ENCUMBERING DEPRESSION
Introduced by: RICHARD J.KOSCIEJEW
Deliberating discussions about depression have often given to effect the linguistic statement as to phraseological expressions applying depression to a strong attachment of subsequent interpretations as affiliated in the raw stock with the common everyday sorts of dispirited gloom. The simplicity as grounded in psychopathology, are the ubiquitous affliction to which most of us are subject from time to time. Such discussions may note that any one time. one fifth of the adult population will have significant depressive symptoms, and that most of this depression goes untreated (Weissman and Meyers, 1981). It may also be suggested that whoever is most likely to become depressed is largely a matter of psychological background and social conditions; depression is a ‘curse of civilization’, and its occurrence is linked to stress and deprivation, the disintegration of relationships, and depressing life circumstances. Thus, Pearlin (1975) has stated that depression is ‘intertwined with the values and aspirations that people acquire, with the hidden nature of the situation in which they are performing major roles, such as in occupation and family; with the location of people in broader social structure, such as age and class; and the coping devices that they use . . .
At the other extreme, the dialectic awareness of depression may begin with an assertion that it is one of the most serious of mental-health problems. The deliberation of depression may then go on to emphasize that it is primarily a biological disturbance, an illness, the predisposition to which lies in genes and biochemistry. While people may react to their circumstance with happiness and unhappiness, this is of questionable relevance to the clinical phenomena of depression.
Advocates of each of the positions can marshal impressive evidence, yet, taken together, they present basic contradiction. They differ not only in their view of the causes of depression but its very definition. Beck (1967) has noted, ‘there are few psychiatric syndromes whose clinical descriptions are so constant through successive eras of history‘. However, as these opposing positions demonstrate, definitional problems continue to plague the study of depression, and they are not going to be readily resolved. There remains considerable disagreement as to what extent and for what purpose a depressed mood in relatively normal persons can be seen as one end of a continuum with the mood disturbance seen in hospitalized psychiatric patients and to what extent the clinical phenomena is distinct and discontinuous with normal sadness and unhappiness.
Should we limit the term ‘depression’ to those people who are most distressed and seeking treatment? And what do we make of the ‘merely miserable’ that we have defined out of the ‘depressed’ category? If we agree to make a sharp distinction, where is it to be drawn? What of the differences among depressed persons? The position on these questions that one takes have major implications for who one studies and who one treats and how, what data are going to be considered relevant, and how one organizes that data. Many of the differences in the theoretical positions to be deliberated with a fundamental difference in how depression is defined. We cannot pretend to resolve these controversies, but we can at least identify them and note some of the definitions and distinctions that are being employed currently.
Depression can take several other forms. In bipolar disorder, sometimes called manic-depressive illness, a person’s mood swings back and forth between depression and mania. People with seasonal affective disorder typically suffer from depression only during autumn and winter, when there are fewer hours of daylight. In dysthymia, people feel depressed, have low self-esteem, and concentrate poorly most of the time - often for a period of years - but their symptoms are milder than in major depression. Some people with dysthymia experience occasional episodes of major depression. Mental health professionals use the term clinical depression to refer to any of the above forms of depression.
Depression is one of the most common mental illnesses. At least 8 percent of adults in the United States experience serious depression at some point during their lives, and estimates range as high as 17 percent. The illness affects all people, regardless of sex, race, ethnicity, or socioeconomic standing. However, women are two to three times more likely than men to suffer from depression. Experts disagree on the reason for this difference. Some cite differences in hormones, and others point to the stress caused by society’s expectations of women.
Depression occurs in all parts of the world, although the pattern of symptoms can vary. The prevalence of depression in other countries varies widely, from 1.5 percent of people in Taiwan to 19 percent of people in Lebanon. Some researchers believe methods of gathering data on depression account for different rates.
A number of large-scale studies indicate that depression rates have increased worldwide over the past several decades. Furthermore, younger generations are experiencing depression at an earlier age than did previous generations. Social scientists have proposed many explanations, including changes in family structure, urbanization, and reduced cultural and religious influences.
Although it may appear anytime from childhood to old age, depression usually begins during a person’s 20s or 30s. The illness may come on slowly, then deepen gradually over months or years. On the other hand, it may erupt suddenly in a few weeks or days. A person who develops severe depression may appear so confused, frightened, and unbalanced that observers speak of a ‘nervous breakdown.’ However it begins, depression causes serious changes in a person’s feelings and outlook. A person with major depression feels sad nearly every day and may cry often. People, work, and activities that used to bring them pleasure no longer do.
Symptoms of depression can vary by age. In younger children, depression may include physical complaints, such as stomachaches and headaches, as well as irritability, ‘moping around,’ social withdrawal, and changes in eating habits. They may feel unenthusiastic about school and other activities. In adolescents, common symptoms include sad mood, sleep disturbances, and lack of energy. Elderly people with depression usually complain of physical rather than emotional problems, which sometimes leads doctors to misdiagnose the illness.
Symptoms of depression can also vary by culture. In some cultures, depressed people may not experience sadness or guilt but may complain of physical problems. In Mediterranean cultures, for example, depressed people may complain of headaches or nerves. In Asian cultures they may complain of weakness, fatigue, or imbalance.
If left untreated, an episode of major depression typically lasts eight or nine months. About 85 percent of people who experience one bout of depression will experience future episodes.
Depression usually alters a person’s appetite, sometimes increasing it, but usually reducing it. Sleep habits often change as well. People with depression may oversleep or, more commonly, sleep for fewer hours. A depressed person might go to sleep at midnight, sleep restlessly, then wake up at 5 am feeling tired and blue. For many depressed people, early morning is the saddest time of the day.
Depression also changes one’s energy level. Some depressed people may be restless and agitated, engaging in fidgety movements and pacing. Others may feel sluggish and inactive, experiencing great fatigue, lack of energy, and a feeling of being worn out or carrying a heavy burden. Depressed people may also have difficulty thinking, poor concentration, and problems with memory.
People with depression often experience feelings of worthlessness, helplessness, guilt, and self-blame. They may interpret a minor failing on their part as a sign of incompetence or interpret minor criticism as condemnation. Some depressed people complain of being spiritually or morally dead. The mirror seems to reflect someone ugly and repulsive. Even a competent and decent person may feel deficient, cruel, stupid, phony, or guilty of having deceived others. People with major depression may experience such extreme emotional pain that they consider or attempt suicide. At least 15 percent of seriously depressed people commit suicide, and many more attempt it.
In some cases, people with depression may experience psychotic symptoms, such as delusions (false beliefs) and hallucinations (false sensory perceptions). Psychotic symptoms indicate an especially severe illness. Compared to other depressed people, those with psychotic symptoms have longer hospital stays, and after leaving, they are more likely to be moody and unhappy. They are also more likely to commit suicide
Some depressions seem to come out of the blue, even when things are going well. Others seem to have an obvious cause: a marital conflict, financial difficulty, or some personal failure. Yet many people with these problems do not become deeply depressed. Most psychologists believe depression results from an interaction between stressful life events and a person’s biological and psychological vulnerabilities.
Clinical depression is one of the most common forms of mental illness. Although depression can be treated with psychotherapy, many scientists believe there are biological causes for the disease. According to the June 1998 Scientific American article, neurobiologist Charles B. Nemeroff discusses the connection between biochemical changes in the brain and depression.
Depression runs in families. By studying twins, researchers have found evidence of a strong genetic influence in depression. Genetically identical twins raised in the same environment are three times more likely to have depression in common than fraternal twins, who have only about half of their genes in common. In addition, identical twins are five times more likely to have bipolar disorder in common. These findings suggest that vulnerability to depression and bipolar disorder can be inherited. Adoption studies have provided more evidence of a genetic role in depression. These studies show that children of depressed people are vulnerable to depression even when raised by adoptive parents.
