Without Thorazine and imipramine and Valium, I don’t know that I would have survived seventh grade. But I did, and by the end of eighth grade my anxious misery had relented somewhat. Dr. L. weaned me off the Thorazine. But since that winter some thirty years ago, I have been on one psychiatric medication or another—and often two, three, or more at a time—more or less continuously, making me a living repository of the pharmacological trends in anxiety treatment of the last half century.
Drug discoveries were of sensational importance for understanding psychiatric illness and the basic nature of the human condition: Our personalities, our intellects, our very culture could presumably be boiled down to a sack of enzymes.
—EDWARD SHORTER, Before Prozac (2009)
For a brief period in the 1980s, I took phenelzine, a monoamine oxidase inhibitor, or MAOI, whose trade name is Nardil. My experience on MAOIs was not notably successful. I didn’t feel any less anxious—but I did do a lot of worrying about whether I would die from complicating side effects of the drug. This is because MAOIs can have dangerous, even lethal, side effects, especially when combined with the wrong elements. When patients taking MAOIs ingest things—such as wine and other fermented alcohol, aged cheeses, pickled foods, some kinds of beans, and many over-the-counter medications—that contain high levels of an amino acid derivative called tyramine, the health effects can be serious: painful headaches, jaundice, a spike in blood pressure, and in some cases severe internal hemorrhaging. Which means MAOIs may not be ideal for people like me who are, even in the best of circumstances, prone to hypochondria and health anxiety.
For this reason, among others, while there are still depressed and anxious patients for whom MAOIs remain the most, or the only, effective pharmacological treatment, MAOIs have not been considered a first-line treatment for mood disorders for many years now.h Though MAOIs played only a cameo role in my own psychiatric history, they are important in the scientific and cultural history of anxiety because they were among the first drugs to be specifically tied to a just-emerging neurochemical theory of mental illness. At midcentury the advent of MAOIs, in conjunction with the arrival of imipramine and the other tricyclics (about which more shortly), helped create the modern scientific understanding of depression and anxiety.
MAOIs have their origins in the later years of the Second World War, when the German Luftwaffe, bombarding English cities with V-2 rockets, ran low on conventional fuel and had to resort to propelling the rockets with a fuel called hydrazine. Hydrazine is poisonous and explosive, but scientists had found that they could modify it in ways that might be medically useful. When the war ended, drug companies bought the leftover hydrazine supplies at a steep discount. The investment paid off. In 1951, scientists working at Hoffmann–La Roche in Nutley, New Jersey, discovered that two modified hydrazine compounds, isoniazid and iproniazid, inhibited the growth of tuberculosis. Clinical trials ensued. By 1952, both isoniazid and iproniazid were on the market for treatment of tuberculosis.
But these antibiotics had an unexpected side effect. After being treated with them, some patients would become, as newspapers recounted, “mildly euphoric,” dancing through the hallways of the tuberculosis wards. Reading these reports, psychiatrists wondered if this mood-elevating effect meant that isoniazid and iproniazid might be used as psychiatric medications. In a 1956 study at Rockland State Hospital in New York, patients with various psychiatric disorders were given iproniazid for five weeks; toward the end of that period the depressed patients had improved markedly. Nathan Kline, the hospital’s research director, observed what he called a “psychic energizing” effect, and he began prescribing iproniazid to the melancholic patients in his private practice. Some of these patients, he subsequently reported, experienced “a complete remission of all symptoms.” Kline would later declare that iproniazid “was the first cure in all of psychiatric history to act in such a manner.” In April 1957, Hoffmann–La Roche began marketing iproniazid with the trade name Marsilid, and it was featured on the front page of The New York Times. Marsilid was the first of the MAOIs and one of the first drugs to become known as an antidepressant.
At midcentury the history of neuroscience, such as it was, was brief. Knowledge of how the brain worked was primitive. Debate churned between the “sparks” and the “soups”—between those scientists who believed that transmission of impulses between neurons was electrical and those who believed it was chemical. “When I was an undergraduate student at Cambridge,” Leslie Iversen, a professor of pharmacology at Oxford recalled of his time there in the 1950s, “we were taught … there was no chemical transmission in the brain—that it was just an electrical machine.”
