Why is depression more common among women than among men?

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Women’s mental health 3 Why is depression more common among women than among men? Christine Kuehner

Women are about twice as likely as are men to develop depression during their lifetime. This Series paper summarises evidence regarding the epidemiology on gender differences in prevalence, incidence, and course of depression, and factors possibly explaining the gender gap. Gender-related subtypes of depression are suggested to exist, of which the developmental subtype has the strongest potential to contribute to the gender gap. Limited evidence exists for risk factors to be specifically linked to depression. Future research could profit from a transdiagnostic perspective, permitting the differentiation of specific susceptibilities from those predicting general psychopathologies within and across the internalising and externalising spectra. An integration of the Research Domain Criteria framework will allow examination of gender differences in core psychological functions, within the context of developmental transitions and environmental settings. Monitoring of changing socioeconomic and cultural trends in factors contributing to the gender gap will be important, as well as the influence of these trends on changes in symptom expression across psychopathologies in men and women.

Introduction Epidemiological research shows substantial genderrelated differences in prevalences for specific mental disorders. Women’s preponderance has been consistently identified within the internalising spectrum, which includes depressive, anxiety, eating, and somatoform disorders, whereas men predominate in externalising disorders such as substance use, impulse control, and antisocial personality disorders.1 This Series paper will focus on gender differences (panel 1)2–8 in depression as part of the internalising spectrum, and on possible factors that might explain the gender gap.

Epidemiological evidence Prevalence A 2003 review9 listed evidence from studies up to the early 2000s yielding sex ratios of about 2·1 for lifetime and 1·7 for point prevalence (women:men) of major depressive disorder and dysthymia in adults, and similar ratios for studies in adolescents. Findings from subsequent national and international studies substantiate these previous findings across multiple sociocultural settings (table).10–16 The gender gap appears to be similar for high-income countries versus low-income and middle-income countries,11 although region-related variations exist.10 Before puberty, prevalence of depression is commonly low, with boys being more likely to meet criteria for major depressive disorder.17 During puberty, up to the age of 18 years, depression increases much more substantially in girls, to about twice that of boys.18–20 Point prevalence estimates derived from multiple studies around the world21 indicate that thereafter, from early adulthood to late in life, both sexes display a remarkable parallel course with predominant prevalence for women in adult age groups. Thus, against popular belief, depression prevalence of

men and women does not converge after menopause; instead, the female preponderance in depression continues into old age.22,23

Incidence and course Findings from studies show consistently higher incidence of depressive disorders for women than for men.24–26 In older age cohorts (>65 years), incidence typically decreases in men and women, but women’s incidence is clearly greater than that of men.27 By contrast, findings from longitudinal studies do not show conclusive gender differences regarding remission, recurrence, or a chronic course of depression.9,28–32 However, two gender-related course-moderating factors exist. First, incidence of completed suicide is higher in men than in women, although the gender ratio varies largely between regions and countries.33 Yet, this observation cannot compensate for the gender gap in depression, because suicide itself is still a rare event. Moreover, whereas most people who died by suicide had suffered from a psychiatric condition,34 not all deaths by suicide occur in the context of depression; they also occur in individuals with other mental disorders such as nonaffective psychotic and substance use disorders, and in individuals without a classifiable mental disorder (which is more frequent in non-European parts of the world).34 Second, observed excess mortality in depressed individuals compared with the general population is clearly higher among depressed men than among depressed women. This observation is only partly attributable to deaths by suicide, or to increased somatic comorbidity or substance use in men.35,36

Lancet Psychiatry 2016 Published Online November 14, 2016 http://dx.doi.org/10.1016/ S2215-0366(16)30263-2 See Online/Comment http://dx.doi.org/10.1016/ S2215-0366(16)30348-0 This is the third in a Series of four papers on Women’s mental health Research Group Longitudinal and Intervention Research, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany (Prof C Kuehner PhD) Correspondence to: Prof Christine Kuehner, Research Group Longitudinal and Intervention Research, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, 68072 Mannheim, Germany [email protected]

Symptom profile Women with depression report more atypical symptoms than do men, mainly increased appetite and

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Key messages

Panel 1: Definitions of sex and gender

• Women are about twice as likely as are men to develop depression during their lifetime. The gender gap in depression rates emerges from women’s higher incidence; it starts to develop during mid-puberty, and the typical 2:1 ratio of depression (girls:boys) is already reached in late adolescence, which is maintained into old age. • Genetic factors might play a part, but empirical evidence for their potential to explain the gender gap in depression is still scarce. Findings from gene by environment studies indicate pleiotropic effects of genes, thereby influencing internalising and externalising phenotypes with unequal gender distribution. • Adolescent girls are particularly susceptible to the activating effects of sex hormones during pubertal transition. These hormones interact with gendered intrapersonal and interpersonal factors, including stress generation, to contribute to the gender gap. The experience of childhood sexual abuse, more common in girls than in boys, might directly or indirectly—eg, by early pubertal timing—contribute to the increased risk of developing depression during adolescence in girls. • A blunted cortisol response to stress in periods with high oestrogen concentrations in women has been linked to evolutionary protective mechanisms, but might confer increased risk of depression. Atypical depression, characterised by hypoactivation of the hypothalamic-pituitary-adrenocortical axis, represents a distinct pathophysiological phenotype, which is particularly common in women. • A small subgroup of women appears to be susceptible to normal hormone fluctuations during premenstrual, peripartal, and perimenopausal phase, pointing to a more homogeneous female-specific reproductive phenotype of depression. • Part of the gender gap might be explained by heightened exposure to severe adversity, particularly childhood sexual abuse and other violence against women and girls, and to structural gender inequity, measured at the macro or societal level. Enhancement of evidence-informed primary and secondary prevention measures at multiple levels, to reduce prevalence and incidence of gender-based violence and discrimination, is an essential global task. • Little evidence exists for risk factors to be specifically linked to depression. Future research should integrate the National Institute for Mental Health Research Domain Criteria framework to examine sex differences in basic psychological functions across diagnostic entities. Longitudinal monitoring of changing societal trends in factors contributing to the gender gap is similarly important.

