(FYI, Marcia Angell, M.D., the author of this essay, is on the
faculty of Harvard Medical School and is the former Editor of the New
England Journal of Medicine.)
The Epidemic of Mental Illness: Why?
New York Review of Books, June 23, 2011
Author: Marcia Angell
(A Review Essay of the Following Books)
The Emperor’s New Drugs: Exploding the Antidepressant Myth
by Irving Kirsch
Basic Books, 226 pp., $15.99 (paper)
Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the
Astonishing Rise of Mental Illness in America
by Robert Whitaker
Crown, 404 pp., $26.00
Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a
Profession in Crisis
by Daniel Carlat
Free Press, 256 pp., $25.00
It seems that Americans are in the midst of a raging epidemic of
mental illness, at least as judged by the increase in the numbers
treated for it. The tally of those who are so disabled by mental
disorders that they qualify for Supplemental Security Income (SSI) or
Social Security Disability Insurance (SSDI) increased nearly two and a
half times between 1987 and 2007—from one in 184 Americans to one in
seventy-six. For children, the rise is even more startling—a
thirty-five-fold increase in the same two decades. Mental illness is
now the leading cause of disability in children, well ahead of
physical disabilities like cerebral palsy or Down syndrome, for which
the federal programs were created.
A large survey of randomly selected adults, sponsored by the National
Institute of Mental Health (NIMH) and conducted between 2001 and 2003,
found that an astonishing 46 percent met criteria established by the
American Psychiatric Association (APA) for having had at least one
mental illness within four broad categories at some time in their
lives. The categories were “anxiety disorders,” including, among other
subcategories, phobias and post-traumatic stress disorder (PTSD);
“mood disorders,” including major depression and bipolar disorders;
“impulse-control disorders,” including various behavioral problems and
attention-deficit/hyperactivity disorder (ADHD); and “substance use
disorders,” including alcohol and drug abuse. Most met criteria for
more than one diagnosis. Of a subgroup affected within the previous
year, a third were under treatment—up from a fifth in a similar survey
ten years earlier.
Nowadays treatment by medical doctors nearly always means psychoactive
drugs, that is, drugs that affect the mental state. In fact, most
psychiatrists treat only with drugs, and refer patients to
psychologists or social workers if they believe psychotherapy is also
warranted. The shift from “talk therapy” to drugs as the dominant mode
of treatment coincides with the emergence over the past four decades
of the theory that mental illness is caused primarily by chemical
imbalances in the brain that can be corrected by specific drugs. That
theory became broadly accepted, by the media and the public as well as
by the medical profession, after Prozac came to market in 1987 and was
intensively promoted as a corrective for a deficiency of serotonin in
the brain. The number of people treated for depression tripled in the
following ten years, and about 10 percent of Americans over age six
now take antidepressants. The increased use of drugs to treat
psychosis is even more dramatic. The new generation of antipsychotics,
such as Risperdal, Zyprexa, and Seroquel, has replaced
cholesterol-lowering agents as the top-selling class of drugs in the
US.
What is going on here? Is the prevalence of mental illness really that
high and still climbing? Particularly if these disorders are
biologically determined and not a result of environmental influences,
is it plausible to suppose that such an increase is real? Or are we
learning to recognize and diagnose mental disorders that were always
there? On the other hand, are we simply expanding the criteria for
mental illness so that nearly everyone has one? And what about the
drugs that are now the mainstay of treatment? Do they work? If they
do, shouldn’t we expect the prevalence of mental illness to be
declining, not rising?
These are the questions, among others, that concern the authors of the
three provocative books under review here. They come at the questions
from different backgrounds—Irving Kirsch is a psychologist at the
University of Hull in the UK, Robert Whitaker a journalist and
previously the author of a history of the treatment of mental illness
called Mad in America (2001), and Daniel Carlat a psychiatrist who
practices in a Boston suburb and publishes a newsletter and blog about
his profession.
The authors emphasize different aspects of the epidemic of mental
illness. Kirsch is concerned with whether antidepressants work.
Whitaker, who has written an angrier book, takes on the entire
spectrum of mental illness and asks whether psychoactive drugs create
worse problems than they solve. Carlat, who writes more in sorrow than
in anger, looks mainly at how his profession has allied itself with,
and is manipulated by, the pharmaceutical industry. But despite their
differences, all three are in remarkable agreement on some important
matters, and they have documented their views well.
First, they agree on the disturbing extent to which the companies that
sell psychoactive drugs—through various forms of marketing, both legal
and illegal, and what many people would describe as bribery—have come
to determine what constitutes a mental illness and how the disorders
should be diagnosed and treated. This is a subject to which I’ll
return.
Second, none of the three authors subscribes to the popular theory
that mental illness is caused by a chemical imbalance in the brain. As
Whitaker tells the story, that theory had its genesis shortly after
psychoactive drugs were introduced in the 1950s. The first was
Thorazine (chlorpromazine), which was launched in 1954 as a “major
tranquilizer” and quickly found widespread use in mental hospitals to
calm psychotic patients, mainly those with schizophrenia. Thorazine
was followed the next year by Miltown (meprobamate), sold as a “minor
tranquilizer” to treat anxiety in outpatients. And in 1957, Marsilid
(iproniazid) came on the market as a “psychic energizer” to treat
depression.
