OF THE PSYCHOPHARMACOLOGISTS I encountered in medical school, only one made an impression. In my final year, I met Jonathan Cole.
Cole’s career spanned the period of modern drug development in psychiatry. In 1953, before imipramine, he helped organize a national conference on psychopharmacology. He went on to head newly established pharmacology divisions at the National Institute of Mental Health. At the NIMH, he supervised the first large-scale trials of antidepressants. Believing in “green thumb” psychiatrists who, like Kuhn, could identify promising drugs through clinical observation, Cole maintained support for informal studies. By the 1970s, Cole was at McLean Hospital, in the Harvard system. I attended his talks. He invited me to his office.
Cole was a congenitally open, happy man. In his later years, residents called him Jolly Old Cole. Cole made no concession to the psychoanalytic convention that gravity and passive listening are the hallmarks of wisdom.
Cole loved to talk about unexpected uses of drugs. For example, he entertained a theory about nicotine. It might act to suppress anger; its ability to take the edge off irritability was part of what made it attractive to smokers.
In his time with me, Cole discussed alternatives to antidepressants. When doctors used amphetamine to energize patients during their hospital stays, some depressives simply recovered. Cole said that when medications such as imipramine failed, he might prescribe amphetamine, especially for patients who seemed apathetic. Stimulants had a bad name. They’d been prescribed for weight loss and abused. If you’re referred a depressed patient on amphetamine, Cole said, the doctor is either incompetent or sophisticated.
Cole was interested in the antidepressant effect of drugs such as Valium. They were called anxiolytics—they lysed, or dissolved, anxiety. GPs were criticized for prescribing “mother’s little helpers” to bored housewives. Perhaps the doctors were savvy. Cole had seen cases, especially when depression was admixed with anxiety, in which anxiolytics helped altogether, restoring energy instead of depleting it. In one study, Valium seemed more successful in this regard than Librium or Miltown.
Did I know a disturbing fact about Valium? Cole asked. Research had shown that patients prescribed Valium liked the doctor better, a worrisome feedback loop. Maybe they were right to do so.
Prescribing was an art. A patient’s requirements might be idiosyncratic because humans are.
Although they were about drugs from other classes, these conversations helped define for me what pharmacologists expected of antidepressants. Many medications could be referred to in terms of a direction, up or down—they induced more or less excitation. On occasion, those same medicines did a more complex and thorough job. They reversed much of a syndrome, many linked symptoms at once. Or they got to the heart of a disorder—in the case of depression, the loss of a future. That job, the one that, when stimulants or anxiolytics pulled it off, occasioned surprise, antidepressants did routinely. I am using Cole’s patter to point to how antidepressants act when they work well.
I spoke with Cole in subsequent years, but I remember the early conversations best. I had seen pharmacology as a matter of memorizing the dose ranges for drugs and then avoiding using them. Cole demonstrated that a lively mind could be engaged by the complexities of prescribing.
From early on—since encountering Cole as I left medical school—I have utilized many classes of medication with depressed patients: stimulants, antianxiety medications, antiepileptics, antipsychotics, mood stabilizers, sedatives, and others. Occasionally, patients respond best to a “wrong” drug or the right drug at the wrong dose. Like Cole, I always have a depressed patient or two in my practice who are taking amphetamine or Ritalin by itself and who do well globally.
I mention Cole’s approach to depression treatment—that there’s more than one way to skin a cat—because of what strikes me as an odd line of argument against traditional antidepressants. Critics have complained that since unrelated sorts of medicine can help in depression, something is suspect about the central group of antidepressants, imipramine and Prozac and the rest. Why are they more “antidepressant” than Valium or Ritalin?
I think that the critics misread the findings. In studies where anxiolytics are tested as depression treatments, they rate well on insomnia, agitation, and anxiety, not the core symptoms. The distinction between Valium and imipramine is real enough.
But if the research results were different, if Valium proved a terrific antidepressant, what of it? Doctors lower blood pressure through varied medications that at the first level act on the brain, kidney, blood vessels, or heart. No one argues that the multiplicity of approaches discredits antihypertensives.
With depression, the expectation of exclusivity seems especially peculiar. If we believe that mood disorders respond to changes in self-awareness, social comfort, and assessment of external circumstances, it follows that, now and again, a medicine that relaxes or focuses the mind might prove useful.
For me, Cole’s was a model approach to the work of psychiatry. We try remedies that have been well tested. When those fail, room is left for efforts grounded in less systematic observation. This method resembled the one I used in psychotherapy, trying one line of inquiry and then another, demanding progress. Cole gave me the permission I wanted, for vigor in the treatment of depressed patients—this in an era when infinite patience was the norm.