Anatomy of an Epidemic (12 page)

From a scientific point of view, it is apparent today that the chemical imbalance hypothesis was always wobbly in kind, and many of the scientists who watched its rise and fall have looked back on it with a bit of embarrassment. As early as 1975, Joseph Mendels and Alan Frazer had concluded that Schildkraut’s hy pothesis of depression had arisen out of “tunnel thinking” that relied on an “inadequate evaluation of certain findings not consistent with the initial assumption.”
²⁹
In 1990, Deniker said that the same was true of the dopamine hypothesis of schizophrenia. When psychiatric researchers recast the drugs as “antischizophrenic” agents, he noted, they had gone “a bit far … one can say that neuroleptics diminish certain phenomena of schizophrenia, but [the drugs] do not pretend to be an etiological treatment of these psychoses.”
³⁰
The chemical-imbalance theory of mental disorders, wrote David Healy, in his book
The Creation of Psychopharmacology
, was embraced by psychiatrists because it “set the stage” for them “to become real doctors.”
³¹
Doctors in internal medicine had their antibiotics, and now psychiatrists could have their “anti-disease” pills too.

Yet a societal belief in chemical imbalances has remained (for reasons that will be explored later), and it has led those who have investigated and written about this history to emphasize, time and again, the same bottom-line conclusion. “The evidence does not support any of the biochemical theories of mental illness,” concluded Elliot Valenstein, a professor of neuroscience at the University of Michigan, in his 1998 book
Blaming the Brain
.
³²
Even U.S. surgeon general David Satcher, in his 1999 report
Mental Health
, confessed that “the precise causes [etiologies] of mental disorders are not known.”
³³
In
Prozac Backlash
, Joseph Glenmullen, an instructor of psychiatry at Harvard Medical School, noted that “in every instance where such an imbalance was thought to be found, it was later proved to be false.”
³⁴
Finally, in 2005, Kenneth Kendler, coeditor in chief of
Psychological Medicine
, penned an admirably succinct epitaph for this whole story: “We have hunted for big simple
neurochemical explanations for psychiatric disorders and have not found them.”
³⁵

This brings us to our next big question: If psychiatric drugs don’t fix abnormal brain chemistry, what do they do?

During the 1970s and 1980s, investigators put together detailed accounts of how the various classes of psychiatric drugs act on the brain, and how the brain in turn reacts to the drugs. We could relate the history of antidepressants, neuroleptics, benzodiazepines, or stimulants, and all of those histories would tell of a somewhat common process at work. But since the story of chemical imbalances in the public mind really took off after Eli Lilly brought Prozac (fluoxetine) to market, it seems appropriate to review what Eli Lilly scientists and other investigators, in reports published in scientific journals, had to say about how this “selective serotonin reuptake inhibitor” actually worked.

As was noted earlier, once a presynaptic neuron has released serotonin into the synaptic gap, it must be quickly removed so that the signal can be crisply terminated. An enzyme metabolizes a small amount; the rest is pumped back into the presynaptic neuron, entering via a channel known as SERT (serotonin reuptake transport). Fluoxetine blocks this reuptake channel, and as a result, Eli Lilly scientist James Clemens wrote in 1975, it causes a “pile-up of serotonin at the synapse.”
³⁶

However, as the Eli Lilly investigators discovered, a feedback mechanism then kicks in. The presynaptic neuron has “auto-receptors” on its terminal membrane that monitor the level of serotonin in the synapse. If serotonin levels are too low, one scientist quipped, these autoreceptors scream “turn on the serotonin machine.” If serotonin levels are too high, they scream “turn it off.” This is a feedback loop designed by evolution to keep the serotonergic system in balance, and fluoxetine triggers the latter message. With serotonin no longer being whisked away from the synapse, the
autoreceptors tell the presynaptic neurons to fire at a dramatically lower rate. They begin to release lower-than-normal amounts of serotonin into the synapse.

Feedback mechanisms also change the postsynaptic neurons. Within four weeks, the density of their serotonin receptors drops 25 percent below normal, Eli Lilly scientists reported in 1981.
³⁷
Other investigators subsequently reported that “chronic fluoxetine treatment” may lead to a 50 percent reduction in serotonin receptors in certain areas of the brain.
³⁸
As a result, the post synaptic neurons become “desensitized” to the chemical messenger.