Genes may influence depression by causing abnormal activity in the brain. Studies have shown that certain brain chemicals called neurotransmitters play an important role in regulating moods and emotions. Neurotransmitters involved in depression include norepinephrine, dopamine, and serotonin. Research in the 1960s suggested that depression results from lower than normal levels of these neurotransmitters in parts of the brain. Support for this theory came from the effects of antidepressant drugs, which work by increasing the levels of neurotransmitters involved in depression. However, later studies have discredited this simple explanation and have suggested a more complex relationship between neurotransmitter levels and depression.
An imbalance of hormones may also play a role in depression. Many depressed people have higher than normal levels of hydrocortisone (cortisol), a hormone secreted by the adrenal gland in response to stress. In addition, an underactive or overactive thyroid gland can lead to depression.
A variety of medical conditions can cause depression. These include dietary deficiencies in vitamin B6, vitamin B12, and folic acid; degenerative neurological disorders, such as Alzheimer’s disease and Huntington’s disease; strokes in the frontal part of the brain; and certain viral infections, such as hepatitis and mononucleosis. Certain medications, such as steroids, may also cause depression.
Psychological theories of depression focus on the way people think and behave. In a 1917 essay, Austrian psychoanalyst Sigmund Freud explained melancholia, or major depression, as a response to loss - either real loss, such as the death of a spouse, or symbolic loss, such as the failure to achieve an important goal. Freud believed that a person’s unconscious anger over loss weakens the ego, resulting in self-hate and self-destructive behaviour.
Cognitive theories of depression emphasize the role of irrational thought processes. American psychiatrist Aaron Beck proposed that depressed people tend to view themselves, their environment, and the future in a negative light because of errors in thinking. These errors include focussing on the negative aspects of any situation, misinterpreting facts in negative ways, and blaming themselves for any misfortune. In Beck’s view, people learn these self-defeating ways of looking at the world during early childhood. This negative thinking makes situations seem much worse than they really are and increases the risk of depression, especially in stressful situations.
In support of this cognitive view, people with ‘depressive’ personality traits appear to be more vulnerable than others to actual depression. Examples of depressive personality traits include gloominess, pessimism, introversion, self-criticism, excessive skepticism and criticism of others, deep feelings of inadequacy, and excessive brooding and worrying. In addition, people who regularly behave in dependent, hostile, and impulsive ways appear at greater risk for depression.
American psychologist Martin Seligman proposed that depression stems from ‘learned helplessness,’ an acquired belief that one cannot control the outcome of events. In this view, prolonged exposure to uncontrollable and inescapable events leads to apathy, pessimism, and loss of motivation. An adaptation of this theory by American psychologist Lynn Abramson and her colleagues argues that depression results not only from helplessness, but also from hopelessness. The hopelessness theory attributes depression to a pattern of negative thinking in which people blame themselves for negative life events, view the causes of those events as permanent, and overgeneralize specific weaknesses as applying to many areas of their life.
Psychologists agree that stressful experiences can trigger depression in people who are predisposed to the illness. For example, the death of a loved one may trigger depression. Psychologists usually distinguish true depression from grief, a normal process of mourning a loved one who has died. Other stressful experiences may include divorce, pregnancy, the loss of a job, and even childbirth. About 20 percent of women experience an episode of depression, known as postpartum depression, after having a baby. In addition, people with serious physical illnesses or disabilities often develop depression.
People who experience child abuse appear more vulnerable to depression than others. So, too, do people living under chronically stressful conditions, such as single mothers with many children and little or no support from friends or relatives.
Depression typically cannot be shaken or willed away. An episode must therefore run its course until it weakens either on its own or with treatment. Depression can be treated effectively with antidepressant drugs, psychotherapy, or a combination of both.
Despite the availability of effective treatment, most depressive disorders go untreated and undiagnosed. Studies indicate that general physicians fail to recognize depression in their patients at least half of the time. In addition, many doctors and patients view depression in elderly people as a normal part of aging, even though treatment for depression in older people is usually very effective.
Up to 70 percent of people with depression respond to antidepressant drugs. These medications appear to work by altering the levels of serotonin, norepinephrine, and other neurotransmitters in the brain. They generally take at least two to three weeks to become effective. Doctors cannot predict which type of antidepressant drug will work best for any particular person, so depressed people may need to try several types. Antidepressant drugs are not addictive, but they may produce unwanted side effects. To avoid relapse, people usually must continue taking the medication for several months after their symptoms improve.
Commonly used antidepressant drugs fall into three major classes: tricyclics, monoamine oxidase inhibitors (MAO inhibitors), and selective serotonin reuptake inhibitors (SSRIs). Tricyclics, named for their three-ring chemical structure, include amitriptyline (Elavil), imipramine (Tofanil), desipramine (Norpramin), doxepin (Sinequan), and nortriptyline (Pamelor). Side effects of tricyclics may include drowsiness, dizziness upon standing, blurred vision, nausea, insomnia, constipation, and dry mouth.
MAO inhibitors include isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). People who take MAO inhibitors must follow a diet that excludes tyramine - a substance found in wine, beer, some cheeses, and many fermented foods - to avoid a dangerous rise in blood pressure. In addition, MAO inhibitors have many of the same side effects as tricyclics.
Selective serotonin reuptake inhibitors include fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). These drugs generally produce fewer and milder side effects than do other types of antidepressants, although SSRIs may cause anxiety, insomnia, drowsiness, headaches, and sexual dysfunction. Some patients have alleged that Prozac causes violent or suicidal behaviour in a small number of cases, but the US Food and Drug Administration has failed to substantiate this claim.
Prozac became the most widely used antidepressant in the world soon after its introduction in the late 1980s by drug manufacturer Eli Lilly and Company. Many people find Prozac extremely effective in lifting depression. In addition, some people have reported that Prozac actually transform their personality by increasing their self-confidence, optimism, and energy level. However, mental health professionals have expressed serious ethical concerns over Prozac’s use as a ‘personality enhancer,’ especially among people without clinical depression.
Doctors often prescribe lithium carbonate, a natural mineral salt, to treat people with bipolar disorder. People often take lithium during periods of relatively normal mood to delay or even prevent subsequent mood swings. Side effects of lithium include nausea, stomach upset, vertigo, and frequent urination.
Studies have shown that short-term psychotherapy can relieve mild to moderate depression as effectively as antidepressant drugs. Unlike medication, psychotherapy produces no physiological side effects. In addition, depressed people treated with psychotherapy appear less likely to experience a relapse than those treated only with antidepressant medication. However, psychotherapy usually takes longer to produce benefits.
There are many kinds of psychotherapy. Cognitive-behavioural therapy assumes that depression stems from negative, often irrational thinking about oneself and one’s future. In this type of therapy, a person learns to understand and eventually eliminate those habits of negative thinking. In interpersonal therapy, the therapist helps a person resolve problems in relationships with others that may have caused the depression. The subsequent improvement in social relationships and support helps alleviate the depression. Psychodynamic therapy views depression as the result of internal, unconscious conflicts. Psychodynamic therapists focus on a person’s past experiences and the resolution of childhood conflicts. Psychoanalysis is an example of this type of therapy. Critics of long-term psychodynamic therapy argue that its effectiveness is scientifically unproven.
Electroconvulsive therapy (ECT) can often relieve severe depression in people who fail to respond to antidepressant medication and psychotherapy. In this type of therapy, a low-voltage electric current is passed through the brain for one to two seconds to produce a controlled seizure. Patients usually receive six to ten ECT treatments over several weeks. ECT remains controversial because it can cause disorientation and memory loss. Nevertheless, research has found it highly effective in alleviating severe depression.
For milder cases of depression, regular aerobic exercise may improve mood as effectively as psychotherapy or medication. In addition, some research indicates that dietary modifications can influence one’s mood by changing the level of serotonin in the brain.
