Depression in Women and Men: What's the Difference?

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Depression in Women and Men:
What's the Difference?

"Depression in Women and Men: What's the Difference?" was the subject of a one-day program co-sponsored by the National Institute of Mental Health (NIMH) and the Society for Women's Health Research (SWHR) on Saturday, March 24, 2001, as part of the Smithsonian Resident Associates series.

To open the meeting, Phyllis Greenberger, SWHR Executive Director, offered a brief overview of the Society's work. Established more than ten years ago, the Society is a Washington DC-based national advocacy organization dedicated to improving the health of women through research. It was founded by researchers, scientists, and activists who were seeking to end inequities in medical research. It now works to increase public and private funding for research on women's health, promote the inclusion of women in medical research studies, and encourage the scientific examination of basic biological and physiological differences between men and women.

A major focus for the Society has been clinical trials, Ms. Greenberger explained. For many years, women were not appropriately and proportionally represented in clinical trials. Therefore, much of medical knowledge came from what was known about the male body; findings from studies done on men were generalized to apply to women.

The Society has worked to change the way clinical trials—and scientific research in general—is performed. The number of ways in which the organization has succeeded is evident in increased funding for women's health research, passage of a federal law requiring women to be included in federally funded medical research, and strengthened Food and Drug Administration guidelines that include women in all phases of a drug's testing; in addition, the Society played a role in the establishment of the Office of Research on Women's Health at the National Institutes of Health.

As more and more researchers are investigating sex differences, Ms. Greenberger stated, they are noting that males and females often have different reactions to drugs, experience different patterns of diseases, and show different symptoms for the same disease.

The knowledge gained from appropriately studying gender differences has broadened the definition of "women's health." The scientific community has gone from focusing narrowly on reproductive organs to looking broadly at diseases and conditions that affect women exclusively, predominately, or differently. "We've gone from thinking of women as 'little men' to studying biological differences between genders," said Ms. Greenberger. "Now we know women's distinct biology sometimes makes it necessary to treat women and men differently."

"I believe we've made great strides in accomplishing what we set out to do," she said. "But there is still much to be done." Though the knowledge base built from clinical research on women is growing, it remains far less than that developed from studies on men. Medicine must progress from simply noting biological distinctions to actively researching why they occur, Ms. Greenberger said.

The Smithsonian program will demonstrate, she explained, that depression is an area with an abundance of gender differences not only at the biological and physiological level but at the sociological level as well. Depression in both women and men is a debilitating disorder that disrupts relationships and daily lives and affects nearly ten percent of the population. Though depression is a treatable disease, about eighty percent of episodes of depression are not diagnosed and treated.

Ms. Greenberger highlighted these issues relating to women and depression:

We are just beginning to learn about the ways in which medications are processed differently in women and men and how this affects treatment choices—such as dosages—and outcomes.
Serotonin is a neurotransmitter used by the brain for mood balance. Males and females process this neurochemical and others, such as estrogen, in different ways.
Suicide attempts are more common in women. Men are more successful in taking their own lives, but more women attempt it.
Men are more likely to be diagnosed with alcohol problems, but women are at higher risk for developing alcohol problems following an episode of depression. Women experiencing depression are more likely to develop alcohol problems within a few years of their first depressive episode.
Depression treatment issues during pregnancy and postpartum are particularly challenging.
Under the age of 13, approximately equal numbers of girls and boys experience depression. Once children reach the age of 13, more girls than boys become depressed.

Understanding why these sex differences occur undoubtedly will help in understanding the biological basis of depression, and how better to treat it in both women and men, concluded Ms. Greenberger.

The Burden of Depression

Steven E. Hyman, M.D., Director of NIMH, spoke next. He said that too often scientists work in the shelter of laboratories and forget that if information is not shared on a routine basis with the public, research findings may be misunderstood. Seminars such as this enable scientists to discuss "where we are in the process of discovery."

