How Everyone Became Depressed (23 page)

What made depression epidemic was flogging it to the public as a concept with a firm scientific basis. This occurred in two steps: First, the rise of what one might call neurotransmitter chatter, as opposed to the solid science of neurotransmission in the brain; and second, the marketing to the public of drugs for depression on the grounds that they rested on an unshakable foundation of neuroscience. In the end, the public was gulled into believing that a disorder of mood called depression was as common as the common cold, but that, unlike the cold, its treatment was based on a firm platform of science.

After World War II, psychiatry began its transformation from a discipline based on Freud’s concepts and on psychotherapy to one based on biological neuroscience and pharmacotherapy. In 1949 the National Institute for Mental Health (NIMH) opened its doors, pouring hundreds of millions of dollars into research on disorders of the mind and brain. Led by towering figures such as pharmacologist Seymour Kety, the NIMH became a great bastion of scientific research in world psychiatry, and pioneered domains such as the genetics of psychiatric illness.

Elsewhere within the vast National Institutes of Health, laboratories led by Bernard Brodie and Julius Axelrod in the mid-1950s were laying bare the mechanics of the reuptake of neurotransmitters: A neurotransmitter, once discharged by the end bulb of a neural cell, or neuron, stays in the synapse between the neurons until it is reabsorbed; the process is called reuptake, a return to the upstream neuron that discharged it. For key neurotransmitters such as serotonin, dopamine, and norepinephrine, it was believed that delaying, or inhibiting, the process of reuptake would lengthen the amount of time the neurotransmitter dwelled in the synapse, thus maximizing its potential to do good: This grounded the assumption that increasing the synapse time of these monoamine neurotransmitters would combat illnesses such as depression and schizophrenia. Whole theories of depression were spun about the neurotransmitters. In 1965 Joseph Schildkraut at Harvard proposed the norepinephrine theory of depression, attributing the illness to a shortage of the catecholamine neurotransmitters, of which norepinephrine is one
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; and serotonin theories of depression had been circulating ever since the work of the Scottish pharmacologist John Henry Gaddum in the early 1950s.
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The early 1960s were alive with vibrant debate about serotonin and norepinephrine and their role in illness. Arvid Carlsson, a pharmacologist then at the University of Lund, recalls taking his group’s ideas about the role of dopamine and noradrenaline in the brain to a Ciba Foundation symposium in London in 1960.
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The Brits, still caught up in ideas about electrophysiology rather than neurochemistry, dismissed the Swedish group’s beautiful graphs showing brain concentrations of norepinephrine after the administration of drugs.
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Five years later it was game over. At a symposium at the Wenner-Gren Center in Stockholm in February 1965, Carlsson brought beautiful photographs showing the presence of norepinephrine in the nerve terminals of the rat.
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The paper was respectfully listened to—helping to win Carlsson a Nobel Prize in 2000. And the British electrophysiologists had either fallen silent or become converted to the hypothesis of the chemical transmission of the nerve impulse.

In 1963 Alec Coppen and colleagues put one group of depressed patients already being treated with a monoamine oxidase inhibiting agent (MAOI) on tryptophan, an amino acid that is a precursor of serotonin; this group got dramatically better than a control group that did not receive the tryptophan supplement.
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This was the first research to suggest that serotonin might be important in depression. (Subsequent research on tryptophan did not produce such brilliant results.
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)

Now this was hugely important research, but the field largely failed to move beyond these concepts. English psychoharmacologist Merton Sandler later reflected somewhat ruefully about these developments: “In the 1950s there were so many major discoveries, the tricyclic antidepressants, the monoamine oxidase inhibitors, the neuroleptics, lithium—and then nothing!”
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Instead, the buzz words of the field were highjacked by the pharmaceutical industry. Chatter about shortages of neurotransmitters became part of the commercial buzz. This is not to disparage the importance of neurotransmission, a fundamental means of communication within the nervous system! Reuptake of neurotransmitters is real, and its inhibition does have demonstrable clinical effects. But neurotransmission is only a small part of the vast world—a world of hitherto unknowable size—of neurochemistry and neurophysiology. And it is not necessarily the central chemical mechanism in psychiatric illness. Nor has any psychiatric illness been convincingly attributed to a shortage of any particular neurotransmitter.

