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Wed Sep 4 08:39:12 PDT 2013

 September 3, 2013
The Psychiatric Drug Crisis
Posted by Gary Greenberg<http://www.newyorker.com/magazine/bios/gary_greenberg/search?contributorName=Gary%20Greenberg>

[image: greenberg-magic-bullets-580.jpeg]

It’s been just 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<http://www.ncbi.nlm.nih.gov/pubmed/23052291>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<http://www.nytimes.com/2013/08/20/health/a-dry-pipeline-for-psychiatric-drugs.html>.
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<http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2813%2961611-6/fulltext>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<http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2560740/pdf/10885180.pdf>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 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2655089/> 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 Tofranil, 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<http://alphachoices.com/repository/assets/pdf/EmperorsNewDrugs.pdf>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<http://www.newyorker.com/reporting/2011/12/12/111212fa_fact_specter>,
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<http://www.ncbi.nlm.nih.gov/pubmed/23052291>,
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<http://www.newyorker.com/online/blogs/newsdesk/2013/02/obamas-brain.html>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 <http://www.garygreenbergonline.com/> is a practicing
psychotherapist and the author of “The Book of Woe: The DSM and the
Unmaking of Psychiatry<http://www.amazon.com/gp/product/0399158537/ref=as_li_ss_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=0399158537&linkCode=as2&tag=garygreenberg-20>.”
*

*Correction: Due to an editing error, the antidepressant Tofranil was
originally identified as Elavil.*

*Photograph by Paul Skelcher/Science Faction/Corbis.*

-- 
Art Deco (Wayne A. Fox)
art.deco.studios at gmail.com
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