Depression is a disease that affects one's mood, Dr. Hyman emphasized, but it also affects one's cognition and manifests itself in physiological ways with symptoms that can include insomnia, decreased sex drive, and weight loss or weight gain. Depression is not only about feelings; it is a disease that involves every system and many aspects of the brain, affecting people's entire lives. Once a person has a single episode of depression, the chances of recurrence are high. The disease is twice as common in women as in men.

Despite its remarkable prevalence (almost 10 percent of the U.S. population), depression—like many mental disorders—has been swept under the rug by misunderstanding. The brain is by far the body's most complex organ, yet it is invisible. Because depression is invisible in the sense that it does not leave obvious markers on the body, it is more difficult to diagnose than physical illness. Its effects are clear, however, and often tragically so. Mental disorders have been marginalized because we measure the burden of illness in a society primarily by mortality, and while mental disorders can be lethal, from suicide for example, they are not lethal as often as some other illnesses, like cancer. Nevertheless, they can destroy lives.

General perceptions about mental illness began to change in 1996, Dr. Hyman explained, when the World Bank, Harvard University, and the World Health Organization developed new criteria for measuring the burden of illnesses. The authors of the study recognized that economic development and well-being worldwide require good health, a change from the old idea that health is a luxury that follows development. The World Bank and the World Health Organization recognized there was a need for measures of disease burden that go beyond mortality.

The new measurement focuses on the years of healthy life lost either to premature mortality or to disability. This new measurement of disease burden demonstrates that mental illnesses have enormous impact on disease burden around the world.

Applying these new criteria to developed countries such as the United States, researchers found that major depression is the leading cause of disability and the leading cause of days lost from work. These findings have had a noticeable impact on policymakers and helped animate the debate on insurance coverage for mental disorders.

Dr. Hyman went on to say that depression, like all mental illnesses, is a product of interactions between genes and environment. One way to determine if something has a genetic component is to ask: how does your risk of having a particular illness correlate with the degree of relatedness with someone else with the illness?

We inherit half of our genes from each of our parents and we share, on average, half of our genes with each of our siblings, unless we have an identical twin, in which case we share our genes one hundred percent. If one identical twin has depression, the other has a very high risk (probably tenfold) for developing depression. One has a two- to threefold risk if one's sibling or parent has the disease and even less risk if an aunt or uncle has it.

Certain mental illnesses have particularly strong genetic components: autism, bipolar disorder, and schizophrenia. The genetic risk of depression, though less than these other mental illnesses, is about the same as type II diabetes.

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These numbers reveal that even an identical twin with 100 percent DNA in common with a sibling with depression is not absolutely certain to develop this illness. "Genes have a role, but they are not fate," said Dr. Hyman. "There are definitely environmental factors involved also. This is a disease of gene and environmental interaction."

While there is a sense of urgency among researchers studying depression, Dr. Hyman said, there is recognition that these are incredibly difficult problems to solve. The human brain, with 100 trillion synaptic connections, is the most complex structure in the body. While the human genome project will enable us to know every gene, understanding how they fit together will challenge us for decades.

In terms of risk of mental illnesses, males and females differ. Boys are much more likely to have autism and attention deficit hyperactivity disorder (ADHD). As males get older, their risk for alcoholism is twice that of women, and men experience onset of schizophrenia earlier in life than women do.

Women are twice as likely to suffer from depression, panic disorder, and other anxiety disorders. While women and men are equally likely to develop bipolar disorder, women are more likely to be diagnosed with "rapid cycling": as many as three episodes in a year. Dr. Hyman also noted, as Ms. Greenberger had, that women are more likely to attempt suicide, and men are more likely to complete it.

Before puberty, he noted, the gender ratio for depression is one to one, but later, women are at greater risk. There also are differences in depression across the reproductive cycle and mood symptoms associated with the menstrual cycle. There is postpartum depression and there are mood symptoms associated with perimenopause. "Gender is not a political issue. It is a true biological issue that affects the frequency and expression of mental illnesses," said Dr. Hyman.

While one may wonder if these differences are an artifact of society, research suggests that is not the case. Across many different societies, the rates of schizophrenia and bipolar disorder are the same. And while depression occurs in different societies at different times at different rates, the symptoms are always the same and the gender ratio is always two to one. "There is some profound biological message we need to decode," concluded Dr. Hyman.