An ubiquitous affliction to which depression in most of us is subject from time to time, in that this distinction may come about as discursive discoursing may take note. In that one fifth of the adult population will have significant depressive symptoms, and that most of this depression goes untreated (Weissman and Meyers, 1981). It may also be suggested that whoever is most likely to become depressed is largely a matter of psychological background and social conditions; depression is a ‘curse of civilization’, and its occurrence is linked to stress and deprivation, the disintegration of relationships, and depressing life circumstances. Thus, Pearlin (1975) has stated that depression is ‘intertwined with the values and aspirations that people acquire, with the hidden nature of the situation in which they are performing major roles, such as in occupation and family; with the location of people in broader social structure, such as age and class; and the coping devices that they use . . . ‘
At the other extreme, the dialectic awareness of depression may begin with an assertion that it is one of the most serious of mental-health problems. The deliberation of depression may then go on to emphasize that it is primarily a biological disturbance, an illness, the predisposition to which lies in genes and biochemistry. While people may react to their circumstance with happiness and unhappiness, this is of questionable relevance to the clinical phenomena of depression.
Advocates of each of the positions can marshal impressive evidence, yet , taken together, they present basic contradiction. They differ not only in their view of the causes of depression but its very definition. Beck (1967) has noted, ‘there are few psychiatric syndromes whose clinical descriptions are so constant through successive eras of history‘. However, as these opposing positions demonstrate, definitional problems continue to plague the study of depression, and they are not going to be readily resolved. There remains considerable disagreement as to what extent and for what purpose a depressed mood in relatively normal persons can be seen as one end of a continuum with the mood disturbance seen in hospitalized psychiatric patients and to what extent the clinical phenomena is distinct and discontinuous with normal sadness and unhappiness.
Should we limit the term ‘depression’ to those people who are most distressed and seeking treatment? And what do we make of the ‘merely miserable’ that we have defined out of the ‘depressed’ category? If we agree to make a sharp distinction, where is it to be drawn? What of the differences among depressed persons? The position on these questions that one takes have major implications for who one studies and who one treats and how, what data are going to be considered relevant, and how one organizes that data. Many of the differences in the theoretical positions to be deliberated with a fundamental difference in how depression is defined. We cannot pretend to resolve these controversies, but we can at least identify them and note some of the definitions and distinctions that are being employed currently.
An overview of the phenomena of depression and to take notice on some of the diagnostic distinctions that are currently being made, where it should become apparent that there is a tremendous heterogeneity to what falls under the broad rubic of depression and that there is an arbitrariness to any boundaries that are drawn on these phenomena. There are striking differences among depressed persons that invite some form of subtyping. However, efforts to derive such subtyping are generally controversial, and any scheme is likely to be more satisfactory for some purposes that for others. Confronted with all of this ambiguity and confusion, one must be cautious and not seek more precision than the phenomena of depression afford, and one should probably be sceptical about any decisive statement about the hidden nature of depression.
Contemplating the phenomena of depression, one can readily detect patterns and come to a conclusion that some aspects of depression are more central than others; some are primary and causal, and others are secondary. One observer may be struck with the frequency of complaints about appetite and sleep disturbance by depressed persons and infer that some sort of biological disturbance must be the key to understanding depression. Another might find their self-derogation and pessimism irrational in away that suggests that there must be some kind of fundamental deficit in self-esteem or cognitive distortion occurring. Still another may listen to the incessant complaining of a depressed person, get annoyed and frustrated, and yet feel guilty in a way that makes it easier to encourage the depressed person to continue to talk in this way than to verbalize these negative feelings. Cognizance of this, the observer might conclude that there is some sort of interpersonal process going on that is critical to any understanding of depression.
A major source of confusion is due to the fact that the term ‘depression’ variously refers to a mood state, a set of symptoms, and a clinical syndrome. As a reference to mood, depression identifies universal human experience. Adjectives from a standard measure of mood (The Multiple Affect Adjective Checklist; Zuckerman and Lubin, 1965) point to subjective feelings associated with a depressed mood; sad, unhappy, blue, low, discouraged, bored. hopeless, dejected and lonely. Similarities between everyday depressed mood and the complaints of depressed patients have encouraged the view that clinical depression is simply an exaggeration of a normal depressed mood. However, patients sometimes indicate that their experience of depression is quite distinct from normal feelings and sadness, even in its extreme form. A patient once remarked that her sadness was overwhelming when her husband died but that it did not compare with her sense of emptiness and her loss of any ability to experience pleasure at the time that she entered the hospital.
The view that depressed mood in otherwise normal persons is quantitatively but not qualitatively different than the depression found in hospitalized patients has been termed the ‘continuity hypothesis’. Beck (1967) has provided a useful analogy to suggest the alternative to the continuity hypothesis. He notes that everyday fluctuations in body temperature can be measured on the same thermometer as the changes associated with a fever. Yet the conditions giving rise to a fever are distinct from those causing fluctuations in temperature in healthy individuals. Similarly, the conditions giving rise to clinical depression may be distinct from those producing fluctuations in normal mood.
Studies have compared the subjective mood of persons who are distressed but not seeking help to those who are seeking treatment for depression or a review (Depur and Monroe, 1978). The two groups may be similar in subjective mood, but they differ in other ways. Those persons who are not seeking treatment for depression tend to lack the anxiety and the physical complaints, including loss of appetite, sleep disturbance, and fatigue shown by the group seeking treatment. Still, it could be argued that there is a continuum between the two groups, with these additional features arising when a normal depressed mood becomes more prolonged or intensified. The controversy is likely to continue until either questions about the etiology of depression are resolved or unambiguous markers for depression and identified.
Advocates of biomedical approaches to depression tend to assume that there is a discontinuity between a normal depressed mood and clinical depression, and that appropriate biological markers will be found. Yet, as the article by Winokur suggests, even if that proves to be the case, there are likely to be many individuals suffering from extremes of depressed mood who do not have these markers.
Advocates of psychoanalytic, cognitive and behavioural, and interpersonal and social perceptives or depression have generally assumed a continuum between a normal depressed mood and clinical depression. They tend to exclude psychotic and bipolar depressed persons from treatment, but, beyond that, they have tended to disregard classification issues (Gilbert, 1984). For unipolar depression, at least, they have assumed that whatever discontinuities the biology of mild and severe moods there might be are not necessarily relevant to the psychological and social processes in which they are most interested.
Writers since antiquity have noted the core symptoms of depression, besides a sad or low mood, reduced ability to experience pleasure, pessimism, inhibition and retardation of action, and a variety of physical complaints. For the purposes of dialogue, we can distinguish among the emotional, cognitive, motivational, and vegetative symptoms of depression, although these features are not always so neatly divisible. Beyond these symptoms, there are some characteristic interpersonal aspects of depression that are not usually considered as formal symptoms. But they are frequently, distinctive, and troublesome enough to warrant attention.
Sadness and dejection are not the only emotional manifestations of depression, although about half of all depressed patient reports these feelings as their principal complaint. Most depressed persons are also anxious and irritable. Classical descriptions of depression tend to emphasize that depressed person’ feelings and distress, disappointment, and frustration are focussed primarily on themselves, yet a number of studies suggest that their negative feelings, including over hostility, are also directed at the people around them. Depressed persons are often intensely angry persons (Kahn, Coyne, Margolin, Weissman and Paykel, 1971).
Perhaps 10 or 15 percent of severely depressed patients deny feelings of sadness, reporting instead that all emotional experience, including sadness, has been blunted or inhibited (Whybrow. Akiskal, and Kinney, 1984). The identification of these persons as depressed depends upon the presence of other symptoms. The inhibition of emotional expression in severely depressed persons may extend to crying. Whereas, mild and moderately depressed persons may readily and frequently cry, as they become more depressed, they may continue to feel like crying, but complain that no tears come.