In the space of three short years, then, drugs had become available to
treat what at that time were regarded as the three major categories of
mental illness—psychosis, anxiety, and depression—and the face of
psychiatry was totally transformed. These drugs, however, had not
initially been developed to treat mental illness. They had been
derived from drugs meant to treat infections, and were found only
serendipitously to alter the mental state. At first, no one had any
idea how they worked. They simply blunted disturbing mental symptoms.
But over the next decade, researchers found that these drugs, and the
newer psychoactive drugs that quickly followed, affected the levels of
certain chemicals in the brain.
Some brief—and necessarily quite simplified—background: the brain
contains billions of nerve cells, called neurons, arrayed in immensely
complicated networks and communicating with one another constantly.
The typical neuron has multiple filamentous extensions, one called an
axon and the others called dendrites, through which it sends and
receives signals from other neurons. For one neuron to communicate
with another, however, the signal must be transmitted across the tiny
space separating them, called a synapse. To accomplish that, the axon
of the sending neuron releases a chemical, called a neurotransmitter,
into the synapse. The neurotransmitter crosses the synapse and
attaches to receptors on the second neuron, often a dendrite, thereby
activating or inhibiting the receiving cell. Axons have multiple
terminals, so each neuron has multiple synapses. Afterward, the
neurotransmitter is either reabsorbed by the first neuron or
metabolized by enzymes so that the status quo ante is restored. There
are exceptions and variations to this story, but that is the usual way
neurons communicate with one another.
When it was found that psychoactive drugs affect neurotransmitter
levels in the brain, as evidenced mainly by the levels of their
breakdown products in the spinal fluid, the theory arose that the
cause of mental illness is an abnormality in the brain’s concentration
of these chemicals that is specifically countered by the appropriate
drug. For example, because Thorazine was found to lower dopamine
levels in the brain, it was postulated that psychoses like
schizophrenia are caused by too much dopamine. Or later, because
certain antidepressants increase levels of the neurotransmitter
serotonin in the brain, it was postulated that depression is caused by
too little serotonin. (These antidepressants, like Prozac or Celexa,
are called selective serotonin reuptake inhibitors (SSRIs) because
they prevent the reabsorption of serotonin by the neurons that release
it, so that more remains in the synapses to activate other neurons.)
Thus, instead of developing a drug to treat an abnormality, an
abnormality was postulated to fit a drug.
That was a great leap in logic, as all three authors point out. It was
entirely possible that drugs that affected neurotransmitter levels
could relieve symptoms even if neurotransmitters had nothing to do
with the illness in the first place (and even possible that they
relieved symptoms through some other mode of action entirely). As
Carlat puts it, “By this same logic one could argue that the cause of
all pain conditions is a deficiency of opiates, since narcotic pain
medications activate opiate receptors in the brain.” Or similarly, one
could argue that fevers are caused by too little aspirin.
But the main problem with the theory is that after decades of trying
to prove it, researchers have still come up empty-handed. All three
authors document the failure of scientists to find good evidence in
its favor. Neurotransmitter function seems to be normal in people with
mental illness before treatment. In Whitaker’s words:
Prior to treatment, patients diagnosed with schizophrenia,
depression, and other psychiatric disorders do not suffer from any
known “chemical imbalance.” However, once a person is put on a
psychiatric medication, which, in one manner or another, throws a
wrench into the usual mechanics of a neuronal pathway, his or her
brain begins to function…abnormally.
Carlat refers to the chemical imbalance theory as a “myth” (which he
calls “convenient” because it destigmatizes mental illness), and
Kirsch, whose book focuses on depression, sums up this way: “It now
seems beyond question that the traditional account of depression as a
chemical imbalance in the brain is simply wrong.” Why the theory
persists despite the lack of evidence is a subject I’ll come to.
Do the drugs work? After all, regardless of the theory, that is the
practical question. In his spare, remarkably engrossing book, The
Emperor’s New Drugs, Kirsch describes his fifteen-year scientific
quest to answer that question about antidepressants. When he began his
work in 1995, his main interest was in the effects of placebos. To
study them, he and a colleague reviewed thirty-eight published
clinical trials that compared various treatments for depression with
placebos, or compared psychotherapy with no treatment. Most such
trials last for six to eight weeks, and during that time, patients
tend to improve somewhat even without any treatment. But Kirsch found
that placebos were three times as effective as no treatment. That
didn’t particularly surprise him. What did surprise him was the fact
that antidepressants were only marginally better than placebos. As
judged by scales used to measure depression, placebos were 75 percent
as effective as antidepressants. Kirsch then decided to repeat his
study by examining a more complete and standardized data set.
The data he used were obtained from the US Food and Drug
Administration (FDA) instead of the published literature. When drug
companies seek approval from the FDA to market a new drug, they must
submit to the agency all clinical trials they have sponsored. The
trials are usually double-blind and placebo-controlled, that is, the
participating patients are randomly assigned to either drug or
placebo, and neither they nor their doctors know which they have been
assigned. The patients are told only that they will receive an active
drug or a placebo, and they are also told of any side effects they
might experience. If two trials show that the drug is more effective
than a placebo, the drug is generally approved. But companies may
sponsor as many trials as they like, most of which could be
negative—that is, fail to show effectiveness. All they need is two
positive ones. (The results of trials of the same drug can differ for
many reasons, including the way the trial is designed and conducted,
its size, and the types of patients studied.)
For obvious reasons, drug companies make very sure that their positive
studies are published in medical journals and doctors know about them,
while the negative ones often languish unseen within the FDA, which
regards them as proprietary and therefore confidential. This practice
greatly biases the medical literature, medical education, and
treatment decisions.
