Spring 1996 Volume 5, Number 2

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More-and Meaner-Than It Seems

BY JERROLD F. ROSENBAUM, M.D.

The term "depression" misleadingly suggests mere transient discouragement or sadness, rather than a pervasive and persisting state of pain and dysfunction. Not only does the patient suffer, but the impact reverberates through family, friends, and fellow workers as well.

Society suffers, too: Estimates of the direct and indirect costs of depression range up to $43 billion a year. And for many, even after recovery, impairments linger in their relationships with friends and family, recreational activities, sexual function, and overall satisfaction with life.

Depression is formally defined by the presence, for two weeks or more, of depressed mood, loss of interest or pleasure, excessive guilt, impaired concentration, fatigue and loss of energy, appetite and sleep changes, agitated or retarded motor behavior and suicidality. Depressions can begin at any age, and vary widely in their course, severity, and predominant symptoms. Occasionally self-limited, depression typically persists or recurs and requires treatment to restore a normal life to the sufferer.

Even patients who only experience some depressive symptoms are more significantly impaired in most aspects of physical and social functioning than patients with common chronic medical illnesses, excepting those with severe coronary artery disease.

Risk and Diagnosis
Studies indicate that at least one in six people will experience a major depressive disorder in their lifetime and that the probability has increased in recent decades among family members of depressed individuals. The age of onset of depression also is dropping, and depression risk in the young is on the increase.

Despite the impact on quality of life and the availability of effective treatments, the majority of people with depression are neither diagnosed nor treated. Further, many who seek treatment are not helped sufficiently to restore well-being. Perhaps least recognized by patients and doctors alike is that depression is a disorder analogous to other chronic and recurrent conditions, such as high blood pressure or diabetes, and needs continuing monitoring and maintenance treatment. This lack of recognition is dangerous:

• The longer a person has suffered depression before treatment, the less likely is recovery. Continual psychological stress, the presence of other co-existing medical and psychiatric ("co-morbid") illnesses, alcohol and substance abuse, and adverse socioeconomic status such as low family income, all limit the prospects for recovery as well.

• The majority of those who do recover will experience a recurrence; the more episodes already experienced, the higher the likelihood of still another recurrence. Three or more prior episodes are a significant risk factor for recurrence after recovery --more than 90 percent. Other risk factors for recurrence include the presence of chronic symptoms, a late age of onset (over age 60), long episodes, a family history of mood disorders, residual symptoms after treatment, and associated anxiety disorders or substance abuse.

• Almost one in six adults whose depression is severe enough to call for hospitalization die of suicide. In adolescents, increasing rates of depression have brought a dramatically expanding teen suicide rate --a four-fold increase for younger adolescents in the last 40 years --making suicide their third leading cause of death. (Kids, tragically, are at particular risk for under-recognition and under-treatment.) Suicides among adolescents in the last three decades rose from 8 per 100,000 to 24 per 100,000.

Milder forms of depression are also important to diagnose and treat: They may be chronic and recurrent, are significant causes of work, social and family dysfunction, are risks for developing other illnesses, and are associated with risk of suicide.

The rate for depression in connection with other medical illnesses is quite high: about 20 percent for people who have had a heart attack; from 25 to 30 percent for Parkinson's disease patients; and, in stroke patients, about 30 to 35 percent.

Depression itself is associated with many physical symptoms such as pain complaints, chest pain, fatigue, and bowel dysfunction. Immune dysfunction also has been associated with depression.

In ill and frail populations, depression is a significant risk factor for death. For example, in studies of nursing home patients with medical illnesses, the presence of depression substantially increased the likelihood of death. Depression has also been associated with increased mortality during recovery from heart attack. However, researchers are still studying whether treating associated depression can actually alter the course of medical illnesses such as cancer.

Treatment
The better news is that, in general, a wide array of antidepressant drugs all appear to be equally effective and doctors can prescribe them according to safety and tolerability for individual patients. The most commonly used medications are the newer class of drugs, "selective serotonin reuptake inhibitors" (SSRI's), which include such agents as fluoxetine, paroxetine, and sertraline. While these are no more effective than the older tricyclic antidepressants (TCA's), many patients find them more tolerable and safe over time, making it easier to stay with treatment --an indispensable requirement for successful therapy.