Defining and Understanding Depression

Ellen Leibenluft, M.D., Chief of the Unit on Affective Disorders in NIMH's Pediatrics and Developmental Neuropsychiatry Branch, discussed the diagnosis of depression and differences between men and women.

To receive a diagnosis of major depressive disorder, an individual must experience depressed mood or anhedonia (the inability to experience pleasure) for two weeks, in addition to five or more of the following symptoms: weight loss or gain, insomnia or excessive sleep, fatigue, feelings of worthlessness, difficulty concentrating, or suicidal thoughts. Most people who seek treatment have experienced symptoms for several months or longer.

Dr. Leibenluft is frequently asked, "How can you tell the difference between the blues and depression?" Among the factors she considers are how many symptoms a person is experiencing, how long the symptoms have been present and how severe they are, and whether the individual is having trouble functioning at home and/or at work. It is particularly important that people with suicidal or self-destructive thoughts seek help.

Dr. Leibenluft noted that many people think that depression is more common in women than men because women are more likely than men to admit to feeling depressed, while men are more likely to deny their symptoms or even to forget them. Her conclusion, based on the data she has reviewed, is that men who are currently depressed are not more likely to deny symptoms than women who are currently depressed, but that men may be somewhat more likely to minimize or forget past episodes. These differences, however, cannot account for the gender differences in depression, she emphasized.

The major gender difference is that women are at higher risk than men to experience a first episode of depression. After that, there is no consistent gender difference in the severity or course of depression—in other words, depressed men and women don't differ in the extent to which depression interferes with their ability to function, or in the length or frequency of their depressive episodes. Women, however, are more likely than men to report a high number of depressive symptoms (i.e., seven or eight). And pure depression—in which the person has no other psychiatric illness, such as substance abuse or anxiety—is more common in women than men.

Most depressed patients, however, do not have pure depression; instead, they also suffer from other psychiatric illnesses. These other mental disorders often appear before the clinical depression. In women, depression often follows anxiety disorders, while in men it often follows substance abuse disorders or conduct disorder (i.e., antisocial behaviors). Although women overall have a lower risk for substance abuse than do men, depressed women are more likely than depressed men to develop substance abuse disorder after they become depressed. Women also tend to develop brain and liver damage relatively early in the course of alcoholism. Dr. Leibenluft suggested that this may relate to body size or rate of metabolism.

Few men or women who have suicidal thoughts get treatment. Suicidal thinking and behavior is particularly common among adolescents and the elderly. More women attempt suicide, but more men complete suicide attempts, partly because they tend to use more lethal methods such as guns rather than medication overdoses.

These important gender differences could have implications for treatment and prevention of depression, concluded Dr. Leibenluft.

Risk Factors for Depression

Carolyn M. Mazure, Ph.D., is Professor of Psychiatry at the Yale University School of Medicine and Director of Women's Health Research at Yale. She began her presentation by emphasizing that while depression is a very common illness, not everyone is equally likely to develop depression and certain risk factors increase the probability of developing this disorder.

A risk factor, she explained, is a condition or behavior that precedes the onset of depression and is found at a higher rate in persons with depression than without depression. Risk factors also can provide a profile of those for whom depression is more likely and, consequently, can serve as targets for treatment and prevention strategies.

One of the most consistently determined risk factors for depression is female gender. It has been shown in many well-conducted studies that lifetime rates of depression are higher for women than men and that the relative difference in the rates between women and men are maintained essentially over the life span.

Some of the other factors that increase risk for depression include prior episodes of depression, family history of depression in first-degree relatives (parents and siblings), and chronic medical illness. With regard to sex differences in these risk factors, prior episodes are not more predictive of depression for women than men. Because women have more first episodes of depression, however, there are more women in the "pool" of those who could have a recurrence. Women are six times more likely than men to develop depression after physical illness or injury; specifically, some data suggest that women are twice as likely to develop depression after myocardial infarction.

