You can tell a book has hit a nerve when its critics question not only the motivations of its author, but the judgment of the reviewers who appear on the book jacket.

That’s the level of contempt many psychiatrists show the new book by Joseph Glenmullen, M.D., Prozac Backlash: Overcoming the Dangers of Prozac, Zoloft, Paxil, and Other Antidepressants With Safe, Effective Alternatives.

Released in April, the book by Glenmullen, a clinical instructor of psychiatry at Harvard Medical School, has touched off a wave of protest for its controversial proposition that selective serotonin reuptake inhibitors, or SSRIs, are causing silent brain damage and effecting chemical lobotomies by destroying the nerve endings they target.

As the title suggests, Glenmullen is urging patients to reconsider their use of the drugs, warning that they cause long-term side effects including disfiguring facial and whole-body tics; that they can cause debilitating withdrawal symptoms; and that they are capable of precipitating suicidal and homicidal behavior.

In Glenmullen’s view, such risks are unnecessary. "In my experience, as many as 75 percent of patients are needlessly on these drugs for mild, even trivial conditions," Glenmullen writes. He contends that those patients would be better treated with exercise, psychotherapy, and/or the herbal antidepressant St. John’s wort. Instead, Glenmullen contends, primary care physicians are prescribing SSRIs without proper diagnosis or follow-up.

Glenmullen is not completely opposed to the use of SSRIs. He believes that patients whose acute psychiatric conditions present greater risks than the medication itself may benefit from the drugs, but he argues that even those patients should limit their exposure by using the medications for discrete periods of time.

Almost as soon as the book hit the stands, psychiatrists around the country assailed it as a sensationalistic threat to the well-being of their patients.

The book "is pure speculation," said Harvey L. Ruben, M.D., a clinical professor of psychiatry at Yale School of Medicine and a corresponding member of APA’s Joint Commission on Public Affairs. "He makes it sound like the worst-case scenario happens to everybody and that terrible things are going to happen to you in future. It scares the life out of our patients."

Much of the criticism revolves around Glenmullen’s dramatic, and many times anecdotal, presentation of adverse reactions to SSRIs, including sexual dysfunction, parkinsonism, agitation, spasms, and tics—among others. His critics say that Glenmullen exaggerates SSRIs’ potential for all such side effects, with perhaps the most important one being compensatory declines in patients’ dopamine levels.

Glenmullen speculated that such drops are responsible for SSRI side effects ranging from sexual dysfunction to tardive dyskinesia, similar to major tranquilizers. With their use, "the brain damage that can result is slowly progressive and often silent, and only manifests itself once it is severe," he warned.

But that doesn’t sit well with some psychiatrists. The warnings are "out of proportion to at least what most of us see as the risks," said Rex Cowdry, M.D., medical director of the National Alliance on Mental Illness. "Dr. Glenmullen enters into a set of unusual reviews of the literature, making connections and warnings about toxic effects of the drugs that I describe as not in fact terribly well grounded in science and intended to be sensational."

Glenmullen’s analysis is largely based on a comparison of SSRIs with major tranquilizers. Critics say his discussions of the drugs are so intertwined that paragraphs beginning with SSRIs switch to major tranquilizers without noting the drugs work by different mechanisms. The result, they fear, is that unsophisticated readers will believe they are at greater risk of developing potentially irreversible tardive dyskinesia than they may actually be.

"This portrayal is quite misleading," said Frederick M. Jacobsen, M.D., a clinical professor of psychiatry at George Washington University School of Medicine. "There are very few data to suggest that the SSRIs have the dramatic dopamine-blocking effects of major tranquilizers."

Jacobsen said less than 5 percent of patients taking SSRIs suffer motoric side effects, while 5 percent to 10 percent end up in amotivational states. "The best treatment for those side effects is not to stop the drug and go on to nothing, if you have an otherwise good response to the drug," he said. The solution, in his view, is to add a second drug to rebalance the system.

Glenmullen, however, said he is issuing an important warning about the drugs to patients and physicians. "I am really conveying to the public what is in psychiatric journals," he commented. "I quote people directly who say that patients should be told about [the existence of extrapyramidal side effects]."

It is a message that Glenmullen said is further supported by research published after his book. "The concerns raised by Prozac Backlash are heightened by a new study in Brain Research suggesting that fluoxetine and sertraline may swell and truncate axons of the serotonin nerves they target," he said.

Glenmullen believes much of the criticism has been driven by pharmaceutical companies and drug proponents, who are displeased by the negative publicity the book has generated. In the month after its publication, several major newspapers and magazines highlighted the portions of the book that allege the drug companies have downplayed and distorted the risk of suicide and have co-opted physicians with research dollars.

That message comes through clearly and without distortion, he said. "I am very careful to say where we have good numbers on systematic studies versus estimates based on small-scale studies and where we lack numbers. I am calling for that research." The result is that readers do "not come away with a mistaken impression. They come away with a sense of everything that we know to date about why one might be concerned, and the limitations of what we know and the research that we need."

To prove it, Glenmullen said his answering machine and Web site were inundated with expressions of gratitude from patients and physicians who said they would not otherwise have known symptoms such as severe fatigue were the result of taking SSRIs.

And many psychiatrists agree. Alan Stone, M.D., a professor of psychiatry and law at Harvard University, praised the book for warning readers that "no one really knows the long-term consequences of these chemicals on the brain."

Stone, a former APA president who has been roped into the controversy for endorsing the book on its jacket, defends Glenmullen to critics.

"Dr. Glenmullen is not a research scientist. He is not a biostatistician. He is just a clinician who is thinking through what he is doing. Every psychiatrist in America has a responsibility to think through these drugs that they are prescribing to their patients and not just accept the advertising or the professors from on high," he said.

Joshua Sparrow, M.D., a child psychiatrist at Children’s Hospital in Boston, agreed that the book raises the important, but disquieting, concern that the long-term effects of these drugs are uncertain. "I don’t think anyone is facing how little we know," he said.

Nor are they paying much attention to the influence of drug companies in determining what research is conducted. "The crisis [that Glenmullen] puts his finger on is that we don’t have a structure which allows us to get the information that we need to serve our patients because there is an imbalance of where these resources are for doing the research," Sparrow observed.

At the very least, the book has sparked a heated debate and gotten people thinking.