Current definitions and use of the terms sex and gender vary broadly, but usually the term sex is narrowly defined to indicate purely biological differences, whereas the term gender is used for psychologically, socially, and culturally defined differences between men and women.2 In practice, however, such a clear distinction is hard to achieve because of the commonly unclear contribution of biological versus environmental factors and their interaction to explain outcomes, together with the fact that environmental factors can result in biological alterations.3,4 As a result of increasing evidence that sex is deeply interwoven with social constructions of gender,5,6 the distinction between the two terms has been proposed to become less meaningful over time.2,4 For pragmatic reasons, the term gender will be used as a collective term for sex and gender differences in this Series paper, unless a difference can be expected to be fully attributable to biological differences. In this case, the term sex is used. This usage is in accordance with the US Institute of Medicine committee on Understanding the Biology of Sex and Gender Differences, who note that “gender is rooted in biology and shaped by environment and experience”,7 and others.8

hypersomnia.37–39 They are also more likely to experience somatic symptoms such as low energy, fatigue, and pain.39,40 Comorbidity with other internalising disorders is higher among women than among men, whereas men show higher comorbidity with externalising and substance use disorders.39

Specific aspects of comorbidity conditions during the peripartum period Although prevalence of depression during the peripartum period (known as peripartum depression) is not increased compared with non-childbearing women in the same age range,9 the negative effect of peripartum depression requires immediate and adequate detection and treatment.41 In this context, some distinct characteristics and consequences of comorbidity of peripartum depression with other mental disorders warrant attention. Traumatic experiences during pregnancy and delivery, and the experience of previous traumas, can result in occurrence and reoccurrence of post-traumatic stress 2

disorder.41,42 Prevalence of post-traumatic stress disorder during the peripartal period is increased compared with non-pregnant women, with most women having exacerbations of pre-existing post-traumatic stress disorder.43 Comorbidity with peripartal depression is high,43 and a risk exists that the comorbid post-traumatic stress disorder condition could be undiagnosed and untreated. Comorbidity of depression with anxiety disorders is similarly high during the peripartum. During this time, anxiety conditions are frequently subsumed by the term peripartum depression, but are not diagnosed independently. Their distinct recognition is important, however, because they increase the risk of both development and a poor clinical course of peripartum depression, particularly generalised anxiety disorder, which is characterised by excessive worry.44,45 A further distinct feature in peripartum depression compared with depressive episodes outside of the peripartum is the increased prevalence of symptoms resembling those of obsessive-compulsive disorder.41 Besides, the prevalence of obsessive-compulsive disorder itself is increased during the peripartum by new onsets or exacerbation of pre-existing obsessive-compulsive disorder,42 which can be accompanied by comorbid peripartum depression. Differential diagnosis can be difficult, but both conditions should be treated appropriately.41

Possible explanations for the gender gap in depression Depression is heterogeneous regarding risk factors and phenotypes, and the importance of specific risk factors to explain the gender gap could plausibly vary across these different conditions. Furthermore, transdiagnostic

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Location

Age (years)

Number of participants

Diagnostic criterion

Gender ratio (women:men)

Lifetime prevalence WMHS: Seedat et al10

Worldwide

··

73 000

DSM-IV major depressive disorder

1·9

WMHS: Seedat et al10

Worldwide

··

73 000

DSM-IV dysthymia

1·9

WMHS: Bromet et al11 (89 000 participants worldwide)

High-income countries

≥18

..

DSM-IV major depressive disorder

1·8

WMHS: Bromet et al11 (89 000 participants worldwide)

Low-income and middle-income countries

≥18

..

DSM-IV major depressive disorder

2·1

NESARC: Hasin et al12

USA

≥18

43 000

DSM-IV major depressive disorder

2·0

NCS-R: Kessler et al13

USA

≥18

9000

DSM-IV major depressive disorder

1·7

NEMESIS: de Graaf et al14

Netherlands

18–64

7000

DSM-IV major depressive disorder

2·1

NEMESIS: de Graaf et al14

Netherlands

18–64

7000

DSM-IV dysthymia

3·4

12 month prevalence EBC/ECNP study: Wittchen et al15 (25 studies)

Europe

≥14

..

DSM-IV major depressive disorder

2·3

NESARC: Hasin et al12

USA

≥18

43 000

DSM-IV major depressive disorder

2·0

NCS-R: Kessler et al13

USA

≥18

9000

DSM-IV major depressive disorder

1·4

DEGS1-MH: Jacobi et al16

Germany

18–74

5300

DSM-IV major depressive disorder

2·5

DEGS1-MH: Jacobi et al16

Germany

18–74

5300

DSM-IV dysthymia

1·9

Odds ratios for major depressive disorder and dysthymia in epidemiological studies of adults since 2003. WMHS=WHO, World Mental Health Survey. DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th edn. NESARC=National Epidemiologic Survey on Alcohol and Related Conditions. NCS-R=National Comorbidity Survey Replication. NEMESIS=Netherlands Mental Health Survey and Incidence Study. EBC=European Brain Council. ECNP=European College of Neuropsychopharmacology. DEGS1-MH=German Health Interview and Examination Survey for Adults.