Mildly and moderately depressed persons may feel every activity is a burden, yet they derive some satisfaction from their accomplishments. Despite their low mood, they may still crack a smile at a joke. Yet, as depression intensifies, a person may report both a loss of and ability to get gratification from activities that had previously been satisfying - family, work, and social life - and a loss of any sense of humour. Life becomes stale flat and not at all amusing. The loss of gratification my extend to the depressed persons’ involvement in close relationships. Often, a loss of affection for the spouse and children, a feeling of not being able to care anymore, a sense of a wall being erected between the depressed person and others are the major reasons for seeking treatment.
In the past decade, a number of theorists, notably Beck and Abramson, Seligman and Teasdale have given particular attention to the cognitive manifestations of depression and have assumed that these features are causal of the other aspects of the disorder. Depressed persons characteristically view themselves, their situations, and their future possibilities in negative and pessimistic terms. They voice discouragement, hopelessness and helplessness. They see themselves as inadequate and deficient in some crucial way. There may be thoughts of death, wishing to be dead, and suicide attempts.
Depressed persons’ involvement in their daily lives are interpreted by them in terms of loss, defeat, an deprivation, and they expect failure when they undertake an activity, they may criticize themselves for minor shortcomings and seemingly search for evidence that confirms their negative views of themselves. Beck and Kovacs suggest that they tailor the facts to fit these interpretations and hold on the in the face of contradictory evidence. Depressed persons over generalize from negative experience, selectively abstract negative details out of context, ignore more positive features of their situations, and negatively characterize themselves in absolutist and dichotomous terms. The revised learned-helplessness model emphasizes that their depressed persons are particularly prone to blame themselves fo their difficulties and to see their defects as stable and global attributes.
Aside from these content aspects of their thinking, depressed persons frequently complain that their thinking processes have slowed down, that they are distracted, and they cannot concentrate. Decisions pose a particular problem. Depressed persons are uncertain, feel in need of more information, and are afraid of making the wrong decision. They may simply feel paralysed, and that the work of making a choice and a commitment is an overwhelming task to be avoided at any cost.
Bipolar disorder, is a categorical mental illness in which a person’s mood alternates between extreme mania and depression. Bipolar disorder is also called manic-depressive illness. When manic, people with bipolar disorder feel intensely elated, self-important, energetic, and irritable. When depressed, they experience painful sadness, negative thinking, and indifference to things that used to bring them happiness.
American psychiatrist Kay Redfield Jamison is regarded as one of the world’s leading authorities on bipolar disorder, also known as manic-depressive illness. In her book An Unquiet Mind: A Memoir of Moods and Madness (1995), Jamison reveals her own struggle against the illness, which caused her to experience violent mood swings. She describes her initial resistance to taking medication that, while necessary to prevent debilitating depression, extinguished the exhilarating highs of mania.
Bipolar disorder is much less common than depression. In North America and Europe, about 1 percent of people experience bipolar disorder during their lives. Rates of bipolar disorder are similar throughout the world. In comparison, at least 8 percent of people experience serious depression during their lives. Bipolar disorder affects men and women about equally and is somewhat more common in higher socioeconomic classes. At least 15 percent of people with bipolar disorder commit suicide. This rate roughly equals the rate for people with major depression, the most severe form of depression.
Bipolar disorder is a mental illness that causes mood swings. In the manic phase, a person might feel ecstatic, self-important, and energetic. But when the person becomes depressed, the mood shifts to extreme sadness, negative thinking, and apathy. Some studies indicate that the disease occurs at unusually high rates in creative people, such as artists, writers, and musicians. But some researchers contend that the methodology of these studies was flawed and their results were misleading. In the October 1996 Discover Magazine article, anthropologist Jo Ann C. Gutin presents the results of several studies that explore the link between creativity and mental illness.
Some research suggests that highly creative people - such as artists, composers, writers, and poets - show unusually high rates of bipolar disorder, and that periods of mania fuel their creativity. Famous artists and writers who probably suffered from bipolar disorder include poets Lord Byron and Anne Sexton, novelists Virginia Woolf and Ernest Hemingway, composers Peter Ilyich Tchaikovsky and Sergey Rachmaninoff, and painters Amedeo Modigliani and Jackson Pollock. Critics of this research note that many creative people do not suffer from bipolar disorder, and that most people with bipolar disorder are not especially creative.
Bipolar disorder usually begins in a person’s late teens or 20s. Men usually experience mania as the first mood episode, whereas women typically experience depression first. Episodes of mania and depression usually last from several weeks to several months. On average, people with untreated bipolar disorder experience four episodes of mania or depression over any ten-year period. Many people with bipolar disorder function normally between episodes. In ‘rapid-cycling’ bipolar disorder, however, which represents 5 to 15 percent of all cases, a person experiences four or more mood episodes within a year and may have little or no normal functioning in between episodes. In rare cases, swings between mania and depression occur over a period of days.
In another type of bipolar disorder, a person experiences major depression and hypomanic episodes, or episodes of milder mania. In a related disorder called cyclothymic disorder, a person’s mood alternates between mild depression and mild mania. Some people with cyclothymic disorder later develop full-blown bipolar disorder. Bipolar disorder may also follow a seasonal pattern, with a person typically experiencing depression in the fall and winter and mania in the spring or summer.
People in the depressive phase of bipolar disorder feel intensely sad or profoundly indifferent to work, activities, and people that once brought them pleasure. They think slowly, concentrate poorly, feel tired, and experience changes - usually an increase - in their appetite and sleep. They often feel a sense of worthlessness or helplessness. In addition, they may feel pessimistic or hopeless about the future and may think about or attempt suicide. In some cases of severe depression, people may experience psychotic symptoms, such as delusions (false beliefs) or hallucinations (false sensory perceptions).
In the manic phase of bipolar disorder, people feel intensely and inappropriately happy, self-important, and irritable. In this highly energized state they sleep less, have racing thoughts, and talk in rapid-fire speech that goes off in many directions. They have inflated self-esteem and confidence and may even have delusions of grandeur. Mania may make people impatient and abrasive, and when frustrated, physically abusive. They often behave in socially inappropriate ways, think irrationally, and show impaired judgment. For example, they may take aeroplane trips all over the country, make indecent sexual advances, and formulate grandiose plans involving indiscriminate investments of money. The self-destructive behaviour of mania includes excessive gambling, buying outrageously expensive gifts, abusing alcohol or other drugs, and provoking confrontations with obnoxious or combative behaviour.
Clinical depression is one of the most common forms of mental illness. Although depression can be treated with psychotherapy, many scientists believe there are biological causes for the disease. In the June, 1998 Scientific American article, neurobiologist Charles B. Nemeroff discusses the connection between biochemical changes in the brain and depression.
The genes that a person inherits seem to have a strong influence on whether the person will develop bipolar disorder. Studies of twins provide evidence for this genetic influence. Among genetically identical twins where one twin has bipolar disorder, the other twin has the disorder in more than 70 percent of cases. But among pairs of fraternal twins, who have about half their genes in common, both twins have bipolar disorder in less than 15 percent of cases in which one twin has the disorder. The degree of genetic similarity seems to account for the difference between identical and fraternal twins. Further evidence for a genetic influence comes from studies of adopted children with bipolar disorder. These studies show that biological relatives of the children have a higher incidence of bipolar disorder than do people in the general population. Thus, bipolar disorder seems to run in families for genetic reasons.
Personal or work-related stress can trigger a manic episode, but this usually occurs in people with a genetic vulnerability. Other factors - such as prenatal development, childhood experiences, and social conditions - seem to have relatively little influence in causing bipolar disorder. One study examined the children of identical twins in which only one member of each pair of twins had bipolar disorder. The study found that regardless of whether the parent had bipolar disorder or not, all of the children had the same high 10-percent rate of bipolar disorder. This observation clearly suggests that risk for bipolar illness comes from genetic influence, not from exposure to a parent’s bipolar illness or from family problems caused by that illness.
