Anatomy of an Epidemic Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America 5. The Hunt for Chemical Imbalances
Author: Robert Whitaker Publisher: New York , NY: Crown Publishing. Publish Date: 2010-3-31 Review Date: Status:📚
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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
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M. Bowers, “Central dopamine turnover in schizophrenic syndromes,” Archives of General Psychiatry 31 (1974): 50–54.
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R. Post, “Cerebrospinal fluid amine metabolites in acute schizophrenia,” Archives of General Psychiatry 32 (1975): 1063–68.
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J. Haracz, “The dopamine hypothesis: an overview of studies with schizophrenic patients,” Schizophrenia Bulletin 8 (1982): 438–58.
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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 D2 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 D2 receptors might “have resulted from the long-term administration of neuroleptics.”20
- T. Lee, “Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains,” Nature 374 (1978): 897–900.
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A variety of studies quickly proved that the drugs were indeed the culprit. When rats were fed neuroleptics, their D2 receptors quickly increased in number.21 If rats were given a drug that blocked D1 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 [D2] 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 D2-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
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D. Burt, “Antischizophrenic drugs: chronic treatment elevates dopa mine receptor binding in brain,” Science 196 (1977): 326–27.
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M. Porceddu, “[3H]SCH 23390 binding sites increase after chronic blockade of d-1 dopamine receptors,” European Journal of Pharmacology 118 (1985): 367–70.
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A. MacKay, “Increased brain dopamine and dopamine receptors in schizophrenia,” Archives of General Psychiatry 39 (1982): 991–97.
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J. Kornhuber, “3H-spiperone binding sites in post-mortem brains from schizophrenic patients,” Journal of Neural Transmission 75 (1989): 1–10.
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J. Martinot, “Striatal D2 dopaminergic receptors assessed with positron emission tomography and bromospiperone in untreated schizophrenic patients,” American Journal of Psychiatry 147 (1990): 44–50; L. Farde, “D2 dopamine receptors in neuroleptic-naïve schizophrenic patients,” Archives of General Psychiatry 47 (1990): 213–19; J. Hietala, “Striatal D2 dopamine receptor characteristics in neuroleptic-naïve schizophrenic patients studied with positron emission tomography,” Archives of General Psychiatry 51 (1994): 116–23.
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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
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M. Bowers, “Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in psychiatric patients,” International Journal of Neuropharmacology 8 (1969): 255–62.
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R. Papeschi, “Homovanillic and 5-hydroxyindoleacetic acid in cerebrospinal fluid of depressed patients,” Archives of General Psychiatry 25 (1971): 354–58.
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M. Bowers, “Lumbar CSF 5-hydroxyindoleacetic acid and homovanillic acid in affective syndromes,” Journal of Nervous and Mental Disease 158 (1974): 325–30.
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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.
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M. Asberg, “Serotonin depression: A biochemical subgroup within the affective disorders?” Science 191 (1976): 478–80; M. Asberg, “5-HIAA in the cerebrospinal fluid,” Archives of General Psychiatry 33 (1976): 1193–97.
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J. Mendels, “Brain biogenic amine depletion and mood,” Archives of General Psychiatry 30 (1974): 447–51.
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D. L. Davies, “Reserpine in the treatment of anxious and depressed patients,” Lancet 2 (1955): 117–20.
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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.
- H. Nagayama, “Postsynaptic action by four antidepressive drugs in an animal model of depression,” Pharmacology Biochemistry and Behavior 15 (1981): 125–30. Also see H. Nagayama, “Action of chronically administered antidepressants on the serotonergic postsynapse in a model of depression,” Pharmacology Biochemistry and Behavior 25 (1986): 805–11.
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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.”*
- J. Maas, “Pretreatment neurotransmitter metabolite levels and response to tricyclic antidepressant drugs,” American Journal of Psychiatry 141 (1984): 1159–71.
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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
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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
- S. Hyman, “Initiation and adaptation: A paradigm for understanding psychotropic drug action,” American Journal of Psychiatry 153 (1996): 151–61.
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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.”
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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.”
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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.
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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.
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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.
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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
- R. Fuller, “Effect of an uptake inhibitor on serotonin metabolism in rat brain,” Life Sciences 15 (1974): 1161–71.
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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.
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D. Wong, “Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine,” Research Communications in Chemical Pathology and Pharmacology 32 (1981): 41–51.
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J. Wamsley, “Receptor alterations associated with serotonergic agents,” Journal of Clinical Psychiatry 48, suppl. (1987): 19–25.
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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
- C. Montigny, “Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers,” Journal of Clinical Psychiatry 51, suppl. B (1990): 4–8.
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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.
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D. Wong, “Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine,” Research Communications in Chemical Pathology and Pharmacology 32 (1981): 41–51.
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C. Montigny, “Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers,” Journal of Clinical Psychiatry 51, suppl. B (1990): 4–8.
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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.
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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 D2 receptors in the brain. In response, the presynaptic neurons begin pumping out more dopamine and the postsynaptic neurons increase the density of their D2 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
- Schatzberg, Textbook of Psychopharmacology, 619.
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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 D2 receptors, and the postsynaptic neurons have an abnormally high density of these receptors. The drugs do not normalize brain chemistry, but disturb it,
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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.
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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.