Table: Gender ratios for depressive disorders

research shows that both distal and proximal risks can be related to multiple outcomes within and across the internalising and externalising spectra.46,47 Considering an isolated inspection of such factors in relation to a specific disorder would therefore be misleading, particularly if non-specific risk factors are linked to different disorders, each with unequal gender distribution. In the following sections, the contribution of possible risk factors at different levels will be assessed (panel 2), together with their grade of specificity in explaining the gender gap in depression, after briefly discussing the evidence for considering the gender gap as valid.

Artefact hypotheses Artefact hypotheses postulate that depression is equally common in both genders, but lower treatment use and lower depression recognition in men than in women, or the existence of gender-specific depressive symptoms, would result in arbitrarily increased depression prevalence among women. However, the evidence for this view is limited. Prevalence estimates are generally derived from representative general population studies and should therefore not be biased by gender differences in treatment. Furthermore, no indication exists for a genderspecific recall of mental disorders, including depression, in the general population,48 or their detection in treatment settings.9,49 Finally, assignment of specific externalising

symptoms to a so-called male depression subtype appears to be of limited value50 except if the aim is to identify a general psychopathology factor. Hierarchical liability models of psychopathology have shown that the internalising and externalising dimensions are gender invariant,1,51 and in particular, major depressive disorder and substance use disorders appear to show the greatest difference in liability to these internalising and externalising factors in both genders.52 Consequently, an unsystematic pooling of externalising and internalising symptoms would impede identification of both common and unique risk factors for the broader liability dimensions and of risk factors possibly linked to more specific phenotypes.

Individual difference susceptibility: biological factors Genetic factors The heritability of major depressive disorder is estimated at 30–40%,53 with mixed evidence for a stronger genetic risk for women than for men.53,54 To date, genome-wide association studies have not been very successful in identifying genetic markers of major depressive disorder,55 probably because of heterogeneity in risk factors. A genome-wide association study for neuroticism56 identified high genetic correlation with major depressive disorder and a similar single-nucleotide polymorphism

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Panel 2: Risk factors potentially responsible for the gender gap in depression Individual difference susceptibility: biological • Genetic risk • Gene–environment interactions • Hormones • Physiological stress response Individual difference susceptibility: psychological • Neuroticism and negative affect • Absence of positive affect • Interpersonal orientation • Rumination and corumination • Body shame and dissatisfaction Environmental factors: micro level • Early adversity: childhood sexual abuse • Interpersonal violence after childhood • Common life events: exposure to stress • Common life events: susceptibility to stress Environmental factors: macro level • Societal structural gender inequities

(SNP)-based heritability for both men and women, concluding that gender differences in neuroticism are due to other factors. Similarly, the search for specific susceptibility genes on the X chromosome has so far been unsuccessful,57 and genes altering the risk for reproductiverelated depression—thereby affecting the genetic risk exclusively for women—have not yet been identified. Gene–environment (G*E) studies investigate whether individual psychological susceptibility towards stressful life events is moderated by genetic factors; some studies also examine a possible moderating effect of gender— ie, if the G*E interaction is stronger in men or in women. In the serotonin transporter-linked polymorphic region (5-HTTLPR), a polymorphism with a long and a short allele variant has been identified. The short allele variant reduces the transcriptional efficiency of the 5-HTT gene promoter, thereby reducing 5-HTT function. Results of a study showed that carriers of the short allele are particularly susceptible to developing depression in response to environmental stress.58,59 Some studies identified this hypothesised G*E interaction only in women,60 and the largest meta-analysis to date59 of the association of 5-HTTLPR with depression identified slightly higher proportions of women than of men in studies supporting the short allele hypothesis. Finally, findings from a review of 78 studies of 5-HTTLPR and gender61 showed that the short allele mainly predicted increased risk for internalising disorders among women and for externalising disorders among men, with the presence of stressful life events enhancing these effects. Genetic polymorphisms within FKBP5, a gene locus involved in the stress system, interact with stressful life 4

events to predict the likelihood of development of depression, but also of other mental health-related outcomes such as aggressive behaviour and psychosis.62 In a first study examining possible gender moderation,63 female, but not male, minor allele carriers of FKBP5 SNP rs1360780 showed more depressive symptoms under high peer stress but fewer symptoms under low peer stress, indicating differential susceptibility.64 Variants of the CRHR1 gene predict development of depression in people exposed to childhood trauma, probably by influencing corticotropin-releasing hormone-dependent neurotransmission.65 A protective effect of CRHR1 SNP rs110402 was found to be specific to men in one study— possibly due to gender differences in types of stress exposure—whereas other studies replicated CRHR1 SNP interactions in only female samples, or did not observe gender-specific interactions.65 In conclusion, genes might play a role in explaining the gender gap, but respective empirical evidence is still scarce. G*E research indicates that genetic factors have pleiotropic effects, thereby conferring common susceptibility towards environmental adversity. Specific syndromes, including those showing large gender ratios in prevalence, are probably shaped by third mechanisms.62 Consequently, identification of further biological (eg, hormonal) or environmental factors, or both is needed to explain how G*E effects are moderated to contribute to specific phenotypes and related gender disparity.