Certain cognitive styles—ways of thinking and viewing the world—also can be risk factors for depression. For example, those who focus extensively on pleasing others to avoid disapproval and those who have an exaggerated need for control have an increased risk for depression. People with these needs establish unattainable goals that make them feel more hopeless. While both women and men with these styles have a higher risk for depression, the first style seems to be more pronounced in women than in men. Another cognitive style is rumination, or replaying negative experiences and their possible meanings and consequences. This ineffective search for control is more common in women than men; it increases negative thinking and impairs problem solving, worsens mood, and promotes depression. With cognitive behavioral therapy, some of these styles can be modified.

Finally, a very important risk factor is life stress, or exposure to adverse experience, and the effect of this factor might be particularly helpful in explaining the gender disparity in rates of depression. Life stress greatly increases risk for depression, and women are preferentially affected by life stress and have more event-related depression than men. Dr. Mazure emphasized that future studies need to translate these findings into treatment strategies that reduce risk for depression.

Visualizing Mood: The Neuroscience of Depression

Richard Davidson, Ph.D., is the Vilas Professor of Psychology and Psychiatry in the Department of Psychology at the University of Wisconsin-Madison. He showed a number of slides that illustrated the state of imaging technology.

Positron emission tomography (PET) scanning, he explained, allows us to visualize the biochemistry of the brain. Functional magnetic resonance imaging (fMRI) does not involve exposing individuals to ionizing radiation and is responsible for the advances in exploring the human brain as it undergoes different emotions and mood changes. As research progresses, scientists are finding that apparently the mechanisms involved in the regulation of emotions may be different from the circuits in the brain involved in the initial generation of that emotion.

Dr. Davidson reviewed several slides depicting the ventral side of the brain, or the "underbelly" of the prefrontal cortex. Patients with damage to this area show aberrant behavior and have difficulty anticipating the emotional consequences of their behaviors. Asked to contemplate a specific choice, these patients are unable to feel the emotion that may be associated with a poor choice and use that to guide their behavior, especially when faced with complex choices.

The old-fashioned view, Dr. Davidson said, is that emotions are disrupters of behavior. In fact, in many ways, the appropriate use of emotions is important to our lives. We make complex decisions such as choosing a house or a mate largely based on our emotions. If the parts of our brain that help us anticipate these emotions are damaged, then our decision-making ability also is damaged.

Dr. Davidson showed slides of the dorsolateral prefrontal cortex which, he explained, is involved in "working memory" and goal instantiation. The left prefrontal cortex is an area of the brain that appears to be particularly important for representing positive goals and organizing behavior toward the acquisition of such goals. Damage to this area of the brain impairs an individual's ability to implement goals and can result in depressive-like behavior when goals are not pursued.

A coronal view of the brain highlighted a part of the amygdala that responds to signals in the environment that represent potential threats. This area of the brain is hyperactive or fails to turn off with certain types of mood or anxiety disorders.

In general, Dr. Davidson explained, research has shown that depression is more prevalent in patients with lesions on the left side of the brain while mania is associated with lesions on the right side. In studies of patients who have suffered a stroke, those with the most severe depression have left prefrontal lesions, leading researchers to hypothesize that areas in the left prefrontal area of the brain play a role in positive emotion and damage to this area may contribute to a deficit in one's capacity to experience pleasure.

In a study of people with no brain damage, researchers exposed participants to pictures designed to elicit either little emotion, positive emotion, or negative emotion and recorded brain activity with PET. Positive pictures tended to activate responses in the prefrontal region in the left hemisphere. Negative pictures tended to activate responses in the right hemisphere, in a different region of the prefrontal cortex.

Dr. Davidson suggested that there may be differences among people in their ability to respond to negative and positive stimuli, an ability based on a complex mix of genetics and environment. Referring to Dr. Mazure's discussion of rumination, Dr. Davidson said that scientists speculate that rumination is the failure to attenuate negative emotion after a negative event occurs, resulting in it persisting in that part of the brain. This notion of persistence of mood beyond the point at which it typically falls off in a nondepressed person may relate to the machinery in the brain involved in the regulation of negative emotion. There also may be a relationship between hormonal changes and changes in brain activity.

