Before Prozac: The Troubled History of Mood Disorders in Psychiatry

According to Edward Shorter, one of the unfounded decisions that created grim consequences for the public health was the premature abandonment of older drugs that held promise as antidepressants and their replacement by less effective antidepressants, particularly the selective serotonin reuptake inhibitors (SSRIs). In a reversal of the usual scenario, the bad guys in this tale are not the drug companies but the Food and Drug Administration (FDA) and, to a lesser extent, the academic psychiatrists who concoct DSM. The drug companies are portrayed as hapless victims of an imperial FDA overstretching its regulatory authority.

Shorter, a prolific medical historian, provides a detailed, lively history of what has been called the “first set” of psychotropic drugs—the antipsychotics, anxiolytics, and antidepressants that showed up in the 1950s. Of course when they first appeared, these drugs weren’t known by those terms. Readers of a certain age will remember major tranquilizers and minor tranquilizers, energizers, and thymoleptics. And that’s one of the points of this book. We don’t know what these drugs are really good for, so we can’t decide what to call them. Shorter reminds us that the phenothiazines have pretty good antidepressant activity; he quotes the redoubtable Jonathan Cole: “I have so far never seen a published study...of an antipsychotic versus placebo in depression that wasn’t positive. I think most of these drugs work across a spectrum of cases and are not anywhere near as specific as the nomenclature suggests they are.” (p. 149).

The development of the first set of psychotropics is set out in rich detail. We hear about the battles between the drug industry, attempting to keep old drugs on the market and bring out new ones, and the FDA and other government agencies, convinced that both old and new drugs were dangerously addictive. We get thumbnail sketches of the main players and delicious historical tidbits. Methylphenidate, first synthesized by the Ciba chemist Leandro Panizzon, was named Ritalin after his wife, Marguerite (Rita). Shorter tells us that both she and her husband tried the new agent. It didn’t have much impact on him, but it made her feel excited and adventuresome. “I used to take it before a tennis match,” she said.

When in 1962 Congress passed the Kefauver-Harris Amendments to the Food, Drug, and Cosmetic Act of 1938, the FDA was authorized to judge the efficacy of drugs as well as their safety. This authorization extended to previously approved and widely used drugs as well as to drugs coming down the line. The FDA—to be sure advised by outside panels of experts—conducted, according to Shorter, a wholesale purge of drugs that the medical community had found safe and useful, getting rid of some drugs entirely—many of the “combos” didn’t make the cut—and demonizing others (e.g., meprobamate, diazepam, and chlordiazepoxide) on at best shaky evidence of addictiveness. Then in the 1980s and 1990s, the FDA seemed to reverse its zeal for efficacy and went on to approve a slew of SSRIs and other new antidepressants on the dubious (to Shorter) grounds that they were better (albeit barely) than placebo. The relatively nonspecific DSM-III and -IV diagnoses of major depression helped make this possible since the many patients who meet the criteria are likely to improve in response to a wide variety of treatments. The new antidepressants, Shorter insists, are far less effective than the older ones.

This book, given the definitions provided for technical psychiatric and neuroscience terms, is meant for both the educated general public and a professional audience. Unfortunately, Shorter makes no, or at least very little, attempt to present a balanced view of the past half century of drug development. It is a compellingly argued and erudite polemic, and as such it interprets information on drug safety and value—much of it admittedly ambiguous—from the perspective that the old drugs were good and the new ones are bad. Shorter overvalues the older drugs, undervalues the new ones, and in particular plays down the side effects of the tricyclics and monamine oxidase inhibitors. In comparing the side effects of tricyclics and SSRIs, he writes, “Which would you rather have, dry mouth or impotence?” (p. 201).

At times biased interpretation crosses the line into errors of fact: “the benzos were probably the most effective and safest class of antidepressant in the history of psychopharmacology,” Shorter writes (p. 103), contradicting the data he himself cites on this matter, which not surprisingly point to quite the opposite conclusion. And although I agree with Shorter’s insistence that melancholia is more of a discrete illness than major depression and should have a category of its own in DSM, his relegation of other depressions to the category of nonmelancholic is both idiosyncratic and bereft of justification.

My major argument with this book is that when it comes to judging the usefulness of drugs, it places unquestioning value on clinical experience, clinical anecdote, and the convictions of wise clinicians. Most of the drugs that the FDA withdrew after 1962 had been deemed as useful strictly on the basis of anecdotal clinical experience. Shorter indicts the FDA—and to a lesser extent the medical community, which accepted the FDA’s recommendations—for giving short shrift to clinical experience in assessing the worth of drugs. He insists that lots of “good” drugs were tossed, including many combination agents, because the long clinical experience with them was not sufficiently appreciated. Clinical observations have, for sure, led to important therapeutic advances, and we can’t expect a randomized controlled clinical trial behind every decision. Maybe a combination drug like Eskatrol (dextroamphetamine and prochlorperazine), hair raising as it sounds, does have its place. But if the history of therapeutics has taught us anything, it’s that clinical experience, the utterances of wise clinicians, and uncontrolled drug studies are more likely to mislead than they are to enlighten.

But these are minor quibbles. The broad strokes in this book are disturbingly pertinent. The Sequenced Treatment Alternatives to Relieve Depression study demonstrates clearly that the current crop of antidepressants is as ineffective as Shorter says they are. The general public and our profession continue to harbor irrational concerns about the addictiveness of benzodiazepines and psychostimulants—concerns that hinder adequate treatment. The FDA restricts and black-boxes drugs on the shakiest of grounds. DSM-V promises to have all the problems of its predecessors; as Shorter reminds us, “the consensus approach to science often produces horse-trading rather than scientific truths” (p. 132). And, most regrettably, the public continues to be deprived of potentially beneficial treatments (e.g., marijuana for pain and nausea, psilocybin for the anguish of terminal illness, 3,4-methylenedioxymethamphetamine [MDMA or ecstasy] for posttraumatic stress disorder, peyote for addiction) not because of their dangers or pharmacologic actions, but because of the meanings we attach to them.