English physiologists had done primitive research on brain chemistry in the late nineteenth century. But not until the 1920s did Otto Loewi, a professor of pharmacology at the University of Graz in Austria, isolate the first neurotransmitter, arguing in a 1926 paper that a chemical called acetylcholine was what mediated the transmission of impulses between one nerve ending and the next.i
Even as sales of Thorazine and Miltown were taking off, the concept of a neurotransmitter—of a chemical that transmitted impulses between brain cells—had not been definitively established.j (The psychiatrists who prescribed these drugs, and even the biochemists who developed them, generally had no idea why the drugs had the effects they did.) But discoveries by two researchers in Scotland swung the pendulum forcefully toward the “soups.” In 1954, Marthe Vogt, a German neuroscientist at the University of Edinburgh, discovered the first convincing evidence of a neurotransmitter—norepinephrine. Later that year, John Henry Gaddum, a colleague of Vogt’s, discovered through a series of unorthodox experiments that serotonin, which until that point was thought to be a gut-based compound involved in digestion, was also a neurotransmitter.k Gaddum took LSD—which he reported made him feel crazy for forty-eight hours and which also, according to laboratory measurements, decreased the level of serotonin metabolites in his cerebrospinal fluid. His broad conclusion: Serotonin helps keep you mentally healthy—and therefore a deficiency of serotonin can make you mentally ill. Thus was born the neurotransmitter-based theory of mental health. This would transform the scientific and cultural view of anxiety and depression.
Canst thou not …
Raze out the written troubles of the brain
And with some sweet oblivious antidote
Cleanse the stuff’d bosom of that perilous stuff
Which weighs upon the heart?
—WILLIAM SHAKESPEARE, Macbeth (CIRCA 1606)
Bernard “Steve” Brodie had built his reputation as a biochemist making antimalarial drugs during World War II. When Thorazine and Miltown came on the market in the 1950s, he was running a lab at the National Heart Institute of the National Institutes of Health in Bethesda, Maryland. Over the next decade, that lab would revolutionize psychiatry.
The seminal experiments were on reserpine. An extract from the plant Rauwolfia serpentina (its root looks like a snake), reserpine had been used for more than a thousand years in India, where it was prescribed for everything from high blood pressure and insomnia to snakebite poisonings and infant colic. But it had also been used, evidently with some success, according to Hindu writings, for treating “insanity.” Reserpine had never gotten much attention in the West. But when Thorazine produced such striking results, executives at Squibb wondered if reserpine could compete with it. They provided funding to Nathan Kline, who tested the compound on a group of his patients at Rockland State Hospital: several of them improved dramatically, and a few whose case reports had described them as “crippled” by anxiety became relaxed enough to leave the hospital and resume their lives.
This led to a much larger study. In 1955, Paul Hoch, the commissioner of mental hygiene for New York, arranged with Governor W. Averell Harriman for $1.5 billion in funding to give reserpine to every single one of the ninety-four thousand patients in all of the state’s psychiatric hospitals. (FDA regulations would never allow a study
like this to be conducted today.) The results: Reserpine worked for some patients but not quite as well as Thorazine—and it had serious, sometimes lethal, side effects. Clinicians largely set it aside as a psychiatric drug.
But not before Steve Brodie and his NIH colleagues had used reserpine to establish a clear link between biochemistry and behavior. Inspired by what John Gaddum had learned about the relationship between LSD and serotonin, Brodie gave reserpine to rabbits to see what it did to their serotonin levels. Brodie found two interesting things: administering reserpine to rabbits decreased the amount of serotonin in their brains, and this decrease in serotonin seemed to produce rabbits who were “lethargic” and “apathetic,” mimicking the behavior of people we would today call depressed. Moreover, Brodie and his colleagues found they could induce and diminish “depressed” behavior in the rabbits by manipulating their serotonin levels. Brodie’s 1955 paper in Science reporting these findings was the first to tie levels of a specific neurotransmitter to behavioral changes in animals. Brodie had, as one medical historian later put it, built a bridge from neurochemistry to behavior.