Different therapies may shorten, delay, or even prevent the extreme moods caused by bipolar disorder. Lithium carbonate, a natural mineral salt, can help control both mania and depression in bipolar disorder. The drug generally takes two to three weeks to become effective. People with bipolar disorder may take lithium during periods of relatively normal mood to delay or prevent subsequent episodes of mania or depression. Common side effects of lithium include nausea, increased thirst and urination, vertigo, loss of appetite, and muscle weakness. In addition, long-term use can impair functioning of the kidneys. For this reason, doctors do not prescribe lithium to bipolar patients with kidney disease. Many people find the side effects so unpleasant that they stop taking the medication, which often results in relapse.
From 20 to 40 percent of people do not respond to lithium therapy. For these people, two anticonvulsant drugs may help dampen severe manic episodes: carbamazepine (Tegretol) and valproate (Depakene). The use of traditional antidepressants to treat bipolar disorder carries risks of triggering a manic episode or a rapid-cycling pattern.
Antidepressant, medication used to treat depression, a mood disorder characterized by such symptoms as sadness, decreased appetite, difficulty sleeping, fatigue, and a lack of enjoyment of activities previously found pleasurable. While everyone experiences episodes of sadness at some point in their lives, depression is distinguished from this sadness when symptoms are present most days for a period of at least two weeks. Antidepressants are often the first choice of treatment for depression.
Although the cause of depression is unknown, researchers have found that some depressed people have altered levels of chemicals called neurotransmitters, chemicals made and released by nerve cells, or neurons. One neuron, referred to as the presynaptic neuron, releases a neurotransmitter into the synapse, or space, between the neuron and a neighbouring cell. The neurotransmitter then attaches, or binds, to a neighbouring cell - the postsynaptic cell - to trigger a specific activity. Antidepressants work by interacting with neurotransmitters at three different points: they can change the rate at which the neurotransmitters are either created or broken down by the body; they can block the process in which a spent neurotransmitter is recycled by a presynaptic neuron and used again, called reuptake; or they can interfere with the binding of a neurotransmitter to neighbouring cells.
The first antidepressants, developed in the 1950s, are the tricyclic antidepressants (TCA) and the monoamine oxidase (MAO) inhibitors. TCAs block the reuptake of neurotransmitters into the presynaptic neurons, keeping the neurotransmitter in the synapse longer, and making more of the neurotransmitter available to the postsynaptic cell. TCAs include amitriptyline, doxepin, imipramine, nortriptyline, and desipramine.
MAO inhibitors decrease the rate at which neurotransmitters are broken down by the body so they are more available to interact with neurons. MAO inhibitors currently available in the United States include phenelzine and tranylcypromine.
Another group of antidepressants, known as selective serotonin reuptake inhibitors (SSRI), became available in 1987. SSRIs block the reuptake of the neurotransmitter serotonin into presynaptic neurons, thereby prolonging its activity. There are currently four SSRIs available for use in the United States: fluoxetine, sertraline, paroxetine, and fluvoxamine. Of this group, the best known is fluoxetine, commonly known by its brand name, Prozac.
Another antidepressant is venlafaxine, which works like TCAs but does not share their chemical structure, and it also causes different side effects. The antidepressant nefazodone prevents serotonin from binding to neighbouring neurons at one specific binding site (serotonin can bind to neurons on many sites). It also weakly blocks the reuptake of serotonin.
All antidepressants decrease symptoms of depression in about 70 percent of depressed people who take them. Most antidepressants take about two to three weeks of treatment before beneficial effects occur. Because no antidepressant is more effective than the others, doctors determine which antidepressant to prescribe according to the type of side effects an individual can tolerate. For instance, a person who takes TCAs and MAO inhibitors may notice dizziness and fainting when standing up, mouth dryness, difficulty urinating, constipation, and drowsiness. If people who take MAO inhibitors eat certain foods, such as aged cheese or some aged meats, they can experience severe headaches and raised blood pressure. SSRIs can cause side effects such as restlessness, difficulty sleeping, and interference with sexual function.
Clinical depression is quite different from the blues everyone feels at one time or another and even from the grief of bereavement. It is more debilitating and dangerous, and the overwhelming sadness combines with a number of other symptoms. In addition to becoming preoccupied with suicide, many people are plagued by guilt and a sense of worthlessness. They often have difficulty thinking clearly, remembering, or taking pleasure in anything. They may feel anxious and sapped of energy and have trouble eating and sleeping or may, instead, want to eat and sleep excessively.
Psychologists and neurobiologists sometimes debate whether ego-damaging experiences and self-deprecating thoughts or biological processes cause depression. The mind, however, does not exist without the brain. Considerable evidence indicates that regardless of the initial triggers, the final common pathways to depression involve biochemical changes in the brain. It is these changes that ultimately give rise to deep sadness and the other salient characteristics of depression. The full extent of those alterations is still being explored, but in the past few decades - and especially in the past several years - efforts to identify them have progressed rapidly.
At the moment, those of us teasing out the neurobiology of depression somewhat resemble blind searchers feeling different parts of a large, mysterious creature and trying to figure out how their deductions fit together. In fact, it may turn out that not all of our findings will intersect: biochemical abnormalities that are prominent in some depressives may differ from those predominant in others. Still, the extraordinary accumulation of discoveries is fuelling optimism that the major biological determinants of depression can be understood in detail and that those insights will open the way to improved methods of diagnosing, treating and preventing the condition.
One subgoal is to distinguish features that vary among depressed individuals. For instance, perhaps decreased activity of a specific neurotransmitter (a molecule that carries a signal between nerve cells) is central in some people, but in others, overactivity of a hormonal system is more influential (hormones circulate in the blood and can act far from the site of their secretion). A related goal is to identify simple biological markers able to indicate which profile fits a given patient; those markers could consist of, say, elevated or reduced levels of selected molecules in the blood or changes in some easily visualizable areas of the brain.
After testing a depressed patient for these markers, a psychiatrist could, in theory, prescribe a medication tailored to that individual's specific biological anomaly, much as a general practitioner can run a quick strep test for a patient complaining of a sore throat and then prescribe an appropriate antibiotic if the test is positive. Today psychiatrists have to choose antidepressant medications by intuition and trial and error, a situation that can put suicidal patients in jeopardy for weeks or months until the right compound is selected. (Often psychotherapy is needed as well, but it usually is not sufficient by itself, especially if the depression is fairly severe.)
Improving treatment is critically important. Although today's antidepressants have fewer side effects than those of old and can be extremely helpful in many cases, depression continues to exact a huge toll in suffering, lost lives and reduced productivity.
The prevalence is surprisingly great. It is estimated, for example, that 5 to 12 percent of men and 10 to 20 percent of women in the US will suffer from a major depressive episode at some time in their life. Roughly half of these individuals will become depressed more than once, and up to 10 percent (about 1.0 to 1.5 percent of Americans) will experience manic phases in addition to depressive ones, a condition known as manic-depressive illness or bipolar disorder. Mania is marked by a decreased need for sleep, rapid speech, delusions of grandeur, hyperactivity and a propensity to engage in such potentially self-destructive activities as promiscuous sex, spending sprees or reckless driving.
Beyond the pain and disability depression brings, it is a potential killer. As many as 15 percent of those who suffer from depression or bipolar disorder commit suicide each year. In 1996 the Centre for Disease Control and Prevention listed suicide as the ninth leading cause of death in the US (slightly behind infection with the AIDS virus), taking the lives of 30,862 people. Most investigators, however, believe this number is a gross underestimate. Many people who kill themselves do so in a way that allows another diagnosis to be listed on the death certificate, so that families can receive insurance benefits or avoid embarrassment. Further, some fraction of automobile accidents unquestionably are concealed suicides.
The financial drain is enormous as well. In 1992 the estimated costs of depression totalled $43 billion, mostly from reduced or lost worker productivity.
