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                                                                                COVER STORIES, Page 57

DEPRESSION

The Growing Role of Drug Therapies

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.