Causes of Gender Differences in Depression

Moods: they are the modulating tone, the ambient pitch and temper of our lives. It would seem that our moods are a matter of mind, part of self awareness and self control; but if the intricate checks and balances of the brain are disturbed, moods, like every part of our being, can become diseased. Psychiatrists call these diseases of mood depression. And they are not rare. It has been estimated that fifteen percent of all Americans will suffer from at least one serious depressive episode, and approximately three million will commit suicide. Beyond the repeatedly confirmed finding that women diagnosed with mood disorders greatly outnumber men lies a widely varying set of hypotheses that attempt to explain the suspected causes, incidence, symptoms, and comorbidities from various perspectives.

Depression is a loss of an important life goal without anyone to blame. Such a loss affects our behavior, our moods, our subjective feelings, our skills, our attitudes and motivations, and our physical functioning and health. This psychiatric disorder features dysphoric mood or pervasive loss of interest or pleasure, which are associated with many somatic symptoms. The explanation of depression and its symptoms are found in the Diagnostic and Statistical Manual of Mental Disorders, 4thed. (DSM-IV,1994) under Axis I, below the classification of mood disorders. The clinical syndrome of depression is assessed most often by clinical interview, based on the DSM-IV criteria. Depression can either be reactive, which is precipitated by some event, or endogenous meaning that it is biological in nature or that one is predisposed to being depressed.

Some researchers say there is not a strong relationship between how happy you were as a child or an adolescent and how happy you are as an adult. Yet, keeping in mind that happiness and depression are independent, several childhood experiences have been related to adult depression: feeling guilty as a child and a strained relationship with the same-sexed parent, especially if a divorce is involved, a mother depressed enough that she needs help caring for the children, and dominant, over-protective parents using poor child-rearing practices, especially if fathers gave poor child care. Depressed adolescents usually involved symptoms of low self-esteem, anti-social behavior, over-involvement with peer group, and little with parents. Younger people (<40) are three times more likely to get depressed than older people (yet suicide goes up with age). Going through a divorce doubles the chance of getting depressed, especially for women.

In adulthood, some studies have found that depression is most likely to occur in unmarried women who are poor and have little education. They are disadvantaged and have little control over their lives so depression is not surprising. What is surprising is the overwhelming preponderance of depressed females compared to males. Women’s increased risk is approximately twice as high as men’s for depressive disorders. The risk that a woman will experience an affective episode associated with her female gender may be surpassed only by the high risk associated with a family history of affective disorders. Despite the clear association between gender and affective disorders, the causes are decidedly unclear.

A great deal of literature has been published on the causes of depression. Researchers have examined factors inherent to the individual, including: genetics, neurochemical, and neuropsychological traits. Attention has also been given to environmental factors, such as: extreme loss, socialization processes that foster helplessness, and severe trauma. In general, it seems most likely that a complex interaction between biologic vulnerability and environmental stress predisposes some people to depression. In an attempt to explain gender differences in depression, many researchers have focused on differing neurobiological tasks that must be carried out by the brain of a woman as compared to that of a man. Some researchers have argued that the neurochemical messenger systems in a woman’s brain are more finely tuned and therefore more likely to be chronically disrupted when normal development processes are interrupted or modified. Another neurobiological phenomenon that has been identified in depression has to do with the relative activity of the two hemispheres of the brain. The goal of this paper is to examine the noted causes of depression, focusing on those that are exclusive to gender differences. Many psychological and medical studies are included to provide evidence for the theories of gender differences in depression.


Gender-related Socialization

A ratio of two to one typically is found in both community survey populations and diagnosed and treated cases of depression. Weissman and Klerman reached the conclusions that the male-female difference in rates of depression is real and not merely an artifact of corresponding sex differences in rate of help-seeking behavior. To be thorough, a brief examination of social and environmental causes of depression is necessary.


