Anatomy of an Epidemic (11 page)

This line of research kept scientists busy for nearly fifteen years.

In 1969, Malcolm Bowers at Yale University became the first to report on whether depressed patients had low levels of serotonin metabolites in their cerebrospinal fluid. In a study of eight depressed patients (all of whom had been previously exposed to antidepressants), he announced that their 5-HIAA levels were lower than normal, but not “significantly” so.
³
Two years later, investigators at McGill University said that they, too, had failed to find a “statistically significant” difference in the 5-HIAA levels of depressed patients and normal controls, and that they also had failed to find any correlation between 5-HIAA levels and the severity of depressive symptoms.
⁴
In 1974, Bowers was back with a more finely tuned follow-up study: Depressed patients who had not been exposed to antidepressants had perfectly normal 5-HIAA levels.
⁵

The serotonin theory of depression did not seem to be panning out, and in 1974, two researchers at the University of Pennsylvania, Joseph Mendels and Alan Frazer, revisited the evidence that had led Schildkraut to advance his theory in the first place. Schildkraut had
noted that reserpine, which depleted monoamines in the brain (norepinephrine, serotonin, and dopamine), regularly made people depressed. But when Mendels and Frazer looked closely at the scientific literature, they found that when hypertensive patients were given reserpine, only 6 percent in fact got the blues. Furthermore, in 1955, a group of physicians in England had given the herbal drug to their depressed patients, and it had
lifted
the spirits of many. Reserpine, Mendels and Frazer concluded, didn’t reliably induce depression at all.
⁶
They also noted that when researchers had given other monoamine-depleting drugs to people, those agents hadn’t induced depression either. “The literature reviewed here strongly suggests that the depletion of brain norepinephrine, dopamine or serotonin is in itself not sufficient to account for the development of the clinical syndrome of depression,” they wrote.
⁷

It seemed that the theory was about to be declared dead and buried, but then, in 1975, Marie Asberg and her colleagues at the Karolinska Institute in Stockholm breathed new life into it. Twenty of the sixty-eight depressed patients they had tested suffered from low 5-HIAA levels, and these low-serotonin patients were somewhat more suicidal than the rest, with two of the twenty eventually committing suicide. This was evidence, the Swedish researchers said, that there might be “a biochemical subgroup of depressive disorder characterized by a disturbance of serotonin turnover.”
⁸

Soon prominent psychiatrists in the United States were writing that “nearly 30 percent” of depressed patients had been found to have low serotonin levels. The serotonin theory of depression seemed at least partly vindicated. But today, if we revisit Asberg’s study and examine her data, we can see that her finding of a “biological subgroup” of depressed patients was mostly a story of wishful thinking.

In her study, Asberg reported that 25 percent of her “normal” group had cerebrospinal 5-HIAA levels below fifteen nanograms per milliliter. Fifty percent had fifteen to twenty-five nanograms of 5-HIAA per milliliter, and the remaining 25 percent had levels above twenty-five nanograms. The bell curve for her “normals” showed that 5-HIAA levels were quite variable. But what she failed
to note in her discussion was that the bell curve for the sixty-eight depressed patients in her study was almost exactly the same. Twenty-nine percent (twenty of the sixty-eight) had 5-HIAA counts below fifteen nanograms, 47 percent had levels between fifteen and twenty-five nanograms, and 24 percent had levels above twenty-five nanograms. Twenty-nine percent of depressed patients may have had “low” levels of serotonin metabolites in their cerebrospinal fluid (this was her “biological subgroup”), but then so did 25 percent of “normal” people. The median level for normals was twenty nanograms, and, it so turned out, more than half of the depressed patients—thirty-seven of sixty-eight—had levels
above
that amount.

Viewed in this way, her study had not provided any new reason to believe in the serotonin theory of depression. Japanese investigators soon revealed, in an unwitting way, the faulty logic at work. They reported that some antidepressants (used in Japan) blocked serotonin receptors, inhibiting the firing of those pathways, and thus they reasoned that depression might be caused by an “excess of free serotonin in the synaptic cleft.”
⁹
They had applied the same backwards reasoning that had given rise to the low-serotonin theory of depression, and if the Japanese scientists had wanted to, they could have pointed to Asberg’s study for support of their theory, as the Swedes had found that 24 percent of depressed patients had “high” levels of serotonin.