Accumulating findings indicate that severe depression also heightens the risk of dying after a heart attack or stroke. And it often reduces the quality of life for cancer patients and might reduce survival time.
Geneticists have provided some of the oldest proof of a biological component to depression in many people. Depression and manic-depression frequently run in families. Thus, close blood relatives (children, siblings and parents) of patients with severe depressive or bipolar disorder are much more likely to suffer from those or related conditions than are members of the general population. Studies of identical twins (who are genetically indistinguishable) and fraternal twins (whose genes generally are no more alike than those of other pairs of siblings) also support an inherited component. The finding of illness in both members of a pair is much higher for manic-depression in identical twins than in fraternal ones and is somewhat elevated for depression alone.
In the past 20 years, genetic researchers have expended great effort trying to identify the genes at fault. So far, though, those genes have evaded discovery, perhaps because a predisposition to depression involves several genes, each of which makes only a small, hard-to-detect contribution.
Preliminary reports from a study of an Amish population with an extensive history of manic-depression once raised the possibility that chromosome 11 held one or more genes producing vulnerability to bipolar disorder, but the finding did not hold up. A gene somewhere on the X chromosome could play a role in some cases of that condition, but the connection is not evident in most people who have been studied. Most recently, various regions of chromosome 18 and a site on chromosome 21 have been suggested to participate in vulnerability to bipolar illness, but these findings await replication.
As geneticists continue their searches, other investigators are concentrating on neurochemical aspects. Much of that work focuses on neurotransmitters. In particular, many cases of depression apparently stem at least in part from disturbances in brain circuits that convey signals through certain neurotransmitters of the monoamine class. These biochemical, all derivatives of amino acids, include serotonin, norepinephrine and dopamine; of these, only evidence relating to norepinephrine and serotonin is abundant.
Monoamines first drew the attention of depression researchers in the 1950s. Early in that decade, physicians discovered that severe depression arose in about 15 percent of patients who were treated for hypertension with the drug reserpine. This agent turned out to deplete monoamines. At about the same time doctors found that an agent prescribed against tuberculosis elevated mood in some users who were depressed. Follow-up investigations revealed that the drug inhibited the neuronal breakdown of monoamines by an enzyme (monoamine oxidase); presumably the agent eased depression by allowing monoamines to avoid degradation and to remain active in brain circuits. Together these findings implied that abnormally low levels of monoamines in the brain could cause depression. This insight led to the development of monoamine oxidase inhibitors as the first class of antidepressants.
But which monoamines were most important in depression? In the 1960s Joseph J. Schildkraut of Harvard University cast his vote with norepinephrine in the now classic "catecholamine" hypothesis of mood disorders. He proposed that depression stems from a deficiency of norepinephrine (which is also classified as a catecholamine) in certain brain circuits and that mania arises from an overabundance of the substance. The theory has since been refined, acknowledging, for instance, that decreases or elevations in norepinephrine do not alter moods in everyone. Nevertheless, the proposed link between norepinephrine depletion and depression has gained much experimental support. These circuits originate in the brain stem, primarily in the pigmented locus coeruleus, and project to many areas of the brain, including to the limbic system - a group of cortical and subcortical areas that play a significant part in regulating emotions.
To understand the recent evidence relating to norepinephrine and other monoamines, it helps to know how those neurotransmitters work. The points of contact between two neurons, or nerve cells, are termed synapses. Monoamines, like all neurotransmitters, travel from one neuron (the presynaptic cell) across a small gap (the synaptic cleft) and attach to receptor molecules on the surface of the second neuron (the postsynaptic cell). Such binding elicits intracellular changes that stimulate or inhibit firing of the postsynaptic cell. The effect of the neurotransmitter depends greatly on the nature and concentration of its receptors on the postsynaptic cells. Serotonin receptors, for instance, come in 13 or more subtypes that can vary in their sensitivity to serotonin and in the effects they produce.
The strength of signalling can also be influenced by the amount of neurotransmitter released and by how long it remains in the synaptic cleft - properties influenced by at least two kinds of molecules on the surface of the releasing cell: autoreceptors and transporters. When an autoreceptor becomes bound by neurotransmitter molecules in the synapse, the receptors signal the cell to reduce its firing rate and thus its release of the transmitter. The transporters physically pump neurotransmitter molecules from the synaptic cleft back into presynaptic cells, a process termed reuptake. Monoamine oxidase inside cells can affect synaptic neurotransmitter levels as well, by degrading monoamines and so reducing the amounts of those molecules available for release.
Among the findings linking impoverished synaptic norepinephrine levels to depression is the discovery in many studies that indirect markers of norepinephrine levels in the brain - levels of its metabolites, or by-products, in more accessible material (urine and cerebrospinal fluid) - are often low in depressed individuals. In addition, postmortem studies have revealed increased densities of certain norepinephrine receptors in the cortex of depressed suicide victims.
Observers unfamiliar with receptor display might assume that elevated numbers of receptors were a sign of more contact between norepinephrine and its receptors and more signal transmission. But this pattern of receptor "up-regulation" is actually one that scientists would expect if norepinephrine concentrations in synapses were abnormally low. When transmitter molecules become unusually scarce in synapses, postsynaptic cells often expand receptor numbers in a compensatory attempt to pick up whatever signals are available.
A recent discovery supporting the norepinephrine hypothesis is that new drugs selectively able to block norepinephrine reuptake, and so increase norepinephrine in synapses, are effective antidepressants in many people. One compound, reboxetine, is available as an antidepressant outside the US and is awaiting approval here.
The data connecting norepinephrine to depression are solid and still growing. Yet research into serotonin has taken centre stage in the 1990s, thanks to the therapeutic success of Prozac and related antidepressants that manipulate serotonin levels. Serious investigations into serotonin's role in mood disorders, however, have been going on for almost 30 years, ever since Arthur J. Prange, Jr., of the University of North Carolina at Chapel Hill, Alec Coppen of the Medical Research Council in England and their co-workers put forward the so-called permissive hypothesis. This view held that synaptic depletion of serotonin was another cause of depression, one that worked by promoting, or "permitting," a fall in norepinephrine levels.
Defects in serotonin-using circuits could certainly dampen norepinephrine signalling. Serotonin-producing neurons project from the raphenuclei in the brain stem to neurons in diverse regions of the central nervous system, including those that secrete or control the release of norepinephrine. Serotonin depletion might contribute to depression by affecting other kinds of neurons as well; serotonin-producing cells extend into many brain regions thought to participate in depressive symptoms - including the amygdala (an area involved in emotions), the hypothalamus (involved in appetite, libido and sleep) and cortical areas that participate in cognition and other higher processes.
Among the findings supporting a link between low synaptic serotonin levels and depression is that cerebrospinal fluid in depressed, and especially in suicidal, patients contains reduced amounts of a major serotonin by-product (signifying reduced levels of serotonin in the brain itself). In addition, levels of a surface molecule unique to serotonin-releasing cells in the brain are lower in depressed patients than in healthy subjects, implying that the numbers of serotonergic cells are reduced. Moreover, the density of at least one form of serotonin receptor - type 2 - is greater in postmortem brain tissue of depressed patients; as was true in studies of norepinephrine receptors, this up-regulation is suggestive of a compensatory response to too little serotonin in the synaptic cleft.
Further evidence comes from the remarkable therapeutic effectiveness of drugs that block presynaptic reuptake transporters from drawing serotonin out of the synaptic cleft. Tricyclic antidepressants (so-named because they contain three rings of chemical groups) joined monoamine oxidase inhibitors on pharmacy shelves in the late 1950s, although their mechanism of action was not known at the time. Eventually, though, they were found to produce many effects in the brain, including a decrease in serotonin reuptake and a consequent rise in serotonin levels in synapses.
