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Ordinarily Well

The Case for Antidepressants

Farrar, Straus and Giroux

The Birth of the Modern

A SWISS PSYCHIATRIST, Roland Kuhn, invented the modern antidepressant. He didn't synthesize a chemical. He created the concept.

Kuhn gave the antidepressant era a birth date, January 18, 1956. Six days earlier, under his care, a forty-nine-year-old hospitalized woman had begun taking 100 milligrams daily of G22355, a substance supplied by the Swiss pharmaceutical firm Geigy. On the eighteenth, Paula J.F. was markedly better — less afflicted by what Kuhn called her "vital depression." By the twenty-first, the ward staff noted that the patient was "totally changed." An entry in the medical record read, "For three days now, it is as if the patient had undergone a transformation."

Kuhn was aware that spontaneous remissions occur, but he knew his patients well. Paula J.F. was different, even from how she had been before the depressive episode. Characteristically aggressive and quarrelsome, now she was friendly. For the first time in years, Paula J.F. enjoyed work and reading. She thought more clearly. Her sleep had improved as well.

Kuhn bridged the old and the new in psychiatry: psychoanalysis and psychopharmacology. Born in Biel, Switzerland, in 1912, he studied medicine in Bern and Paris. In 1939, he took a post at the psychiatric hospital in Münsterlingen, a hundred-odd miles from his birthplace. Kuhn had chosen the assignment in hopes of learning from the psychoanalyst and existential philosopher Ludwig Binswanger, who worked nearby and whom Kuhn considered a genius in his understanding of mood disorder. At the core of Binswanger's practice was attention to Martin Heidegger's concept Dasein — personhood or presence, the reality of being here. Kuhn practiced Daseinsanalyse, receiving supervision from Binswanger and interacting with philosophers, including Heidegger. Kuhn treated inpatients and clinic patients both. Thus far, nothing unusual: the psychiatry of midcentury was psychoanalytic. Kuhn was a generalist, working in obscurity.

But Kuhn was a polymath. Interested in psychiatric classification, he developed his own diagnostic approach. He also employed the direct biological interventions of the time, including insulin shock therapy, where, via a rapid lowering of their blood sugar, patients were thrown into epileptic seizures. Kuhn prescribed drugs like morphine and amphetamine. Opiates and stimulants were what passed for psychotherapeutic medications. They might calm or arouse patients, but nothing targeted schizophrenia, depression, or mania directly.

The breakthrough came in the early 1950s with the development of Thorazine — called Largactil in Europe — the first effective drug for psychosis. Kuhn requested a supply for his hospital. For six months, the manufacturer offered Largactil gratis: "The whole clinic was swallowing Largactil, as one could imagine." The drug replaced the life -threatening therapies, and it worked. But at the end of the trial phase, the company began to charge for Largactil.

Kuhn understood — the whole small society of psychiatrists who dealt with pharmaceuticals understood — that the world had changed. For the first time in history, doctors could offer medication to schizophrenic patients and have a fair hope of making a difference.

With depressed patients, Kuhn observed, Largactil might calm agitation, but it left the core symptoms untouched. In any event, the hospital could not afford Largactil. But Kuhn had a relationship with Geigy. He asked whether the company had similar chemicals.

The first preparation that Geigy delivered helped relieve schizophrenia, but poorly, and it had unpleasant side effects. Kuhn then asked for a chemical like the one he had previewed but with a molecular structure more like Largactil's. As it happened, Geigy had synthesized that substance, G22355.

In retrospect, after decades' more progress in molecular biochemistry, Kuhn's request looks to be a shot in the dark. Even with sophisticated imaging capabilities, scientists cannot readily predict function from structure. And other accounts differ from Kuhn's. Alan Broadhurst, a chemist in charge of pharmaceuticals for Geigy in Britain, was one of the first people to ingest G22355, in a test of its safety. He said that once Largactil had shown its worth, Geigy took an interest in G22355. The company, Broadhurst recalled, had proposed a meeting with Kuhn, despite his known allegiance to "the old, strictly non-biological school of psychiatry, with a strong psychodynamic and psychotherapeutic component."

One way or another, Kuhn obtained a supply of G22355, later christened imipramine. He tried the medication on three hundred patients. It was a weak antipsychotic. But Kuhn noticed that on G22355 some schizophrenic patients got less depressed. He wondered whether the medication might be useful for depression.

At the distance of sixty years, it is difficult to appreciate how original Kuhn's thinking was. Psychoanalysts addressed depression piecemeal. A neurotic man might lose his energy because it remained bound in feelings for his dead mother and, separately, feel suicidal because anger toward his father had been deflected to the self. Kuhn saw depression as a syndrome composed of symptoms that wax and wane in concert and that might be responsive to direct effects on the brain.