Despite the emergence of clear gender differences in mood disorders only after adolescence and reports of slight male preponderance prepubertally, developmental perspectives have placed the origins of women's later vulnerability to mood disorders in childhood socialization. Traditionally, psychoanalytic theory emphasized the extent to which biological sex was a significant determinant of personality differences between men and women, but it had relatively less to say about sex differences in loss experiences hypothesized to predispose to depression. Notman, incorporating gender socialization experiences into a psychoanalytic model, has provided a further explanation of women’s vulnerability to depression. Others have hypothesized that early childhood sexual abuse is a relatively common occurrence in the early development of girls and constitutes a major risk for later mood disorders. Notman sights that an estimated 37 % of all females will experience sexual abuse by the age of 21. The significance and specificity of early abuse in accounting for women’s increased population rates of depression remain largely unassessed.

Developmental psychology uses learning principles in theories of socialization that account for gender differences to vulnerability to depression. Sex-stereotypical socialization practices by caregivers are hypothesized to lead to gender differences in self-concept and depressive vulnerability in boys and girls. For instance, Ruble and colleagues argued that the research base supports the hypothesis that parents have different expectations for girls and boys, including belief that girls will be more nurturing and concerned with social evaluations of others and that boys will be more independent. According to this theory, stereotypical gender socialization leads to a lower sense of mastery and control and a higher concern for external evaluation in girls than in boys. Their analysis of a large body of published literature on childhood self-evaluation for success and failure in physical, school-related, and social achievement domains found support for such differences. Differences are seen as forming a stable basis in the self-concept of depressive vulnerability.

Theories that stress early developmental socialization processes as the basis for depressive vulnerability generally are not integrated with most current adult psychopathology research. Relatively little is known about continuities and discontinuities between child and adult behavior. Nor is much known about the relationship between childhood socialization and abnormal adult development as defined by specific diagnostic categories in psychiatry. Developmental learning theories view socialization agents as predominantly influencing the child’s behavior and gender differences as the outcome of primarily unidirectional processes. Elsewhere, however, there is evidence of the inheritance of stable temperamental traits that influence caregiver/child interaction and also predispose to characteristic responses. In this regard, more research on the influence of sex steroids on the developing brain and on observed gender differences in child’s behavior is needed to provide a more complete and integrated picture of reciprocal influences on sex differences in caregiver/child interaction, child behavior, personality, and psychopathology.

Nolen-Hoeksema has developed a theory of women’s increased vulnerability to depression based on the identification of a self-focused coping style in response to depressed mood. In her research, she found relatively weak support for overall gender differences in personality characteristics of passivity and assertiveness, but she noted that differences occur in women’s response to depression; they focus on negative emotions while men use distracting responses to cope with depression. Their Aruminative style is seen as providing a general link to women’s tendency to have longer and more severe depressive episodes, specifically, rapid cycling and mixed-state bipolar forms. According to this theory, higher rates of depression in girls at adolescence are triggered by their greater exposure at this time to concerns with personal appearance, safety, and self-worth. Nolan-Hoeksema found that men are more likely to engage themselves in distracting activity, especially sports and athletic activities. Physical activity has been found to enhance the self concept of women who are depressed. These findings may be related to research that has shown exercise to produce a shift in cerebral activation such that the left frontal region becomes more active relative to the right.

Some researchers suggest that aerobic exercises are as effective as other forms of psychotherapy, and that the exercises have an antidepressant effect on patients with mild to moderate forms of depression. There is also evidence that women experience more life events than men. Karp and Frank report more life events six months before the onset of a depressive episode in women than men in a treated sample and raise the possibility that women experience higher rates of reactive depression than men. Such research may provide a link between epidemiologic risk findings and specific vulnerability factors in a large percentage of women. The generality of cognitive risk factor findings needs study in representative samples of depressed women but it has clearly testable gender-related hypothesis and treatment implications.


