IN terms of perception, these are hard times for antidepressants. A number of
articles have suggested that the drugs are no more effective than placebos.
Last month brought an especially high-profile debunking. In an essay in The New
York Review of Books, Marcia Angell, former editor in chief of The New England
Journal of Medicine, favorably entertained the premise that “psychoactive drugs
are useless.” Earlier, a USA Today piece about a study done by the psychologist
Robert DeRubeis had the headline, “Antidepressant lift may be all in your head,”
and shortly after, a Newsweek cover piece discussed research by the psychologist
Irving Kirsch arguing that the drugs were no more effective than a placebo.
Could this be true? Could drugs that are ingested by one in 10 Americans each
year, drugs that have changed the way that mental illness is treated, really be
a hoax, a mistake or a concept gone wrong?
This supposition is worrisome. Antidepressants work — ordinarily well, on a par
with other medications doctors prescribe. Yes, certain researchers have
questioned their efficacy in particular areas — sometimes, I believe, on the
basis of shaky data. And yet, the notion that they aren’t effective in general
is influencing treatment.
For instance, not long ago, I received disturbing news: a friend had had a
stroke that paralyzed the right side of his body. Hoping to be of use, I
searched the Web for a study I vaguely remembered. There it was: a group in
France had worked with more than 100 people with the kind of stroke that
affected my friend. Along with physiotherapy, half received Prozac, and half a
placebo. Members of the Prozac group recovered more of their mobility.
Antidepressants are good at treating post-stroke depression and good at
preventing it. They also help protect memory. In stroke patients,
antidepressants look like a tonic for brain health.
When I learned that my friend was not on antidepressants, I suggested he raise
the issue with his neurologists. I e-mailed them the relevant articles. After
further consideration, the doctors added the medicines to his regimen of
physical therapy.
Surprised that my friend had not been offered a highly effective treatment, I
phoned Robert G. Robinson at the University of Iowa’s department of psychiatry,
a leading researcher in this field. He said, “Neurologists tell me they don’t
use an antidepressant unless a patient is suffering very serious depression.
They’re influenced by reports that say that’s all antidepressants are good for.”
Critics raise various concerns, but in my view the serious dispute about
antidepressant efficacy has a limited focus. Do they work for the core symptoms
(such as despair, low energy and feelings of worthlessness) of isolated episodes
of mild or moderate depression? The claim that antidepressants do nothing for
this common condition — that they are merely placebos with side effects — is
based on studies that have probably received more ink than they deserve.
The most widely publicized debunking research — the basis for the Newsweek and
New York Review pieces — is drawn from data submitted to the Food and Drug
Administration in the late 1980s and the 1990s by companies seeking approval for
new drugs. This research led to its share of scandal when a study in The New
England Journal of Medicine found that the trials had been published
selectively. Papers showing that antidepressants work had found their way into
print; unfavorable findings had not.
In his book “The Emperor’s New Drugs: Exploding the Antidepressant Myth,” Dr.
Kirsch, a psychologist at the University of Hull in England, analyzed all the
data. He found that while the drugs outperformed the placebos for mild and
moderate depression, the benefits were small. The problem with the Kirsch
analysis — and none of the major press reports considered this shortcoming — is
that the F.D.A. material is ill suited to answer questions about mild
depression.
As a condition for drug approval, the F.D.A. requires drug companies to
demonstrate a medicine’s efficacy in at least two trials. Trials in which
neither the new drug nor an older, established drug is distinguishable from a
placebo are deemed “failed” and are disregarded or weighed lightly in the
evaluation. Consequently, companies rushing to get medications to market have
had an incentive to run quick, sloppy trials.
Often subjects who don’t really have depression are included — and (no surprise)
weeks down the road they are not depressed. People may exaggerate their symptoms
to get free care or incentive payments offered in trials. Other, perfectly
honest subjects participate when they are at their worst and then spontaneously
return to their usual, lower, level of depression.
