Barbara, a 39 year-old woman who had studied operatic singing, suffered from manic episodes. During one of them she started keeping her family up all night with prayer and loud singing. She was often not tired for days, scarcely sleeping at all. During one manic period she slept only two and a half hours a day. When interviewed by the psychiatrist at the hospital, she was wearing a flamboyant long red skirt with a peasant blouse and was heavily ornamented with huge earrings and numerous necklaces, bracelets, and medals pinned to her shirt. She talked fast, too loudly, and too much, frequently breaking into song. She could not be interrupted to answer the doctor’s questions.
Her talking and singing emphasized her intimate relationship with God, and she said that her beautiful singing voice was God’s gift, which she had to share with those less fortunate. She drove to New York City to inform the Metropolitan Opera that she might have time for several performances in between her other vocal activi-ties. Although Barbara has a beautiful voice and grandiose plans, she has not managed to create a career in singing due to the intrusion of mental illness and multiple hospitalizations, often for suicide attempts (Lickeyand Gordon, 1991).
The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) describes two principal types of affective disorder: major depression and bipolar disorder. Both of these are characterized by extreme and inappropriate exaggeration of mood (or affect). Major depression, also called unipolar depression, is characterized by recurring episodes of dysphoria and negative thinking that is also reflected in behavior. Bipolar disorder (also called bipolar depression), is also cyclic, but moods swing from depression to mania over time. The thinking and behavior of individuals with affective disorders are consistent with the exaggerated mood, but the mood does not reflect a realistic appraisal of the environment. Mood disorders are among the most common form of mental illness today and were described as early as 400 B.C. by Hippocrates. The Greeks called depression melancholia, meaning “black bile,” and recognized that it was associated with anxiety and heavy alcohol use. However, only in the last 150 years has it been recognized as a disorder of brain function.
Major depression damages the quality of life
We are all familiar with the essential feelings associated with depression: feeling down and blue, feeling listless, and lacking energy to do even the fun things we normally enjoy. The state of sadness that occurs in response to situations such as the loss of a loved one, failure to achieve goals, or disappointment in love is called reactive depression and does not constitute mental illness unless symptoms are disproportionate to the event or significantly prolonged. The fact that we all have experienced depression does not make the clinical condition any easier to understand. In clinical depression, the mood disorder is so severe that the individual withdraws from life and all social interactions. The intense pain and loneliness may make suicide seem like the only option. Pathological depression resembles the emotional state that we have all experienced but differs significantly both in intensity and duration.
The dysphoric mood is characterized by a loss of interest in almost everything and an inability to experience pleasure in anything (anhedonia). Most depressed patients express feelings of hopelessness, worthlessness, sadness, guilt, and desperation. Frequently, patients exhibit loss of appetite, insomnia, crying, diminished sexual desire, loss of ambition, fatigue, and either motor retardation or agitation. Self-devaluation and loss of self-esteem are very common and are combined with a complete sense of hopelessness about the future. Individuals may stop eating or caring for themselves physically, sometimes remaining in bed for prolonged periods. Other physical symptoms may include localized pain, severe digestive disturbances, and difficulty breathing.
Thoughts of suicide are common; one estimate of suicide rates suggests that 7 to 15% of depressed individuals commit suicide, in contrast to a rate of 1 to 1.5% in the overall population. The DSM-IV criteria for major depression and manic episodes. Although there are some common features of clinical depression, symptom clusters do vary with the individual. Furthermore, particular patterns of symptoms suggest that there are depression subtypes that may or may not be associated with distinct pathophysiologies.
If left untreated, most episodes of unipolar depression improve in about 6 to 9 months. However, the episodes usually recur throughout life, often increasing in frequency and intensity in later years. Although stress often precedes the first episodes of depression, later episodes are more likely to occur without the influence of psychosocial stress. Estimates of the incidence of depression vary significantly, but it is generally believed that 15 to 20% of the population experience depressive symptoms at any given time. The lifetime risk for a first episode of unipolar depression is between 3 and 4% for men and from 5 to 9% for women. The gender difference in the risk for depression is a topic of considerable interest and debate. The mean age of onset for depression is 27 years. This figure has decreased in recent years: Among Americans born before 1905, only 1% developed depression by age 75, whereas among those born since 1955, 6% had become depressed by age 24.