Kirsch and his colleagues used the Freedom of Information Act to
obtain FDA reviews of all placebo-controlled clinical trials, whether
positive or negative, submitted for the initial approval of the six
most widely used antidepressant drugs approved between 1987 and
1999—Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. This was a
better data set than the one used in his previous study, not only
because it included negative studies but because the FDA sets uniform
quality standards for the trials it reviews and not all of the
published research in Kirsch’s earlier study had been submitted to the
FDA as part of a drug approval application.
Altogether, there were forty-two trials of the six drugs. Most of them
were negative. Overall, placebos were 82 percent as effective as the
drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely
used score of symptoms of depression. The average difference between
drug and placebo was only 1.8 points on the HAM-D, a difference that,
while statistically significant, was clinically meaningless. The
results were much the same for all six drugs: they were all equally
unimpressive. Yet because the positive studies were extensively
publicized, while the negative ones were hidden, the public and the
medical profession came to believe that these drugs were highly
effective antidepressants.
Kirsch was also struck by another unexpected finding. In his earlier
study and in work by others, he observed that even treatments that
were not considered to be antidepressants—such as synthetic thyroid
hormone, opiates, sedatives, stimulants, and some herbal remedies—were
as effective as antidepressants in alleviating the symptoms of
depression. Kirsch writes, “When administered as antidepressants,
drugs that increase, decrease or have no effect on serotonin all
relieve depression to about the same degree.” What all these
“effective” drugs had in common was that they produced side effects,
which participating patients had been told they might experience.
It is important that clinical trials, particularly those dealing with
subjective conditions like depression, remain double-blind, with
neither patients nor doctors knowing whether or not they are getting a
placebo. That prevents both patients and doctors from imagining
improvements that are not there, something that is more likely if they
believe the agent being administered is an active drug instead of a
placebo. Faced with his findings that nearly any pill with side
effects was slightly more effective in treating depression than an
inert placebo, Kirsch speculated that the presence of side effects in
individuals receiving drugs enabled them to guess correctly that they
were getting active treatment—and this was borne out by interviews
with patients and doctors—which made them more likely to report
improvement. He suggests that the reason antidepressants appear to
work better in relieving severe depression than in less severe cases
is that patients with severe symptoms are likely to be on higher doses
and therefore experience more side effects.
To further investigate whether side effects bias responses, Kirsch
looked at some trials that employed “active” placebos instead of inert
ones. An active placebo is one that itself produces side effects, such
as atropine—a drug that selectively blocks the action of certain types
of nerve fibers. Although not an antidepressant, atropine causes,
among other things, a noticeably dry mouth. In trials using atropine
as the placebo, there was no difference between the antidepressant and
the active placebo. Everyone had side effects of one type or another,
and everyone reported the same level of improvement. Kirsch reported a
number of other odd findings in clinical trials of antidepressants,
including the fact that there is no dose-response curve—that is, high
doses worked no better than low ones—which is extremely unlikely for
truly effective drugs. “Putting all this together,” writes Kirsch,
leads to the conclusion that the relatively small difference
between drugs and placebos might not be a real drug effect at all.
Instead, it might be an enhanced placebo effect, produced by the fact
that some patients have broken [the] blind and have come to realize
whether they were given drug or placebo. If this is the case, then
there is no real antidepressant drug effect at all. Rather than
comparing placebo to drug, we have been comparing “regular” placebos
to “extra-strength” placebos.
That is a startling conclusion that flies in the face of widely
accepted medical opinion, but Kirsch reaches it in a careful, logical
way. Psychiatrists who use antidepressants—and that’s most of them—and
patients who take them might insist that they know from clinical
experience that the drugs work. But anecdotes are known to be a
treacherous way to evaluate medical treatments, since they are so
subject to bias; they can suggest hypotheses to be studied, but they
cannot prove them. That is why the development of the double-blind,
randomized, placebo-controlled clinical trial in the middle of the
past century was such an important advance in medical science.
Anecdotes about leeches or laetrile or megadoses of vitamin C, or any
number of other popular treatments, could not stand up to the scrutiny
of well-designed trials. Kirsch is a faithful proponent of the
scientific method, and his voice therefore brings a welcome
objectivity to a subject often swayed by anecdotes, emotions, or, as
we will see, self-interest.
Whitaker’s book is broader and more polemical. He considers all mental
illness, not just depression. Whereas Kirsch concludes that
antidepressants are probably no more effective than placebos, Whitaker
concludes that they and most of the other psychoactive drugs are not
only ineffective but harmful. He begins by observing that even as drug
treatment for mental illness has skyrocketed, so has the prevalence of
the conditions treated:
The number of disabled mentally ill has risen dramatically since
1955, and during the past two decades, a period when the prescribing
of psychiatric medications has exploded, the number of adults and
children disabled by mental illness has risen at a mind-boggling rate.
Thus we arrive at an obvious question, even though it is heretical in
kind: Could our drug-based paradigm of care, in some unforeseen way,
be fueling this modern-day plague?
Moreover, Whitaker contends, the natural history of mental illness has
changed. Whereas conditions such as schizophrenia and depression were
once mainly self-limited or episodic, with each episode usually
lasting no more than six months and interspersed with long periods of
normalcy, the conditions are now chronic and lifelong. Whitaker
believes that this might be because drugs, even those that relieve
symptoms in the short term, cause long-term mental harms that continue
after the underlying illness would have naturally resolved.