At this point, it may seem that the brain has successfully adapted to the drug. Fluoxetine blocks the normal reuptake of serotonin from the synapse, but the presynaptic neurons then begin releasing less serotonin and the postsynaptic neurons become less sensitive to serotonin and thus don’t fire so readily. The drug was designed to accelerate the serotonergic pathway; the brain responded by putting on the brake. It has kept its serotonergic pathway more or less in balance, an adaptive response that researchers have dubbed “synaptic resilience.”
³⁹
However, there is one other change that occurs during this initial two-week period, and it ultimately short-circuits the brain’s compensatory response. The autoreceptors for serotonin on the presynaptic neurons decline in number. As a result, this feedback mechanism becomes partially disabled, and the “turn off the serotonin machine” message dims. The presynaptic neurons begin to fire at a normal rate again, at least for a while, and to release more serotonin than normal each time.
^40
*

As the Eli Lilly scientists and others put together this picture of fluoxetine’s effects on the brain, they speculated as to what part of this process was responsible for the drug’s antidepressant properties. Psychiatrists had long observed that antidepressants took two or three weeks to “work,” and thus the Eli Lilly researchers reasoned in 1981 that it was the decline in serotonin receptors, which took several weeks to occur, that was “the underlying mechanism associated with the therapeutic response.”
⁴¹
If so, the drug could be
said to work because it drove the serotonergic system into a less responsive state. But once researchers discovered that fluoxetine partially disabled the feedback mechanism, Claude de Montigny at McGill University argued that this was what allowed the drug to begin working. This disabling process also took two or three weeks to occur, and it allowed the presynaptic neurons to begin pumping higher amounts of serotonin than normal into the synapse. At that point, with fluoxetine continuing to block serotonin’s removal, the neurotransmitter could now indeed “pile up” in the synapse, and that would lead “to an enhancement of central serotonergic neurotransmission,” de Montigny wrote.
⁴²

That is the scientific story of how fluoxetine alters the brain, and it may be that this process helps depressed people get well and stay well. Only the outcomes literature can reveal whether that is so. But the medicine clearly doesn’t
fix
a chemical imbalance in the brain. Instead, it does precisely the opposite. Prior to being medicated, a depressed person has no known chemical imbalance. Fluoxetine then gums up the normal removal of serotonin from the synapse, and that triggers a cascade of changes, and several weeks later the serotonergic pathway is operating in a decidedly
abnormal
manner. The presynaptic neuron is putting out more serotonin than usual. Its serotonin reuptake channels are blocked by the drug. The system’s feedback loop is partially disabled. The postsynaptic neurons are “desensitized” to serotonin. Mechanically speaking, the serotonergic system is now rather mucked up.

Eli Lilly’s scientists were well aware that this was so. In 1977, Ray Fuller and David Wong observed that fluoxetine, since it disrupted serotonergic pathways, could be used to study “the role of serotonin neurons in various brain functions—behavior, sleep, regulation of pituitary hormone release, thermoregulation, pain responsiveness and so on.” To conduct such experiments, researchers could administer fluoxetine to animals and observe which functions became compromised. They would look for
pathologies
to appear. This type of research in fact was already being done: Fuller and Wong reported in 1977 that the drug stirred “stereotyped hyperactivity” in rats and “suppressed REM sleep” in both rats and cats.
⁴³

In 1991, in a paper published in the
Journal of Clinical Psychiatry
, Princeton neuroscientist Barry Jacobs made this very point about SSRIs. He wrote:

During the 1970s and 1980s, researchers studying the effects of neuroleptics fleshed out a similar story. Thorazine and other standard antipsychotics block 70 to 90 percent of all D
₂
receptors in the brain. In response, the presynaptic neurons begin pumping out more dopamine and the postsynaptic neurons increase the density of their D
₂
receptors by 30 percent or more. In this manner, the brain is trying to “compensate” for the drug’s effects so that it can maintain the transmission of messages along its dopaminergic pathways. However, after about three weeks, the pathway’s feedback mechanism begins to fail, and the presynaptic neurons begin to fire in irregular patterns or turn quiescent. It is this “inactivation” of dopaminergic pathways that “may be the basis for the antipsychotic action,” explains the American Psychiatric Association’s
Textbook of Psychopharmacology
.
⁴⁵

Once again, this is a story of neurotransmitter pathways that have been transformed by the medication. After several weeks, their feedback loops are partially disabled, the presynaptic neurons are releasing less dopamine than normal, the drug is thwarting dopamine’s effects by blocking D
₂
receptors, and the postsynaptic neurons have an abnormally high density of these receptors. The drugs do not normalize brain chemistry, but disturb it, and if Jacob’s reasoning is followed, to a degree that could be considered “pathological.”

