Angier, Natalie. "Drug Works, but Questions Remain," New York Times, 13 December 1993, p.


Angier, Natalie. "Drug Works, but Questions Remain," New York Times, 13 December 1993, p.

It was not so very long ago that people who were on antidepressant medication wanted above all
else to get off it. The original drugs had many unpleasant side effects, from dizziness and painful
dry mouth to weight gain and sluggishness. Doctors, too, were uneasy about the potency of the
pills, and thus prescribed the medications for short courses, up to nine months maximum.

Many doctors say that are comfortable keeping their patients on the newer antidepressants for
long stretches. They say the drugs are safer than the older generation of pills, are almost
impossible to overdose on, have fewer side effects and work wonderfully for patients who were
difficult to treat before, including those who suffer from panic disorders, anxiety attacks, bulimia,
anorexia, or obsessive-compulsive disorder.

Yet the medical portrait of a Prozac and related compounds emerging from years of use among
millions of patients is not a simple sunburst of unfettered success. The drugs bear their own
disturbing consequences and question marks, particularly in their long-term risks. Some doctors
worry that, with all the pep talk surrounding the novel antidepressants, the trouble spots are being
ignored and the pills being presented as the pharmacological equivalent of a Snackwell fat-free
cookie: a chance at bliss without paying the price.

"Drugs like Prozac are so deceptively easy to take and tolerate that they can excuse a physicians
from respecting the complexity of depression," said Dr. Frederick K. Goodwin, director of the
National Institute of Mental Health.

But that has not stopped some patients. Rebecca L. Morgan of Monaca Pa., has been on Prozac
for three years, since she was 27, and she has no intention of quitting, ever. The drug is the
flagship member of a new fleet of antidepressants, and it has transformed her life. Before Prozac,
she could not keep a job for more than a few months at a time. For the past year and a half, she
had been a counselor for the mental health association in Beaver County. Before Prozac, she
suffered five episodes of major depression, during which she could hardly drag herself off her
couch or feel enough to realize she was miserable. Now, she still has emotional peaks and
troughs, but when she is faced with an adverse event, she does not slide into a depression as she
says she would have in the past.

"I don't know what the long-term effects of the drug are," she said, "but if 20 years from now
they say it affects the kidneys or the lungs or whatever, I'm willing to pay the price. Prozac helps
me now."

Ms. Morgan is snot alone in embracing Prozac as a permanent therapy for the chronic problem
that is her melancholic nature. Since Prozac was introduced five years ago, it popularity has
soared to tropospheric heights. More than 10 million people have taken the drug worldwide, early
for its maker, Eli Lilly & Company, about $1 billion a year. Many other people are using even
newer, chemically related drugs called by the trade names Paxil and Zoloft. And while most
remain on the medication for less than a year, a sizable minority are staying on the drugs for two
years or longer.

Much of the relative safety of the new class of drugs, called serotonin re-uptake inhibitors, lies in
the biochemical specificity. The original antidepressants, introduced in the 1950s and known as
the tricyclics and the monoamine oxidase inhibitors, jiggle multiple biochemical pathways in the
brain and reconfigure the balance of several different types of signaling molecules, or
neurotransmitters. By comparison, Prozac and its cousins zero in on one neurotransmitter,
serotonin, brightening mood and lessening anxiety by keeping pools of the chemical available in
the brain for nerve cells to use and reuse. Greater specificity in the nervous system means fewer
side effects throughout the body.

Nevertheless, some researchers warned that serotonin is a muscular chemical and that
manipulating it even with exquisite specificity is bound to reverberate in unexpected ways.
Although early fears that Prozac may occasionally initiate violent or suicidal behavior have not
been supported by extensive clinical studies, new studies show that serotonin re-uptake inhibitors
have a more sever impact on sexuality than at first estimated, causing symptoms like impotence,
an inability to ejaculate, an inability to reach orgasm a loss of sensation in the vagina, and an all
round loss in one's erotic affairs.

"The early studies on this suggested an incidence of about 2 percent, but that was based on
self-reporting, from the patients," said Dr. Peter Kramer, author of the best seller "Listening to
Prozac." "When researchers went out and vigorously interviewed people, they found 40 percent
had some sexual dysfunction."

Another common side effect of the new antidepressants that had been underemphasized until
recently, said Dr. Brian Doyle, director of the Georgetown Anxiety Disorders program, is sleep
disturbances. Perhaps a third of the Prozac users suffer severe insomnia, and some who manage
to fall asleep report excessively vivid dreams that can verge on nightmares.

For those Prozac users in whom insomnia becomes unbearable, some doctors prescribe small
doses of, oddly enough, the older tricyclic antidepressants, which can be sedating. But physicians
never mix the serotonin re-uptake inhibitors with the monoamine oxidase inhibitors; that
combination can be extremely dangerous, causing rigidity, rapid fluctuations in vital signs,
extreme agitation progressing to delirium, coma and even death.

Researchers also warned that the serotonin compounds do not work for 20 percent to 40 percent
of depressed or anxious people who try them, the same failure rate seen with the older
antidepressants. Some patients say they find drugs like Prozac disorienting or too
amphetamine-like in their properties, causing problems in concentration and memory.

Apart from know side effects, the risks of taking any antidepressant drug for years is not yet
clear, for the simple reason so far no one has taken the drug for very long. In studies with mice
and pigs, Canadian investigators have found that antidepressants can act as tumor promoters,
hastening the growth of nascent malignancies. These preliminary results have yet to be confirmed
by others, and there is no evidence to suggest that antidepressant contribute to cancer in humans,
but some researchers admit that the long-term risks remain to be gauged.

Because women suffer a disproportionate rate of depression and thus are more likely to be takers
of Prozac, a few studies have looked at the effect of the antidepressants on pregnant women. So
far, researchers have seen no increase in birth defects from the drugs, but women who take any
sort of antidepressant drug, including Prozac, have about twice the rate of miscarriages during the
first trimester of pregnancy as do women not on the medications.

Nor can researchers be sure that exposing a fetus to a drug capable of altering the balance of
neuronal signaling molecules does not have a subtle impact on the brain that only shows up years
later, say, as a learning disorder./ In addition, a nursing mother on Prozac may transmit traces of
the medication to her infant, again width unknown effects.

The trend toward treating recurrent depression as a chronic disease, deserving of long-term, if not
lifetime treatment with antidepressants, is likely to accelerate, doctors said.

Eighty to 90 percent of people who had one episode of depression will have another," said Dr.
David Kupfer, a professor and chairman of psychiatry at the University of Pittsburgh School of
Medicine. "That realization makes me much more aggressive. People need long-term treatment,
and we need to figure out the best strategy."

But some researchers observe with concern that the drift toward extended drug regimens is
occurring in parallel with another trend: prescribing antidepressants for people who are not really
depressed.Prozac is now being given with some regularity to patients diagnosed as "dysthymic,"
jargon for perpetually crabby, under the weather, insecure, malcontent.

"Dysthymia has less of a biological feel to it," than does full-blown depression, said Dr. Doyle of
Georgetown Anxiety Disorders program. "There's not as much of the sleep disturbances or the
appetite problems. These are people who realize they're more unhappy than the situation calls
for, and the meditation, exercise, talking to friends just doesn't do the trick."

As it turns out, Dr. Doyle said, many dysthymics do very well on Prozac and its chemical
siblings, finding in the drugs a brightening of mood that therapy sessions along may have failed
to bring.

But whether the syndrome is a true disease is a matter of considerable debate among doctors.
And to some critics, the idea of people who are not really sick taking potent psychiatric drugs for
months or years is a sobering prospect indeed.