NO PRESCRIPTION FOR HAPPINESS

Could It Be That Antidepressants Do Little More Than Placebos?

America's love affair with antidepressant drugs is peculiar indeed.

The big three - Prozac, Zoloft and Paxil - rank among the six best-selling
drugs of any kind, and more than 130 million prescriptions were written for
all antidepressants last year, according to IMS Health, a consulting firm.
But these drugs are much less effective than many consumers and doctors
believe. The newer antidepressant drugs post only marginal advantages over
placebos in clinical trials for major depression, and cause frequent and
unpleasant side effects.

Today's antidepressant drugs should be less appealing than the mood-altering
drugs that preceded them: A century ago, so many medicines were laced with
opium that we imported the equivalent of 15 doses to every man, woman, and
child in the country. No sooner had opium been curbed with early narcotics
laws that cocaine became popular. It was the original stimulant in Coca-Cola
and the darling of Sigmund Freud.

Starting in the 1930s, barbiturates became the drug of choice and eventually
more than 30 different drugs were on the market. In the 1950s came the next
boom, amphetamines, which were prescribed for everything from depression to
weight loss. This was followed by Valium and Librium and the tranquilizer
decade.

All these drugs altered moods and perception in a fundamentally pleasant
way. They produce outright mood elevation (opium), heightened energy and
concentration (amphetamines), or provided a calming effect (barbiturates and
tranquilizers). It is not hard to imagine why people wanted to take them.

However, by no stretch of the imagination are antidepressant drugs pleasant
to take for most patients. Consider Prozac, the drug that began the
antidepressant boom because it supposedly eliminated many of the side
effects that limited the popularity of its predecessors.

Prozac, according to Eli Lilly, causes rashes or hives in 7 percent of the
people who take it, insomnia in 20 percent, sedation in 13 percent, tremors
in 10 percent, nausea in 23 percent, diarrhea in 12 percent, and loss of
appetite in 12 percent. Because it was not well studied during testing,
sexual dysfunction was understated in the official ranking. Depending on
definitions, from 10 to 70 percent find their sex lives diminished.

Still, Prozac is by no means uniquely unpleasant. While there are
differences, a similar pattern of frequent adverse effects can be found
among all the popular antidepressants. Psychiatrists, of course, know this.
Here's what an important text, "Synopsis of Psychiatry," recommends to
doctors: "It is almost always good practice to explain side effects in
detail but to emphasize that they are signs the drug is working."

But is the drug really working? Is it producing important benefits in
relieving depression - benefits great enough to offset the side effects? Eli
Lilly, its manufacturer, declares that Prozac is, indeed, "significantly
more effective than placebo." But how much more effective?

According to the official record at the Food and Drug Administration, the
benefits are surprisingly similar to the effects of a placebo.

To get FDA approval, manufacturers conduct FDA-supervised clinical trials in
which some patients get a placebo and others the active drug. Neither
patient nor investigator is supposed to know who is taking the drug.

Lilly had conducted 10 such clinical trials for Prozac, according to FDA
records. However, in six of these trials no measurable overall difference
could be detected between those treated with Prozac and those who got the
placebo. Prozac was usually ahead slightly, but within a margin that often
could be explained by chance.

One trial deemed successful was based on such a small group of participants
that only eight patients taking Prozac completed it. The FDA discarded
another "successful" trial because no one could explain why one investigator
got so much better results than others giving the same drug to similar patients.

If one combines all the Prozac studies in FDA files, it becomes clear that
nearly 90 percent of the improvements reported by patients taking Prozac
were also reported by the patients taking placebos.

Prozac is not the only antidepressant to post marginal benefits in clinical
trials. Failure to produce a measurable effect is a routine event in the
testing of drugs for depression. Serzone, for example, was tested in eight
clinical trials, and produced a measurable benefit in only two. Another
drug, Paxil, was tested six times in identical protocols and failed to
produce a measurable effect in three of them.

It's possible that a drug effect existed in these many failed experiments
that was too small to be measured without a bigger study. However, such a
tiny effect is also too small to be of clinical interest.

It's also possible that the drugs really don't work in depression and that
the small effects seen are the results of other flaws in the clinical trials.

So how did so many doctors and patients get persuaded that these drugs are
so much more effective than the impartial and official scientific record
demonstrates? Here are some of the most important reasons:

Striking anecdotes. We all love those stories about people whose lives were
transformed by a drug. Some may describe a rare but real benefit. In other
cases, spontaneous improvement gets mistaken for a drug effect. Peter Kramer
filled an entire bestseller, "Listening to Prozac," with fetching anecdotes
he concedes do not portray the usual effects. But how many readers absorbed
this fine print?

Misleading statistics. Many scientific reports and medical textbooks cite
response rates that are inflated in one of several ways. In most studies, a
responder is someone whom the investigator judged to be much improved during
one weekly visit. But included as responders were people who improved in one
visit but later dropped out either because of adverse effects, lack of
efficacy, or both. Another approach is to ignore those who drop out. One
published trial of Effexor proclaimed that 90 percent of "completers" had
responded even though 36 percent abandoned the drug for adverse reactions,
lack of effect or other problems before the trial ended.

Selective publication of trial results. A recent federal study of 315
published clinical trials of 29 antidepressant drugs noted that every one
which identified a sponsor came from a drug company. While the FDA requires
companies to submit failed trials, reports of drugs with no effect seldom
make it to the medical journals.

For example, one published trial of Serzone with a marginal result matches
the FDA records. But an identical trial with no measurable drug effect did
not get published, according to the federal study. How many drug companies
are going to publish a study that makes their drug look bad?

Doctors' overestimates of benefits. A few studies submitted to the FDA
included the patient's evaluation as well as the doctor's opinion. In most
cases, patient reports indicated no difference between drug and placebo,
even when doctors thought they observed improvement.

For example, in two identical trials of Paxil, medical investigators thought
more Paxil patients improved, compared with those on a placebo. But
according to the patients' own evaluations, there was no difference between
treatment and placebo. In a third identical study, neither evaluation showed
a drug effect. Because doctors want to help people, it leads them to believe
drugs are working better than they do.

Misleading psychoactive effects. Even though the measured effects on
depression are marginal, these are still powerful psychoactive drugs that
change how people feel in many ways. Many patients report a lack of emotion
or being more detached from problems and everyday events that otherwise
might trouble them. Others get jittery, lose a lot of weight or break into
sweats. If changes do occur for the better, the drug may mistakenly be credited.

Giving the wrong credit for improvement. Over six weeks of treatment, a
majority of patients do improve, according to the trials conducted for FDA
approval. As measured by the Hamilton Depression scale, the scores drop
about 40 percent.

While far from a cure, this is a marked improvement. But as noted, patients
getting a placebo improved by a nearly similar amount. That means the
improvement comes for some other reason. What a pity so many give undeserved
credit to the drug, and not to their own efforts.

These factors - along with the billions spent on savvy drug marketing -
partly explain why millions of people and thousands of doctors came to
embrace a family of psychoactive drugs with marginal benefits and numerous
adverse effects.

But it is still troubling to discover how easily we ended up spending
billions of dollars on these questionable drugs. Maybe before our next love
affair with a new group of psychoactive drugs, doctors and patients alike
will take a more critical look at what they actually accomplish.

Editor's note: The analysis of FDA records was done in cooperation with
Irving Kirsch, professor of psychology at the University of Connecticut at
Storrs.