Depression, a Sugar Pill Is Hard to Beat
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.
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
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
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
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
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.
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
Mayberg likened depression to a room with a hole in one window.
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
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.
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.
Comment to article above
Drug Companies Want Us to Believe
The Post's May 7 front-page article reporting that placebos are
as effective in treating depression as Prozac and similar antidepressant
medications comes as no surprise to those who have been reading
scientific literature carefully over the past decade. Three points
are important in this story:
First, because drug companies require researchers to sign an agreement
giving the company the right to veto publication of negative findings,
which the drug companies exercise scrupulously, the scientific
literature is now highly biased.
Second, the placebo effect has been strengthened in the past decade
by the promotion of antidepressant drugs. By increasing the belief
that your product is good, you can sell more drugs in the same
way that you can sell more Wheaties. Witness, for example, the
TV ads for prescription drugs.
Third, it is specious for researchers to argue, given the results
of such studies, that drugs have some effect beyond the placebo
effect. The reason for this experimental design is to determine
exactly that point. This is not science, it is dogma. This attitude,
unfortunately, has been governing the field of mental health for
ALLAN M. LEVENTHAL
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