THIS improvement may have nothing to do with faith in dummy pills; it is an
artifact of the recruitment process. Still, the recoveries are called “placebo
responses,” and in the F.D.A. data they have been steadily on the rise. In some
studies, 40 percent of subjects not receiving medication get better.
The problem is so big that entrepreneurs have founded businesses promising to
identify genuinely ill research subjects. The companies use video links to
screen patients at central locations where (contrary to the practice at centers
where trials are run) reviewers have no incentives for enrolling subjects. In
early comparisons, off-site raters rejected about 40 percent of subjects who had
been accepted locally — on the ground that those subjects did not have severe
enough symptoms to qualify for treatment. If this result is typical, many
subjects labeled mildly depressed in the F.D.A. data don’t have depression and
might well respond to placebos as readily as to antidepressants.
Nonetheless, the F.D.A. mostly gets it right. To simplify a complex matter:
there are two sorts of studies that are done on drugs: broad trials and narrow
trials. Broad trials, like those done to evaluate new drugs, can be difficult
these days, because many antidepressants are available as generics. Who
volunteers to take an untested remedy? Research subjects are likely to be an odd
bunch.
Narrow studies, done on those with specific disorders, tend to be more reliable.
Recruitment of subjects is straightforward; no one’s walking off the street to
enter a trial for stroke patients. Narrow studies have identified many specific
indications for antidepressants, such as depression in neurological disorders,
including multiple sclerosis and epilepsy; depression caused by interferon, a
medication used to treat hepatitis and melanoma; and anxiety disorders in
children.
New ones regularly emerge. The June issue of Surgery Today features a study in
which elderly female cardiac patients who had had emergency operations and were
given antidepressants experienced less depression, shorter hospital stays and
fewer deaths in the hospital.
Broad studies tend to be most trustworthy when they look at patients with
sustained illness. A reliable finding is that antidepressants work for chronic
and recurrent mild depression, the condition called dysthymia. More than half of
patients on medicine get better, compared to less than a third taking a placebo.
(This level of efficacy — far from ideal — is typical across a range of
conditions in which antidepressants outperform placebos.) Similarly, even the
analyses that doubt the usefulness of antidepressants find that they help with
severe depression.
In fact, antidepressants appear to have effects across the depressive spectrum.
Scattered studies suggest that antidepressants bolster confidence or diminish
emotional vulnerability — for people with depression but also for healthy
people. In the depressed, the decrease in what is called neuroticism seems to
protect against further episodes. Because neuroticism is not a core symptom of
depression, most outcome trials don’t measure this change, but we can see why
patients and doctors might consider it beneficial.
Similarly, in rodent and primate trials, antidepressants have broad effects on
both healthy animals and animals with conditions that resemble mood disruptions
in humans.
One reason the F.D.A. manages to identify useful medicines is that it looks at a
range of evidence. It encourages companies to submit “maintenance studies.” In
these trials, researchers take patients who are doing well on medication and
switch some to dummy pills. If the drugs are acting as placebos, switching
should do nothing. In an analysis that looked at maintenance studies for 4,410
patients with a range of severity levels, antidepressants cut the odds of
relapse by 70 percent. These results, rarely referenced in the
antidepressant-as-placebo literature, hardly suggest that the usefulness of the
drugs is all in patients’ heads.
The other round of media articles questioning antidepressants came in response
to a seemingly minor study engineered to highlight placebo responses. One effort
to mute the placebo effect in drug trials involves using a “washout period”
during which all subjects get a dummy pill for up to two weeks. Those who report
prompt relief are dropped; the study proceeds with those who remain symptomatic,
with half getting the active medication. In light of subject recruitment
problems, this approach has obvious appeal.
Dr. DeRubeis, an authority on cognitive behavioral psychotherapy, has argued
that the washout method plays down the placebo effect. Last year, Dr. DeRubeis
and his colleagues published a highly specific statistical analysis. From a
large body of research, they discarded trials that used washouts, as well as
those that focused on dysthymia or subtypes of depression. The team deemed only
six studies, from over 2,000, suitable for review. An odd collection they were.
