Anatomy of an Epidemic (10 page)

Evidence for this theory arose from investigations into Parkinson’s disease. In the late 1950s, Sweden’s Arvid Carlsson and others suggested that Parkinson’s might be due to a deficiency in dopamine. To test this possibility, Viennese neuropharmacologist Oleh Hornykiewicz applied iodine to the brain of a man who’d died from the illness, as this chemical turns dopamine pink. The basal ganglia, an area of the brain that controls motor movements, was known to be rich in dopaminergic neurons, and yet in the basal ganglia of the Parkinson’s patient, there was “hardly a tinge of pink discoloration,” Hornykiewicz reported.
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Psychiatric researchers immediately understood the possible relevance of this to schizophrenia. Thorazine and other neuroleptics regularly induced Parkinsonian symptoms—the same tremors, tics, and slowed gait. And if Parkinson’s resulted from the death of dopaminergic neurons in the basal ganglia, then it stood to reason that antipsychotic drugs, in some manner or another, thwarted dopamine transmission in the brain. The death of dopaminergic neurons and the blocking of dopamine transmission would both produce a dopamine malfunction in the basal ganglia. Carlsson soon reported that Thorazine and the other drugs for schizophrenia did just that.

This was a finding, however, that told of drugs that “disconnected” certain brain regions. They weren’t normalizing brain
function; they were creating a profound pathology. However, at this same time, researchers reported that amphetamines—drugs known to trigger hallucinations and paranoid delusions—elevated dopamine activity in the brain. Thus, it appeared that psychosis might be caused by too much dopamine activity, which the neuroleptics then curbed (and thus brought back into balance). If so, the drugs could be said to be antipsychotic in kind, and in 1967, Dutch scientist Jacques Van Rossum explicitly set forth the dopamine hypothesis of schizophrenia. “When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology” of the disease.
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The revolution in mental health care that Congress had hoped for when it created the NIMH twenty years earlier was now—or so it seemed—complete. Psychiatric drugs had been developed that were antidotes to biological disorders, and researchers believed that the drugs worked by countering chemical imbalances in the brain. The horrible mental hospitals that had so shamed the nation at the end of World War II could now be shuttered, as schizophrenics—thanks to the new drugs—could be treated in the community. Those suffering from a milder disorder, like depression or anxiety, simply needed to reach into their medicine cabinets for relief. In 1967, one in three American adults filled a prescription for a “psychoactive” medication, with total sales of such drugs reaching $692 million.
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This was a narrative of a scientific triumph, and in the late 1960s and early 1970s, the men who had been the pioneers in this new field of “psychopharmacology” looked back with pride at their handiwork. “It was a revolution and not just a transition period,” said Frank Ayd Jr., editor of the
International Drug Therapy Newsletter
. “There was an actual revolution in the history of psychiatry and one of the most important and dramatic epics in the
history of medicine itself.”
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Roland Kuhn, who had “discovered” imipramine, reasoned that the development of antidepressants could properly be seen as “an achievement of the progressively developing human intellect.”
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Anti-anxiety medicines, said Frank Berger, the creator of Miltown, were “adding to happiness, human achievement, and the dignity of man.”
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Such were the sentiments of those who had led this revolution, and finally, at a 1970 symposium on biological psychiatry in Baltimore, Nathan Kline summed up what most of those in attendance understood to be true: They all had earned a place in the pantheon of great medical men.

“Medicine and science will be
just that much different
because we have lived,” Kline told his colleagues. “Treatment and understanding of [mental] illness will forever be altered … and in our own way we will persist for all time in that small contribution we have made toward the Human Venture.”
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Today, by retracing the discovery of the first generation of psychiatric drugs and following their transformation into magic bullets, we can see that by 1970 two possible histories were unfolding. One possibility is that psychiatry, in a remarkably fortuitous turn of events, had stumbled on several types of drugs that, although they produced abnormal behaviors in animals, nevertheless fixed various abnormalities in the brain chemistry of those who were mentally ill. If so, then a true revolution was indeed under way, and we can expect that when we review the long-term outcomes produced by these drugs, we will find that they help people get well and stay well. The other possibility is that psychiatry, eager to have its own magic pills and eager to take its place in mainstream medicine, turned the drugs into something they were not. These firstgeneration drugs were simply agents that perturbed normal brain function in some way, which is what the animal research had shown, and if that is so, then it stands to reason that the
long-term
outcomes produced by the drugs might be problematic in kind.

Two possible histories were under way, and in the 1970s and 1980s, researchers investigated the critical question: Do people diagnosed with depression and schizophrenia suffer from a chemical imbalance that is then corrected by the medication? Were the new drugs truly
antidotes
to something chemically amiss in the brain?