In bipolar disorder moods alternate from mania to depression
The second type of exaggerated mood is mania. Mania rarely occurs alone but rather alternates with periods of depression to form bipolar disorder. The primary symptom of mania is elation. Manic individuals feel faultless, full of fun, and bursting with energy. Their need for sleep is significantly reduced. They tend to be more talkative than usual and experience racing thoughts and ideas. In some individuals the predominant mood is irritability, belligerence, and impatience because the rest of us are just too slow. They tend to make impulsive decisions of the grandiose sort and have unlimited confidence in themselves.
The manic individual becomes involved in activities that have a high potential for negative consequences that often go unrecognized by the individual, such as foolish business investments, reckless driving, buying sprees, or sexual indiscretions. However, some individuals during a manic phase are capable of highly productive efforts when channeled appropriately. A high proportion of creative individuals in the arts and sciences have experienced bipolar disorder and find that during the manic periods their thought processes quicken and they feel both creative and productive. Is creativity linked to mental illness? Box 16.1 considers that possibility.
The incidence of bipolar disorder is the same in men and women: it occurs in approximately 1% of the population. The time of onset for bipolar illness is typically between 20 and 30 years of age, and episodes continue throughout the life span.
Risk factors for mood disorders are biological and environmental
Most scientists agree that psychiatric disorders develop in a given individual because of the interaction of genes and environmental events. Individuals with particular clusters of genes inherit the tendency to express certain traits or behaviors that increase their vulnerability to specific disorders. Having those genes does not mean you will develop the disorder, but exposure to particular environmental events is more likely to trigger the disorder in the vulnerable individual. Heredity, environmental stress, and altered biological rhythms are risk factors for affective disorders.
Role of heredity Evidence for a genetic contribution to affective disorders comes from several sources. Adoption studies help to clarify the role of genetics and family environment. In these studies, individuals with a firm diagnosis who were adopted at an early age are the focus of the research. If a heritable component exists, one would expect to see that, compared with controls, the individual with affective disorder has more biological relatives with the same disorder, despite being raised in a different environment. Although adoption studies suggest a role for genetics, the results have not always been consistent.
The best evidence for a heritable component to affective illness comes from twin studies, which show a significant difference between monozygotic (identical) and dizygotic (fraternal) twins in the rate of concordance for the disorders. If one twin has a mood disorder, the concordance rate (i.e., the likelihood of the other twin sharing the trait) for a monozygotic twin is approximately 65%. This means that if one of the pair of identical twins (having the same genes) experiences affective illness, the probability that the other twin will also experience some affective disorder is 65%. In contrast, the concordance rate for dizygotic twins (who are genetically no more similar than other siblings) is 20%. The difference in these two rates suggests the extent to which genetics contributes to the disorder. Keep in mind that if genetics were the only determining factor, the concordance rate in identical twins would be 100%. The genetics of an individual can certainly make him more vulnerable, but whether or not he actually develops the disorder must also depend on other psychosocial or pathophysiological factors.
Tthe concordance rate is also dependent on the severity of clinical depression: more severe mood disorders may have a stronger genetic contribution than less severe disorders. The genetic contribution to bipolar disorder is significantly greater than that to major depression. Eighty percent concordance in monozygotic twins compared to 16% in dizygotic twins indicates a very strong role for heredity in bipolar disorder.
Despite linkage studies, which look for similarities in gene location on chromosomes in families with affected members, and other more sophisticated methods of molecular biology that examine DNA fragments, no single dominant gene for affective disorders is known. We may well find that the genes involved confer a general vulnerability to a host of mood and anxiety disorders. The particular disorder that is expressed in an individual may ultimately be deter-mined by developmental or psychosocial factors.
Role of stress Both neurobiological studies and family studies indicate that anxiety and depression are closely related. First, anxiety along with its associated physiological symptoms is a frequent accompaniment to depression. Second, intense environmental stress and anxiety often precede episodes of depression, particularly early on in the course of the disorder. Further, altered patterns of stress hormone levels are frequently found in depressed patients. The realtionship between anxiety and depresssion. Despite the importance of environmental stress, keep in mind that identical life stresses may be perceived very differently by individuals. Many people seem resilient and capable of coping despite extraordinary stresses, while others seem to succumb to relatively minor problems. It is likely that genetics plays a role in determining how one responds physically and behaviorally to daily traumas and stress. The dual importance of nature (genetics) and nurture (environment) can never be ignored.
