhood or adolescence are more likely to experience depression as an adult. Furthermore, previous exposure to early life adversity, even in the absence of a previous depressive episode, also can contribute to the upregulation of negative effect in adult women [57,63,121]. Sex steroids may play a role in susceptibility and manifestation of major depressive disorder in women, even when uncoupled from major hormonal shifts. Recently, several studies have suggested an association between the use of oral contraceptives and manifestation of major depressive disorder [122]. In addition, an association between suicide attempts, and suicide, with use of oral contraceptives has been reported, with the greatest risks in adolescents [123]. However, it is important to note that, given the robust number of women taking oral contraceptives, the associations between depression and oral contraceptives are quite limited [124]. These observations do provide potential additional insight into mechanisms of female bias in depression including potential effects through the kynurenine pathway [125] and neuroinflammatory activation [126]. Whether independent from, or related to, other mechanisms of depression, impaired hippocampal volume is a wellknown characteristic of depressed patients. Interestingly, decreased hippocampal volume in depressed women appears dependent on previous childhood trauma. Only depressed women who had experienced childhood trauma exhibit a volumetric deficit compared to depressed women without a history of childhood trauma [127]. This suggests that hippocampal volume may be related to vulnerabilities for depression as opposed to a source of the disease itself [128]; however, treatment with antidepressants increases hippocampal volume in women—an effect which is not seen in men [129]. Investigations beyond overall hippocampal volume have revealed more subtle differences in women with depression. Depressed women have a larger ratio of immature to mature neurons compared to nondepressed women [130]. Also of note is the established role of estrogen as an influential driver of structural alterations in the hippocampus [131–133]. Sex differences in treatment response in depressed men and women have been reported in some, but not all, studies [134]. Differences in treatment response may be attributable to both sex differences in the underlying biology of depression in men versus women and/or to physiological differences in pharmacokinetics of the drugs employed. Premenopausal women have been reported to respond more favorably to SSRIs and SNRIs as compared to men [135–138]. Conversely, there does not appear to be a sex difference in responsivity to cognitive behavioral therapy [139]. The collective evidence suggests that interactions between sex steroids, in particular estrogen, and the serotonergic system may confer the treatment advantages of SSRIs in women, which dissipate with the perimenopause transition [19,140].

CUMULATIVE EXPOSURES, HORMONE WITHDRAWAL, AND AGING As with adolescence, pregnancy, and parturition, reproductive senescence is characterized by a significant hormonal shift. While earlier studies argued that depression that accompanied the transition into menopause was linked to a variety of social and environmental factors—such as a loss of fertility [141,142], it is now appreciated that biological drivers increase susceptibility. During perimenopause, women experience a regression of ovarian hormones and this change can be accompanied by depressed mood [8], and as in other life phases, interactions with stress physiology are influential [143]. For instance, women who have not experienced an episode of depression prior to the menopausal transition, but who have a history of early life adversity, are at increased risk of manifesting depression during the menopause transition as compared to women without a history of early life adversity [121]. In addition, a history of postpartum depression, as well as having no live births, is a positive predictor of depression during the menopausal transition [141]. Finally, vasomotor symptoms, including hot flashes and vaginal dryness, increase the likelihood of depressive symptoms such that the more vasomotor symptoms a perimenopausal women experiences, the higher the likelihood of depressive symptoms [144,145]. In addition, an episode of depression during the menopause transition can be more pronounced than in earlier life with augmented symptom presentation [146]. These findings suggest that destabilization of the cyclic fluctuations of ovarian hormones may increase the risk of a woman developing depression during the menopausal transition. These findings are consistent with the ovarian steroid withdraw hypothesis, possibly driving postpartum depression [108–110]. Intriguingly, a history of major depressive episodes is associated with earlier decline in ovarian function [147], suggesting that the relationship between ovarian steroids and depression may be bidirectional.

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Similar to PMDD and postpartum depression, depression during the menopause transition can also prove to be hormone-responsive. Treatment with 17β estradiol for just 3 weeks can alleviate depressive symptoms in perimenopausal women [148]. Women who are postmenopausal are also responsive to estradiol treatments after 4 weeks of transdermal treatments [149]. Furthermore, estrogen treatment can successfully enhance effectiveness of antidepressants in perimenopausal women such that women experiencing partial remission of depressive symptoms after 8 weeks of antidepressant regimen had a significant decrease in symptoms after 6 weeks of estrogen supplementation [150]. The previous data suggests that antidepressants may act directly or indirectly through an estrogen-dependent mechanism. As estrogen synthesis, metabolism, and cyclic fluctuations are altered during the menopausal transition, it is possible that by stabilizing these changes antidepressants can be more effective. At the conclusion of the menopausal transition, the rates of depression in women become similar to those of men [151], suggesting that the activational effects of hormones have been removed. However, it should not be forgotten that neurosteroids remain active in the brain even after the menopause transition. In addition, the cumulative effects of organization and life experiences will remain in place. As such, the hormonal history of a woman, even after the menopause transition, may render her more or less susceptible to additional episodes of depression [152].

CONCLUSIONS Depression in women is a prevalent and complex disease. The mechanisms that drive depression vary across the lifespan and, when combined, create a complex etiology that is specific to each individual. Genetics can lay a foundation for vulnerability to altered mood in women [24,34,36]; however, the early life environment [71,73,77] as well as robust, bidirectional hormonal shifts that occur across the lifespan in females [146] play a prominent role in the onset and recurrence of depressive symptoms. The complexity of these associations and activational influences of ovarian hormones across the lifespan can complicate treatment of depression in women, in particular in women with a history of early life trauma such as physical abuse [153,154]. Taken together, the factors that drive depression in women are multifaceted and treatment through SSRI administration is highly efficacious in women generally, it may be essential to consider genetics, early life exposures, and hormonal status when identifying patient-specific treatment interventions.

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