Only studies using Paxil and imipramine, a medicine introduced in the 1950s,
made the cut — and other research had found Paxil to be among the least
effective of the new antidepressants. One of the imipramine studies used a very
low dose of the drug. The largest study Dr. DeRubeis identified was his own. In
2005, he conducted a trial in which Paxil did slightly better than psychotherapy
and significantly better than a placebo — but apparently much of the drug
response occurred in sicker patients.
Building an overview around your own research is problematic. Generally, you use
your study to build a hypothesis; you then test the theory on fresh data.
Critics questioned other aspects of Dr. DeRubeis’s math. In a re-analysis using
fewer assumptions, Dr. DeRubeis found that his core result (less effect for
healthier patients) now fell just shy of statistical significance. Overall, the
medications looked best for very severe depression and had only slight benefits
for mild depression — but this study, looking at weak treatments and
intentionally maximized placebo effects, could not quite meet the scientific
standard for a firm conclusion. And yet, the publication of the no-washout paper
produced a new round of news reports that antidepressants were placebos.
In the end, the much heralded overview analyses look to be editorials with
numbers attached. The intent, presumably to right the balance between
psychotherapy and medication in the treatment of mild depression, may be
admirable, but the data bearing on the question is messy.
As for the news media’s uncritical embrace of debunking studies, my guess, based
on regular contact with reporters, is that a number of forces are at work.
Misdeeds — from hiding study results to paying off doctors — have made Big
Pharma an inviting and, frankly, an appropriate target. (It’s a favorite of Dr.
Angell’s.) Antidepressants have something like celebrity status; exposing them
makes headlines.
It is hard to locate the judicious stance with regard to antidepressants and
moderate mood disorder. In my 1993 book, “Listening to Prozac,” I wrote, “To my
mind, psychotherapy remains the single most helpful technology for the treatment
of minor depression and anxiety.” In 2003, in “Against Depression,” I
highlighted research that suggested antidepressants influence mood only
indirectly. It may be that the drugs are “permissive,” removing roadblocks to
self-healing.
That model might predict that in truth the drugs would be more effective in
severe disorders. If antidepressants act by usefully perturbing a brain that’s
“stuck,” then people who retain some natural resilience would see a lesser
benefit. That said, the result that the debunking analyses propose remains
implausible: antidepressants help in severe depression, depressive subtypes,
chronic minor depression, social unease and a range of conditions modeled in
mice and monkeys — but uniquely not in isolated episodes of mild depression in
humans.
BETTER-DESIGNED research may tell us whether there is a point on the continuum
of mood disorder where antidepressants cease to work. If I had to put down my
marker now — and effectively, as a practitioner, I do — I’d bet that “stuckness”
applies all along the line, that when mildly depressed patients respond to
medication, more often than not we’re seeing true drug effects. Still, my
approach with mild depression is to begin treatments with psychotherapy. I aim
to use drugs sparingly. They have side effects, some of them serious.
Antidepressants help with strokes, but surveys also show them to predispose to
stroke. But if psychotherapy leads to only slow progress, I will recommend
adding medicines. With a higher frequency and stronger potency than what we see
in the literature, they seem to help.
My own beliefs aside, it is dangerous for the press to hammer away at the theme
that antidepressants are placebos. They’re not. To give the impression that they
are is to cause needless suffering.
As for my friend, he had made no progress before his neurologists prescribed
antidepressants. Since, he has shown a slow return of motor function. As is true
with much that we see in clinical medicine, the cause of this change is
unknowable. But antidepressants are a reasonable element in the treatment —
because they do seem to make the brain more flexible, and they’ve earned their
place in the doctor’s satchel.
January 6, 2010
The New York Times
By BENEDICT CAREY
Some widely prescribed drugs for depression provide relief in extreme cases
but are no more effective than placebo pills for most patients, according to a
new analysis released Tuesday.
The findings could help settle a longstanding debate about antidepressants.
While the study does not imply that the drugs are worthless for anyone with
moderate to serious depression — many such people do seem to benefit — it does
provide one likely explanation for the sharp disagreement among experts about
the drugs’ overall effectiveness.
