There is an active debate underway in the popular literature about whether antidepressant medications actually do anything chemically helpful for depressed patients. No one doubts that many patients report feeling better, and that most evidence less depression on standardized rating scales, following treatment. But much of that improvement appears to be due to psychological factors, i.e., the placebo effect. The debate is over how much improvement is not due to the placebo effect. What beneficial effects can be attributed to the active ingredients in the tablet or capsule?

It's disconcerting to enter this debate decades after the popularization of antidepressants. These are among the most common prescriptions in America: In 2010, antidepressants were the second most commonly prescribed class of drugs in the U.S., according to IMS Health. They are so widely used that Consumer Reports publishes "best buy" recommendations about which ones to try first. Yet recent reanalyses of efficacy data have called into question whether antidepressants help more than inert pills. In a two-part piece in the New York Review of Books, Marcia Angell MD, the former editor-in-chief of the New England Journal of Medicine, favorably reviews these skeptical findings. (I won't summarize the arguments here, but I do very much recommend her review.) In the other corner is Peter Kramer MD, author of Listening to Prozac and other books, who offers a spirited defense of antidepressants in his op-ed rebuttal in the New York Times. The 300 comments that follow the online version of the op-ed also make for fascinating reading: Many are first-person accounts of the lifesaving benefit of antidepressants.

What to make of all this? Those conversant in research methodology will pick apart the various arguments. Do the studies have enough statistical "power"? Does it matter that typical efficacy studies recruit subjects who differ from patients in clinical practice? How much difference does an "active" placebo make? Is it preferable to use subjective mood ratings, or ratings from trained observers? How many weeks or months should subjects be assessed? Should subjects with co-morbidities, i.e., additional diagnoses, be included or excluded? Are there advantages to including a third study arm (a known effective intervention) to the usual two (the drug being assessed, and placebo)?

There are many such questions that need to be resolved, and professional researchers are probably in the best position to discuss them. Meanwhile, the rest of us are left with a seeming paradox. Thousands - millions? - of individuals claim relief from antidepressant treatment, and virtually any psychiatrist will swear that antidepressants really have helped many of his or her depressed patients. (This is my own experience, by the way - it's nearly inconceivable to me that antidepressants are no more than placebos. I've seen too many patients improve before my very eyes.) Meanwhile, there are also many patients, equally depressed, who obtain little or no benefit from antidepressants, and a large number of carefully conducted studies that find little benefit in the active ingredients of these pills, once placebo effects are factored out.

While I can't prove it, my sense is that the answer lies in the heterogeneity of depression. Some patients get dramatically better on antidepressants (in entirely believable ways, as opposed to reactive "flight into health" and the like), some only a little, and others appear not to change at all. Widely varying responses can easily "average out" in the usual randomized controlled trials used to assess efficacy, and could account for lackluster findings in group studies. Since I do have some research background and training myself, I'd want to see the scatterplots of individual subject ratings, to see if they cluster into responsive, partly responsive, and unresponsive groups.

Of course, it is not a new idea that some depression responds to medication and some doesn't. When I started medical school, psychiatrists distinguished "endogenous" and "exogenous" depression - i.e., depression that originated within the patient chemically, and depression that originated from external stress or loss. (For a concise summary of the idea, see the first paragraph of this editorial.) Antidepressants were thought to help the former but not the latter.

Unfortunately, that wasn't true. As it turns out, knowing whether an external event precedes a depression doesn't predict whether an antidepressant will help. The search has gotten more sophisticated lately, and measurable genetic subtypes may one day tell us who will benefit by antidepressants and who won't. But we're not there yet. At this point, we cannot predict whether an individual patient will improve with antidepressant medication.

I'll end this post by noting that the placebo effect, a vexing complication in clinical research, isn't a bad thing in real life. If a patient feels better, I don't worry too much about who or what gets the credit. Maybe it's the citalopram or sertraline in the pill. Maybe it's the patient's belief in the pill and in the medical science behind it. Maybe it's the fact that I gave the patient something that our culture imbues with symbolic healing powers. Maybe my words were healing and the prescription was a mere distraction. Or maybe I had no effect at all, and the patient healed himself or herself. Usually it's impossible to know. In my view, being a psychiatrist in clinical practice requires this kind of agnosticism and humility.

© 2011 Steven P Reidbord MD.  All rights reserved.

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