The evidence he marshals for this theory varies in quality. He doesn’t
sufficiently acknowledge the difficulty of studying the natural
history of any illness over a fifty-some-year time span during which
many circumstances have changed, in addition to drug use. It is even
more difficult to compare long-term outcomes in treated versus
untreated patients, since treatment may be more likely in those with
more severe disease at the outset. Nevertheless, Whitaker’s evidence
is suggestive, if not conclusive.
If psychoactive drugs do cause harm, as Whitaker contends, what is the
mechanism? The answer, he believes, lies in their effects on
neurotransmitters. It is well understood that psychoactive drugs
disturb neurotransmitter function, even if that was not the cause of
the illness in the first place. Whitaker describes a chain of effects.
When, for example, an SSRI antidepressant like Celexa increases
serotonin levels in synapses, it stimulates compensatory changes
through a process called negative feedback. In response to the high
levels of serotonin, the neurons that secrete it (presynaptic neurons)
release less of it, and the postsynaptic neurons become desensitized
to it. In effect, the brain is trying to nullify the drug’s effects.
The same is true for drugs that block neurotransmitters, except in
reverse. For example, most antipsychotic drugs block dopamine, but the
presynaptic neurons compensate by releasing more of it, and the
postsynaptic neurons take it up more avidly. (This explanation is
necessarily oversimplified, since many psychoactive drugs affect more
than one of the many neurotransmitters.)
With long-term use of psychoactive drugs, the result is, in the words
of Steve Hyman, a former director of the NIMH and until recently
provost of Harvard University, “substantial and long-lasting
alterations in neural function.” As quoted by Whitaker, the brain,
Hyman wrote, begins to function in a manner “qualitatively as well as
quantitatively different from the normal state.” After several weeks
on psychoactive drugs, the brain’s compensatory efforts begin to fail,
and side effects emerge that reflect the mechanism of action of the
drugs. For example, the SSRIs may cause episodes of mania, because of
the excess of serotonin. Antipsychotics cause side effects that
resemble Parkinson’s disease, because of the depletion of dopamine
(which is also depleted in Parkinson’s disease). As side effects
emerge, they are often treated by other drugs, and many patients end
up on a cocktail of psychoactive drugs prescribed for a cocktail of
diagnoses. The episodes of mania caused by antidepressants may lead to
a new diagnosis of “bipolar disorder” and treatment with a “mood
stabilizer,” such as Depokote (an anticonvulsant) plus one of the
newer antipsychotic drugs. And so on.
Some patients take as many as six psychoactive drugs daily. One well-
respected researcher, Nancy Andreasen, and her colleagues published
evidence that the use of antipsychotic drugs is associated with
shrinkage of the brain, and that the effect is directly related to the
dose and duration of treatment. As Andreasen explained to The New York
Times, “The prefrontal cortex doesn’t get the input it needs and is
being shut down by drugs. That reduces the psychotic symptoms. It also
causes the prefrontal cortex to slowly atrophy.”*
Getting off the drugs is exceedingly difficult, according to Whitaker,
because when they are withdrawn the compensatory mechanisms are left
unopposed. When Celexa is withdrawn, serotonin levels fall
precipitously because the presynaptic neurons are not releasing normal
amounts and the postsynaptic neurons no longer have enough receptors
for it. Similarly, when an antipsychotic is withdrawn, dopamine levels
may skyrocket. The symptoms produced by withdrawing psychoactive drugs
are often confused with relapses of the original disorder, which can
lead psychiatrists to resume drug treatment, perhaps at higher doses.
Unlike the cool Kirsch, Whitaker is outraged by what he sees as an
iatrogenic (i.e., inadvertent and medically introduced) epidemic of
brain dysfunction, particularly that caused by the widespread use of
the newer (“atypical”) antipsychotics, such as Zyprexa, which cause
serious side effects. Here is what he calls his “quick thought
experiment”:
Imagine that a virus suddenly appears in our society that makes
people sleep twelve, fourteen hours a day. Those infected with it move
about somewhat slowly and seem emotionally disengaged. Many gain huge
amounts of weight—twenty, forty, sixty, and even one hundred pounds.
Often their blood sugar levels soar, and so do their cholesterol
levels. A number of those struck by the mysterious illness—including
young children and teenagers—become diabetic in fairly short order….
The federal government gives hundreds of millions of dollars to
scientists at the best universities to decipher the inner workings of
this virus, and they report that the reason it causes such global
dysfunction is that it blocks a multitude of neurotransmitter
receptors in the brain—dopaminergic, serotonergic, muscarinic,
adrenergic, and histaminergic. All of those neuronal pathways in the
brain are compromised. Meanwhile, MRI studies find that over a period
of several years, the virus shrinks the cerebral cortex, and this
shrinkage is tied to cognitive decline. A terrified public clamors for
a cure.
Now such an illness has in fact hit millions of American children
and adults. We have just described the effects of Eli Lilly’s
best-selling antipsychotic, Zyprexa.
If psychoactive drugs are useless, as Kirsch believes about
antidepressants, or worse than useless, as Whitaker believes, why are
they so widely prescribed by psychiatrists and regarded by the public
and the profession as something akin to wonder drugs? Why is the
current against which Kirsch and Whitaker and, as we will see, Carlat
are swimming so powerful? I discuss these questions in Part II of this
review.