Genetics

The role of genetic factors in increased occurrences of depression has been shown to be the most significant. Linkage analysis studies aimed at the disclosure of the location of a gene on a particular chromosome used biological characteristics as genetic markers, linking their occurrence to patients with mental disorder. The hope was that knowledge of the genetic locus of such a physical characteristic would eventually lead to the identification of the genetic locus for the disorder under study. In fact, through DNA analysis, a gene on chromosome eleven of patients with major depression has been identified as a marker for depressive illness.


In linkage studies of the Old Order Amish of Lancaster County, Pennsylvania, Medical Anthropologist Janice A. Egeland PhD suggested that the tyrosine hydroxylase gene, which maps to chromosome 11, should be considered as a candidate gene for depressive illness because this enzyme catalyzes an important step in the dopamine synthesis pathway. This gene is merely a marker, and has not been shown to positively indicate depression in all of its inheritors.

Genetic imprinting with different phenotypes based on transmitting parent and clinical evidence of mitochondrial inheritance in mood disorders provide genetic models of sex effects on depression. An epidemiologic twin study that modeled sources of variance in rates of mood disorders in a sample of women found evidence for direct and indirect genetic factors as well as proximate (current life events) and distal (childhood loss) environmental influences. There may be gender differences in the inheritance of a number of predisposing susceptibility traits, with environmental influences modifying the specific clinical results differently for the two sexes.


Female Reproductive Cycle

Biological explanations for the female excess of mood disorders have tended to focus on intervals of well-defined hormonal changes such as those experienced at menarche, menstruation, postpartum, and menopause, The implicit or explicit assumptions of such research are that changes in levels of female reproductive hormones provide a general model for women's increased vulnerability to depression. In preadolescent samples, depression in girls is relatively rare: in fact, a slight male preponderance is typically found. Once girls enter puberty, rates of mood disorders begin to rise. Girls’ risk relative to boys increases dramatically. Problematic, however, is the identification of casual factors operating at this time. The few studies that have examined mood changes in relation to hormonal changes in adolescence do not generally indicate direct relationships between hormone levels and mood in girls. In a prospective study of adolescent depression female gender failed to explain increased risk for depressive episode once psychosocial and life-event variables were included in a predictive model. Angold and Worthman proposed a model of adolescent psychopathology in which girls’ increased susceptibility to mood disorders results from a complex interplay of biological, social, and developmental factors as they are interpreted by the adolescent in relationship to peers.

Human male and female bodies are distinctly different in numerous ways besides relative size and reproductive structure and function. Basic biological principles underlie these hormonal based sex differences. Hormonal influences on sex differentiation may be categorized as organizational or operational. Organizational sex differences occur during embryonic and fetal differentiation. They affect primary sex characteristics and brain development. Numerous sex-specific anatomic differences have been identified in the hypothalamus, the region of the brain that mediates gonadotropin production, including four discrete nuclei that vary in size and cell number between females and males. Sexual orientation and preference have also been linked to sex-specific anatomic differences in other hypothalamic nuclei. Numbers of callosal fibers and lateralization of specific cognitive functions like language and spatial reasoning relate to the prenatal influence of sex steroid hormones.