Taken together, previous studies have painted a confusing picture. On one hand,
industry-supported trials have generally found that the drugs sharply reduce
symptoms. On the other, many studies that were not initially published, or were
buried, showed no significant benefits compared with placebos.
The new report, appearing in The Journal of the American Medical Association,
reviews data from previous trials on two types of drugs and finds that their
effectiveness varies according to the severity of the depression being treated.
Previous analyses had found a similar pattern. But the new study is the first to
analyze responses from hundreds of people being treated for more moderate
symptoms, as are most people who seek care.
“I think the study could dampen enthusiasm for antidepressant medications a bit,
and that may be a good thing,” said Dr. Erick H. Turner, a psychiatrist at
Oregon Health and Science University. “People’s expectations for the drugs won’t
be so high, and doctors won’t be surprised if they’re not curing every patient
they see with medications.”
But Dr. Turner added, “The findings shouldn’t dampen expectations so much that
people refuse to even try medication.”
A team of researchers, including psychologists who favor talk therapy and
doctors who consult widely with drug makers, performed the new analysis, using
government grants. The group evaluated six large drug trials, including 728 men
and women, about half of them with severe depression and half with more moderate
symptoms.
Three of the trials were of Paxil, from GlaxoSmithKline, a so-called S.S.R.I.,
and the other three were of imipramine, an older generic drug from the class
known as tricyclics. The team, led by Jay C. Fournier and Robert J. DeRubeis of
the University of Pennsylvania, found that compared with placebos, the drugs
caused a much steeper reduction in symptoms of severe depression (cases scoring
25 or higher on a standard scale of severity, putting them in the top quarter of
the sample). Patients with scores of less than 25 got little or no added benefit
from the medications.
“We were able to give an overall estimate of effectiveness for the first time in
this more moderate severity range, from 14 to 20 on the scale, in which there’s
no question that doctors would likely consider prescribing medication,” Dr.
DeRubeis said.
His co-authors included Steven D. Hollon and Dr. Richard C. Shelton of
Vanderbilt University, Sona Dimidjian of the University of Colorado, Dr. Jan
Fawcett of the University of New Mexico and Dr. Jay D. Amsterdam of Penn.
The effects of other popular S.S.R.I.’s like Lexapro and Prozac are not likely
to be much different than those of Paxil, experts said.
Dr. DeRubeis and others said antidepressants’ inability to outperform placebos
against moderate symptoms stemmed partly from the sustained attention that
patients in drug trials received from top doctors — which itself can help
relieve symptoms, drug or no drug. For some people, too, the drugs’ side effects
may cancel any benefit.
“The message for patients with mild to moderate depression,” Dr. DeRubeis said,
“is, ‘Look, medications are always an option, but there’s little evidence that
they add to other efforts to shake the depression — whether it’s exercise,
seeing the doctor, reading about the disorder or going for psychotherapy.’ ”
“I’ve grown
up on medication,” my patient Julie told me recently. “I don’t have a sense of
who I really am without it.”
At 31, she had been on one antidepressant or another nearly continuously since
she was 14. There was little question that she had very serious depression and
had survived several suicide attempts. In fact, she credited the medication with
saving her life.
But now she was raising an equally fundamental question: how the drugs might
have affected her psychological development and core identity.
It was not an issue I had seriously considered before. Most of my patients, who
are adults, developed their psychiatric problems after they had a pretty clear
idea of who they were as individuals. During treatment, most of them could tell
me whether they were back to their normal baseline.
Julie could certainly remember what depression felt like, but she could not
recall feeling well except during her long treatment with antidepressant
medications. And since she had not grown up before getting depressed, she could
not gauge the hypothetical effects of antidepressants on her emotional and
psychological development.
Her experience is far from unique. Since their emergence in the late 1980s,
serotonin reuptake inhibitors like Prozac and Zoloft have become some of the
most widely prescribed drugs in the world, for depressed teenagers as well as
adults. Because depression is often a chronic, recurring illness, there are
certain to be many young people, like Julie, who are coming of age on these
newer antidepressants.