—This is the first part of a two-part article.
faculty of Harvard Medical School and is the former Editor of the New
England Journal of Medicine.)
The Epidemic of Mental Illness: Why?
New York Review of Books, June 23, 2011
Author: Marcia Angell
(A Review Essay of the Following Books)
The Emperor’s New Drugs: Exploding the Antidepressant Myth
by Irving Kirsch
Basic Books, 226 pp., $15.99 (paper)
Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the
Astonishing Rise of Mental Illness in America
by Robert Whitaker
Crown, 404 pp., $26.00
Unhinged: The Trouble With Psychiatry—A Doctor’s Revelations About a
Profession in Crisis
by Daniel Carlat
Free Press, 256 pp., $25.00
It seems that Americans are in the midst of a raging epidemic of
mental illness, at least as judged by the increase in the numbers
treated for it. The tally of those who are so disabled by mental
disorders that they qualify for Supplemental Security Income (SSI) or
Social Security Disability Insurance (SSDI) increased nearly two and a
half times between 1987 and 2007—from one in 184 Americans to one in
seventy-six. For children, the rise is even more startling—a
thirty-five-fold increase in the same two decades. Mental illness is
now the leading cause of disability in children, well ahead of
physical disabilities like cerebral palsy or Down syndrome, for which
the federal programs were created.
A large survey of randomly selected adults, sponsored by the National
Institute of Mental Health (NIMH) and conducted between 2001 and 2003,
found that an astonishing 46 percent met criteria established by the
American Psychiatric Association (APA) for having had at least one
mental illness within four broad categories at some time in their
lives. The categories were “anxiety disorders,” including, among other
subcategories, phobias and post-traumatic stress disorder (PTSD);
“mood disorders,” including major depression and bipolar disorders;
“impulse-control disorders,” including various behavioral problems and
attention-deficit/hyperactivity disorder (ADHD); and “substance use
disorders,” including alcohol and drug abuse. Most met criteria for
more than one diagnosis. Of a subgroup affected within the previous
year, a third were under treatment—up from a fifth in a similar survey
ten years earlier.
Nowadays treatment by medical doctors nearly always means psychoactive
drugs, that is, drugs that affect the mental state. In fact, most
psychiatrists treat only with drugs, and refer patients to
psychologists or social workers if they believe psychotherapy is also
warranted. The shift from “talk therapy” to drugs as the dominant mode
of treatment coincides with the emergence over the past four decades
of the theory that mental illness is caused primarily by chemical
imbalances in the brain that can be corrected by specific drugs. That
theory became broadly accepted, by the media and the public as well as
by the medical profession, after Prozac came to market in 1987 and was
intensively promoted as a corrective for a deficiency of serotonin in
the brain. The number of people treated for depression tripled in the
following ten years, and about 10 percent of Americans over age six
now take antidepressants. The increased use of drugs to treat
psychosis is even more dramatic. The new generation of antipsychotics,
such as Risperdal, Zyprexa, and Seroquel, has replaced
cholesterol-lowering agents as the top-selling class of drugs in the
US.
What is going on here? Is the prevalence of mental illness really that
high and still climbing? Particularly if these disorders are
biologically determined and not a result of environmental influences,
is it plausible to suppose that such an increase is real? Or are we
learning to recognize and diagnose mental disorders that were always
there? On the other hand, are we simply expanding the criteria for
mental illness so that nearly everyone has one? And what about the
drugs that are now the mainstay of treatment? Do they work? If they
do, shouldn’t we expect the prevalence of mental illness to be
declining, not rising?
These are the questions, among others, that concern the authors of the
three provocative books under review here. They come at the questions
from different backgrounds—Irving Kirsch is a psychologist at the
University of Hull in the UK, Robert Whitaker a journalist and
previously the author of a history of the treatment of mental illness
called Mad in America (2001), and Daniel Carlat a psychiatrist who
practices in a Boston suburb and publishes a newsletter and blog about
his profession.
The authors emphasize different aspects of the epidemic of mental
illness. Kirsch is concerned with whether antidepressants work.
Whitaker, who has written an angrier book, takes on the entire
spectrum of mental illness and asks whether psychoactive drugs create
worse problems than they solve. Carlat, who writes more in sorrow than
in anger, looks mainly at how his profession has allied itself with,
and is manipulated by, the pharmaceutical industry. But despite their
differences, all three are in remarkable agreement on some important
matters, and they have documented their views well.
First, they agree on the disturbing extent to which the companies that
sell psychoactive drugs—through various forms of marketing, both legal
and illegal, and what many people would describe as bribery—have come
to determine what constitutes a mental illness and how the disorders
should be diagnosed and treated. This is a subject to which I’ll
return.
Second, none of the three authors subscribes to the popular theory
that mental illness is caused by a chemical imbalance in the brain. As
Whitaker tells the story, that theory had its genesis shortly after
psychoactive drugs were introduced in the 1950s. The first was
Thorazine (chlorpromazine), which was launched in 1954 as a “major
tranquilizer” and quickly found widespread use in mental hospitals to
calm psychotic patients, mainly those with schizophrenia. Thorazine
was followed the next year by Miltown (meprobamate), sold as a “minor
tranquilizer” to treat anxiety in outpatients. And in 1957, Marsilid
(iproniazid) came on the market as a “psychic energizer” to treat
depression.