Investigators suspected that this last effect accounted for their antidepressant action, but confirmation awaited the introduction in the late 1980s of Prozac and then other drugs (Paxil, Zoloft and Luvox) able to block serotonin reuptake transporters without affecting other brain monoamines. These selective serotonin reuptake inhibitors (SSRIs) have now revolutionized the treatment of depression, because they are highly effective and produce much milder side effects than older drugs do. Today even newer antidepressants, such as Effexor, block reuptake of both serotonin and norepinephrine.
Studies of serotonin have also offered new clues to why depressed individuals are more susceptible to heart attack and stroke. Activation and clumping of blood platelets (cell-like structures in blood) contribute to the formation of thrombi that can clog blood vessels and shut off blood flow to the heart and brain, thus damaging those organs. Work in my laboratory and elsewhere has shown that platelets of depressed people are particularly sensitive to activation signals, including, it seems, to those issued by serotonin, which amplifies platelet reactivity to other, stronger chemical stimuli. Further, the platelets of depressed patients bear reduced numbers of serotonin reuptake transporters. In other words, compared with the platelets of healthy people, those in depressed individuals probably are less able to soak up serotonin from their environment and thus to reduce their exposure to platelet-activation signals.
Disturbed functioning of serotonin or norepinephrine circuits, or both, contributes to depression in many people, but compelling work can equally claim that depression often involves dysregulation of brain circuits that control the activities of certain hormones. Indeed, hormonal alterations in depressed patients have long been evident.
The hypothalamus of the brain lies at the top of the hierarchy regulating hormone secretion. It manufactures and releases peptides (small chains of amino acids) that act on the pituitary, at the base of the brain, stimulating or inhibiting the pituitary's release of various hormones into the blood. These hormones - among them growth hormone, thyroid-stimulating hormone and adrenocorticotropic hormone (ACTH) - control the release of other hormones from target glands. In addition to functioning outside the nervous system, the hormones released in response to pituitary hormones feed back to the pituitary and hypothalamus. There they deliver inhibitory signals that keep hormone manufacture from becoming excessive.
Depressed patients have repeatedly been demonstrated to show a blunted response to a number of substances that normally stimulate the release of growth hormone. They also display aberrant responses to the hypothalamic substance that normally induces secretion of thyroid-stimulating hormone from the pituitary. In addition, a common cause of nonresponse to antidepressants is the presence of previously undiagnosed thyroid insufficiency.
All these findings are intriguing, but so far the strongest case has been made for dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis—the system that manages the body's response to stress. When a threat to physical or psychological well-being is detected, the hypothalamus amplifies production of corticotropin-releasing factor (CRF), which induces the pituitary to secrete ACTH. ACTH then instructs the adrenal gland atop each kidney to release cortisol. Together all the changes prepare the body to fight or flee and cause it to shut down activities that would distract from self-protection. For instance, cortisol enhances the delivery of fuel to muscles. At the same time, CRF depresses the appetite for food and sex and heightens alertness. Chronic activation of the HPA axis, however, may lay the ground for illness and, it appears, for depression.
As long ago as the late 1960s and early 1970s, several research groups reported increased activity in the HPA axis in unmedicated depressed patients, as evinced by raised levels of cortisol in urine, blood and cerebrospinal fluid, as well as by other measures. Hundreds, perhaps even thousands, of subsequent studies have confirmed that substantial numbers of depressed patients - particularly those most severely affected - display HPA-axis hyperactivity. Indeed, the finding is surely the most replicated one in all of biological psychiatry.
Deeper investigation of the phenomenon has now revealed alterations at each level of the HPA axis in depressed patients. For instance, both the adrenal gland and the pituitary are enlarged, and the adrenal gland hypersecretes cortisol. But many researchers, including my colleagues and me at Emory University, have become persuaded that aberrations in CRF-producing neurons of the hypothalamus and elsewhere bear most of the responsibility for HPA-axis hyperactivity and the emergence of depressive symptoms.
Notably, study after study has shown CRF concentrations in cerebrospinal fluid to be elevated in depressed patients, compared with control subjects or individuals with other psychiatric disorders. This magnification of CRF levels is reduced by treatment with antidepressants and by effective electroconvulsive therapy. Further, postmortem brain tissue studies have revealed a marked exaggeration both in the number of CRF-producing neurons in the hypothalamus and in the expression of the CRF gene (resulting in elevated CRF synthesis) in depressed patients as compared with controls. Moreover, delivery of CRF to the brains of laboratory animals produces behavioural effects that are cardinal features of depression in humans, namely, insomnia, decreased appetite, decreased libido and anxiety.
Neurobiologists do not yet know exactly how the genetic, monoamine and hormonal findings piece together, if indeed they always do. The discoveries nonetheless suggest a partial scenario for how people who endure traumatic childhoods become depressed later in life. This is know by its hypothesis, the stress-diathesis model of mood disorders, in recognition of the interaction between experience (stress) and inborn predisposition (diathesis).
The observation that depression runs in families means that certain genetic traits in the affected families somehow lower the threshold for depression. Conceivably, the genetic features directly or indirectly diminish monoamine levels in synapses or increase reactivity of the HPA axis to stress. The genetically determined threshold is not necessarily low enough to induce depression in the absence of serious stress but may then be pushed still lower by early, adverse life experiences.
Most people who experience episodes of mania also experience spells of severe depression. This pattern of mood swings between mania and depression defines a mental illness known as bipolar disorder, also called manic-depressive illness. In bipolar disorder, episodes of mania usually begin abruptly and last from several weeks to several months. Mild manic episodes can last a year or more. Depression may follow immediately or begin after a period of relatively normal functioning. Manic episodes may require hospitalization because of impaired social behaviour or the presence of psychotic symptoms
The symptoms of depression range from uncomfortable to debilitating: sleep disturbances, hopelessness, feelings of worthlessness, difficulty concentrating, fatigue and sometimes even delusions. Most of us have watched a relative or friend struggle with depression - and many of us have experienced it ourselves. Even so, few people realize just how common depression is, how severe it can be or that it is most prevalent among women. In 1990 the World Health Organization found depression to be the leading cause of "disease burden" (a composite measure including both illness and death) among women, noting that it affects almost 20 percent of the female population in the developed world. Epidemiological studies indicate that 12 percent of US women - compared with only 6 percent of US men - have suffered from clinically significant depression at some time in their lives.
The big question, of course, is why such a gender gap exists. Over the years various explanations have surfaced to account for the fact that, from one study to the next, depression is between two and three times more common among women than it is among men. Some mental health workers have pointed to psychology, arguing that women are better trained to recognize their feelings and seek help, so they come to the attention of health professionals more often than men. Others have suggested that oppression - in the form of physical or sexual abuse, harassment or discrimination - is to blame. Others still have attributed the increased rates of depression among women to the female reproductive system and the menstrual cycle.
Data from a variety of studies show that depression clearly has psychological, environmental and biological roots. Modern neuroscience is beginning to teach us how these roots can become intertwined and reinforce one another. In other words, an increased risk for depression in women might stem from genetics, the effects of stressful events or social pressures, or some combination of all three. Neuroimaging of the brain's circuitry by PET and MRI scans reveals that psychological phenomena such as anger and sadness have biological underpinnings; we can now see circuits of brain cells becoming activated when these emotions arise.
Similarly, neuroimages demonstrate that environmental and psychological experiences can alter our brain chemistry. For example, Lewis R. Baxter and his colleagues at the University of California at Los Angeles found similar changes on the PET scans of patients with obsessive-compulsive disorder who responded to treatment, regardless of whether the patients were treated with medication or with behavioural therapy.
To figure out why depression is more common among women, scientists have to study how genetics and environment divide the sexes - and how the two conspire to produce the symptoms we describe as depression. It is difficult work, and progress is necessarily slow. But what is coming into focus is that certain environmental factors - including stress, seasonal changes and social rank - may produce different physiological responses in females than they do in males. These findings, are small pieces in what is proving to be an incredibly complex puzzle. Laying them out at this stage does not begin to explain depression's double standard. Nevertheless, it could help scientists develop more effective treatments for depressed individuals - both women and men - in the meantime.