We know a lot about the course of untreated depression, probably more than we do
about very long-term antidepressant use in this population. We know, for
example, that depression in young people is a very serious problem; suicide is
the third-leading cause of death in adolescents, not to mention the untold
suffering and impaired functioning this disease exacts.
By contrast, the risk of antidepressant treatment is small. A 2004 review by the
Food and Drug Administration, analyzing clinical trials of the drugs, did show
an elevated risk of suicidal thinking and nonlethal suicide attempts in young
people taking antidepressants — 3.5 percent, compared with 1.7 percent of those
taking a placebo. But since the lifetime risk of actual suicide in depressed
people ranges from 2.2 to 12 percent, risk from treatment is dwarfed by the
risks of the disease itself.
Still, what do we know about the effects of, say, 15 to 20 years of
antidepressant drug treatment that begins in adolescence or childhood? Not
enough.
The reason has to do with the way drugs are tested and approved. To get F.D.A.
approval, a drug has to beat a placebo in two randomized clinical trials that
typically involve a few hundred subjects who are treated for relatively short
periods, usually 4 to 12 weeks.
So drugs are approved based on short-term studies for what turns out to be
long-term — often lifelong — use in the world of clinical practice. The longest
maintenance study to date of one of the newer antidepressants, Effexor, lasted
only two years and showed the drug to be superior to a placebo in preventing
relapses of depression.
What do I say to a depressed patient who is doing well after five years on such
a drug but can’t stop without a depressive relapse and who wants reassurance
that the drug has no long-term adverse effects?
I usually say that we have no evidence that the drug poses a risk with long-term
use; and since the risk of untreated depression is much greater than the
hypothetical risk of the drug, it makes sense to stay on it.
This large gap in our clinical knowledge is compounded by the public’s growing
and well-founded skepticism about research sponsored by drug makers. A study in
the January 2008 issue of The New England Journal of Medicine, involving 74
clinical trials with 12 antidepressants, found that 97 percent of positive
studies were published, versus 12 percent of negative studies.
Clearly, physicians and the public need much better data on the safety and
efficacy of drugs after they hit the market, which at present consists mainly of
anecdotes and case reports.
Congress recently reauthorized the Prescription Drug User Fee Act, which will
expand the F.D.A.’s post-marketing drug surveillance, though I think it did not
go far enough in mandating the use of powerful epidemiological strategies to
monitor drugs over the long term.
Beyond these concerns, there are other important issues to consider in long-term
use of antidepressants, especially in young people. One patient, a woman in her
mid-20s, told me that she felt pressured by her boyfriend to have sex more often
than she wanted. “I’ve always had a low sex drive,” she said.
For the past eight years she had been taking Zoloft, which like all the
antidepressants in its class is known to lower libido and to interfere with
sexual performance. She had understandably mistaken the side effect of the drug
for her “normal” sexual desire and was shocked when I explained it: “And I
thought it was just me!”
This just underscores how tricky it can be to use psychotropic drugs during
adolescence — when the brain is still developing, when one’s identity is still
work in progress.
The drugs save lives, and we often have no choice but to use them — even if we
have questions about their long-term use. But the questions are big ones, and we
owe it to our patients to try to answer them.
Richard A. Friedman is a professor of psychiatry
at Weill Cornell Medical
College.
The makers
of antidepressants like Prozac and Paxil never published the results of about a
third of the drug trials that they conducted to win government approval,
misleading doctors and consumers about the drugs’ true effectiveness, a new
analysis has found.
In published trials, about 60 percent of people taking the drugs report
significant relief from depression, compared with roughly 40 percent of those on
placebo pills. But when the less positive, unpublished trials are included, the
advantage shrinks: the drugs outperform placebos, but by a modest margin,
concludes the new report, which appears Thursday in The New England Journal of
Medicine.