Once there was glory to be claimed, Geigy scientists recalled that they, too, had considered approaching depression as a medical disorder, but the bigger truth seems clear: Geigy had little interest in inventing or marketing an antidepressant.

Most practicing doctors were unprepared to accept the concept. Some schools of thought understood schizophrenia to be "extrapsychic," a result of an organic disease whose cause had not been identified. To approach it with medication was not unthinkable. Depression was another matter. Freud had defined the field with "Mourning and Melancholia," the essay that located the source of even severe depression in ambivalent feelings about loved ones. If Freud had also been open to ideas of biological causation, his followers dropped that consideration. They focused on meaning, depression as unresolved emotional attachment. Depressive neuroses were at the heart of psychoanalytic practice.

Kuhn knew that depression often responded to electroconvulsive therapy, or ECT, where current is applied to the scalp, causing the equivalent of a seizure in the brain. He reasoned the disorder must also have an organic basis. When he saw that patients' mood states, more than their psychoses, were altered by G22355, he tried using the drug to treat depression in nonpsychotic patients.

He began with the condition that he considered most biological, "vital depression." Patients with vital depression suffered "feelings of fatigue, lethargy, confinement, oppression, and inhibition, accompanied by a slowing-down of thinking, acting, and decision." The disturbance was worse in the morning. In contrast, "reactive depression" was triggered by a psychological cause and worsened as the day progressed.

Kuhn considered vital depression difficult to identify. Patients might reveal the nature of their affliction only in the course of a long relationship with a doctor. In his practice outside the hospital, Kuhn diagnosed vital depression in patients with gastrointestinal distress whose cause had been hard to pin down. Overall, Kuhn's notion of depression corresponded to an informal understanding we might have today, a substantial psychological impairment with despondency at the core.

After administering G22355 to three depressed patients, Kuhn concluded that it was likely an antidepressant — the first specific medication treatment for mood disorders ever discovered. The drug reversed the fatigue, oppression, and impaired thinking all at once. It resolved the syndrome — the cluster of symptoms — of depression.

Kuhn notified Geigy and went on to study the effects of G22355 on forty patients whom he could observe closely over time. Most were seriously ill inpatients, but Kuhn also medicated outpatients whose depression was not immediately apparent. The medicine worked even for patients whose black mood had an obvious cause. Kuhn mentioned a young woman who had developed depression in the face of "a criminal abortion under difficult circumstances" and an older woman who had faltered in response to paralysis from polio.

In August of 1957, Kuhn reported his findings in a Swiss medical weekly. The short paper is a classic in the psychiatric literature. Kuhn got many points right. He characterized imipramine's side effects: dry mouth, rapid heartbeat, and constipation. He estimated the dosage needed for efficacy, often up to 200 or 250 milligrams. He described the drug's course of action. Some patients responded within days, but many took one to four weeks to improve. Kuhn had not seen enough patients to be confident of his estimates, but he believed that on imipramine a quarter to a half of patients would achieve full remission directly. Another group would gain enough relief to make their condition bearable while they awaited a natural remission. In all, three-quarters to four-fifths of patients would benefit.

On imipramine, Kuhn explained, patients did not regain one faculty only — energy, say, as on amphetamine. They woke in the morning without the discouragement that had dogged them. They took renewed interest in family life. They slept without the aid of a sleeping pill. Their suicidal impulses disappeared. The nurses reported fluent conversations, free of whines and sighs.

Stories of medical priority tend to have asterisks. In the early 1950s, a medication for tuberculosis was noted to rev up and remoralize patients. Later, simultaneously with Kuhn's paper, a drug related to the antituberculars was promoted as a "psychic energizer." The word antidepressant was first applied to this class of substances, the monoamine oxidase inhibitors, or MAOIs, drugs that interfere broadly with the breakdown of transmitter chemicals in the brain, the monoamines. (Imipramine, and medications like it, would be called tricyclics, a reference to their three-ring chemical structure.) I tell the MAOIs' story briefly in Listening to Prozac.

Because the MAOIs presented medical risks, they did not achieve the popularity of tricyclics. Also, conceptually the MAOIs were unsurprising. Often, they acted as stimulants first, before moderating patients' depression. In contrast, imipramine had calming properties and lifted mood nonetheless. Remarkably, Kuhn had taken a drug that was not energizing and employed it as a specific for melancholy.

Kuhn's discovery of the therapeutic powers of imipramine illustrates one way of coming to know, scientifically: seeing a medicine do something that no substance has done before. Kuhn's assessment of imipramine had virtues that formal drug trials rarely duplicate. He knew his patients well and interviewed them extensively. He could be confident of their diagnoses. He gave imipramine when it became available — at an arbitrary moment — and so avoided the confusion that can arise when volunteers sign on for treatment, perhaps in an interval of optimism, when their depression is waning. Kuhn tested imipramine for eighteen months, without deviating from his customary administration of care.