Many scientists have wondered whether there is some quirk in the way depression is inherited, such that a depressed parent or grandparent is more likely to pass on a predisposition for the disorder to female than to male descendants. Based on studies that trace family histories of depression, the answer to that question appears to be no. Women and men with similar heritage seem equally likely to develop the disorder. Simply tracing family histories, though, without also considering environmental influences, might not offer a complete picture of how depression is inherited.
Indeed, Kenneth S. Kendler and his colleagues at the Medical College of Virginia found in a study of 2,060 female twins that genetics might contribute to how women respond to environmental pressures. The researchers examined twins with and without a family history of depression; some twins in both groups had recently undergone a trauma, such as the death of a loved one or a divorce. The investigators found that among the women who did not have a family history of depression, stressful events raised their risk for depression by only 6 percent. But the same risk rose almost 14 percent among the women who did have a family history of depression. In other words, these women had seemingly inherited the propensity to become depressed in the wake of crises.
A similar study has not been done in men, leaving open the question of whether environmental stress and genetic risk for depression interact similarly in both sexes. But research is being done to determine whether men and women generally experience similar amounts and types of stress. Studies of key hormones hint that they do not. Hormones are not new to depression researchers. Many have wondered whether the gonadal steroids estrogen and progesterone - whose cyclic fluctuations in women regulate menstruation - might put women at a greater risk for depression. There are at least two ways in which they might do so.
First, because of differences between the X and Y chromosomes, male and female brains are exposed to different hormonal milieus in utero. These hormonal differences may affect brain development so that men and women have different vulnerabilities - and different physiological reactions to environmental stressors - later in life. Indeed, animal experiments show that early hormonal influences have marked behavioural consequences later on, although the phenomenon is of course difficult to study in humans.
Second, the fact that postpubertal men and women have different levels of circulating gonadal steroids might somehow put women at higher risk for depression. Research shows girls become more susceptible to depression than boys only after puberty, when they begin menstruating and experience hormonal fluxes. Even so, scientists have never been able to establish a direct relation between emotional states and levels of estrogen and progesterone in the blood of women. For example, Peter J. Schmidt and David R. Rubinow of the National Institute of Mental Health recently reported that manipulations of estrogen and progesterone did not affect mood, except in women who suffer from severe premenstrual mood changes.
It now appears, however, that estrogen might set the stage for depression indirectly by priming the body's stress response. During stressful times, the adrenal glands - which sit on top of the kidneys and are controlled by the pituitary gland in the brain - secrete higher levels of a hormone called cortisol, which increases the activity of the body's metabolic and immune systems, among others. In the normal course of events, stress increases cortisol secretion, but these elevated levels have a negative feedback effect on the pituitary, so that cortisol levels gradually return to norm
Evidence is emerging that estrogen might not only increase cortisol secretion but also decrease cortisol's ability to shut down its own secretion. The result might be a stress response that is not only more pronounced but also longer-lasting in women than in men.
For example, Nicholas C. Vamvakopoulos, George P. Chrousos and their colleagues at the National Institute of Child Health and Human Development recently found that increased levels of estrogen heighten the activity of the gene for human corticotropin-releasing hormone (CRH). This gene controls the secretion of CRH by a region of the brain called the hypothalamus. CRH makes the pituitary gland release adrenocorticotropic hormone (ACTH), which circulates in the blood and eventually reaches the adrenal glands, where it prompts the secretion of cortisol. Thus, estrogen can, by increasing CRH secretion, ultimately boost cortisol secretion. And Elizabeth A. Young of the University of Michigan and others have shown that female rats are more "resistant" to cortisol's negative feedback effects than are either male rats or spayed female rats. She has also shown that women have longer-lasting cortisol responses during the phase of the menstrual cycle when estrogen and progesterone levels are high.
It is unclear whether depression is a cause or a consequence of elevated cortisol levels, but the two are undoubtedly related. Over the past few decades, a number of studies have shown that cortisol levels are elevated in about half of all severely depressed people, both men and women. So the idea is this: if estrogen raises cortisol levels after stress or decreases cortisol's ability to shut down its own secretion, then estrogen might render women more prone to depression - particularly after a stressful event.
Despite their importance, estrogen and cortisol are not the only hormones involved in female depression, and stress is not the only environmental influence that might hold more sway over women than men. Recent findings by Thomas A. Wehr, Norman E. Rosenthal and their colleagues at the National Institute of Mental Health indicate that women might be more responsive physiologically than men to changes in exposure to light and dark. These investigators have had a long-standing interest in seasonal affective disorder (SAD), or so-called winter depression (although it can occur in the summer as well), and the role that the hormone melatonin might play in the illness. Similar to the gender ratio in other forms of depression, SAD is three times more common in women than in men.
Melatonin has been a prime suspect in SAD because organisms (including humans) secrete it only when they are in the dark and only when the body's internal clock (located in the hypothalamus) believes it is nighttime. The pineal gland, a small structure that resides deep in the mammalian brain, begins to secrete melatonin in the evening, as daylight wanes. Melatonin levels drop in the morning, when light hits the retinas of the eyes. Because nights are longer in winter than in summer, animals living in the wild secrete melatonin for longer periods each day during winter. Among animals that breed in summer, the onset of this extended daily melatonin secretion signals the presence of winter and shuts down the secretion of gonadal steroids that facilitate reproduction.
SAD researchers have long wondered whether a wintertime increase in the duration of melatonin secretion might also trigger depressive symptoms in susceptible individuals. In a series of ongoing studies designed to address this question, Wehr and his colleagues first asked whether humans, like animals, undergo seasonal changes in melatonin secretion. It is an important question, given that artificial light provides humans with an "endless summer" of sorts compared with animals in the wild. To find out, Wehr measured melatonin secretion in 15 humans when they were exposed to 14 hours of darkness and later to only eight hours of darkness each night. The results of this experiment, conducted mostly among men, were positive: people experiencing longer periods of darkness secreted melatonin for longer periods during the night, as wild animals do.
Next, the researchers asked whether this natural sensitivity to the seasonal day-length change persisted when people were allowed to follow their usual schedules, turning on artificial lights at night as they normally would. Here the researchers were surprised to find a gender difference. Under normal living conditions, women were more likely than men to retain a sensitivity to seasonal changes in day length. In other words, for women the duration of nocturnal melatonin secretion was longer in winter than summer; in men, however, there was no seasonal difference.
These results suggest that women are more sensitive to natural light than men - and that in a society where artificial light is everywhere, women somehow still detect seasonal changes in natural day length. Whether this gender difference puts women at increased risk for SAD is unclear; paradoxically, there is evidence that women with SAD symptoms may be less likely than unaffected women to have an increased duration of melatonin secretion in winter.
To complicate the story further, the relation between these findings and those regarding cortisol and estrogen are also unclear, because we don't know whether the duration of melatonin secretion affects reproductive function in women, as it surely does in animals. Researchers are now working to unravel the complicated relations between these hormonal systems and to determine whether, and how, they may influence individuals' risk for depression.
If women's bodies are in fact particularly sensitive to environmental changes, the explanation may lie within the system that controls serotonin, one of many so-called neurotransmitters that nerve cells use to communicate with one another. Serotonin modulates both cortisol and melatonin secretion. (The similarity in names between serotonin and melatonin is no accident: the latter is synthesized directly from the former, and the two have very similar chemical structures.) And a great deal of evidence indicates that dysfunction in the serotonergic, or serotonin-secreting, system contributes to depression and anxiety disorders, which are also more common in women than men. Recently research in animals and humans has provided preliminary, but key, insights into this system.
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