Hormonal influences Sex hormones modulate various neurotransmitter systems in the brain, including serotonergic, dopaminergic, and GABAergic systems, and affect sensitivity to environmental influences across development. Their organisational effects occur during the prenatal period, and both increased prenatal androgen concentrations and maternal stress increase the risk of early neurodevelopmental disorders in boys compared with girls.4 Activational effects of sex hormones, starting during puberty, activate the previously organised structures, and hormonal fluctuations during pubertal transition and other hormone-related transitional periods have been linked to women’s increased risk of depression.66 Both advancing pubertal stage, after transition to mid-puberty, and early pubertal timing are clearly linked to the onset of girls’ increasing risk of depressive disorders.9,19,20,67 By contrast with boys, early maturation in girls is associated with more severe and longer-lasting psychopathology, and with depressive disorders in particular.67 Contextual adversities, such as a poor parent– child relationship and childhood sexual abuse (CSA), predict early maturation in girls, but not in boys; therefore, female pubertal transition seems to be more responsive to adverse environments than the male transition.67 Direct, but small effect sizes of sex hormone concentrations on negative affect have been identified in adolescent girls.68 More likely, however, are indirect

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effects of sex hormones—eg, through girls’ negative self-evaluation in response to hormonally induced body changes, and interactive effects of pubertal status with environmental adversities.9,69 Premenstrual dysphoric disorder, with a lifetime prevalence of 2–5%,70 includes affective core symptoms restricted to the premenstrual phase according to DSM-5.70 Results of studies suggest heightened sensitivity to fluctuating concentrations of reproductive hormones and their metabolites, particularly allopregnanolone.71 Allopregnanolone enhances GABAergic transmission and confers sedative effects in the context of stress, and women with premenstrual dysphoric disorder do not show a typical allopregnanolone increase in response to acute stress.72 DSM-570 has broadened the previous definition of postpartum depression to major depressive episodes with an onset during pregnancy or within 4 weeks postpartum— ie, “major depressive disorder with peripartal onset”.70 This broad definition, however, could obscure heterogeneity in risk factors, clinical phenotypes, and prognostic features.41,73,74 For example, postpartal episodes with rapid onset after delivery include more incident cases and have a higher family load for major depressive disorder, higher premenstrual dysphoric disorder comorbidity, and a higher risk of developing bipolar disorder than other peripartal episodes,74 indicating a higher biological load of this subgroup. A more homogeneous, hormone-sensitive post-partum depression phenotype has been suggested, with rapid onset and recurrences restricted to the postpartal period.73 Initial evidence from a few hormone provocation studies suggests that these women are sensitive to normal perinatal fluctuations of reproductive hormones and their metabolites.73 Cross-sectional and longitudinal studies have investigated a possible increase in depressive symptoms during menopausal transition, with inconclusive evidence.75 Investigators of three studies76–78 showed mixed results for an association between first-onset depression and menopausal status among women with no lifetime history of depression. Data from the 30-year prospective Zurich study79 showed no increase in psychopathological syndromes, including depression during menopausal transition, and suggest that whereas pre-existing susceptibility to psychopathology and concurrent psychosocial problems are important predictors of psychopathology between the ages of 41 and 50 years, transitions to perimenopausal or postmenopausal stages are not. Most episodes during menopausal transition are recurrences of previous episodes,80 and the search for direct associations with reproductive hormones has produced inconclusive results.81 As with peripartal depression, however, perimenopausal depression could represent a heterogeneous concept. Results of a small study82 showed a co-occurrence of perimenopausal depressive symptoms with premenstrual mood symptoms in some women, and depressive status during

menopausal transition was predicted by a history of premenstrual dysphoric disorder and post-partum depression.76,83 Fluctuations in reproductive hormones and their metabolites have been proposed to result in altered GABAergic regulation of the hypothalamicpituitary-adrenocortical (HPA) axis in these women.84

Physiological stress responsiveness Generally, men show larger physiological responses to a broader variety of psychosocial stressors than do women, including greater HPA axis activation, higher diastolic blood pressure, more negative and aggressive emotional responses, and greater conditioned fear reactions.85 Sex differences in HPA axis activation start in adolescence86 and are small or absent before puberty and after menopause.87 Among women, physiological stress responses further vary depending on cycle phase, contraceptive use, pregnancy, and menopausal status.87 Stress responses also vary with the nature of the stressor, with men showing larger responses towards achievement challenges and women showing increased responses to social rejection and conflict.88,89 Oestrogen shows attenuating effects on sympathoadrenal responsiveness, and can exert activating or blunting effects on HPA axis responses.87 Differences in arginine vasopressin, oxytocin, and corticosteroid-binding globulin concentrations have also been implicated in sex differences in HPA axis activation.87 An evolutionary hypothesis for women’s attenuated stress response is the pressure to protect the fetus from adverse effects of maternal stress.87 However, a blunted HPA axis response to stress could confer risk of depression.86 Findings from experimental studies90,91 show that cortisol is able to buffer subjective stress and negative affect, thereby contributing to the normalisation of emotional circuits after exposure to stressors. Hypoactivation of the HPA axis is seen in various stress-related disorders92 and premenstrual dysphoric disorder, for which stress-related HPA axis hypoactivation is associated with increased premenstrual symptoms.93 Studies of HPA axis dysregulation in major depressive disorder revealed both hypercortisolism and hypocortisolism, and inconsistent evidence has also emerged for possible sex differences in the association of major depressive disorder with HPA axis activity.94 Atypical depression, characterised by blunted HPA axis activation and related symptomatology of profound fatigue and reversed neurovegetative symptoms, represents a more homogeneous phenotype, which is particularly common among women.37,38,95