A significant proportion of women report moderate mood changes in relation to their menstrual cycle, with dysphoric mood, peaking in the late luteal phase of the cycle. In fact, approximately four percent of all women report changes of sufficient severity to meet DSM-IV criteria for late luteal phase dysphoric disorder. Some researchers have proposed that late luteal phase changes may serve as a model for women's general vulnerability to depression. Parry has proposed that chronological changes in the late luteal phase lead to alteration in circadian rhythms, and there is evidence from animal studies that gonadal steroids affect circadian rhythms and activity level. Parry also found some preliminary evidence of variable phase and amplitude of melatonin rhythms in women with late luteal phase disorder, but direct evidence of cycling variability in melatonin in normal women over the menstrual cycle is lacking. The hormonal triggers for ovulation are the pituitary hormones luteinizing hormone (LH) and follicle stimulating hormone (FSH). But the more psychoactive hormones seem to be estrogen and progesterone. Estrogen peaks before the woman ovulates, and there is a smaller peak afterward. Progesterone peaks after ovulation, but before menses. These are big changes. Some women are very vulnerable to the emotional effects of hormonal changes, increasing vulnerability to depression. Leibenluft examined the menstrual cycle variability in a number of biological measures commonly assessed in psychiatric research on depression. Findings indicated the potential for significant confounding in biological research that fails to take menstrual status into account, depending on the specific measure. For example, there is little evidence of significant menstrual cycle variability in such traditionally prominent biological assessments as cortisol, but there may be considerable variability in others such as serotonin-binding parameters which is examined later in this paper.

Despite the seriousness of postpartum psychosis, it does not contribute greatly to increased prevalence of major mood disorders in women. While hospitalizations rise in the postpartum period, they account for only a small portion of all mood episodes in women. Hormonal changes that occur in the puerperium are dramatic and massive. During the course of a full-term pregnancy, the levels of hormones secreted by the corpus luteum and the placenta rise dramatically. For example, from eight to thirty-eight weeks, progesterone rises up to seven times, estradiol up to 130 times, and prolactin up to nineteen times. A major reason why these hormone levels are so high is that the placenta is an endocrine organ that produces hormones, many of which are psychoactive. When the baby and placenta are delivered, estrogen and progesterone drop dramatically. Some people are more vulnerable to hormonal changes, and thus are more vulnerable to depressed or sometimes hypomanic. The people who are most vulnerable are the ones who have a history of affective illness either independent or related to reproductive events.

Despite earlier clinical beliefs that menopause was associated with increased depression, the preponderance of evidence now indicates that the climactic stage in a female’s reproductive cycle is not associated with increased risk for affective episodes. Incident or recurrent rates of mood disorders in fact decline in women after menopause and rise in men in later years, so that gender difference in mood disorders narrow with age. Such trends are more consistent with psychiatric models that link depression to psychosocial vulnerability factors than they are with simple biological models linking estrogen deprivation to depression. Reports of diminished anxiety and depressive symptoms in women receiving estrogen-replacement therapy after menopause do offer validity to the linkage between the risk of depression in women, estrogens, and female biology. Menopausal women treated with hormone replacement levels of estrogen or estrogen/androgen combination experienced more positive moods. Estrogen treatment was also associated with better performance on verbal memory tasks, while the women receiving androgens alone or in combination with estrogens had higher levels of sexual desire and arousal. Nonetheless, estrogen has generally not been shown to be antidepressant for women during the menopausal transition. The evidence for the antidepressant role of estrogens in clinical mood disorders is ambiguous. There is some indication of their effectiveness in alleviating the mood and somatic symptoms of menopause.

Young indicated that postmenopausal women with recurrent depression have higher cortisol levels than premenopausal depressed women. She hypothesized that estrogens buffer depressed women premenopausally against cognitive or affective changes resulting from hippocampal neuronal loss. With the loss of such protection at menopause, special clinical and treatment issues may arise. Young also reported evidence of gender differences in normal samples of older men and women on biological parameters such as MHPG which may indicate dysregulation of the norepinephrine system. She found lower levels of serotonin and cortisol in women than in men.

Emotional factors have been shown to influence the pituitary-ovarian axis at the level of the hypothalamus. Relatively little work has been focused on the interacting effects of the ovarian hormones on the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-thyroid (HPT) axes or neurotransmitter systems in relation to depression. Young hypothesized that estrogens buffer the HPA axis in premenopausal women, but that depressed postmenopausal women fail to suppress cortisol production, leading to mean cortisol concentrations higher than those found in postmenopausal women. The significance of this finding is somewhat tempered, however, since the depressed men in the sample did not exhibit significant evidence of HPA axis activation.


