September 3,
2013
Posted by Gary Greenberg
over twenty-five years since Prozac came to
market, and more than twenty per cent of Americans now regularly take
mind-altering drugs prescribed by their doctors. Almost as familiar as brands
like Zoloft and Lexapro is the worry about what it means that the daily routine
in many households, for parents and children alike, includes a dose of
medications that are poorly understood and whose long-term effects on the body
are unknown. Despite our ambivalence, sales of psychiatric drugs amounted
to more than seventy billion dollars in 2010. They have become yet another
commodity that consumers have learned to live with or even enjoy, like S.U.V.s
or Cheetos
Yet the psychiatric-drug industry is in trouble. “We are
facing a crisis,” the Cornell psychiatrist and New York Times contributor
Richard Friedman warned last week.
In the past few years, one pharmaceutical giant after another—GlaxoSmithKline,
AstraZeneca, Novartis, Pfizer, Merck, Sanofi—has shrunk or shuttered its
neuroscience research facilities. Clinical trials have been halted, lines of
research abandoned, and the new drug pipeline has been allowed to run dry.
Why would an industry beat a hasty retreat from a market
that continues to boom? (Recent surveys
indicate that mental illness is the leading cause of impairment and disability
worldwide.) The answer lies in the history of psychopharmacology, which is more
deeply indebted to serendipity than most branches of medicine—in particular, to
a remarkable series of accidental discoveries made in the fifteen or so years
following the end of the Second World War.
In 1949, John Cade published an article in the
Medical Journal of Australia describing his discovery that lithium
sedated people who experienced mania. Cade had been testing his theory that
manic people were suffering from an excess of uric acid by injecting patients’
urine into guinea pigs, who subsequently died. When Cade diluted the uric acid
by adding lithium, the guinea pigs fared better; when he injected them with
lithium alone, they became sedated. He noticed the same effect when he tested
lithium on himself, and then on his patients. Nearly twenty years after he first
recommended lithium to treat manic depression, it became the standard treatment
for the disorder.
In the nineteen-forties and fifties, schizophrenic
patients in some asylums were treated with cold-induced “hibernation”—a state
from which they often emerged lucid and calm. In one French hospital, the
protocol also called for chlorpromazine, a new drug thought to increase the
hibernation effect. One day, some nurses ran out of ice and administered the
drug on its own. When it calmed the patients, chlorpromazine, later named
Thorazine, was recognized in 1952 as the first drug
treatment for schizophrenia—a development that encouraged doctors to believe
that they could use drugs to manage patients outside the asylum, and thus
shutter their institutions.
In 1956, the Swiss firm Geigy wanted in on the
antipsychotics market, and it asked a researcher and asylum doctor, Roland Kuhn,
to test out a drug that, like Thorazine, was an antihistamine—and thus was
expected to have a sedating effect. The results were not what Kuhn desired: when
the schizophrenic patients took the drug, imipramine, they became more agitated,
and one of them, according to a member of the research team, “rode, in his
nightshirt, to a nearby village, singing lustily.” He added, “This was not
really a very good PR exercise for the hospital.” But it was the inspiration for
Kuhn and his team to reason that “if the flat mood of schizophrenia could be
lifted by the drug, then could not a depressed mood be elevated also?” Under the
brand name Elavil, imipramine went on to become the first antidepressant—and one
of the first blockbuster psychiatric drugs.
American researchers were also interested in
antihistamines. In 1957, Leo Sternbach, a chemist for Hoffmann-La Roche who had
spent his career researching them, was about to throw away the last of a series
of compounds he had been testing that had proven to be pharmacologically inert.
But in the interest of completeness, he was convinced to test the last sample.
“We thought the expected negative pharmacological results would cap our work on
this series of compounds,” one of his colleagues later recounted. But the drug
turned out to have muscle-relaxing and sedative properties. Instead of becoming
the last in a list of failures, it became the first in a series of spectacular
successes—the benzodiazepenes, of which Sternbach’s Librium and Valium were the
flagships.
By 1960, the major classes of psychiatric drugs—among
them, mood stabilizers, antipsychotics, antidepressants, and anti-anxiety drugs,
known as anxiolytics—had been discovered and were on their way to becoming a
seventy-billion-dollar market. Having been discovered by accident, however, they
lacked one important element: a theory that accounted for why they worked (or,
in many cases, did not).
That didn’t stop drug makers and doctors from claiming
that they knew. Drawing on another mostly serendipitous discovery of the
fifties—that the brain did not conduct its business by sending sparks from
neuron to neuron, as scientists previously thought, but rather by sending
chemical messengers across synapses—they fashioned an explanation: mental
illness was the result of imbalances among these neurotransmitters, which the
drugs treated in the same way that insulin treats diabetes.
