1

The Birth of the Modern

a swiss psychiatrist, Roland Kuhn, invented the modern antidepressant. He didnt 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,
PaulaJ.F. was markedly betterless 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. PaulaJ.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, PaulaJ.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

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hospital in Mnsterlingen, 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 Binswangers practice was attention
to Martin Heideggers concept Daseinpersonhood 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 Europethe 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 lifethreatening therapies, and it worked. But at the end of the trial phase, the
company began to charge for Largactil.
Kuhn understoodthe whole small society of psychiatrists who
dealt with pharmaceuticals understoodthat 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 molec-

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ular structure more like Largactils. As it happened, Geigy had synthesized that substance, G22355.
In retrospect, after decades more progress in molecular biochemistry, Kuhns 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 Kuhns. 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 nonbiological 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 Kuhns 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.

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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, Kuhns 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 antidepressantthe first specific medication treatment for mood disorders ever discovered. The drug reversed
the fatigue, oppression, and impaired thinking all at once. It resolved
the syndromethe cluster of symptomsof 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 imipramines side effects: dry

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mouth, rapid heartbeat, and constipation. He estimated the dosage

needed for efficacy, often up to 200 or 250 milligrams. He described
the drugs 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 Kuhns 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.
Kuhns 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. Kuhns assessment of
imipramine had virtues that formal drug trials rarely duplicate. He
knew his patients well and interviewed them extensively. He could
beconfident of their diagnoses. He gave imipramine when it became

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availableat an arbitrary momentand 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 practicean unrepresentative sample. Kuhn had access to a population nave, that is, never before
exposed, to antidepressants. Although it lacked rigor, Kuhns 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 audiences 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 Kuhns 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.