ROLAND KUHN’S REPORT on imipramine arrived a decade after the Research Council’s paper on streptomycin. Scientists at Geigy understood that imipramine would have to be evaluated via the new technology. But what would play the role of the chest X-ray—the basis for measuring the drug’s efficacy?
Alan Broadhurst, the chemist who had served as a guinea pig in the early testing of imipramine, contacted Max Hamilton, a German-born British psychiatrist who specialized in statistics. Hamilton had just formulated a depression rating scale. Broadhurst convinced researchers to apply it in clinical trials.
Like Kuhn, Hamilton began with patients. He asked them about the burdens of depression—sadness, disturbed sleep, suicidal thoughts—and attached numbers to represent levels of intensity. He focused on severely afflicted patients in hospitals but also interviewed outpatients. Then he composed a rating scale intended to characterize a discrete syndrome, “affective disorder of the depressive type.”
This specificity appealed to Broadhurst. Hamilton’s scale made an argument for viewing depression as a conventional medical disorder, characterized by symptoms that could be assessed in a patient interview.
In the 1950s, psychiatry worked differently. Freudians classed patients broadly, as psychotic and in need of a simplified psychotherapy or neurotic and likely to be good candidates for psychoanalysis. Either way, the core disturbance was unconscious emotional conflict, turmoil that might be protean in its expression. Symptoms were mutable—of interest mostly as clues to the origins (in childhood experiences, in sexual repression) of patients’ distorted perception and behavior.
Existential psychoanalysis, in Kuhn’s version, had more in common with conventional medicine. Kuhn recognized diagnoses. But he remained an analyst in this sense: he did not take patients’ initial reports at face value. Kuhn said, “One needs to realize that the symptoms of vital depression are often not spontaneously mentioned … They are often concealed by other symptoms which may seem to be more severe. They may not come to the patient’s mind even with questioning. Patients admit to these symptoms only as the links of an integral whole in a dialogue that is free and comprehensible.”
No one knows precisely how Kuhn arrived at a diagnosis. If less deeply, I, like Kuhn, trained in existential psychotherapy. My mentor, Leston Havens, believed that a doctor should “sit alongside” patients psychologically, looking out at the world with them. If the view was bleak, perhaps they were depressed. Les spoke of the “imprint” of depression. After a group had witnessed a clinical interview, a latecomer might discern the diagnosis in the bodily posture of the observers. Depression was profound hopelessness best apprehended through empathy. The number of symptoms was unimportant. In patients who “put a good face on it” and said chipper things, depression might nonetheless be detected—by psychiatrists, through self-monitoring.
In contrast, Hamilton put stock in the surface manifestations of illness. He built his scale on seventeen rating factors—low mood, work problems, expressions of guilt, and so on—each with points assigned according to severity. Doctors were to act as raters, but in that role they might rely on patients’ reports. Under “suicide,” the response “feels life is not worth living” merits a score of one point; “wishes he were dead” scores two; “suicidal ideas or gestures” scores three; and a recent history of attempts scores four.
Many Hamilton items correspond to a commonsense take on depression: listlessness, indecision, self-reproach, and the slowing of speech and movement that psychiatrists call psychomotor retardation. But the scale has its oddities. Bodily symptoms such as indigestion, constipation, menstrual disturbances, and backache can contribute ten points. Hypochondria can add four. Somatic complaints were common on the psychiatry wards of the 1950s, where patients might be warehoused in long stays. For Hamilton, sleep disturbance played an outsize role. He gave separate ratings to problems in falling asleep, staying asleep, and waking at a suitable hour. Likewise, anxiety makes repeated appearances. The instrument was one doctor’s portrait of depression at a moment in time.
Despite its idiosyncrasies, the Hamilton scale was embraced as a means of documenting the course of a depression. Psychiatrists could run through the checklist and attach numbers to symptoms. The sum was the Hamilton score. Subsequent scores could be contrasted with the baseline to track responses to treatment.
The Hamilton scale tops out at 50, but totals above the low 30s are rare. The field constantly debates definitions of severity, but in simple terms a Hamilton of 30 represents severe depression; 20, moderate; and 10, mild. Most patients in antidepressant trials have scores in the 20s. In typical outpatient practices, Hamiltons average 19 or 20.
As for degrees of change, from early on, the criterion for a response was a halving of the initial Hamilton score, improvement that would move most severely depressed patients into the mild category and mildly depressed patients to normality. Remission, ending the bout of illness, required driving the total below 8. In the streptomycin study, researchers had used informal categories—“considerable” or “moderate or slight” resolution of the X-ray—and Kuhn had written of full and partial relief from depression. Whether Hamilton’s numbers added precision was an open question, but the scale looked scientific.
Between 1959 and 1965, more than a thousand patients were assessed in brief randomized trials testing imipramine as a treatment for depression. About two-thirds of subjects on medication responded, versus close to a third of those in the control arm, a pattern that echoed the outcome for partial chest X-ray clearing in the streptomycin study.
Imipramine, randomized trials, and the Hamilton worked synergistic magic. Its ability to capture the medication’s efficacy validated the scale. Meanwhile, the research results validated antidepressants. The new tools served a political role, pushing psychiatry toward mainstream medicine, with its emphasis on diagnosis.
Over time, the scale had extraordinary impact. Increasingly, doctors looked to symptoms, their pattern, number, and severity, to define mental illnesses. As Kuhn had invented the antidepressant, so Hamilton had invented a new understanding of depression.