Dr. Davidson concluded by emphasizing that understanding the brain machinery responsible for persistence of emotions may eventually help researchers understand what may be responsible for gender differences in mood disorders since there is some evidence to suggest that women and men ruminate to different degrees.

Stress and Depression

Ned Kalin, M.D., is Hedberg Professor and Chair of the Department of Psychiatry at the University of Wisconsin Medical School in Madison explained that understanding the stress response, how it varies among individuals, and the factors that affect its development will lead to new ideas about the linkages between stress and depression.

The stress response is important for survival and adaptation. The stress response, which involves both emotional and physiological changes, is an adaptive response that motivates our behavior so we can protect ourselves. It is turned on by the brain working in specific neural circuits modulated by neurotransmitters and hormones.

There are important individual differences in humans. Some people may have the ability to shut down quickly their emotional, behavioral, and hormonal responses to stressful situations, while others may have prolonged responses. Over time, these prolonged responses could affect physiology and brain function. For example, increased release of cortisol over a long time could affect glucose regulation, bone density, immune function, and the function of specific brain cells. These individuals could become vulnerable to developing physical and mental diseases. Evidence suggests that overactivity of corticotropin-releasing factor, a brain neurochemical, may play a role in why some people become excessively anxious and depressed. For example, about 50 percent of depressed patients have overactivity of the stress hormone response, which is regulated by corticotropin-releasing factor. Whether this overactivity causes or contributes to depression is unclear. It is also possible that overactivity of this system may play a role in altering the structure and function of certain brain cells.

Dr. Kalin described studies of childhood experiences that may reveal a connection between stress hormone levels and depression. A study in 1945 by Spitz examined the psychological condition of orphans who were hospitalized and provided with a clean and healthy environment but with very little contact or comfort by the nurses. These children were described as withdrawn, and social interactions with them became increasingly difficult. In more recent studies, data suggests that children who have been deprived of contact or comfort develop alterations in their stress hormonal responses.

Studies of monkeys also can provide some insight into the relationship between stress hormones and depression, Dr. Kalin said. One long-ago experiment by Harlow focused on monkeys who were raised apart from their mothers with little or no physical contact with other animals. When these monkeys became mothers, they were either indifferent and withdrawn or violent and abusive to their offspring; they were unable to regulate their own emotions. This suggests that their early experience promoted the development of a vulnerability that proved to be very important when they became adults.

The offspring of these motherless mothers, moreover, began to exhibit similar abnormal behavior. The fact that some of the motherless monkeys were withdrawn and others were abusive reflects the differences among individuals who experience trauma, said Dr. Kalin. "We can't give a complete answer as to why one individual responds in one way and another responds in a completely different manner," he said. "We're dealing with very complicated brain systems involving numerous brain chemicals interacting across many brain regions."

Scientists hope that by studying how the stress response system relates to development and depression they may be able to develop early recognition and new treatment strategies, perhaps targeting early environmental factors as well as the hormonal systems that may be affected.

The Limbic System and Depression

Huda Akil, Ph.D., is the Gardner Quarton Distinguished University Professor of Neuroscience in the Department of Psychiatry at the University of Michigan and Co-director of the University's Mental Health Research Institute.

While we are improving our understanding of how the brain mediates emotion and mood, Dr. Akil said, there is much still to be done. "It's hard enough to understand how we move our hands and aim at a target," she said. "It's even harder to understand something more subtle, like feelings." For example, what is the biological basis of rumination? Do rats and mice ruminate?

Depression is a complex genetic disorder, Dr. Akil emphasized. Patterns of gene activity or "gene expression" in specific brain circuits are the result not only of genetic endowment, but also of the impact of experience on the brain. Thus, the brain is where genes and environment meet, and their interaction results in unique patterns of genetic activity that mediate specific behaviors. Hormones play a role in modulating these patterns of activity in the emotional circuitry. Women and men differ physically and psychologically, and they differ in the social demands made upon them. Women and men perceive social stress differently, and that stress, in turn, differs in its impact on their brains.