In 1984, NIMH investigators studied the low-serotonin theory of depression one more time. They wanted to see whether the “biological subgroup” of depressed patients with “low” levels of serotonin were the best responders to an antidepressant, amitriptyline, that selectively blocked its reuptake. If an antidepressant was an antidote to a chemical imbalance in the brain, then amitriptyline should be most effective in that subgroup. But, lead investigator James Maas wrote, “contrary to expectations, no relationships between cerebrospinal 5-HIAA and response to amitriptyline were found.”
¹⁰
Moreover, he and the other NIMH researchers discovered—just as Asberg had—that 5-HIAA levels varied widely in depressed patients. Some had high levels of serotonin metabolites in their cerebrospinal
fluid, while others had low levels. The NIMH scientists drew the only possible conclusion: “Elevations or decrements in the functioning of serotonergic systems per se are not likely to be associated with depression.”
^*

Even after this report, the serotonin theory of depression did not completely go away. The commercial success of Prozac, a “selective serotonin reuptake inhibitor” brought to market in 1988 by Eli Lilly, fueled a new round of public claims that depression was due to low levels of this neurotransmitter, and once again any number of investigators conducted experiments to see if that were so. But this second round of studies produced the same results as the first. “I spent the first several years of my career doing full-time research on brain serotonin metabolism, but I never saw any convincing evidence that any psychiatric disorder, including depression, results from a deficiency of brain serotonin,” said Stanford psychiatrist David Burns in 2003.
¹¹
Numerous others made this same point. “There is no scientific evidence whatsoever that clinical depression is due to any kind of biological deficit state,” wrote Colin Ross, an associate professor of psychiatry at Southwest Medical Center in Dallas, in his 1995 book,
Pseudoscience in Biological Psychiatry
.
¹²
In 2000, the authors of
Essential Psychopharmacology
told medical students “there is no clear and convincing evidence that monoamine deficiency accounts for depression; that is, there is no ‘real’ monoamine deficit.”
¹³
Yet, fueled by pharmaceutical advertisements, the belief lived on, and it caused Irish psychiatrist David Healy, who has written a number of books on the history of psychiatry,
to quip in 2005 that this theory needed to be put into the medical dustbin, where other such discredited theories can be found. “The serotonin theory of depression,” he wrote, with evident exasperation, “is comparable to the masturbatory theory of insanity.”
¹⁴

When Van Rossum set forth his dopamine hypothesis of schizophrenia, he noted that the first thing that investigators needed to do was “further substantiate” that antipsychotic drugs did indeed thwart dopamine transmission in the brain. This took some time, but by 1975, Solomon Snyder at Johns Hopkins Medical School and Philip Seeman at the University of Toronto had fleshed out how the drugs achieved that effect. First, Snyder identified two distinct types of dopamine receptors, known as D
₁
and D
₂
. Next, both investigators found that antipsychotics blocked 70 to 90 percent of the D
₂
receptors.
¹⁵
Newspapers now told of how these drugs might be correcting a chemical imbalance in the brain.

“Too much dopamine function in the brain could account for the overwhelming flood of sensations that plagues the schizophrenic,” the
New York Times
explained. “By blocking the brain’s receptor sites for dopamine, neuroleptics put an end to sights and sounds that are not really there.”
¹⁶

However, even as Snyder and Seeman were reporting their results, Malcolm Bowers was announcing findings that cast a cloud over the dopamine hypothesis. He had measured the level of dopamine metabolites in the cerebrospinal fluid of unmedicated schizophrenics and found them to be quite normal. “Our findings,” he wrote, “do not furnish neurochemical evidence for an over-arousal in these patients emanating from a midbrain dopamine system.”
¹⁷
Others soon reported similar results. In 1975, Robert Post at the NIMH determined that HVA levels in the cerebrospinal fluid of twenty unmedicated schizophrenics “were not significantly different from controls.”
¹⁸
Autopsy studies also revealed that the brain tissue of drug-free schizophrenics did not have abnormal levels of
dopamine. In 1982, UCLA’s John Haracz reviewed this body of research and drew the obvious bottom-line conclusion: “These findings do not support the presence of elevated dopamine turnover in the brains of [unmedicated] schizophrenics.”
¹⁹