Today, as provost of Harvard University, Steve Hyman is mostly engaged in the many political and administrative tasks that come with leading a large institution. But he is a neuroscientist by training, and in 1996 to 2001, when he was the director of the NIMH, he wrote a paper, one both memorable and provocative in kind, that summed up all that had been learned about psychiatric drugs. Titled “Initiation and Adaptation: A Paradigm for Understanding Psychotropic Drug Action,” it was published in the
American Journal of Psychiatry
, and it told of how all psychotropic drugs could be understood to act on the brain in a common way.
⁴⁶

Antipsychotics, antidepressants, and other psychotropic drugs, he wrote, “create perturbations in neurotansmitter functions.” In response, the brain goes through a series of compensatory adaptations. If a drug blocks a neurotransmitter (as an antipsychotic does), the presynaptic neurons spring into hyper gear and release more of it, and the postsynaptic neurons increase the density of their receptors for that chemical messenger. Conversely, if a drug increases the synaptic levels of a neurotransmitter (as an antidepressant does), it provokes the opposite response: The presynaptic neurons decrease their firing rates and the postsynaptic neurons decrease the density of their receptors for the neurotransmitter. In each instance, the brain is trying to nullify the drug’s effects. “These adaptations,” Hyman explained, “are rooted in homeostatic mechanisms that exist, presumably, to permit cells to maintain their equilibrium in the face of alterations in the environment or changes in the internal milieu.”

However, after a period of time, these compensatory mechanisms break down. The “chronic administration” of the drug then causes “substantial and long-lasting alterations in neural function,” Hyman wrote. As part of this long-term adaptation process, there are changes in intracellular signaling pathways and gene expression. After a few weeks, he concluded, the person’s brain is functioning in a manner that is “qualitatively as well as quantitatively different from the normal state.”

His was an elegant paper, and it summed up what had been learned from decades of impressive scientific work. Forty years earlier, when Thorazine and the other first-generation psychiatric drugs were discovered, scientists had little understanding of how neurons communicated with one another. Now they had a remarkably detailed understanding of neurotransmitter systems in the brain and of how drugs acted on them. And what science had revealed was this: 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, as Hyman observed,
abnormally
.

While Dr. Hyman’s paper may seem startling, it serves as a coda to a scientific narrative that is, in fact, consistent from beginning to end. His was not a conclusion that should be seen as unexpected, but rather one that was predicted by psychopharmacology’s opening chapter.

As we saw, Thorazine, Miltown, and Marsilid were all derived from compounds that had been developed for other purposes—for use in surgery or as possible “magic bullets” against infectious diseases. Those compounds were then found to cause alterations in mood, behavior, and thinking that were seen as helpful to psychiatric patients. The drugs, in essence, were perceived as having beneficial
side effects
. They perturbed normal function, and that understanding was reflected in the initial names given to them. Chlorpromazine was a “major tranquilizer,” and it was said to produce a change in being similar to frontal lobotomy. Meprobamate was a “minor tranquilizer,” and in animal studies, it had been shown to be a powerful muscle relaxant that blocked normal emotional response to environmental stressors. Iproniazid was a “psychic stimulator,” and if the report of TB patients dancing in the
wards was truthful, it was a drug that could provoke something akin to mania. However, psychiatry then reconceived the drugs as “magic bullets” for mental disorders, the drugs hypothesized to be antidotes to chemical imbalances in the brain. But that theory, which arose as much from wishful thinking as from science, was investigated and it did not pan out. Instead, as Hyman wrote, psychotropics are drugs that perturb the normal functioning of neuronal pathways in the brain. Psychiatry’s first impression of its new drugs turned out to be the scientifically accurate one.