In the space of three short years, then, drugs had become available to
treat what at that time were regarded as the three major categories of
mental illness—psychosis, anxiety, and depression—and the face of
psychiatry was totally transformed. These drugs, however, had not
initially been developed to treat mental illness. They had been
derived from drugs meant to treat infections, and were found only
serendipitously to alter the mental state. At first, no one had any
idea how they worked. They simply blunted disturbing mental symptoms.
But over the next decade, researchers found that these drugs, and the
newer psychoactive drugs that quickly followed, affected the levels of
certain chemicals in the brain.
Some brief—and necessarily quite simplified—background: the brain
contains billions of nerve cells, called neurons, arrayed in immensely
complicated networks and communicating with one another constantly.
The typical neuron has multiple filamentous extensions, one called an
axon and the others called dendrites, through which it sends and
receives signals from other neurons. For one neuron to communicate
with another, however, the signal must be transmitted across the tiny
space separating them, called a synapse. To accomplish that, the axon
of the sending neuron releases a chemical, called a neurotransmitter,
into the synapse. The neurotransmitter crosses the synapse and
attaches to receptors on the second neuron, often a dendrite, thereby
activating or inhibiting the receiving cell. Axons have multiple
terminals, so each neuron has multiple synapses. Afterward, the
neurotransmitter is either reabsorbed by the first neuron or
metabolized by enzymes so that the status quo ante is restored. There
are exceptions and variations to this story, but that is the usual way
neurons communicate with one another.
When it was found that psychoactive drugs affect neurotransmitter
levels in the brain, as evidenced mainly by the levels of their
breakdown products in the spinal fluid, the theory arose that the
cause of mental illness is an abnormality in the brain’s concentration
of these chemicals that is specifically countered by the appropriate
drug. For example, because Thorazine was found to lower dopamine
levels in the brain, it was postulated that psychoses like
schizophrenia are caused by too much dopamine. Or later, because
certain antidepressants increase levels of the neurotransmitter
serotonin in the brain, it was postulated that depression is caused by
too little serotonin. (These antidepressants, like Prozac or Celexa,
are called selective serotonin reuptake inhibitors (SSRIs) because
they prevent the reabsorption of serotonin by the neurons that release
it, so that more remains in the synapses to activate other neurons.)
Thus, instead of developing a drug to treat an abnormality, an
abnormality was postulated to fit a drug.
That was a great leap in logic, as all three authors point out. It was
entirely possible that drugs that affected neurotransmitter levels
could relieve symptoms even if neurotransmitters had nothing to do
with the illness in the first place (and even possible that they
relieved symptoms through some other mode of action entirely). As
Carlat puts it, “By this same logic one could argue that the cause of
all pain conditions is a deficiency of opiates, since narcotic pain
medications activate opiate receptors in the brain.” Or similarly, one
could argue that fevers are caused by too little aspirin.
But the main problem with the theory is that after decades of trying
to prove it, researchers have still come up empty-handed. All three
authors document the failure of scientists to find good evidence in
its favor. Neurotransmitter function seems to be normal in people with
mental illness before treatment. In Whitaker’s words:
Prior to treatment, patients diagnosed with schizophrenia,
depression, and other psychiatric disorders do not suffer from any
known “chemical imbalance.” However, once a person is put on a
psychiatric medication, which, in one manner or another, throws a
wrench into the usual mechanics of a neuronal pathway, his or her
brain begins to function…abnormally.
Carlat refers to the chemical imbalance theory as a “myth” (which he
calls “convenient” because it destigmatizes mental illness), and
Kirsch, whose book focuses on depression, sums up this way: “It now
seems beyond question that the traditional account of depression as a
chemical imbalance in the brain is simply wrong.” Why the theory
persists despite the lack of evidence is a subject I’ll come to.
Do the drugs work? After all, regardless of the theory, that is the
practical question. In his spare, remarkably engrossing book, The
Emperor’s New Drugs, Kirsch describes his fifteen-year scientific
quest to answer that question about antidepressants. When he began his
work in 1995, his main interest was in the effects of placebos. To
study them, he and a colleague reviewed thirty-eight published
clinical trials that compared various treatments for depression with
placebos, or compared psychotherapy with no treatment. Most such
trials last for six to eight weeks, and during that time, patients
tend to improve somewhat even without any treatment. But Kirsch found
that placebos were three times as effective as no treatment. That
didn’t particularly surprise him. What did surprise him was the fact
that antidepressants were only marginally better than placebos. As
judged by scales used to measure depression, placebos were 75 percent
as effective as antidepressants. Kirsch then decided to repeat his
study by examining a more complete and standardized data set.
The data he used were obtained from the US Food and Drug
Administration (FDA) instead of the published literature. When drug
companies seek approval from the FDA to market a new drug, they must
submit to the agency all clinical trials they have sponsored. The
trials are usually double-blind and placebo-controlled, that is, the
participating patients are randomly assigned to either drug or
placebo, and neither they nor their doctors know which they have been
assigned. The patients are told only that they will receive an active
drug or a placebo, and they are also told of any side effects they
might experience. If two trials show that the drug is more effective
than a placebo, the drug is generally approved. But companies may
sponsor as many trials as they like, most of which could be
negative—that is, fail to show effectiveness. All they need is two
positive ones. (The results of trials of the same drug can differ for
many reasons, including the way the trial is designed and conducted,
its size, and the types of patients studied.)
For obvious reasons, drug companies make very sure that their positive
studies are published in medical journals and doctors know about them,
while the negative ones often languish unseen within the FDA, which
regards them as proprietary and therefore confidential. This practice
greatly biases the medical literature, medical education, and
treatment decisions.