The limbic system, essential to processing emotions and handling stress, is a part of the brain relevant to depression. The component that interfaces between emotional processing and higher order cognition is the prefrontal cortex. The combination of thinking and feeling is important for mediating language, remembering, and anticipating. Humans do not live only moment-to-moment; emotions can persist from the past, and we can project them into the future. It is this ability to sustain emotions over long periods of time that represents a hallmark of human emotional responsiveness, and distinguishes immediate emotional reactions that might be shared with animals from longstanding changes in mood and affect.

In her studies of hamsters, Dr. Akil has identified brain circuits that are critical to psychosocial emotions, including social defeat. These circuits are not only generic stress circuits, but also they are quite specific and readily distinguishable from circuits that are activated during fighting that results in winning. Interestingly, these defeat circuits found in rodents parallel the circuits found to be disrupted in human depression. Though they are primitive, they represent a fundamental circuitry that encodes emotion and affect. This circuitry is further modulated in humans by the higher-order cortical information.

Dr. Akil described some possible future directions for research. Microarray technology involves placing on a small slide an entire genome of an animal or human. If a specific gene is expressed in a particular part of the brain, it will be detected by researchers using a dye of a particular color. When comparing two individuals and using a different color dye for each individual, researchers can use the interaction between the colors to detect whether the genes are active to a same or a different extent between the two subjects. This allows researchers to compare patterns of gene expression in particular brain regions across two groups of animals or two sets of human subjects. Since the entire genome is being examined, this not only focuses on the genes we already know, but allows us to discover the potential alterations in novel or previously unstudied genes. Such information can be applied to humans in an effort to understand psychiatric disorders that are not easily modeled in animals. Dr. Akil and her collaborators (members of the Conte Center Grant and the Pritzker Consortium: Drs. W. E. Bunney, E. Jones, D. Cox, S.J. Watson, A. Schatzberg) are beginning to use this microarray technology to uncover the unique patterns of gene expression in severely depressed individuals. They are studying differences between men and women as well as the differences among depressed and nondepressed men and women. The ultimate goal is to develop novel therapeutic targets. Using the human genome, Dr. Akil said, "We can come up with new directions on how to treat and think about depression."

Treating Depression

Kimberly Ann Yonkers, M.D., is Associate Professor in the Department of Psychiatry at the Yale School of Medicine. Dr. Yonkers focused on the treatment of depression. About 70 percent of people treated for depression will respond initially to treatment, she said. That does not necessarily mean they become totally well or stay well. "We need to come up with more pervasive and enduring treatments."

Among available treatments are antidepressant agents, including tricyclics (Elavil®, Tofranil®), monoamine oxidase inhibitors (Nardil®, Parnate®), and selective serotonin reuptake inhibitors (Paxil®, Prozac®, Zoloft®); psychotherapy; and electroconvulsive therapy (ECT). Alternative therapies include herbals such as St. John's wort and acupuncture.

Studying sex differences in treatment response may lead to an increased understanding of illness mechanisms; sex differences may provide a window into understanding the pathophysiology of psychiatric disorders, Dr.Yonkers said. Gender may influence depression treatment responses because:

Sex-specific processes may be associated with the cause of subtypes of mood disorders, such as premenstrual dysphoric disorder and postpartum depression
Sex-specific processes may affect the ways treatments work
Differences in brain function or structure may relate to responses
Some medications are absorbed, distributed, or metabolized differently in men and women
Hormone receptors could be interacting with other receptors and could reflect differences in treatment responses

Sex-specific responses are related to certain mood disorders. Women experience premenstrual dysphoria, postpartum depression, and perimenopausal depression. Men manifest late-life minor depression and hypogonadal depression.

In the past ten years or so, new federal guidelines mandate that researchers conducting clinical trials compare how women and men respond to medications instead of just comparing the efficacy of a medication versus a placebo. Research suggests that men respond better to tricyclics than monoamine oxidase inhibitors, while younger women respond better to monoamine oxidase inhibitors, Dr. Yonkers said. In postmenopausal women, however, tricyclics and monoamine oxidase inhibitors work equally well. Women are more likely to respond to ECT. Men and women are equally likely to respond either to cognitive behavior therapy or interpersonal psychotherapy.