We may analogize to the world of computers: How does your desktop computer work? Let’s unravel the code. But if we unravel only the code that controls communication between the keyboard and the central processor, we have not really answered the question. Knowing how the keyboard communicates with the rest of the thing is important but not necessarily central. Similarly, in the brain there are vast domains of transmission between neurons that we understand little of, to say nothing of chemical events taking place within the neurons and the other brain cells; hypotheses about serotonin and norepinephrine clarify little of this. Even at the height of his involvement in neurotransmitter research, Alec Coppen, at the Medical Research Council’s Neuropsychiatric Research Unit at Carshalton in Surrey and one of the chief players in the serotonin story, was able to step back reflectively and say that “We must face the very real possibility that we are far from the primary disturbance in depression [in studying neurotransmitters]. The changes may all be secondary to other abnormalities which have not been taken into account at all.”
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The point is not to retrospectively judge who was wrong and right in the scientific debates of the 1960s, but to show how exciting they were, and how avidly they were pursued. The whole discipline of psychopharmacology and clinical neuroscience was being opened up, and researchers around the world were on the edge of their seats.

But there were reflective observers who saw peril in all this excited discovery, and they were not just psychoanalysts who feared endangerment of their bread and butter with the implosion of the Freudian edifice. Yale epidemiologist Alvan Feinstein, generally considered one of the cleverest minds of his day, said in 1972 that “The concept of pharmacologic action is a fashion of this era. It represents whatever particular patterns of physiologic, biochemical, and mechanistic thought exist at any given point in time.” The problem, said Feinstein, was that for many effective treatments we had no idea how they worked. Take acupuncture. “What shall we do with the fact that acupuncture works, and yet, we haven’t got the foggiest idea of its pharmacologic mechanism except that it may move yin molecules to yang molecules.”
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In other words, there was more to the brain than neurotransmitter reuptake. Yet these words fell upon fallow ground.

By 1976 people had progressed to the belief, as Marie Asberg and colleagues at the Karolinska Institute in Stockholm put it, in “the existence of a biochemical subgroup of depressive disorders, characterized by a disturbance of serotonin turnover.”
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This appeared in the journal Science, adding full weight to what Thomas Ban, professor of psychopharmacology at Vanderbilt University, later referred to as “the whole biobabble about receptors.”
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These beliefs in the reuptake activity of certain neurotransmitters in depression were even divided up on the basis of country. “The Anglo-Saxon countries were the 5-HT [serotonin] countries,” said Peter Waldmeier in retrospect, a scientist at what was then Ciba-Geigy (later Novartis). “The more German-speaking countries, including the Scandinavian countries, were more catecholamine [norepinephrine and dopamine] countries.” Alec Coppen, who advocated a serotonin hypothesis, was a dominant figure in the United Kingdom, whereas Arvid Carlsson, and Norbert Matussek in Munich “were noradrenaline [norepinephrine] people,” Waldmeier said.
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The neurotransmitters serotonin, dopamine, and norepinephrine are called monoamines, and theories about which monoamines caused which illnesses would dominate psychiatry for the next 30 years, despite a lack of evidence about a shortage of any of these chemicals in the brains of ill individuals. This dubiety began to build from the mid-1960s. In 1973 George Ashcroft, an Edinburgh pharmacologist, showed that in some depressions, notably the bipolar variety, levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) were not lower than in controls. “These findings are against the amine hypothesis which postulated in depression a lowered concentration of transmitter amine at synaptic junction,” he wrote.
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Ashcroft’s work progressed further. He later told David Healy in an interview that administering the precursor tryptophan to neurological patients would produce a rise in serotonin in the cerebrospinal fluid. “Then we did it in a range of psychiatric patients and showed, to our horror, that there was no failure of production of 5HT [serotonin] in depression. People with depression or recovered depressives had exactly the same maximal synthetic capacity as people without depression.” So, in depression more must be going on “than just the release of the transmitter.”
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At a conference in Marbella, Spain, in March 1976, the doubts started to pile up. Coppen expressed skepticism that there might be two groups of depressives, a serotonin-deficient group and a norepinephrine-deficient group. “If this were so, you would expect a different response rate to a good all-round drug like amitriptyline or imipramine [early tricyclic antidepressants], which presumably affects both systems equally, than you would to a drug like maprotiline, which seems to be mainly an inhibitor of noradrenaline. Yet there seems to be almost no evidence of any difference in the clinical response rate between depressives treated with [the two drugs].”
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This was one of the early statements of uneasiness—and from an investigator who had championed the serotonin hypothesis!