And Kuhn had a good sense of what placebo aficionados call the counterfactual condition, how his patients would have fared had the new treatment not been given. The ward had observed Largactil work wonders for psychosis, yet depressed patients did only so well with it. Other Geigy drugs had proved disappointing. Neither pill taking nor psychotherapy, the best-supported treatment of the time, did what imipramine did. The new medication produced unprecedented levels of change.

Kuhn tested imipramine at a moment that can arrive only once, when an antidepressant is available but no one has been treated with one. Today, trials of new drugs attract people who have failed on readily available medications or people outside the medical system, not diagnosed in the ordinary course of practice — an unrepresentative sample. Kuhn had access to a population "naïve," that is, never before exposed, to antidepressants. Although it lacked rigor, Kuhn's experiment was of singular evidentiary value. Kuhn would say as much. He had witnessed the full power of an antidepressant.

In September of 1957, Kuhn discussed his results at an international psychiatric congress in Zurich. A dozen participants attended the talk, and the reception was mixed. Looking back, one attendee compared the presentation to the Gettysburg Address. He was referring to the high quality of expression and the audience's belated appreciation of the message.

Only after an important Geigy shareholder tried the pills on his wife to good effect did the company push imipramine forward.

Kuhn understood that imipramine represented a new category of medication. His discovery helped to redefine the disorder, depression, and to invigorate a branch of psychiatry, psychopharmacology. Robert Domenjoz, who oversaw all pharmacological research at Geigy, later emphasized the uniqueness of Kuhn's contribution: "One thing is certain, Roland Kuhn was the person who discovered the antidepressant effect, without a shadow of a doubt. No-one else realized this."

Interlude

Anecdote

IF KUHN'S STORY plays an important role in my imagination, it is because all psychiatrists of my generation were discoverers. Each of us came upon antidepressants for the first time — the first in our own careers, anyway.

I saw imipramine in action in my freshman year of medical school, at Harvard. When I arrived, in 1972, the medical school was a Brigadoon, caught in the psychiatry of fifteen or even fifty years earlier. Other programs had moved on. Harvard remained a bastion of Freudianism.

I liked the outdated orthodoxy. After college, while studying literature and philosophy in London, I had undergone psychoanalysis and decided to become a psychiatrist. I entered medical school not knowing the location of the liver or the cause of measles. To maintain my sanity in the early going, I signed on to spend spare hours interviewing psychiatric patients at Boston's Beth Israel Hospital, steps from the academic campus.

The clinic was my haven from anatomy and biochemistry. One chief resident, a tall woman, called me the departmental mascot, although perhaps that was because I ventured upward glances at her with puppy -dog eyes. At twenty-three, I could scarcely have been greener. Still, by the second semester I had achieved the privilege of conducting psychotherapy.

One of my first patients was a twenty-six-year-old elementary-school teacher, Adele. Since her teens, Adele had suffered intervals of moodiness in which she had functioned poorly. In the months before her visit to the clinic, a down period had deepened. She was distraught. She considered suicide.

Adele had her reasons. A two-year romantic relationship had ended. When her fiancé moved on, Adele had returned home to a disorganized mother. Adele's younger sister was involved with an abusive older man, and Adele had attempted a futile rescue effort. Meanwhile, she was under pressure from a rigid school principal who seemed jealous of Adele's youth and idealism.

I gave what I had from my time on the couch. I listened. I inquired. Suicide?

Adele was half-Irish, half-Italian, a Boston type, the sober member of a loud, impulsive family. Her only dramatic act had been cutting herself, in high school. Then, she felt dejection. Now, she was coming out of her skin.

That last remark made me curious. For a first-year adviser, Harvard had assigned me an endocrinologist, another Boston type, the lone professional in a working-class, left-wing family from the North End. Psychiatry was on the list of indulgences she disdained. If I wanted to understand mood disorders, I should learn about glands. I knew that thyroid abnormalities could produce the psychic and bodily discomfort that Adele described.

Because my adviser had half my loyalty (psychotherapy had the rest) and because Adele was convincing when she called her agitation unfamiliar, I tested her thyroid. When initial blood results came back normal, I had vials run for a second form of thyroid hormone, one that had only lately been implicated in disease.

Adele did have an overactive gland. News of my "catch" sped through the psychiatry department. The holdout from the circle of admiration was my supervisor for the prolonged elective, Theodore Nadelson.

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Excerpted from Ordinarily Well by Peter D. Kramer. Copyright © 2016 Peter D. Kramer. Excerpted by permission of Farrar, Straus and Giroux.
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