Brodie’s reserpine research intersected in intriguing ways with what psychiatrists were then discovering about MAOIs. To oversimplify a little, brain researchers in the 1950s were just figuring out that neurotransmitters are discharged by “upstream” neurons into the synapses—the tiny spaces between nerve cells—in order to make “downstream” neurons fire. Each neurotransmitter travels quickly from one neuron to the next, where it attaches to a receptor—its molecular mirror image—embedded in the neuron’s membrane. Each time one of these neurotransmitters latches onto its receptor on the postsynaptic neuron (serotonin attaching to serotonin receptors, norepinephrine to norepinephrine receptors), the receiving neuron changes shape: its membrane becomes porous, allowing atoms from the outside of the neuron to rush toward the interior, causing a sudden change in the neuron’s electric voltage. This change causes the receiving neuron to fire, releasing its own supply of neurotransmitters into the surrounding synapses. These neurotransmitters then land on receptors on still other neurons. This cascade of activity—neurons firing, releasing neurotransmitters, causing other neurons to fire—throughout the one hundred billion neurons and the trillions of synapses in our brain is what gives rise to our emotions, perceptions, and thoughts. Neurons and neurotransmitters are, in ways scientists are still struggling to understand, the physical stuff of emotion and thought.
Early research on iproniazid had revealed that the antibiotic inactivated an enzyme called monoamine oxidase (MAO), whose function is to break down and clear away the serotonin and norepinephrine that build up in the synapses. After a neurotransmitter is squirted into the synapse, it ordinarily gets quickly cleared out by MAO, allowing for the next transmission to happen. But the “inhibition” of the monoamine oxidase enzyme by iproniazid allowed the neurotransmitters to remain in the nerve terminals longer. The extra buildup of these neurotransmitters in the synapses, Brodie’s researchers theorized, accounted for iproniazid’s antidepressant effects. Sure enough, when rabbits were given iproniazid before reserpine was administered, these rabbits did not become lethargic the way the other reserpine rabbits did. The iproniazid, Brodie and his colleagues concluded, kept the rabbits from getting “depressed” by boosting the levels of norepinephrine and serotonin in their synapses.
This was the moment the pharmaceutical industry awoke to the idea that it could sell psychiatric drugs by marketing them as correcting “chemical imbalances,” or deficiencies of certain neurotransmitters. In one of its first advertisements for iproniazid, in 1957, Hoffmann–La Roche promoted the drug as “an amine oxidase inhibitor which affects the metabolism of serotonin, epinephrine, norepinephrine and other amines.”
Research on another new drug lent further support to this idea. In 1954, Geigy, a Swiss pharmaceutical company, had tweaked Thorazine’s chemical structure to create the compound G22355, which it called imipramine, the first tricyclic. (Drugs in this category have a three-ring chemical structure.) Roland Kuhn, a Swiss psychiatrist who was trying to develop a better sleeping pill, had tried giving imipramine to some of his patients. Because Thorazine and imipramine were chemically similar (only two atoms were different), Kuhn assumed that imipramine, like Thorazine, would have a sedating effect. It didn’t: rather than putting patients to sleep, imipramine energized them and elevated their moods. In 1957, after treating more than five hundred patients with imipramine, Kuhn delivered a paper to the International Congress of Psychiatry in Zurich, reporting that even deeply depressed patients had improved dramatically after several weeks on the drug. Their moods lifted, their energy surged, their “hypochondriacal delusions” disappeared, and their “general inhibition” dissipated. “Not infrequently the cure is complete, sufferers and their relatives confirming the fact that they had not been so well for a long time,” he declared. Geigy took imipramine out of mothballs and brought it to the European market in 1958 under the trade name Tofranil.l
On the day imipramine was released in the United States, September 6, 1959, The New York Times published an article headlined “Drugs and Depression” about both Marsilid (iproniazid, the first MAOI) and Tofranil (imipramine, the first tricyclic). The Times called these drugs “anti-depressants”—seemingly the first use of the term in the press or in popular culture.
While some estimates put the number of Americans taking anti-depressant medications today at over forty million, there was no such thing as an antidepressant when Roland Kuhn addressed the International Congress of Psychiatry in 1957. The concept simply didn’t exist. The MAOIs and the tricyclics had created a new drug category.
In the early 1960s, Julius Axelrod, an NIH biochemist and a veteran of Steve Brodie’s lab, began to identify the effects of imipramine on various chemicals in the brain. Axelrod discovered that imipramine blocked the reuptake of norepinephrine in the synapses. (A few years later, he would find that it also blocked the reuptake of serotonin.) Axelrod theorized that antidepressants’ effect on the reuptake of norepinephrine was what accounted for the elevation of mood and the relief of depression. This was a transformative idea: if imipramine blocked the reuptake of norepinephrine, and if it made patients less anxious and depressed, that meant there must be a correlation between norepinephrine and mental health. Marsilid or Tofranil—or cocaine, for that matter, which has a similar effect—seemed to cure anxiety and depression by boosting the levels of norepinephrine in the synapses, delaying its reuptake into the neurons.