The adult human brain weighs about three pounds, and when you see it close up, removed from the skull, it is a bit larger than you imagined it to be. I had thought a brain could rest fairly easily in the palm of one’s hand, but you really need both hands to lift it securely into the air. If the brain is fresh, not yet pickled in formaldehyde, a spiderweb of blood vessels pinkens the surface, and the tissue feels soft, almost gelatinous. It is definitely “biological” in kind, and yet somehow it gives rise to all of the mysterious and remarkable talents of the human mind. At the invitation of a friend, Jang-Ho Cha, who is a neuroscientist at Massachusetts General Hospital, I attended a brain-cutting seminar at the hospital, with the thought that seeing a human brain would help me better visualize the neurotransmitter pathways that are said to give rise to depression and psychosis, but naturally my visit turned into something more than that. The human brain up close takes your breath away.

The mechanics of its messaging system are fairly well understood. There are, Cha noted, 100 billion neurons in the human brain. The cell body of a “typical” neuron receives input from a vast web of dendrites, and it sends out a signal via a single axon that may project to a distant area of the brain (or down the spinal cord). At its end, an axon branches into numerous terminals, and it is from
these terminals that chemical messengers—dopamine, serotonin, etc.—are released into the synaptic cleft, which is a gap about twenty nanometers wide (a nanometer is one-billionth of a meter). A single neuron has between one thousand and ten thousand synaptic connections, with the adult brain as a whole having perhaps 150 trillion synapses.

The axons of neurons that use the same neurotransmitter are regularly bundled together, almost like the strands of a telecommunications cable, and once scientists discovered that dopamine, norepinephrine, and serotonin fluoresced different colors when exposed to formaldehyde vapors, it became possible to track those neurotransmitter pathways in the brain. Although Joseph Schildkraut, when he formulated his theory of affective disorders, thought that norepinephrine was the neurotransmitter most likely to be in short supply in those who were depressed, researchers fairly quickly turned much of their attention to serotonin, and so for our purposes, in regard to our investigation of the chemical imbalance theory of mental disorders, we need to look at that pathway in the brain for depression, and at the dopaminergic pathway for schizophrenia.

The serotonergic pathway is one with ancient evolutionary roots. Serotonergic neurons are found in the nervous systems of all vertebrates and most invertebrates, and in humans their cell bodies are located in the brain stem, in an area known as the raphe nuclei. Some of these neurons send long axons down the spinal cord, a system that is involved in the control of respiratory, cardiac, and gastrointestinal activities. Other serotonergic neurons have axons that ascend into all areas of the brain—the cerebellum, the hypothalamus, the basal ganglia, the temporal lobes, the limbic system, the cerebral cortex, and the frontal lobes. This pathway is involved in memory, learning, sleep, appetite, and the regulation of moods and behaviors. As Efrain Azmitia, a professor of biology at NYU, has noted, “the brain serotonin system is the single largest brain system known and can be characterized as a ‘giant’ neuronal system.”
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There are three major dopaminergic pathways in the brain. The cell bodies of all three systems are located atop the brain stem, in either the substantia nigra or the ventral tegmentum. Their axons project to the basal ganglia (nigrostriatal system), the limbic region (mesolimbic system), and the frontal lobes (mesocortical system). The basal ganglia initiates and controls movement. The limbic structures—the olfactory tubercle, the nucleus accumbens, and the amygdala, among others—are located behind the frontal lobes and help regulate our emotions. It is here that we feel the world, a process that is vital to our sense of self and our conceptions of reality. The frontal lobes are the most distinguishing feature of the human brain, and provide us with the godlike capacity to monitor our own selves.

All of this physiology—the 100 billion neurons, the 150 trillion synapses, the various neurotransmitter pathways—tell of a brain that is almost infinitely complex. Yet the chemical imbalance theory of mental disorders boiled this complexity down to a simple disease mechanism, one easy to grasp. In depression, the problem was that the serotonergic neurons released too little serotonin into the synaptic gap, and thus the serotonergic pathways in the brain were “underactive.” Antidepressants brought serotonin levels in the synaptic gap up to normal, and that allowed these pathways to transmit messages at a proper pace. Meanwhile, the hallucinations and voices that characterized schizophrenia resulted from overactive dopaminergic pathways. Either the presynaptic neurons pumped out too much dopamine into the synapse or the target neurons had an abnormally high density of dopamine receptors. Antipsychotics put a brake on this system, and this allowed the dopaminergic pathways to function in a more normal manner.

That was the chemical imbalance theory put forth by Schildkraut and Jacques Van Rossum, and the very research that had led Schildkraut to his hypothesis also provided investigators with a method for testing it. The studies of iproniazid and imipramine had
shown that neurotransmitters were removed from the synapse in one of two ways. Either the chemical was taken back up into the presynaptic neuron and restored for later use, or it was metabolized by an enzyme and carted off as waste. Serotonin is metabolized into 5-hydroxyindole acetic acid (5-HIAA); dopamine is turned into homo vanillic acid (HVA). Researchers could comb the cerebrospinal fluid for these metabolites, and the amounts found would serve as an indirect gauge of the synaptic levels of the neurotransmitters. Since low serotonin was theorized to cause depression, anyone in that emotional state should have lower-than-normal levels of 5-HIAA in his or her cerebrospinal fluid. Similarly, since an overactive dopamine system was theorized to cause schizophrenia, people who heard voices or were paranoid should have abnormally high cerebrospinal levels of HVA.