Kirsch and his colleagues used the Freedom of Information Act to
obtain FDA reviews of all placebo-controlled clinical trials, whether
positive or negative, submitted for the initial approval of the six
most widely used antidepressant drugs approved between 1987 and
1999—Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. This was a
better data set than the one used in his previous study, not only
because it included negative studies but because the FDA sets uniform
quality standards for the trials it reviews and not all of the
published research in Kirsch’s earlier study had been submitted to the
FDA as part of a drug approval application.
Altogether, there were forty-two trials of the six drugs. Most of them
were negative. Overall, placebos were 82 percent as effective as the
drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely
used score of symptoms of depression. The average difference between
drug and placebo was only 1.8 points on the HAM-D, a difference that,
while statistically significant, was clinically meaningless. The
results were much the same for all six drugs: they were all equally
unimpressive. Yet because the positive studies were extensively
publicized, while the negative ones were hidden, the public and the
medical profession came to believe that these drugs were highly
effective antidepressants.
Kirsch was also struck by another unexpected finding. In his earlier
study and in work by others, he observed that even treatments that
were not considered to be antidepressants—such as synthetic thyroid
hormone, opiates, sedatives, stimulants, and some herbal remedies—were
as effective as antidepressants in alleviating the symptoms of
depression. Kirsch writes, “When administered as antidepressants,
drugs that increase, decrease or have no effect on serotonin all
relieve depression to about the same degree.” What all these
“effective” drugs had in common was that they produced side effects,
which participating patients had been told they might experience.
It is important that clinical trials, particularly those dealing with
subjective conditions like depression, remain double-blind, with
neither patients nor doctors knowing whether or not they are getting a
placebo. That prevents both patients and doctors from imagining
improvements that are not there, something that is more likely if they
believe the agent being administered is an active drug instead of a
placebo. Faced with his findings that nearly any pill with side
effects was slightly more effective in treating depression than an
inert placebo, Kirsch speculated that the presence of side effects in
individuals receiving drugs enabled them to guess correctly that they
were getting active treatment—and this was borne out by interviews
with patients and doctors—which made them more likely to report
improvement. He suggests that the reason antidepressants appear to
work better in relieving severe depression than in less severe cases
is that patients with severe symptoms are likely to be on higher doses
and therefore experience more side effects.
To further investigate whether side effects bias responses, Kirsch
looked at some trials that employed “active” placebos instead of inert
ones. An active placebo is one that itself produces side effects, such
as atropine—a drug that selectively blocks the action of certain types
of nerve fibers. Although not an antidepressant, atropine causes,
among other things, a noticeably dry mouth. In trials using atropine
as the placebo, there was no difference between the antidepressant and
the active placebo. Everyone had side effects of one type or another,
and everyone reported the same level of improvement. Kirsch reported a
number of other odd findings in clinical trials of antidepressants,
including the fact that there is no dose-response curve—that is, high
doses worked no better than low ones—which is extremely unlikely for
truly effective drugs. “Putting all this together,” writes Kirsch,
leads to the conclusion that the relatively small difference
between drugs and placebos might not be a real drug effect at all.
Instead, it might be an enhanced placebo effect, produced by the fact
that some patients have broken [the] blind and have come to realize
whether they were given drug or placebo. If this is the case, then
there is no real antidepressant drug effect at all. Rather than
comparing placebo to drug, we have been comparing “regular” placebos
to “extra-strength” placebos.
That is a startling conclusion that flies in the face of widely
accepted medical opinion, but Kirsch reaches it in a careful, logical
way. Psychiatrists who use antidepressants—and that’s most of them—and
patients who take them might insist that they know from clinical
experience that the drugs work. But anecdotes are known to be a
treacherous way to evaluate medical treatments, since they are so
subject to bias; they can suggest hypotheses to be studied, but they
cannot prove them. That is why the development of the double-blind,
randomized, placebo-controlled clinical trial in the middle of the
past century was such an important advance in medical science.
Anecdotes about leeches or laetrile or megadoses of vitamin C, or any
number of other popular treatments, could not stand up to the scrutiny
of well-designed trials. Kirsch is a faithful proponent of the
scientific method, and his voice therefore brings a welcome
objectivity to a subject often swayed by anecdotes, emotions, or, as
we will see, self-interest.
Whitaker’s book is broader and more polemical. He considers all mental
illness, not just depression. Whereas Kirsch concludes that
antidepressants are probably no more effective than placebos, Whitaker
concludes that they and most of the other psychoactive drugs are not
only ineffective but harmful. He begins by observing that even as drug
treatment for mental illness has skyrocketed, so has the prevalence of
the conditions treated:
The number of disabled mentally ill has risen dramatically since
1955, and during the past two decades, a period when the prescribing
of psychiatric medications has exploded, the number of adults and
children disabled by mental illness has risen at a mind-boggling rate.
Thus we arrive at an obvious question, even though it is heretical in
kind: Could our drug-based paradigm of care, in some unforeseen way,
be fueling this modern-day plague?
Moreover, Whitaker contends, the natural history of mental illness has
changed. Whereas conditions such as schizophrenia and depression were
once mainly self-limited or episodic, with each episode usually
lasting no more than six months and interspersed with long periods of
normalcy, the conditions are now chronic and lifelong. Whitaker
believes that this might be because drugs, even those that relieve
symptoms in the short term, cause long-term mental harms that continue
after the underlying illness would have naturally resolved.