Neurotransmitter Model

The difference in the rates of depression in women versus men are similar using the serotonin model. Lepage and Steiner hypothesized that serotonergic insufficiency causes depression more in women and violence more in men. Impulsive eating and mood disorders are also suspected results of an insufficiency. Men with depression are more likely than women to make lethal suicide attempts; and a link between suicide and serotonin deficiency has been established. In a healthy male brain, serotonin is synthesized at a much higher rate than in a female brain. When deprived of tryptophan, a precursor to serotonin, serotonin synthesis drops four times more in women than in men. ALower brain serotonin levels or function have been implicated in various types of psychopathology, including depression, suicide, aggression, anxiety, and bulimia, reported Dr. Diksic. He hypothesized that the female brain has a harder time adjusting to the newer levels of tryptophan. If men and women have similar stores of brain serotonin, then a lower rate of synthesis in women may be insufficient in maintaining adequate stores during stressful moments. Tryptophan depletion can also reverse the effects of selective serotonin reuptake inhibitors (SSRI) in depression. During stressful situations, increased levels of the neurotransmitter may be utilized. This might explain why emotional insults may affect women more than men.

As we continue to learn more about serotonin and other neurotransmitters involved in depression, it is apparent how deficiencies in neurotransmitter precursor molecules such as folate might contribute to psychopathologic states. Under experimental conditions, clinical depression can arise or worsen as a result of lowering the CNS availability of building blocks for serotonin and possibly other neurotransmitters. Yet it remains unknown to what extent deficiencies of neurotransmitter precursors such as folic acid or tryptophan are responsible for depression that arises under non-experimental conditions. Albert and Fava site several studies suggesting that RBC folic acid concentrations are abnormally low in up to thirty-eight percent of depressed patients. A negative correlation has been reported between serum folate and duration of a current episode of depression in a sample of 44 depressed patients whose folate levels fell within the normal range. These findings seem to indicate that folate deficiency is associated with the emergence and severity of depressive illness. Lower folate concentrations may be linked to greater persistence of depressive symptoms. In response to antidepressant treatment, the individuals who had low serum folate levels prior to receiving treatment were less likely to respond to eight weeks of treatment with SSRI’s than were patients with normal folate levels.

The association between low folate levels and depression has suggested a potential role for folate in the treatment of depressive disorders. Psychiatric surveys report that patients treated with folic acid spent less time in the hospital and exhibited mood improvement and better social functioning than those with low folate levels who did not receive supplemental folate. Although the relationship between low folate levels and depression is well supported, as is the importance of correcting folate deficiency in the treatment of depression, the potential neuropsychiatric morbidity associated with increased folate levels among depressed patients remains unclear. The evaluation of folate level, however, and the supplementation with folate is still considered valuable in effective antidepressant treatment.


Conclusions

If we return to the fact that the female gender is nearly equivalent to family history in accounting for risk for mood disorders, certain conclusions are inevitable. One is that future research on mood disorders must explicitly incorporate study of gender in relation to genetic contributions, environmental and psychological factors, and biological factors in depression. Of these approaches, muck work has been done in the area of genetics, with an uncertain yield and very little information to address women’s differential vulnerability. The biological factors remain the weakest in terms of what research can tell us about gender and depression. Many studies have provided evidence to support various hypotheses of why the gender gap in depression is so large. Based on models of differences in socialization, genetics, hormonal variations throughout a woman’s reproductive cycle, and neurotransmitter deficits, researchers attempt to explain the enigma of gender differences in depression. Depressed patients of the future are likely to be referred to a radiologist to determine his or her structural and functional brain characteristics, including the localization of brain activity, the status of the neuroreceptors, neuronal cell structure, and neurotransmitter distribution. Genetic testing of the patient and his or her close family will also play a key role in diagnosis and treatment, whether pharmacological or psychotherapeutic.

Author: Jesup C. Szatkowski

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