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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 Antipsychotics, antidepressants, and other psychotropic drugs, he wrote, “create perturbations in neurotransmitter 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.
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Robert Whitaker (Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America)