http://www.washingtonpost.com/wp-dyn/articles/A42930-2002May6.html
Against Depression, a Sugar Pill Is Hard to Beat
Placebos Improve Mood, Change Brain Chemistry in Majority
of Trials of Antidepressants
By Shankar Vedantam
Washington Post Staff Writer
Tuesday, May 7, 2002; Page A01
After thousands of studies,
hundreds of millions of
prescriptions and tens of
billions of dollars in sales,
two things are certain about
pills that treat depression:
Antidepressants like Prozac,
Paxil and Zoloft work. And
so do sugar pills.
A new analysis has found that in the majority of trials
conducted by drug companies in recent decades, sugar pills
have done as well as -- or better than -- antidepressants.
Companies have had to conduct numerous trials to get two that
show a positive result, which is the Food and Drug
Administration's minimum for approval.
What's more, the sugar pills, or placebos, cause profound
changes in the same areas of the brain affected by the
medicines, according to research published last week. One
researcher has ruefully concluded that a higher percentage of
depressed patients get better on placebos today than 20 years
ago.
Placebos -- or dud pills -- have long been used to help
scientists separate the "real" effectiveness of medicines from
the "illusory" feelings of patients. The placebo effect -- the
phenomenon of patients feeling better after they've been
treated with dud pills -- is seen throughout the field of
medicine. But new research suggests that the placebo may play
an extraordinary role in the treatment of depression -- where
how people feel spells the difference between sickness and
health.
The new research may shed light on findings such as those
from a trial last month that compared the herbal remedy St.
John's wort against Zoloft. St. John's wort fully cured 24
percent of the depressed people who received it, and Zoloft
cured 25 percent -- but the placebo fully cured 32 percent.
The confounding and controversial findings do not mean that
antidepressants do not work. But clinicians and researchers say
the results do suggest that Americans may be overestimating
the power of the drugs, and that the medicines' greatest
benefits may come from the care and concern shown to
patients during a clinical trial -- a context that does not exist
for millions of patients using the drugs in the real world.
"The drugs work, and I prescribe them, but they are not what
they are cracked up to be," said Wayne Blackmon, a
Washington psychiatrist whose practice largely comprises
patients who suffer from depression. "I know from clinical
experience the drugs alone don't do the job."
Still, drugs may have become the reflexive treatment for the
vast majority of Americans receiving medical attention for
depression: As the number of doctor visits for depression rose
from 14 million in 1987 to almost 25 million last year,
medications were prescribed for nine in 10 patients, according
to research published last week.
It is not clear how many patients received medicines in a
context of therapy, although research has indicated that
combining medicines with psychotherapy produces the best
results.
But Randall Stafford, the Stanford University physician who
conducted the study on doctor visits, found that less than
one-third of them in 2001 were to psychiatrists and two-thirds
of them were to primary care physicians. The former are more
likely to situate the medicines in a larger context of therapy,
while the latter are less knowledgeable about therapy, more
pressed for time and less likely to offer patients anything like
the attention they would receive in a clinical trial.
The average participant in an eight-week trial spends about 20
hours being examined by top experts and highly trained
caregivers, said Seattle psychiatrist Arif Khan, who studied the
placebo effect in trials submitted to the FDA. Participants --
including those being given sugar pills -- are asked detailed
questions about how they are feeling, and their every
psychological change is closely noted.
In comparison, Khan noted, the average patient with
depression sees a doctor perhaps 20 minutes a month.
His analysis of 96 antidepressant trials between 1979 and 1996
showed that in 52 percent of them, the effect of the
antidepressant could not be distinguished from that of the
placebo. Khan said the makers of Prozac had to run five trials
to obtain two that were positive, and the makers of Paxil and
Zoloft had to run even more. He analyzed trials that were made
public in the medical literature, which tend to show positive
results, and those that were not.
"It speaks to the difficulty we have in classifying and identifying
the disorders we deal with," said Thomas Laughren, who heads
the group of scientists at the FDA that evaluates the medicines.
"Psychiatric diagnosis is descriptive. We don't really
understand psychiatric disorders at a biological level."
Patients with similar symptoms, he explained, may have
different problems with their brain chemistry. Scientists don't
understand the neural mechanisms of depression -- or why
medicines like Prozac and Paxil work.
"We like to think we give people treatments and they get
better," said Andrew Leuchter, a professor of psychiatry at
UCLA. "We have this fallacy of success, but we don't know in
any individual why they get better. Undoubtedly one of those
factors is the time we spend with people and the connectedness
that gives patients."
In January, Leuchter published a study in the American Journal
of Psychiatry, in which he tracked some of the brain changes
associated with drugs such as Prozac and Effexor, which are
called selective serotonin reuptake inhibitors. When Leuchter
compared the brain changes in patients on placebos, he was
amazed to find that many of them had changes in the same
parts of the brain that are thought to control important facets
of mood.
Patients who got better on placebos showed heightened activity
in the prefrontal lobe, and that activity continued to rise during
the eight weeks of the study. Those who responded to medicine
initially showed a decline in prefrontal brain activity, then a
rise that eventually tapered off. Thirty-eight percent of
patients responded to the placebo, and 52 percent to the
medicines.
Once the trial was over and the patients who had been given
placebos were told as much, they quickly deteriorated. People's
belief in the power of antidepressants may explain why they do
well on placebos. Patients in trials are not told which they are
receiving.
Likewise, sea changes in the treatment of depression --
including the reduction in the stigma attached to mental
illness, the widespread use of antidepressants and the immense
marketing efforts by their manufacturers -- may explain why
Timothy Walsh, a psychiatrist at Columbia University, recently
found that the placebo effect has grown in recent years. He
found that greater percentages of people tended to get better on
placebos during trials of antidepressants in 2000 than in 1981.
Some observers assert that the medicines themselves work
because of the placebo effect, but most psychiatrists believe the
drugs do have an effect of their own. Drugs are a
"placebo-plus" treatment, said Helen Mayberg, head of
neuropsychiatry at the Rotman Research Institute at the
University of Toronto.
In a study published last week in the American Journal of
Psychiatry, Mayberg evaluated brain changes during trials using
a sophisticated brain imaging technique. She found that
medicines, besides working on areas that are activated by
placebos, also work on areas deep in the brain stem, the
hippocampus and striatum.
Since both depression and the effect of the medicines are still
not well understood, it's not clear what these changes mean.
While they could be irrelevant effects, Mayberg said a better
explanation is that the drugs affect areas deep within the brain
and then work upward to affect parts of the brain that control
mood. Placebos may work in the reverse direction. In part, this
may explain why drug effects tend to be more reliable than
placebos in the long run.
Mayberg likened depression to a room with a hole in one
window.
"You are trying to set a thermostat -- it's 100 degrees outside
and you want it to be 70," she said. "If you set the thermostat to
70, that doesn't work. But if I set my thermostat to 50, that
fools the system and gets the temperature back to 70."
Both drugs and placebos -- chemicals and beliefs -- may
impose different chemical pressures on the brain that reset the
"temperature." The real problem, of course, is that no one
knows how to fix the hole in the window, or even where exactly
it is. "This is a thousand-piece puzzle with no picture on the
box," sighed Mayberg.
Blackmon, the Washington psychiatrist, said it behooved
mental health clinicians to better integrate the power of
biological treatments with the effects of belief and therapy.
"We would say it's absurd if an internist says, 'I believe in
penicillin, so everyone should get penicillin whether they have
cancer or a broken bone," he said.
© 2002 The Washington Post Company |