Previous research had found a similar bias toward reporting positive results for
a variety of medications; and many researchers have questioned the reported
effectiveness of antidepressants. But the new analysis, reviewing data from 74
trials involving 12 drugs, is the most thorough to date. And it documents a
large difference: while 94 percent of the positive studies found their way into
print, just 14 percent of those with disappointing or uncertain results did.
The finding is likely to inflame a continuing debate about how drug trial data
is reported. In 2004, after revelations that negative findings from
antidepressant trials had not been published, a group of leading journals agreed
to stop publishing clinical trials that were not registered in a public
database. Trade groups representing the world’s largest drug makers announced
that members’ companies would begin to release more data from trials more
quickly, on their own database, clinicalstudyresults.org.
And last year, Congress passed legislation that expanded the type of trials and
the depth of information that must be submitted to clinicaltrials.gov, a public
database operated by the National Library of Medicine. The Food and Drug
Administration’s Web site provides limited access to recent reviews of drug
trials, but critics say it is very hard to navigate.
“This is a very important study for two reasons,” said Dr. Jeffrey M. Drazen,
editor in chief of The New England Journal. “One is that when you prescribe
drugs, you want to make sure you’re working with best data possible; you
wouldn’t buy a stock if you only knew a third of the truth about it.”
Second, Dr. Drazen continued, “we need to show respect for the people who enter
a trial.”
“They take some risk to be in the trial, and then the drug company hides the
data?” he asked. “That kind of thing gets us pretty passionate about this
issue.”
Alan Goldhammer, deputy vice president for regulatory affairs at the
Pharmaceutical Research and Manufacturers of America, said the new study
neglected to mention that industry and government had already taken steps to
make clinical trial information more transparent. “This is all based on data
from before 2004, and since then we’ve put to rest the myth that companies have
anything to hide,” he said.
In the study, a team of researchers identified all antidepressant trials
submitted to the Food and Drug Administration to win approval from 1987 to 2004.
The studies involved 12,564 adult patients testing drugs like Prozac from Eli
Lilly, Zoloft from Pfizer and Effexor from Wyeth.
The researchers obtained unpublished data on the more recently approved drugs
from the F.D.A.’s Web site. For older drugs, they tracked down hard copies of
unpublished studies through colleagues, or using the Freedom of Information Act.
They checked all of these studies against databases of published research, and
also wrote to the companies that conducted the studies to ask if specific trials
had been published.
They found that 37 of 38 trials that the F.D.A. viewed as having positive
results were published in journals. The agency viewed as failed or unconvincing
36 other trials, of which 14 made it into journals.
But 11 of those 14 journal articles “conveyed a positive outcome” that was not
justified by the underlying F.D.A. review, said the new study’s lead author, Dr.
Erick H. Turner, a psychiatrist and former F.D.A. reviewer who now works at
Oregon Health and Sciences University and the Portland Veterans Affairs Medical
Center. His co-authors included researchers at Kent State University and the
University of California, Riverside.
Dr. Turner said the selective reporting of favorable studies sets up patients
for disappointment. “The bottom line for people considering an antidepressant, I
think, is that they should be more circumspect about taking it,” he said, “and
not be so shocked if it doesn’t work the first time and think something’s wrong
with them.”
For doctors, he said, “They end up asking, ‘How come these drugs seem to work so
well in all these studies, and I’m not getting that response?’ ”
Dr. Thomas P. Laughren, director of the division of psychiatry products at the
F.D.A., said the agency had long been aware that favorable studies of drugs were
more likely to be published.
“It’s a problem we’ve been struggling with for years,” he said in an interview.
“I have no problem with full access to all trial data; the question for us is
how do you fit it all on a package insert,” the information that accompanies
many drugs.
Dr. Donald F. Klein, an emeritus professor of psychiatry at Columbia, said drug
makers were not the only ones who can be reluctant to publish unconvincing
results. Journals, and study authors, too, may drop studies that are
underwhelming.
“If it’s your private data, and you don’t like how it came out, well, we
shouldn’t be surprised that some doctors don’t submit those studies,” he said.