PANEL DISCUSSION

Following Dr. Yonkers's presentation, Mary Blehar, Ph.D., Chief of the Women's Mental Health Program at NIMH, moderated a panel that addressed questions from the audience. Presenters were joined by Peter Schmidt, M.D., Chief, Unit on Reproductive Endocrinology, in the Behavioral Endocrinology Branch, NIMH. Questions and answers were wide ranging.

Q: Could depression be contagious?

A: There is evidence that depression is increasing in younger age groups, which has led some researchers to suggest a role for a changing incidence of environmental triggers, such as use of street drugs or environmental stress. There is no evidence, however, that depression is "contagious" in the sense of being caused by a specific pathogen such as a germ or virus. There is evidence that some pediatric obsessive-compulsive disorders might result from the response of the autoimmune system to streptococcal infections. It is highly likely that infections that affect the immune system also can impact the brain and mood, but the precise cause-and-effect relationship has not been established.

Q: What do we know about the contribution of genetic factors to depression? Is there any evidence of a gender difference in these factors? Is a daughter more likely to inherit depression than a son? Does it matter whether depression is inherited from a mother or a father?

A: Family and twin studies indicate that major depression tends to run in families. Beyond that, we know little as yet about specific genetic factors predisposing to depression, so we also know little about possible gender differences. Twin studies indicate that depression is heritable in both women and men, and there is some evidence from these studies that the extent of heritability may differ between the sexes. These studies also suggest that somewhat different constellations of genetic, biological, and environmental risk factors may predispose to depression in men and women. NIMH currently is funding molecular genetic studies to identify vulnerability genes in one form of highly heritable depression—recurrent early-onset depression. This work also may further elucidate the role of gender differences in depression.

Q: If women are twice as likely as men to suffer from depression, are women also twice as likely as men to become depressed as a reaction to life events?

A: This is a complicated question. Approximately 70% of episodes of major depression are preceded close in time by a stressful life event, so we know that stress plays some role in triggering depression. And there is evidence suggesting that women and men may differ in their behavioral—and even biological—responses to stress. Therefore, researchers are investigating the mechanisms by which stress contributes to depression and the role that gender plays in this.

Some evidence shows that women and men differ in the life events they perceive as highly stressful, and there are some studies indicating that women develop depression following a greater range of stressful events than men. For example, one study found that women and men are likely to report events as stressful that occur to their immediate family, but women also are adversely affected by events occurring to a range of people in their social network. Differences, then, in "stress potential" of different events also may contribute to gender differences in rates of depression.

Q: Are there developmental or lifespan differences in risk for depression? How do these play out in the two sexes?

A: The childbearing years are the time of highest risk for depression in women. This is particularly important not only for the affected women but also for families because maternal depression, such as postpartum depression, is reported to have a negative impact on child mental health. Although fewer men than women are diagnosed with depression, men with depression are at higher risk for completed suicide and the risk is particularly high in older men. However, women with depression are more likely to attempt suicide than are men. A recent report suggests that women with early-onset chronic depression may have poorer occupational and social functional outcomes relative to other women with depression or men with early-onset chronic depression.

Q: How about depression following the onset and diagnosis of an illness such as cancer? What do we know about gender differences here?

A: Women are more likely to seek health care both for mental health problems in specialized settings and for physical conditions in primary care settings. We know that depression accompanying other medical conditions is the most common mental illness in primary care settings, and we know that women are more likely to be diagnosed as having depression in these settings. Thus, co-occurring depression in general medical settings does exhibit a pattern of gender differences similar to that found in community settings. We also know that it is important to identify depression in primary care settings because untreated depression that accompanies other medical conditions has a worse outcome than conditions that are uncomplicated by depression.

People with undiagnosed depression may report physical symptoms that are, in fact, a manifestation of their depression. This may lead to higher health care costs for unnecessary medical screening tests. There is also some evidence that in primary care settings women are more likely than men to manifest forms of depression characterized by bodily complaints (for example, fatigue, aches, and pains).