Individual difference susceptibility: psychological factors Temperament, personality, and coping styles Consistent gender differences in early childhood emerge in effortful control, indicating a better ability of girls than of boys to regulate attention and inhibit impulses, in line with boys’ greater incidence of externalising problems.96

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Boys also score higher on surgency than do girls, linked to the Big Five personality trait of extraversion, indicating that boys are slightly more active and impulsive, and derive more pleasure from high-intensity stimuli.96 Findings from prospective studies show mixed evidence for low extraversion to predict depression, probably because of the broadness of the construct; a lack of positive affectivity, a subfacet of extraversion, has, however, been associated with increased risk of depression.97 Evidence for a mediating effect of extraversion on the gender gap in depression is missing. Negative affectivity, related to neuroticism, does not differ between boys and girls in early childhood.96 Neuroticism scores of girls substantially increase relative to those of boys during adolescence, and their greater neuroticism and negative affectivity scores are maintained over the further lifespan.98 In adolescent boys and girls, negative affectivity increases anhedonic symptoms, particularly when combined with low positive affectivity.99 Neuroticism is a robust risk factor for major depression,97 but also for the broader dimensions of both the internalising and externalising spectra.46 Mixed evidence exists that the relevance of neuroticism as a risk factor for depression is larger for women than for men.100,101 A mediating effect of neuroticism on the gender gap in depression has been reported, although merely from cross-sectional studies to date.102,103 The magnitude of the gender gap in personality traits such as neuroticism shows cross-cultural variation, pointing to culture-related gender stereotypes in shaping these traits.98 The highest gender difference in neuroticism is typically found in developed countries. This difference has been related to attribution processes to the extent that gendered behaviour is more likely to be attributed to gender role demands in more traditional societies, and to intrinsic trait-like characteristics in more egalitarian societies.98 Small but consistent gender differences already seen in early childhood involve complex traits indicating interpersonal orientation such as empathy and prosociality,104 and agreeableness and warmth.98 Although empathy is generally linked to positive mental health outcomes, various models have proposed trajectories from empathy to internalising problems in women, starting in adolescence.66,98,105,106 Although this view is compatible with women’s higher susceptibility towards interpersonal stress than men’s, a formal test of causal effects of empathy on gender differences in depression is still missing. A meta-analysis of self-conscious emotions107 showed gender differences in guilt and shame, with the highest effect for body shame in adolescent and adult samples. Body shame and dissatisfaction have been implicated in the development of gender differences in depression in adolescents.69 Gender differences in body shame and dissatisfaction precede those in depression, and mediate the association between gender and the increase in depression in adolescents.108 6

A ruminative response style—ie, the tendency to passively and repetitively analyse one’s distress, problems, and concerns, without taking actions109—has been proposed to account for a substantial part of the gender gap in depression. Rumination predicts depressive symptoms over time and the onset of depressive episodes, and also interacts with stress to predict depressive symptoms.110 It is linked to neuroticism but shows incremental effects in predicting depressive symptoms.97 Findings from studies show transdiagnostic qualities of rumination in predicting various types of mainly internalising, but also externalising psychopathologies and their co-occurrence.111 Two meta-analyses112,113 identified higher rumination tendencies in women than in men. The gender difference increases from childhood (Cohen’s d=0·14) to adolescent samples (Cohen’s d=0·36),112 and is modest in adult samples (Cohen’s d=0·24).113 Rumination partly accounts for the gender gap in adolescent and adult depression.110,114 Furthermore, corumination, the tendency to extensively discuss problems in dyadic relationships, is more common among adolescent girls than among boys. It explains a part of the gender gap—ie, that over time, adolescent girls develop more internalising symptoms than boys115—and contributes to stress generation.116 In general, effects of rumination on internalising symptom development are similar across genders,114 but corumination in response to stress appears to be particularly more detrimental for adolescent girls than for boys.115

Previous anxiety disorders Comorbidity of depressive and anxiety disorders is higher in women than in men, in both clinical and general population samples.9,39,117 Anxiety disorders, particularly those starting in childhood and adolescence, often take a chronic course and tend to precede the subsequent onset of depression.9,118,119 Previous anxiety increases the risk of depression similarly in men and women, but higher prevalences of lifetime anxiety disorders in women than in men could contribute to their higher risk of depression.9,104

Environmental factors: individual (micro) level Common stress exposure and stress susceptibility Adolescent girls have a greater number of interpersonal stressors and are more susceptible to these stressors than boys.19,104,115 Moreover, gender differences in stress generation have been identified: depression associated with subsequent dependent stress is more common in girls than in boys.116,120 Stress generation is rather specific to depression, is especially pronounced in adolescent girls, and predicts subsequent depressive symptoms.116 In a large longitudinal study,120 adolescent girls had more independent and dependent interpersonal stressors than did boys; these stressors partly mediated the association between gender and depression. In adult samples, data from the Netherlands Mental Health Survey and Incidence Study121 showed that paid