The evidence he marshals for this theory varies in quality. He doesn’t
sufficiently acknowledge the difficulty of studying the natural
history of any illness over a fifty-some-year time span during which
many circumstances have changed, in addition to drug use. It is even
more difficult to compare long-term outcomes in treated versus
untreated patients, since treatment may be more likely in those with
more severe disease at the outset. Nevertheless, Whitaker’s evidence
is suggestive, if not conclusive.
If psychoactive drugs do cause harm, as Whitaker contends, what is the
mechanism? The answer, he believes, lies in their effects on
neurotransmitters. It is well understood that psychoactive drugs
disturb neurotransmitter function, even if that was not the cause of
the illness in the first place. Whitaker describes a chain of effects.
When, for example, an SSRI antidepressant like Celexa increases
serotonin levels in synapses, it stimulates compensatory changes
through a process called negative feedback. In response to the high
levels of serotonin, the neurons that secrete it (presynaptic neurons)
release less of it, and the postsynaptic neurons become desensitized
to it. In effect, the brain is trying to nullify the drug’s effects.
The same is true for drugs that block neurotransmitters, except in
reverse. For example, most antipsychotic drugs block dopamine, but the
presynaptic neurons compensate by releasing more of it, and the
postsynaptic neurons take it up more avidly. (This explanation is
necessarily oversimplified, since many psychoactive drugs affect more
than one of the many neurotransmitters.)
With long-term use of psychoactive drugs, the result is, in the words
of Steve Hyman, a former director of the NIMH and until recently
provost of Harvard University, “substantial and long-lasting
alterations in neural function.” As quoted by Whitaker, the brain,
Hyman wrote, begins to function in a manner “qualitatively as well as
quantitatively different from the normal state.” After several weeks
on psychoactive drugs, the brain’s compensatory efforts begin to fail,
and side effects emerge that reflect the mechanism of action of the
drugs. For example, the SSRIs may cause episodes of mania, because of
the excess of serotonin. Antipsychotics cause side effects that
resemble Parkinson’s disease, because of the depletion of dopamine
(which is also depleted in Parkinson’s disease). As side effects
emerge, they are often treated by other drugs, and many patients end
up on a cocktail of psychoactive drugs prescribed for a cocktail of
diagnoses. The episodes of mania caused by antidepressants may lead to
a new diagnosis of “bipolar disorder” and treatment with a “mood
stabilizer,” such as Depokote (an anticonvulsant) plus one of the
newer antipsychotic drugs. And so on.
Some patients take as many as six psychoactive drugs daily. One well-
respected researcher, Nancy Andreasen, and her colleagues published
evidence that the use of antipsychotic drugs is associated with
shrinkage of the brain, and that the effect is directly related to the
dose and duration of treatment. As Andreasen explained to The New York
Times, “The prefrontal cortex doesn’t get the input it needs and is
being shut down by drugs. That reduces the psychotic symptoms. It also
causes the prefrontal cortex to slowly atrophy.”*
Getting off the drugs is exceedingly difficult, according to Whitaker,
because when they are withdrawn the compensatory mechanisms are left
unopposed. When Celexa is withdrawn, serotonin levels fall
precipitously because the presynaptic neurons are not releasing normal
amounts and the postsynaptic neurons no longer have enough receptors
for it. Similarly, when an antipsychotic is withdrawn, dopamine levels
may skyrocket. The symptoms produced by withdrawing psychoactive drugs
are often confused with relapses of the original disorder, which can
lead psychiatrists to resume drug treatment, perhaps at higher doses.
Unlike the cool Kirsch, Whitaker is outraged by what he sees as an
iatrogenic (i.e., inadvertent and medically introduced) epidemic of
brain dysfunction, particularly that caused by the widespread use of
the newer (“atypical”) antipsychotics, such as Zyprexa, which cause
serious side effects. Here is what he calls his “quick thought
experiment”:
Imagine that a virus suddenly appears in our society that makes
people sleep twelve, fourteen hours a day. Those infected with it move
about somewhat slowly and seem emotionally disengaged. Many gain huge
amounts of weight—twenty, forty, sixty, and even one hundred pounds.
Often their blood sugar levels soar, and so do their cholesterol
levels. A number of those struck by the mysterious illness—including
young children and teenagers—become diabetic in fairly short order….
The federal government gives hundreds of millions of dollars to
scientists at the best universities to decipher the inner workings of
this virus, and they report that the reason it causes such global
dysfunction is that it blocks a multitude of neurotransmitter
receptors in the brain—dopaminergic, serotonergic, muscarinic,
adrenergic, and histaminergic. All of those neuronal pathways in the
brain are compromised. Meanwhile, MRI studies find that over a period
of several years, the virus shrinks the cerebral cortex, and this
shrinkage is tied to cognitive decline. A terrified public clamors for
a cure.
Now such an illness has in fact hit millions of American children
and adults. We have just described the effects of Eli Lilly’s
best-selling antipsychotic, Zyprexa.
If psychoactive drugs are useless, as Kirsch believes about
antidepressants, or worse than useless, as Whitaker believes, why are
they so widely prescribed by psychiatrists and regarded by the public
and the profession as something akin to wonder drugs? Why is the
current against which Kirsch and Whitaker and, as we will see, Carlat
are swimming so powerful? I discuss these questions in Part II of this
review.
—This is the first part of a two-part article.