Many more followed and in 1985 William Potter’s group at the National Institute of Mental Health provided a definitive scientific burial: If you take the most powerful serotonin reuptake inhibitor you can find, and the most powerful norepinephrine inhibitor, their effect on serotonin and norepinephrine levels was equal.
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Potter later said, “Each drug, after several weeks of administration, influenced both norepinephrine and serotonin metabolism,” and a Lilly scientist (where Potter later became scientific director) told him, “It was the most important clinical paper he had ever seen; it has had a large impact in the way people think by supporting a shift in focus from single neurotransmitters to interacting and coupling systems.”
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Today, these theories are widely disbelieved. Shortages of the standard monoamine neurotransmitters and receptors turned out to have little role in depressive illness except in pharmaceutical advertising and in the explanations that doctors give to patients. In an interview in 1998, Ross Baldessarini, a senior research psychiatrist at the McLean Hospital, flicked the exaggerated interest in neurotransmitter deficiencies and surpluses dismissively from the table: “We have [pursued fads] in much of biological psychiatry, including grossly overvaluing our partial understanding of the pharmacodynamics [effect on the body] of some drugs as a putative route to clarifying the pathophysiology [mechanism] of psychiatric illnesses.” Baldessarini indicted “largely fruitless efforts to support a dopamine excess hypothesis of schizophrenia or mania, a norepinephrine or serotonin deficiency of major depression, a serotonin deficiency hypothesis in obsessive-compulsive disorder, and so on.” Baldessarini said these emphases had kept the field stuck on the study of “old mechanisms and old theories.”
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But if science was stuck, the public was stuck as well. For decades, people clung to Prozac-style remedies in the view that their nervous troubles stemmed from a lack of serotonin or norepinephrine. Even though the drugs work on some anxious and agitated patients, in the area of affective disorders, drugs that inhibit the reuptake of serotonin, the selective serotonin reuptake inhibitors (SSRIs), do not work very well, and even less well on the millions of people who take them because their basic problem is unhappiness, not illness. The SSRI-type drugs, the Prozac-type drugs, failed over 50% of their licensing trials. One scholar considers them virtual placebos.
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So how did this public health disaster come about, putting much of the population on pharmacological agents from which they would derive few of the benefits but many of the side effects?

It happened because the pharmaceutical companies badly needed these neurotransmitter reuptake theories in their communications with the medical profession and with the public.

In the early 1970s the pharmaceutical industry was not at all interested in this research and saw little promise in the pursuit of drugs that inhibited the reuptake of anything. It was in 1969 that pharmacologist Archie Todrick at the Crichton Royal Hospital in Dumfries, Scotland, established that the tricyclic antidepressant clomipramine inhibited the reuptake of serotonin.
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This was a continuation of his important findings showing that the tricyclics acted both on imipramine and serotonin. But only in 1990 did Geigy begin mentioning this in its ads for clomipramine, a drug they marketed as Anafranil and, by this time, were also indicating for obsessive-compulsive disorder. Thereafter, however, the floodgates opened, not just for Anafranil but for everything else.

Among the earliest attempts to market antidepressants with neurotransmitter chatter was Geigy’s ad campaign for its tricyclic drug desipramine (Pertofrane) in 1974. Desipramine, a metabolite of imipramine, had been on the market since 1965 (“a rapid lift from the hell of depression”
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) and had trouble distinguishing itself from the slew of competing tricyclic antidepressants. In 1974 the company emphasized that desipramine was not a “tranquilizer” but was indicated “specifically for depression.” How do we know? “It is hypothesized that in depression there exists a deficit of specific CNS neurotransmitters known as biogenic amines (e.g. norepinephrine and serotonin),” and that desipramine reduced the “deficit . . . by blocking their reuptake and permitting these neurotransmitters to accumulate in the synaptic clefts. Result: amelioration of depression.”
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This is the first known piggybacking of a pharmaceutical product on a theory of disease-specific neurotransmission. Further ads offered large drawings of the synapse, showing norepinephrine’s reuptake being blocked by Pertofrane. Psychiatric readers of the medical journals running these ads who had not been at the conference at Marbella and had not followed insider discussions could not have failed to be impressed.