For some types of depression, particular drugs may be more effective than others. For example, "atypical" depression (featuring variability of mood over time, reactivity of mood to stressful life events, and overeating, oversleeping and intense fatigue) appears to respond particularly well to drugs known as "MAO inhibitors" compared to the TCA's. Whether the SRRI's are also better than the TCA's for this condition is being studied. The critical issue is to make sure that the patient receives a tolerable agent and an adequate dose, for long enough to produce successful treatment.

Interestingly, research has been able to produce good treatment without fully understanding the underlying neurobiological dysfunction in depression. The effective drugs target very specific brain systems --systems using "monoamine" neurotransmitters, in particular norepinephrine, serotonin, and dopamine. These neurotransmitters broadly influence brain function in regulating activity of brain stem, limbic system, and cerebral cortex, areas important in arousal, attention, vigilance, and emotion.

A relatively small number of cells make norepinephrine and serotonin, but they project to much of the rest of the brain, where they play their part in arousal, information processing, and hormone release. Dopamine, for its part, is involved in the control of motivated behavior and movement as well. That drugs aimed at these neurotransmitters bring relief indicates that disturbances in these systems account for many of depression's core symptoms, such as dysregulation of mood, sleep, appetite, energy, and even cognition.

Answers still missing
But gleaning this much from observing the action of drugs does not explain all the features of depression, nor indeed does it even to explain how antidepresssants manage to relieve the disorder. For example, even though antidepressant medications rapidly alter monoamine transmission, it takes many days or weeks for patients to notice the effect. This suggests that other brain events occur after administration of these drugs and somewhere other than in the monamine systems.

Accounting for this is a challenge. The brain's monoamine systems alone are quite complex; for example, there are 14 known subtypes of the receptor (a molecule on the surface of a nerve cell) to which serotonin attaches. Taking an antidepressant most likely initiates a neurobiological process of adaptation, beginning with the nerve cell receptors, followed by "second messenger signals" from other chemicals inside the nerve cell, these ultimately modifying the activity of genes within the nerve cells. This hypothesis is consistent with the delayed arrival of relief from depression symptoms.

The full story of depression in the brain must be discovered, because a substantial minority of patients are not adequately treated by any drugs available today. Ten to 15 percent do not respond, and 30 percent more continue to suffer symptoms despite partial improvement. In particular, research has been inadequate for depression in women of childbearing potential, the elderly and medically ill, and children and adolescents.

For people who respond poorly to the drugs now available, electroconvulsive therapy is very effective. Other people eventually recover after many drugs are tried, suggesting that, for them, certain antidepressants are more effective than others, despite the lack of evidence that one class of agents is superior to another for most people with depression.

Research at the Massachusetts General Hospital Depression Program indicates that the most common reason for treatment failure in depression is that a patient is simply receiving too little medication. But, for people who respond poorly to treatment, strategies such as adding lithium or combining different types of antidepressants appear to be helpful.

The long-term implications of taking antidepressants are an ongoing issue of research. Since the course of many patients with depression is that the likelihood of recurrence increases and the period of wellness between episodes shortens, many researchers argue for early, vigorous and lengthy treatment to prevent the disorder's apparent escalation over time. Whether this strategy does blunt the typical accelerating course remains an important question for study, but, to date, there has been no evidence of long-term cumulative adverse effects for maintaining on antidepressants.

Another area that begs for more study is the role of genes. Depression is a family affair: If a parent is depressed, children have a one in four chance of developing depression by age 17, increasing to a 50-50 chance if both parents are depressed. Although psychosocial factors and environmental stressors are known to be important to the onset and course of depression, the best data available suggest that these events are risks particularly in those with mood disorders running in the family.

Long-term studies do suggest that psychosocial stressors are important in triggering for early depression episodes. But once a pattern of mood disorders is established, patients appear to become more vulnerable even without precipitating traumatic events. This suggests that the depressive illness itself, once initiated, can become autonomous and accelerating, a potent argument for establishing long-term maintenance treatment in many patients.

Making the diagnosis of depression is critical. For many, it finally identifies what has been plaguing them, helps them understand the illness that they have been confronting and reveals that the failure to defeat their demons represents not a moral failing, but a disease --one that ought to have a name that says what it really is. *