Having discovered that dopamine levels in never-medicated schizophrenics were normal, researchers turned their attention to a second possibility. Perhaps people with schizophrenia had an overabundance of dopamine receptors. If so, the postsynaptic neurons would be “hypersensitive” to dopamine, and this would cause the dopaminergic pathways to be overstimulated. In 1978, Philip See-man at the University of Toronto announced in
Nature
that this was indeed the case. At autopsy, the brains of twenty schizophrenics had 70 percent more D
₂
receptors than normal. At first glance, it seemed that the cause of schizophrenia had been found, but Seeman cautioned that all of the patients had been on neuroleptics prior to their deaths. “Although these results are apparently compatible with the dopamine hypothesis of schizophrenia in general,” he wrote, the increase in D
₂
receptors might “have resulted from the long-term administration of neuroleptics.”
²⁰

A variety of studies quickly proved that the drugs were indeed the culprit. When rats were fed neuroleptics, their D
₂
receptors quickly increased in number.
²¹
If rats were given a drug that blocked D
₁
receptors, that receptor subtype increased in density.
²²
In each instance, the increase was evidence of the brain trying to compensate for the drug’s blocking of its signals. Then, in 1982, Angus MacKay and his British colleagues reported that when they examined brain tissue from forty-eight deceased schizophrenics, “the increases in [D
₂
] receptors were seen only in patients in whom neuroleptic medication had been maintained until the time of death, indicating that they were entirely iatrogenic [drug-caused].”
²³
A few years later, German investigators reported the same results from their autopsy studies.
²⁴
Finally, investigators in France, Sweden, and Finland used positron emission topography to study D
₂
-receptor densities in living patients who had never been exposed to neuroleptics, and all reported “no significant differences” between the schizophrenics and “normal controls.”
²⁵

Since that time, researchers have continued to study whether there might be something amiss with the dopaminergic pathways in people diagnosed with schizophrenia, and now and then someone reports having found an abnormality of some type in a subset of patients. But by the end of the 1980s, it was clear that the chemical-imbalance hypothesis of schizophrenia—that this was a disease characterized by a hyperactive dopamine system that was then put somewhat back into balance by the drugs—had come to a crashing end. “The dopaminergic theory of schizophrenia retains little credibility for psychiatrists,” observed Pierre Deniker in 1990.
²⁶
Four years later, John Kane, a well-known psychiatrist at Long Island Jewish Medical Center, echoed the sentiment, noting that there was “no good evidence for any perturbation of the dopamine function in schizophrenia.”
²⁷
Still, the public continued to be told that people diagnosed with schizophrenia had overactive dopamine systems, with the drugs likened to “insulin for diabetes,” and thus former NIMH director Steve Hyman, in his 2002 book,
Molecular Neuropharmacology
, was moved to once again remind readers of the truth. “There is no compelling evidence that a lesion in the dopamine system is a primary cause of schizophrenia,” he wrote.
²⁸

The low-serotonin hypothesis of depression and the high-dopamine hypothesis of schizophrenia had always been the twin pillars of the chemical-imbalance theory of mental disorders, and by the late 1980s, both had been found wanting. Other mental disorders have also been touted to the public as diseases caused by chemical imbalances, but there was never any evidence to support those claims. Parents were told that children diagnosed with attention deficit hyperactivity disorder suffered from low dopamine levels, but the only reason they were told that was because Ritalin stirred neurons to release extra dopamine. This became the storytelling formula that was relied upon by pharmaceutical companies again and again:
Researchers would identify the mechanism of action for a class of drugs, how the drugs either lowered or raised levels of a brain neurotransmitter, and soon the public would be told that people treated with those medications suffered from the opposite problem.