The Growing Role of Drug Therapies

July 06, 1992

As doctors learn more about the biology of mental illness, they are unlocking the mysteries of depression and creating a new science of the mind

By PHILIP ELMER-DEWITT -- With reporting by Andrew Purvis/New York and Dick Thompson/Washington

Mental illness can wear many masks. Most are subtler than the deranged face of schizophrenia, but they can be just as paralyzing. Take the case of Dick Cavett. To many TV viewers, the talk-show host and actor seemed to have it all -- wit, charm, fame and fortune. But behind the glib facade, Cavett was falling apart. About 12 years ago, a chronic depression that had haunted him for years rose up and began undermining what he believed was his most valuable asset: his intellect. He became convinced that his brain was "broken" and that life without it was hardly worth living. "Everything seemed to be growing gray," he recalls. "All the things that used to give me pleasure suddenly weren't worth the effort."

Desperate, Cavett checked into a hospital, where for five weeks he was protected from himself while a seemingly mild but potent drug called an MAO inhibitor took effect. Such antidepressants cause subtle changes in the concentrations of certain neurotransmitters, the chemicals that carry electrical messages to and from nerve cells in the brain. The medication, which he still takes on a maintenance dose in conjunction with psychotherapy, worked. His wit, humor and facility for words returned, good as new. And Cavvett came away from the experience with a conviction that his disorder was, as he puts it, "absolutely chemical."

That conviction reflects a growing consensus among scientists that dysfunctions like depression and schizophrenia -- and indeed most mental disorders -- are at their core disruptions of normal brain chemistry and can often be treated as such. The talk-therapy tradition pioneered by Freud and others still has its place. Subconscious issues are believed to affect brain chemistry, and most studies show that drug treatments work best when administered along with some form of talk therapy. But it is the psychopharmacologists, not the psychiatrists, who are making the breakthroughs in mental-health circles.

"There is an explosion of activity," says Richard Wyatt, chief of neuropsychiatry at the National Institute of Mental Health (NIMH) in Bethesda, Md. With computerized scanners, researchers are peering at the chemistry of the working mind. Meanwhile, molecular biologists are beginning to map abnormal behavior to specific strands of dna. And by tracing the action of drugs like clozapine for schizophrenia and Prozac (fluoxetine) for depression, scientists can link moods and feelings to the action of certain chemicals in the brain. The result is a burst of new ideas about how the mind works -- and what is going on when it does not -- unequaled since the days of Freud and Jung.

Advances are being made against virtually every affliction to which the human mind is prey. Generalized anxiety can be treated with surprising success with benzodiazepines like Valium, as well as with a new drug called BuSpar (buspirone). Manic depression was effectively treated with lithium long before anyone knew why it worked; now therapy is being fine-tuned with medications like the anticonvulsant Tegretol (carbamazepine) and drugs that ameliorate lithium's side effects. Debilitating panic attacks can be prevented with both antidepressants and benzodiazepines. Hyperactivity, addictive disorders, phobias, sleep disturbances, even dementia -- all are succumbing to the new science of the brain.

But it is the treatment of ordinary depression -- the crushing despondency that strikes more than 12 million Americans each year and accounts for at least half the nation's suicides -- that represents mental health's greatest success story. The condition once called melancholia, and now better known as clinical or major depression, has been the target of an all-fronts research assault over the past decade. The immediate result is a crop of new, highly specific antidepressant drugs that offer fast relief with relatively few side effects. Today depression can be treated -- quickly and effectively -- in 7 cases out of 10. If a second round of treatment is required, the cure rate jumps to 90%.

Depression comes in many flavors, from seasonal depressions that come and go with the short days of winter to low-level chronic depressions that linger for months. Among the symptoms of clinical depression are weight loss, early waking, diminished sex drive and a general hopelessness. But some people have what are called atypical depressions in which they put on weight and sleep much of the day.

Of course not everyone who has the blues is depressed. Feelings of sadness, frustration and unhappiness are natural reactions to real-life problems -- a painful loss, a relationship gone sour, a conflict that won't go away. Psychiatrists refer to such reactions as "adjustment disorders," and the people who suffer from them as the "worried well." A simple rule of thumb prevails: If the symptoms gradually clear up as the problem subsides, you've probably had an ordinary adjustment disorder. If not, you may be suffering from clinical depression.