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work, including full-time employment, was associated with a decreased prevalence of depressive and anxiety disorders for men and women, but in women, the protective role of working was restricted to those without children. For both genders, the partner role was protective, whereas the parental role was not. These and other findings suggest that the beneficial effect of employment on mental health among women is reduced if there is role overload due to multiple roles.9,122 Results of a 2014 twin study100 showed gender-specific stressors contributing to major depressive disorder: among women, perceived failure in interpersonal relationships; in men, current work, financial, and legal problems were the major contributing factors. Similar gender role-related stressor susceptibilities have been identified elsewhere.102,123 Furthermore, absence of social support appears to be a stronger predictor for depression among women than among men.124 Although these studies point to a different relevance of work-related versus network-related events across genders, daily life-stress exposure or differential susceptibility do not appear to contribute substantially to the gendered risk of depressive disorders.125 Most studies in this context, however, do not differentiate between associations of stressors with first-onset versus recurrent episodes. The National Epidemiologic Survey on Alcohol and Related Conditions126 identified no gender difference in stress exposure during a 12 month period in individuals with no lifetime history of depression or alcohol-related disorders. Cumulative stressors more strongly predicted first onset of major depressive disorder among men than among women, and similarly predicted onset of alcohol dependence in both genders. These results argue against a stress-induced, gender-specific path into depression for women, and into alcohol dependence for men. By contrast, findings from the Netherlands Mental Health Survey and Incidence Study 224 showed that whereas most stressors were similarly related to new onsets of several disorders across genders over a 3 year period, partner separation during the interval was more strongly related to new onsets of substance use disorders in men than in women.

Violence against girls and women Violence against girls and women is a serious worldwide public health and human rights problem. It takes multiple forms, including CSA, intimate physical and sexual violence, rape, sex trafficking, and, in some world regions, female genital mutilation, child or forced marriage, or violence in the name of so-called honour. Gender-based violence has serious effects on mental, physical, and reproductive health, and a huge economic impact.127,128 Most studies to date focus on mental health effects of CSA and intimate partner violence, whereas data for effects of other forms of gender-based violence are scarce.

Childhood sexual abuse Early adversity, such as physical and emotional abuse and neglect and CSA, constitutes a major non-specific risk

factor for various mental and somatic disorders with child, adolescent, and adult onsets.129,130 Neurobiological effects involve dysfunctional development of the endocrine stress response, dysfunctions in autoimmune processes, structural and functional brain changes, and epigenetic effects such as reduced telomerase length and altered DNA methylation.131–133 The prevalence of most types of early adversity is similar in boys and girls, whereas girls are more frequently victims of CSA than are boys. Worldwide estimates of CSA134 indicate self-reported lifetime prevalence of about 18% in girls and 8% in boys. Generally, victims of CSA have higher internalising and externalising symptomatology than do those with a history of non-CSA maltreatment.135 Results of epidemiological studies show that exposure to CSA reduces the gender gap in depression.136,137 Evidence is mixed for a higher susceptibility of women to severe early adversity than of men.138,139 Authors of a large review of community-based studies139 found no gender effect in most studies. For both genders, outcomes were distributed across internalising and externalising disorders. In some studies, gender differences were dependent on age at assessment. In adult samples, psychiatric risk was higher for women than for men, whereas in adolescent samples, it was higher for boys.135,139 In summary, some evidence exists that higher prevalence of depression among women than among men is partly due to their higher exposure to CSA, whereas this increased prevalence cannot be clearly attributed to women’s higher susceptibility towards adversity.138,139 However, victimisation might show extended or delayed-onset effects in women, resulting in increased early adversity-related psychiatric risk in adolescence and adulthood. Possibly, severe early adversity such as CSA increases further risks during pubertal transition, particularly in girls (eg, through early timing of puberty, early sexual relationships, or revictimisation), resulting in increased psychopathology later in life.

Other forms of interpersonal violence WHO127 estimates that 30% of women worldwide have been victims of physical and sexual partner violence, and 7% have had non-partner sexual assaults. Women are at greater risk of being victims of multiple coercive, sexual, and severe physical partner violence than are men.140 Female violence victims are twice as likely to develop depression and substance-related disorders as are nonaffected women.127 An important risk factor for being a victim of adult sexual abuse is CSA, and revictimisation further increases the risk of psychopathology in adulthood above that of CSA alone.141 Intimate partner violence is also of particular relevance in the context of peripartal depression. Findings from a systematic review and meta-analysis142 found a prevalence of past-year domestic violence of 27–30% in women with peripartal depression, and the longitudinal studies included in the literature review revealed that women

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Panel 3: Proposed gender-related subtypes of depression Early-onset subtype* • Childhood onset prior to puberty • Frequently comorbid with early neurodevelopmental disorders Developmental subtype† • Adolescent onset • Direct, indirect, and interactive effects of sex hormones • Temperamental and cognitive susceptibility: • Neuroticism • Rumination and corumination • Body shame • Interpersonal stressors: • Exposure • Susceptibility • Stress generation Reproductive subtype‡ • Triggered by reproductive cycle-related hormonal fluctuations • Premenstrual dysphoric disorder • Early-onset post-partum depression • Perimenopausal transition subgroup Pathophysiological subtype§ • Atypical depression • Reversed neurovegetative signs • Hypothalamic-pituitary-adrenocortical axis hypoactivity *Female to male sex ratio girls≤boys. †Female to male sex ratio about 2:1. ‡Female specific. §Female to male sex ratio about 2·4:1.

who experience partner violence or pregnancy during their lifetime have about a three-times increased odds of postpartal depression.142 Longitudinal data for other mental health outcomes were scarce, but individual cross-sectional studies indicate similar associations of domestic violence with peripartal depression, anxiety, and post-traumatic stress disorder symptom outcomes.142