Q: How does exercise help combat depression?

A: Exercise, when it causes the body to release endorphins, seems to have a beneficial effect on mood, but very little is known about its effects in persons with clinical major depression. One practical obstacle to using exercise for the treatment of depression is that many people who are depressed do not have the energy or motivation to initiate exercise so they never get to the point where they can recognize this effect. We need to do more research to determine what role exercise can play in preventing and treating depression and for which types of depression it may be more appropriate. Some animal studies suggest that exercise can contribute to increasing the production of new brain cells, so it is possible that exercise has real salutary effects on mood and cognition.

Q: Does treatment of depression in adolescent females differ from treatment of depression in adolescent males?

A: Unfortunately, we have very little information about the treatment of adolescent depression in terms of the most effective medications and/or therapy. There are currently only a few pharmacological studies of depression in adolescent samples and a few studies of psychotherapies. Although these studies indicate that both of these treatments are effective, they have not reported on gender differences in outcome. We do know that adolescent depression has more frequent comorbidity with conduct disorders and substance abuse in males and with anxiety disorders and eating disorders in females. A good direction for future study might well be to focus on devising treatments that address these differing comorbid conditions in the course of treating depression in adolescent males and females.

Q: Do people develop a tolerance for an antidepressant so that the medication they take becomes less effective?

A: People taking antidepressants over a period of time following an acute episode of depression are at less risk for a relapse or recurrent episode than those who discontinue medication after the acute episode, but new relapses and recurrences happen even in those on medication. In that sense, an antidepressant's effects may "wear off" over time. Researchers are looking at strategies to prevent this from happening, but at this point we do not know if this lessening of effectiveness is a counter-response to the medication—that is, the systems that were out of balance over-respond—or if the lessening of effectiveness is a result of the patient's metabolism. NIMH research is currently focusing not only on acute treatment of an episode of depression but also on maintenance and relapse prevention strategies, which may be different than the interventions used for acute phase treatment.

We are learning that depression is more complex than we realized. Currently, we conceive of depression as a single illness; ten years from now, we may see it as ten different illnesses. Depression may be more like fever, a nonspecific condition that tells us that something is severely wrong in the emotional-cognitive interface.

Q: Can we realistically speak of "curing" depression?

A: Just as we have many types of respiratory conditions ranging from acute infections to chronic or recurrent conditions such as asthma and bronchitis, we have different manifestations of mood disorders. Some individuals report only one episode of depression over a lifetime; more people with depression have a chronic course or recurrent episodes. The prevalence of chronic depression, including dysthymia, chronic major depression, and major depression with incomplete symptomatic recovery is more than 5%. Recurrent depression is also common. One study found that after one year, 30% of persons with depression had not recovered completely. Of those who recovered, 60% had a relapse within five years. Other data suggest that each recurrence increases the likelihood of another episode. Some research suggests that depression actually changes the brain circuitry, so becoming depressed makes us more vulnerable to further episodes of depression. In these cases, clinicians are coming to view depression as a chronic condition to be managed using strategies used for the treatment of other chronic conditions.

Q: What is the most exciting research going on now?

A: NIMH's budget is about $1.1 billion. Of that, about $140 million is going to depression research; this disorder affects 20 million Americans and we have some promising scientific leads.

One of those is research into identifying genes that increase vulnerability to depression. Identifying vulnerability factors will provide us with novel targets for developing treatments. We would like to be able to ask, "What is it about this version of this gene that puts you at risk? At what point does it affect the developing brain? Could understanding this gene lead us to behavioral prevention?"

We also are finding that emotional tuning is controlled by very precise circuitry, just as motor control and vision are controlled by precise circuitry.

Finally, we are convinced that more research into potential commonalities in human societies could help account for the similar ratios in depression and other mood disorders across cultures.

Source: National Instititute of Mental Health - September 07, 2001

Depression in Women and Men: What's the Difference?

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Depression in Women and Men:
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