Increasingly, researchers are seeing depression as a "disregulation" of the brain's reaction to stress. Even a bad case of clinical depression will not go on forever: the disease tends to run its course in nine months to a year. Unfortunately, it often returns. The initial episode has what researchers call a "kindling effect"; it seems to carve a pathway in the brain that leaves 70% of its victims vulnerable to another attack. "While a psychosocial stress can be involved in the onset of the first episode, the triggering mechanism for subsequent depressions can be more autonomous," says Robert Post, the NIMH scientist who developed the kindling theory. "Once someone has a number of depressions, they are likely to happen on their own."

As with Thorazine for schizophrenia, the first breakthrough for treating depression with drugs came accidentally. Doctors using a tuberculosis drug called iproniazid in 1952 discovered that the medicine had a remarkable effect on the mood of their patients: they literally began dancing in the halls.

Five years later, scientists found out why. Iproniazid falls into the category of antidepressant medications known as MAO inhibitors, which work by blocking the breakdown of two potent neurotransmitters -- norepinephrine and serotonin -- and allowing them to bathe the nerve endings for an extended length of time. A second category of antidepressants, the tri cyclics (so named for their triple-carbon-ring structure), raises the level of these neurotransmitters in the brain by slowing the rate at which they are reabsorbed by nerve cells. The third and newest category of medications, represented by the popular Prozac and a number of other drugs, inhibits the uptake of zero serotonin alone. As a result of this specificity, these newest drugs reverse depressive symptoms without the severe side effects of other antidepressants, which can cause low blood pressure, dizziness and blurred vision if not monitored. (Some people allege, however, that Prozac can cause irrational behavior and suicidal tendencies.)

The effectiveness of Prozac, which is the world's top-selling antidepressant, has led some researchers to speculate that serotonin is the key regulator of mood, and that depression is essentially a shortfall of serotonin. But the theory has some serious flaws. If serotonin is so important, why do the tricyclics (which affect both norepinephrine and serotonin) work slightly better than the drugs that act on serotonin alone? And why, since these drugs act quickly to change the serotonin levels in the brain, does it take up to a month for their effects to be felt? Finally, some scientists wonder how a single neurotransmitter could trigger the disruptions of sleep, appetite, memory, learning and sexuality that characterize a typical depressive episode. The nerve endings responsible for these functions, after all, are located in totally different regions of the brain.

Some scientists believe that the neurotransmitters are just links in a chain of reactions and that the real master molecules of mood reside higher up in that chain. One leading candidate: a substance called corticotropin-releasing hormone, or crh, which is pumped directly into the spinal fluid and thus bathes the entire brain at once. Discovered in 1981 by researchers studying the biochemistry of stress, crh is known to promote vigilance and decrease interest in food and sex when administered in small doses. In higher doses, it triggers anxiety. When Philip Gold, chief of the clinical neuroendocrinology branch of the NIMH, began looking for the hormone in his depressed patients, he found it was not only elevated, but elevated all the time -- even during sleep. What looked like depression was really a state of hyper-arousal, a kind of permanent flight-or-fight response. "In melancholia," explains Gold, "CRH gets stuck."

CRH may be the master molecule of more than just depression. This stress-related substance is also elevated in people suffering from obsessive-compulsive disorders and eating disorders such as anorexia and bulimia. Equally intriguing is the fact that the same drugs used to treat depression are effective against all these conditions and against panic attacks as well. Some researchers have therefore concluded that the diverse disorders may in fact be linked. "Depression may be only the tip of the iceberg of a family of dysfunctions," says James Hudson, a psychiatrist at Harvard.

Much work remains to be done to explain the connection between these disorders and determine why abnormal levels of CRH would lead to one set of symptoms in one person and another in someone else. Genetics may ultimately hold many of the answers. But it is clear that the study of depression and the drugs that relieve it has opened a breathtaking view on the mysterious world of human mood and emotion -- and provided new ways to calm some of its most troubling storms.

Copyright (c) TIME Magazine, 1995 TIME Inc. Magazine Company; (c) 1995 Compact Publishing, Inc.

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