Environmental factors: macro level Gender is associated with various mental health determinants such as economic position, access to resources, and social status. Relatedly, the degree of structural gender equality, measured at the macro or state level in terms of political participation, economic autonomy, and reproductive rights, affects the gender ratio in depression. Women in US states with lower gender equality report more depressive symptoms than those from states with higher gender equality.143 In a representative European survey,144 a high degree of macro-level gender equality was linked to low depression scores among men and women, and reduced the gender gap in depression. Women living alone and, particularly, employed women profited from high gender equality, although these women showed higher depression scores when state-level equality was low. Data from the National 8

Epidemiologic Survey on Alcohol and Related Conditions study145 showed that gender discrimination in terms of gendered wage gap in the workforce explained a significant part of gender disparities in mood and anxiety disorders, after controlling for gender differences in individual-level productivity. Similarly, gender-related social norms and structures are implicated in violence against women.146 Results of an analysis146 of macro-level predictors at state or region level, from 30 countries and 56 surveys, showed that gender-related structural factors, such as educational achievement and access to property, predicted the population prevalence of partner violence. Particularly, norms related to male authority over women and gender discrimination in family laws, and in access to productive resources (such as access to land, credit or banking, or property), predicted levels of partner violence across settings. Cross-level effects indicated that girls’ secondary or tertiary education reduced the risk of partner violence in countries with high partner abuse rates, whereas being in paid employment increased women’s risk in countries with low proportions of women in the formal workforce.

Summary The assessment of possible factors contributing to the gender gap in depression in this Series paper suggests several gender-related depressive subtypes, which might deserve specific assessment in future research (panel 3). These subtypes of depression—early onset, developmental, reproductive, and pathophysiological—are not exhaustive and might overlap in risk factors and clinical phenotypes. Whereas the early-onset subtype has no potential to explain the gender gap, and might mainly include depressive episodes comorbid with boys’ higher incidence of early neurodevelopmental disorders,17 the developmental subtype with adolescent onset has strong potential to contribute to explanation of the gap. Extensive research in this area provides evidence for the interplay of activating sex hormones, intrapersonal susceptibility, and interpersonal factors in explanation of the disproportionately high increase in depression rates during pubertal transition in girls.18,19,67,69,86,104,136 Unresolved questions involve the causal role of intrapsychic factors such as neuroticism and rumination because the gender difference in their onset parallels the onset of the gender gap in depression. To systematically disentangle genetic and environmental or cultural influences and their possible interaction in shaping these gendered styles in response to stress will also be important. Further evidence has emerged for a reproductive cycleassociated subtype of depression. A small subgroup of women appears to be particularly susceptible to normal reproductive cycle-associated hormonal fluctuations, and shows co-occurrence of hormonally triggered symptoms, probably characterising a more homogeneous, femalespecific, cycle-related phenotype.147 Although transitional periods during women’s adult lives do not substantially

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affect the overall gender ratio in depression, careful assessment of these women is essential because of long-term prognostic and therapeutic implications, particularly in the context of peripartum depression.41,74 A blunted cortisol response to stress in periods with high oestrogen concentrations among women has been linked to evolutionary protective mechanisms but might confer increased risk of depression. Atypical depression, characterised by blunted HPA axis activation,38 thereby representing a distinct pathophysiological depressive phenotype, is particularly common among women.37 HPA axis hypoactivation is similarly seen in chronic stress and somatic illness conditions in which women also predominate.92 Future research should have an integrated view on these particular stress-related phenotypes, and on influencing effects of hormonal and environmental factors. Moreover, possible sexrelated effects regarding metabolic and inflammatory dysregulation in atypical depression warrant further investigation.38,148

Gender-based discrimination A common risk factor contributing to increased depression among women across the lifespan in general, including the proposed subtypes above, is their exposure to severe stressors, particularly CSA, and other adversities linked to gender-based discrimination. This risk factor is not specific for depression, however, but might similarly be increased in other mental disorders with a female preponderance (eg, anxiety disorders and post-traumatic stress disorder) and probably contributes to the high comorbidity of these disorders. Conditions linked to these factors constitute risk for both men and women.129,130 However, they are more common among women than among men, and accounting for them in respective models attenuates the gender gap.136,137 By contrast, gender-specific susceptibility has not been identified for severe interpersonal adversity, such as CSA, so far.138,139 Similarly, research related to common everyday stressors in adult populations shows gendered susceptibility towards different classes of stressors, but no clear indication of a generally increased stress susceptibility in women.24,100,102,123,125,126

Conclusion Generally, only limited evidence exists for gendered risk factors to be specific for depression. Future research can clearly profit from incorporating a transdiagnostic perspective that includes dimensional assessment of multiple areas of psychopathology. Application of hierarchical models might help to differentiate depression-specific susceptibilities from those predicting general psychopathology, within and across the internalising and externalising spectra.46,51,149 Particularly, gender research in depression could profit from integration of the National Institute for Mental Health Research Domain Criteria framework based on behavioural and neurobiological measures at basic levels