Around this time, Joseph Schildkraut was a psychiatrist at the Massachusetts Mental Health Center who believed that anxiety and psychoneurosis were caused by childhood trauma or unresolved psychic conflicts and were therefore best treated by Freudian psychotherapy. Then he gave imipramine to a few of his patients. “These drugs seemed like magic to me,” he would say later. “I became aware that there was a new world out there, a world of psychiatry informed by pharmacology.” In 1965, he published an article in The American Journal of Psychiatry, “The Catecholamine Hypothesis of Affective Disorders: A Review of the Supporting Evidence”; building on the work of Steve Brodie and Julius Axelrod, he argued that depression was caused by elevated brain levels of catecholamines, the fight-or-flight hormones (such as norepinephrine) that are released by the adrenal glands in times of stress. Schildkraut’s paper became one of the most cited journal articles in the history of psychiatry, enshrining the chemical imbalance theory of anxiety and depression at the center of the field.
The first pillar of biological psychiatry had been constructed. The Freudian model of psychiatry had sought to treat anxiety and depression by resolving unconscious psychic conflicts. With the advent of the antidepressants, mental illness and emotional disorders were increasingly attributed to malfunctions of specific neurotransmitter systems: schizophrenia and drug addiction were believed to be caused by problems in the dopamine system; depression was a consequence of stress hormones released by the adrenal glands; anxiety r
esulted from defects in the serotonin system.
But pharmacology’s most transformative effect on the history of anxiety was still to come, beginning with studies on imipramine that would reshape the psychiatric establishment’s understanding of anxiety.
* * *
* Actually, Dr. Stanford also conceded a strong biological component to anxiety; her view was that biology can be overcome by cognitive retraining. And research does suggest that cognitive retraining, as well as other forms of talk therapy, can change biology in the same way that medication does, sometimes more profoundly and enduringly—a literal manifestation of mind over matter.
† Freud was also, by his own admission, addicted to nicotine, smoking twenty or more cigars a day for most of his life, a habit that would reward him with mouth cancer in his sixties.
‡ Some doctors prescribed straight alcohol. In the 1890s, Adolphus Bridger, an influential London physician and the author of such popular medical books as The Demon of Dyspepsia and Man and His Maladies, told patients suffering from tension and melancholy to drink port and brandy. He wrote that “a suitable form of alcohol”—especially “full-bodied Burgundy, high class claret, port, the better white French, German, and Italian wines, stout or good brandy”—would “do more to restore nervous health” than any other medicine.
§ Two years later, Bayer brought out another analgesic, acetylsalicylic acid, under the brand name Aspirin. In time, as Heroin and Aspirin became ubiquitous, both went from being brand names to generic terms. Turn-of-the-century physicians in America and England had a somewhat backward understanding of these medications, often giving Heroin to their patients for physical pain (which, in fairness, made a certain sense) and administering Aspirin for “nervousness” (which did not).
‖ Potassium bromide, a compound introduced at a British medical conference in 1857, was originally used as an antiseizure medication and was, from the late nineteenth century into the early twentieth, popular as a sedative. Eventually, the toxicity and side effects of bromides, ranging from a bitter aftertaste and acne to dizziness, severe nausea, and vomiting, led to their abandonment (today they are used almost exclusively in veterinary medicine for dogs and cats with epilepsy), but their use was widespread enough for long enough that the word “bromide” also came to mean a soporific platitude. Chloral hydrate, a sleep-inducing agent first synthesized in 1832, was added to doctors’ psychotropic toolkit in 1869 after Otto Liebrich, a professor of pharmacology in Berlin, gave the substance to melancholic patients and observed that it alleviated their insomnia. A hundred years later, my great-grandfather would be prescribed chloral hydrate for his tension and insomnia. (Chloral hydrate was also one of the active ingredients, along with alcohol, in the Mickey Finn, a doctored drink that often featured in Depression-era potboilers.)
My Age of Anxiety: Fear, Hope, Dread, and the Search for Peace of Mind Page 21