The importance of stress to the etiology of depression and its mediation by the hypothalamic-pituitary-adrenal (HPA) axis is a significant focus in neuroscience. In response to stress, multiple neurotransmitters (including norepinephrine, acetylcholine, and y-aminobutyric acid [GABA]) regulate the secretion of corticotropin-releasing factor (CRF) from hypothalamic cells. CRF controls the release of adrenocorticotropic hormone (ACTH) from the pituitary into the blood. ACTH in turn acts on the adrenal gland to increase secretion of cortisol and other glucocorticoids, which all play a role in the mobilization of energy to deal with stress. Normally, cortisol feeds back to shut down HPA activation, resulting in transient activity of the system and brief surges in cortisol.
Among the most consistent neuroendocrine abnormalities in depressed individuals is abnormal secretion of cortisol, which is demonstrated in several ways. First, many depressed patients have elevated levels of cortisol in response to a greater-than-normal release of ACTH. Although both the pituitary and adrenal glands are enlarged due to hypersecretion, evidence from several sources suggests that the abnormality is not in the glands but is in the brain. The hypersecretion is most likely due to abnormal regulation of CRF by the hypothalamus. Numerous studies have found higher-than-normal levels of CRF in the cerebrospinal fluid (CSF) of depressed patients and increased numbers of CRF-producing cells in the hypothalamus in postmortem brain tissue. It is important to note that antidepressant drug treatment and electroconvulsive therapy reduce CRF levels in depressed patients.
Second, the high level of cortisol found in depressed patients is characterized by an abnormal circadian rhythm in cortisol secretion. The elevated and relatively flat pattern may reflect a more general abnormality in the biological clock, since altered rhythmicity also occurs for body temperature changes and sleep patterns (see below). Third, since many depressed individuals have elevated cortisol, it is not surprising that some fail to respond to dexamethasone challenge. Dexamethasone is a synthetic glucocorticoid that should act as a negative-feedback stimulus to suppress hypothalamic release of CRF and pituitary release of ACTH, resulting in decreased cortisol levels. Several studies have suggested that patients who remain nonresponders to dexamethasone (i.e., fail to have cortisol release suppressed) after successful antidepressant treatment have a higher probability of relapse than those who show normal response.
Although usually adrenal glucocorticoids (including cortisol) are helpful in preparing an organism for stress, when the levels are persistently elevated, several systems begin to show pathological changes. Besides having damaging effects on immune-system and organ function, glucocorticoids are also associated with neuronal atrophy in the hippocampus, leading to cognitive impairment, imbalances in the serotonin (5- HT) system correlated with anxiety, and hormonal changes associated with depression (McEwen et al., 1994). The section on the neurobiological models of depression later in a future post will provide more detail on the role of glucocorticoids in depression.
Altered biological rhythms Cortisol secretion is not the only biological rhythm that is disturbed in major depression. Altered sleep rhythms are among the most common and persistent symptoms of depression. Circadian rhythm controls the onset, pattern, and termination of sleep. The normal sleep cycle is quite regular, having four stages of non-REM sleep (stages 1 to 4) lasting a total of 70 to 100 minutes followed by a 10- to 15-minute period of rapid eye movement (REM) sleep, during which time dreaming occurs. This cycle is repeated four or five times a night. Depressed individuals show several distinct abnormalities in their sleep rhythm. First, there is a long period before sleep onset.
Second, there is a significant decrease in the time spent in slow-wave sleep, or deep sleep (stages 3 and 4), which leads to repeated awakenings during the night. Third, the onset of REM sleep occurs much earlier after the onset of sleep. In extreme cases, the individual may enter REM sleep almost immediately after falling asleep. Fourth, REM sleep is significantly increased during the first one third of the night in depressed individuals, while nondepressed individuals have proportionately more REM sleep in the final one third of sleep. Also, while normal REM periods tend to increase in duration during the night, depressed patients do not show such a pattern. Finally, when ocular movement is measured, depressed individuals show more frequent and vigorous eye movements during REM sleep, which suggests more-intense dreaming.
Although we don’t know what the altered rhythms mean, the irregularities in sleep patterns found in depressed individuals resemble the sleep patterns of normal individuals who must alter their time of sleep by 12 hours. Since other indicators of biological rhythms, such as body temperature fluctuation and hormonal secretion (e.g., cortisol), are often also altered, one might consider the possibility that the biological clocks of people with depression are “phase-shifted.” In some individuals, the three rhythms are out of harmony (called desynchronization) or are mismatched. The implications of these irregularities have led to several novel treatment strategies.