and across diagnostic entities.150 This integration would allow detailed examination of possible gender differences in core psychological functions and associated neural circuits within the context of developmental transitions and environmental settings. Current research mainly focuses on gender-related negative affectivity and related cognitive styles.150 Future research could benefit from investigating possible gender differences in the positive valence domain—eg, regarding anhedonia and reward sensitivity, which appear to emerge early in development96 and are reflected in gender differences in brain activity.151 Whereas negative affect characterises both depression and anxiety, anhedonia might be more specific for depression.152 Additionally, longitudinal research across the lifespan, using detailed measures of risk factors and transdiagnostic outcomes, is needed. Clear conceptualisation of courserelated trajectories with respect to illness onset, severity, comorbidity, and chronicity is also important. Research suggests that whereas women and men differ in their risk of developing first-onset episodes of depression, their further clinical course is similar. This finding might point to a particular role of environmental adversities—which are known to have a major effect on the development of first episodes153—for depression among women, whereas internal scar processes (ie, biological and psychological changes after the onset of depression154) moderating the further course appear to similarly operate in men and women. Finally, monitoring of changing socioeconomic and cultural trends in environmental risk factors possibly contributing to the gender gap at the macro level is of particular importance, as well as their influence on future symptom distributions across psychopathologies among

Search strategy and selection criteria I searched PubMed and PsycINFO for large national and multinational studies and reviews published in the last decade, until June 5, 2016, for the epidemiological part of the Series paper. I included individual studies if they used population-based samples, covered large sample sizes (>5000), used structured or standardised assessments to assess depressive disorders, and allowed the calculation of sex-related odds ratios. For the analytical part of the paper, I primarily searched PubMed and PsycINFO for the most recent and largest reviews and meta-analyses from the last 5 years in English using the terms (“depression” OR “depressive disorder”) AND (“gender” OR “sex” OR “women” OR “men” OR “sex difference” OR “gender difference”). I combined these search terms with additional search terms for the different sections of this paper, specifically “childhood”, “adolescence”, “internalizing”, “externalizing”, “symptom profile”, “artifact”, “recall”, “predictor”, “genetics”, “GWAS”, “twin study”, “gene-environment interactions”, “hormones”, “adolescence”, “puberty”, “premenstrual dysphoric disorder”, “peripartal”, “perimenopausal”, “stress responsiveness”, “HPA axis”, “cortisol”, “atypical depression”, “temperament”, “personality”, “cognitive vulnerability”, “neuroticism”, “extraversion”, “rumination”, “early adversity”, “childhood sexual abuse”, ”life events”, “susceptibility”, ”gender equality”, “gender-based violence”, “macro level”, and “research domain criteria”. I also examined reviews, meta-analyses, and individual studies from the last 15 years, if evidence was scarce, or if they were of particular importance.

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men and women. On one hand, findings from cross-national studies suggest a temporal trend of a converging gender gap in depressive disorders in countries with less traditional gender roles.10 On the other, suicide has increased among both men and women in Europe and North America in recent years, with conflicting results as to whether the gender gap in suicide is widening155 or narrowing.156 Rising suicide in these countries has been associated with unemployment related to the 2008 global economic crisis.157 Importantly, egalitarian gender norms can buffer the suicidal consequences of economic shocks, particularly in men,158 thereby further pointing to the need for intensified efforts for gender equality policies to promote mental health for both women and men. Strengthening of evidence-based primary and secondary prevention measures at multiple levels to reduce incidence and prevalence of gender-based violence against women will also be an important global task.128 Contributors I developed the outline of the Series paper, did the literature search, and wrote the manuscript. Declaration of interests I have received grants from the German Research Foundation for projects on cognitive, psychosocial, and neurobiological risk factors and mechanism-based interventions for depression and stress processing in premenstrual dysphoric disorder. Acknowledgments This work is partly supported by the German Research Foundation grant KU1464/6-1. The funding source had no role in the writing of the manuscript or in the decision to submit it for publication. References 1 Eaton NR, Keyes KM, Krueger RF, et al. An invariant dimensional liability model of gender differences in mental disorder prevalence: evidence from a national sample. J Abnorm Psychol 2012; 121: 282–88. 2 Muehlenhard CL, Peterson ZD. Distinguishing between sex and gender: history, current conceptualizations, and implications. Sex Roles 2011; 64: 791–803. 3 Rippon G, Jordan-Young R, Kaiser A, Fine C. Recommendations for sex/gender neuroimaging research: key principles and implications for research design, analysis, and interpretation. Front Hum Neurosci 2014; 8: 650. 4 Altemus M, Sarvaiya N, Neill Epperson C. Sex differences in anxiety and depression clinical perspectives. Front Neuroendocrinol 2014; 35: 320–30. 5 Kaiser A, Haller S, Schmitz S, Nitsch C. On sex/gender related similarities and differences in fMRI language research. Brain Res Rev 2009; 61: 49–59. 6 Springer KW, Mager Stellman J, Jordan-Young RM. Beyond a catalogue of differences: a theoretical frame and good practice guidelines for researching sex/gender in human health. Soc Sci Med 2012; 74: 1817–24. 7 Institute of Medicine Committee on Understanding the Biology of Sex and Gender Differences. In: Wizemann TM, Pardue ML, eds. Exploring the biological contributions to human health: does sex matter? Washington, DC: National Academies Press, 2001. 8 Kautzky-Willer A. Gender medicine. Sex- and gender-specific aspects of clinical medicine. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2014; 57: 1022–30 (in German). 9 Kuehner C. Gender differences in unipolar depression: an update of epidemiological findings and possible explanations. Acta Psychiatr Scand 2003; 108: 163–74. 10 Seedat S, Scott KM, Angermeyer MC, et al. Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys. Arch Gen Psychiatry 2009; 66: 785–95.

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