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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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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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