The appeal of this account is obvious: it combines ancient
notions of illness (specifically, the idea that sickness resulted from
imbalanced humors) with the modern understanding of the molecular culprits that
make us suffer—germs. It held out the hope that mental illness could be treated
in the same way as pneumonia or hypertension: with a single pill. Drug companies
wasted no time in promulgating it. Merck, the manufacturer of Elavil,
commissioned the psychiatrist Frank Ayd to write a book called Recognizing
the Depressed Patient, in which he extolled the “chemical revolution in
psychiatry” and urged doctors to reassure patients they weren’t losing their
minds, but rather suffering a “common illness” with a “physical basis” and a
pharmacological cure. Merck sent Ayd’s book to fifty thousand doctors around the
country. In 1965, Joseph Schildkraut, a psychiatrist at the National Institute
of Mental Health, reverse-engineered antidepressants and offered an actual
theory: at least when it came to depression, the imbalances were to be found in
the neurotransmitters he thought were affected by the drugs, dopamine and
norepinephrine. Seven years after antidepressants were invented, and five years
after Ayd asserted that depression was a chemical problem, psychiatrists finally
had a precise, scientific explanation for why they worked. The paper quickly
became one of the most cited articles in the medical literature.
But Schildkraut was wrong. Within a few years, as
technology expanded our ability to peer into the brain, it became clear that
antidepressants act mostly by increasing the availability of the
neurotransmitter serotonin—rather than dopamine and norepinephrine, as
previously thought. A new generation of antidepressants—the selective serotonin
reuptake inhibitors (S.S.R.I.s), including Prozac, Zoloft, and Paxil—was
developed to target it. The ability to claim that the drugs targeted a specific
chemical imbalance was a marketing boon as well, assuring consumers that the
drugs had a scientific basis. By the mid-nineties, antidepressants were the
best-selling class of prescription medications in the country. Psychiatry
appeared to have found magic bullets of its own.
The serotonin-imbalance theory, however, has turned out to
be just as inaccurate as Schildkraut’s. While S.S.R.I.s surely alter serotonin
metabolism, those changes do not explain why the drugs work, nor do they explain
why they have proven to be no more effective than placebos in clinical trials.
Within a decade of Prozac’s approval by the F.D.A. in 1987, scientists had
concluded that serotonin was only a finger pointing at one’s mood—that the
causes of depression and the effects of the drugs were far more complex than the
chemical-imbalance theory implied. The ensuing research has mostly yielded more
evidence that the brain, which has more neurons than the Milky Way has stars and
is perhaps one of the most complex objects in the universe, is an elusive target
for drugs.
Despite their continued failure to understand how
psychiatric drugs work, doctors continue to tell patients that their troubles
are the result of chemical imbalances in their brains. As Frank Ayd pointed out,
this explanation helps reassure patients even as it encourages them to take
their medicine, and it fits in perfectly with our expectation that doctors will
seek out and destroy the chemical villains responsible for all of our suffering,
both physical and mental. The theory may not work as science, but it is a
devastatingly effective myth.
Whether or not truthiness, as one might call it, is good
medicine remains to be seen. No one knows how important placebo effects are to successful
treatment, or how exactly to implement them, a
topic Michael Specter wrote about in the magazine in 2011. But the dry pipeline
of new drugs bemoaned by Friedman is an indication that the drug industry has
begun to lose faith in the myth it did so much to create. As Steven Hyman, the
former head of the National Institute of Mental Health, wrote last year, the notion that
“disease mechanisms could … be inferred from drug action” has succeeded mostly
in “capturing the imagination of researchers” and has become “something of a
scientific curse.” Bedazzled by the prospect of unraveling the mysteries of
psychic suffering, researchers have spent recent decades on a fool’s
errand—chasing down chemical imbalances that don’t exist. And the result, as
Friedman put it, is that “it is hard to think of a single truly novel
psychotropic drug that has emerged in the last thirty years.”
Despite the BRAIN initiative recently
announced by the Obama Administration, and the
N.I.M.H.’s renewed efforts to stimulate research on the neurocircuitry of mental
disorder, there is nothing on the horizon with which to replace the old story.
Without a new explanatory framework, drug-company scientists don’t even know
where to begin, so it makes no sense for the industry to stay in the
psychiatric-drug business. And if loyalists like Hyman and Friedman continue to
say out loud what they have been saying to each other for many years—that, as
Friedman told Times readers, “just because an S.S.R.I. antidepressant
increases serotonin in the brain and improves mood, that does not mean that
serotonin deficiency is the cause of the disease”—then consumers might also lose
faith in the myth of the chemical imbalance.
Gary
Greenberg is a practicing psychotherapist and the
author of “The Book of Woe: The DSM and the Unmaking of
Psychiatry.”
Correction: Due to an editing error, the antidepressant Tofranil was originally identified as Elavil.
