Peter Kramer’s Defense of Antidepressants

Cover of Listening to Prozac

“Could drugs that are ingested by one in 10 Americans each year, drugs that have changed the way that mental illness is treated, really be a hoax, a mistake or a concept gone wrong?”  asks Brown University psychiatrist Peter Kramer in this article. Kramer lambasts the current meme that antidepressants are no better than placebo, especially for mild depression. His major point is that the research on which that conclusion is based was contaminated by a recruitment process that selected many subjects who were not truly depressed. Thus, when followed over time, they got better regardless of whether they were on antidepressants or placebos, obscuring the value of the drugs for truly depressed patients.(For a more sophisticated discussion, in my opinion, of the reasons why there has been a lessening gap between medications and placebos, see this article in Wired by Steve Silberman.)

Kramer is best known for his popular 1993 book, Listening to Prozac, in which he argued that some people feel “better than well” when treated with such medications. In particular, energy, assertiveness and self-confidence can be enhanced even if they were not pathologically diminished before the patient was treated. Kramer discusses the prospect of “cosmetic psychopharmacology” — when a medication can improve socially desirable traits even in people without pathology, should it be used in such a fashion? Raising the issue should inform, narrowly, psychiatrists’ prescribing practices, and, more broadly, both values-based and fiscally-based societal considerations of antidepressant use.


Indeed, antidepressant use has continued to grow wildly in the almost two decades since, and with it the windfall for the drugs’ manufacturers. But you will find very few prescribers, consumers or insurance payors who believe this is the “cosmetic” treatment of those who are not truly ill merely to give them an edge in a competitive society. Instead, the trend has been justified by the redrawing of the boundaries of illness so that a far broader set of conditions are said to be medication-responsive. This is a concern whether you are a naive materialist, who believes in the strictly biological explanation for medication efficacy, or if you attribute the benefits to placebo effect and self-fulfilling prophecy. (Despite the fact that I am a psychopharmacologist, I tend to believe we understand so little about the ‘black box’ of the brain that we are a long way away from being able to tell the difference.)

Kramer worries that newly-skeptical physicians affected by the emperor-has-no-clothes backlash against antidepressant use will fail to treat deserving patients appropriately:

“…It is dangerous for the press to hammer away at the theme that antidepressants are placebos. They’re not. To give the impression that they are is to cause needless suffering…”

He centers his article around a vignette in which a friend of his with post-stroke depression had not been placed on an antidepressant despite the research supporting improved outcome. (Notably, I think, unlike what he did in Listening to Prozac, he is not reflecting on his own prescribing practices, merely those of his colleagues.) But if the meme about antidepressant efficacy changes profoundly enough, some patients will not get better even when they are prescribed these medications, because of the undercutting of the self-fulfilling prophecy. And is that a good thing or a bad thing?

Given that my bias in my work is toward treating sicker patients (I work in a hospital with only a limited outpatient practice with the “worried well”), I am among those who decry the creeping medicalization of everyday life. I don’t know if antidepressants are less “effective” in healthier patients because of the diffuseness and ambiguity about the meaning of “effective”. (Throughout psychiatric research, I see profound confusion and lack of consensus about how to measure outcome.) Severely depressed patients, because core aspects of severe depression include pessimism and despondency, are probably far less susceptible to suggestibility. I don’t know if the research has been done but I would suspect that severe depression sabotages the placebo effect. Thus the observed benefit of antidepressants in this class of patients is more likely to be biological. A nervous system out of whack for some reason can probably be rebalanced better with some pharmacological influence that counteracts the imbalance.

BERLIN - NOVEMBER 22:  Singer and guitarist Br...
Placebo (Brian Molko)

In less ill patients, the balance may indeed shift in favor of placebo effects as the basis for observed benefits. But I have another concern, which has fueled my reluctance to prescribe them too readily, about the expansion of antidepressant use in our society. Although the medications are not, in the formal sense of the term, addictive (i.e. they do not hijack the brain’s craving and pleasure circuitry and there is no tolerance and no acute withdrawal syndrome from abrupt discontinuation of use), I have long worried that too readily prescribing antidepressants for those who do not necessarily start out ‘needing’ them may make them ‘need’ them down the line. Think of it this way. The CNS is a homeostatic mechanism. If it is in balance, it resists and counters changes. (Disease is a perturbation in function outside of the range in which it can by intrinsic mechanisms restore itself to homeostasis.) Give antidepressants to a brain in balance, to amp up certain functions, and counteractive mechanisms may be put into play to restore balance. A new set-point may be established that may persist even after the removal of the medication which was the original influence. Someone who did not need the medication in the first place may be converted into someone who does, perhaps for the rest of their life.

Placebo Response Under Genetic Control

Prozac, a selective serotonin reuptake inhibit...

Monoamine Oxidase A and Catechol-O-Methyltransferase Functional Polymorphisms and the Placebo Response in Major Depressive Disorder: “The placebo response shows pronounced interindividual variability. Placebos are postulated to act through central reward pathways that are modulated by monoamines. Because monoaminergic signaling is under strong genetic control, we hypothesized that common functional polymorphisms modulating monoaminergic tone would be related to degree of improvement during placebo treatment of subjects with major depressive disorder. We examined polymorphisms in genes encoding the catabolic enzymes catechol-O-methyltransferase and monoamine oxidase A. Subjects with monoamine oxidase A G/T polymorphisms (rs6323) coding for the highest activity form of the enzyme (G or G/G) had a significantly lower magnitude of placebo response than those with other genotypes. Subjects with Val158Met catechol-O-methyltransferase polymorphisms coding for a lower-activity form of the enzyme (2 Met alleles) showed a statistical trend toward a lower magnitude of placebo response. These findings support the hypothesis that genetic polymorphisms modulating monoaminergic tone are related to degree of placebo responsiveness in major depressive disorder.” (Journal of Clinical Psychopharmacology)

Some behavioral scientists consider the placebo response to be a nuisance that confounds psychopharmacological research; patients get better even when they do not get the active drug. Some of us, however, feel that the placebo response is a good friend of clinical psychiatry. Some meta-analyses of antidepressant efficacy studies suggest that the medications may not be that effective and that much of the therapeutic response to antidepressants may in fact be ascribable to the placebo response. (The psychiatrist’s role, as a corollary, may be not the art of picking a drug to prescribe but enlisting the individual into a mindset that mobilizes their self-healing capacities.) We already know that depression is related to the reward circuitry in the brain and that genetic susceptibility to depressive disorders relates to polymorphism in the catecholamine system. If the placebo response as well varies with differences in that circuitry, could it be that those patients with lower capacity for the placebo response could also be those patients prone to become depressed int he first place? If we cannot as effectively mobilize their placebo response when they are in the placebo wing of a drug study, perhaps they cannot as effectively bring self-suggestion, affirmation and other coping strategies to bear on the distressing situations in their lives?


U.S. Doctors Regularly Prescribe Real Drugs As Placebo Treatments, Study Claims

Prescription placebos used in research and pra...

“Many rheumatologists and general internal medicine physicians in the US say they regularly prescribe ‘placebo treatments’ including active drugs such as sedatives and antibiotics, but rarely admit they are doing so to their patients, according to a study on

The use of placebo treatments in clinical practice has been widely criticised because it is claimed that the practice by its very nature is deceptive and therefore violates patients’ autonomy. But advocates of placebo treatments argue that they could offer effective treatment for many chronic conditions without necessarily deceiving patients. Despite the controversy, to date there has been little data on doctors’ attitudes towards and the use of placebo treatments in the US.” (Science Daily)

The only people bent out of shape by this are those unsophisticated physicians who can believe only in the concrete and materialistic explanations for how they ‘heal’. Most of medicine mobilizes patients’ healing resources through symbolism, ritual and enlistment into a belief system. That’s why I have such a hard time with the (equally concrete) critics of Western allopathic medicine. It is not that they offend me by not believing in what I do, but rather that they undermine the power of belief which is the basis of how physicians heal. In short, most treatment is probably mediated by the placebo response. Patients inherently give up their autonomy by consulting a health professional, and treatment will not work without an element of faith on their part.