For obvious reasons, drug companies make very sure that their positive studies are published in medical journals and doctors know about them, while the negative ones often languish unseen within the FDA, which regards them as proprietary and therefore confidential. This practice greatly biases the medical literature, medical education, and treatment decisions.
Kirsch and his colleagues used the Freedom of Information Act to obtain FDA reviews of all placebo-controlled clinical trials, whether positive or negative, submitted for the initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999—Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. This was a better data set than the one used in his previous study, not only because it included negative studies but because the FDA sets uniform quality standards for the trials it reviews and not all of the published research in Kirsch’s earlier study had been submitted to the FDA as part of a drug approval application.
Altogether, there were forty-two trials of the six drugs. Most of them were negative. Overall, placebos were 82 percent as effective as the drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely used score of symptoms of depression. The average difference between drug and placebo was only 1.8 points on the HAM-D, a difference that, while statistically significant, was clinically meaningless. The results were much the same for all six drugs: they were all equally unimpressive. Yet because the positive studies were extensively publicized, while the negative ones were hidden, the public and the medical profession came to believe that these drugs were highly effective antidepressants.
Kirsch was also struck by another unexpected finding. In his earlier study and in work by others, he observed that even treatments that were not considered to be antidepressants—such as synthetic thyroid hormone, opiates, sedatives, stimulants, and some herbal remedies—were as effective as antidepressants in alleviating the symptoms of depression. Kirsch writes, “When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree.” What all these “effective” drugs had in common was that they produced side effects, which participating patients had been told they might experience.
It is important that clinical trials, particularly those dealing with subjective conditions like depression, remain double-blind, with neither patients nor doctors knowing whether or not they are getting a placebo. That prevents both patients and doctors from imagining improvements that are not there, something that is more likely if they believe the agent being administered is an active drug instead of a placebo. Faced with his findings that nearly any pill with side effects was slightly more effective in treating depression than an inert placebo, Kirsch speculated that the presence of side effects in individuals receiving drugs enabled them to guess correctly that they were getting active treatment—and this was borne out by interviews with patients and doctors—which made them more likely to report improvement. He suggests that the reason antidepressants appear to work better in relieving severe depression than in less severe cases is that patients with severe symptoms are likely to be on higher doses and therefore experience more side effects.
To further investigate whether side effects bias responses, Kirsch looked at some trials that employed “active” placebos instead of inert ones. An active placebo is one that itself produces side effects, such as atropine—a drug that selectively blocks the action of certain types of nerve fibers. Although not an antidepressant, atropine causes, among other things, a noticeably dry mouth. In trials using atropine as the placebo, there was no difference between the antidepressant and the active placebo. Everyone had side effects of one type or another, and everyone reported the same level of improvement. Kirsch reported a number of other odd findings in clinical trials of antidepressants, including the fact that there is no dose-response curve—that is, high doses worked no better than low ones—which is extremely unlikely for truly effective drugs. “Putting all this together,” writes Kirsch,
leads to the conclusion that the relatively small difference between drugs and placebos might not be a real drug effect at all. Instead, it might be an enhanced placebo effect, produced by the fact that some patients have broken [the] blind and have come to realize whether they were given drug or placebo. If this is the case, then there is no real antidepressant drug effect at all. Rather than comparing placebo to drug, we have been comparing “regular” placebos to “extra-strength” placebos.
That is a startling conclusion that flies in the face of widely accepted medical opinion, but Kirsch reaches it in a careful, logical way. Psychiatrists who use antidepressants—and that’s most of them—and patients who take them might insist that they know from clinical experience that the drugs work. But anecdotes are known to be a treacherous way to evaluate medical treatments, since they are so subject to bias; they can suggest hypotheses to be studied, but they cannot prove them. That is why the development of the double-blind, randomized, placebo-controlled clinical trial in the middle of the past century was such an important advance in medical science. Anecdotes about leeches or laetrile or megadoses of vitamin C, or any number of other popular treatments, could not stand up to the scrutiny of well-designed trials. Kirsch is a faithful proponent of the scientific method, and his voice therefore brings a welcome objectivity to a subject often swayed by anecdotes, emotions, or, as we will see, self-interest.
Whitaker’s book is broader and more polemical. He considers all mental illness, not just depression. Whereas Kirsch concludes that antidepressants are probably no more effective than placebos, Whitaker concludes that they and most of the other psychoactive drugs are not only ineffective but harmful. He begins by observing that even as drug treatment for mental illness has skyrocketed, so has the prevalence of the conditions treated:
The number of disabled mentally ill has risen dramatically since 1955, and during the past two decades, a period when the prescribing of psychiatric medications has exploded, the number of adults and children disabled by mental illness has risen at a mind-boggling rate. Thus we arrive at an obvious question, even though it is heretical in kind: Could our drug-based paradigm of care, in some unforeseen way, be fueling this modern-day plague?
Moreover, Whitaker contends, the natural history of mental illness has changed. Whereas conditions such as schizophrenia and depression were once mainly self-limited or episodic, with each episode usually lasting no more than six months and interspersed with long periods of normalcy, the conditions are now chronic and lifelong. Whitaker believes that this might be because drugs, even those that relieve symptoms in the short term, cause long-term mental harms that continue after the underlying illness would have naturally resolved.
The evidence he marshals for this theory varies in quality. He doesn’t sufficiently acknowledge the difficulty of studying the natural history of any illness over a fifty-some-year time span during which many circumstances have changed, in addition to drug use. It is even more difficult to compare long-term outcomes in treated versus untreated patients, since treatment may be more likely in those with more severe disease at the outset. Nevertheless, Whitaker’s evidence is suggestive, if not conclusive.
If psychoactive drugs do cause harm, as Whitaker contends, what is the mechanism? The answer, he believes, lies in their effects on neurotransmitters. It is well understood that psychoactive drugs disturb neurotransmitter function, even if that was not the cause of the illness in the first place. Whitaker describes a chain of effects. When, for example, an SSRI antidepressant like Celexa increases serotonin levels in synapses, it stimulates compensatory changes through a process called negative feedback. In response to the high levels of serotonin, the neurons that secrete it (presynaptic neurons) release less of it, and the postsynaptic neurons become desensitized to it. In effect, the brain is trying to nullify the drug’s effects. The same is true for drugs that block neurotransmitters, except in reverse. For example, most antipsychotic drugs block dopamine, but the presynaptic neurons compensate by releasing more of it, and the postsynaptic neurons take it up more avidly. (This explanation is necessarily oversimplified, since many psychoactive drugs affect more than one of the many neurotransmitters.)
With long-term use of psychoactive drugs, the result is, in the words of Steve Hyman, a former director of the NIMH and until recently provost of Harvard University, “substantial and long-lasting alterations in neural function.” As quoted by Whitaker, the brain, Hyman wrote, begins to function in a manner “qualitatively as well as quantitatively different from the normal state.” After several weeks on psychoactive drugs, the brain’s compensatory efforts begin to fail, and side effects emerge that reflect the mechanism of action of the drugs. For example, the SSRIs may cause episodes of mania, because of the excess of serotonin. Antipsychotics cause side effects that resemble Parkinson’s disease, because of the depletion of dopamine (which is also depleted in Parkinson’s disease). As side effects emerge, they are often treated by other drugs, and many patients end up on a cocktail of psychoactive drugs prescribed for a cocktail of diagnoses. The episodes of mania caused by antidepressants may lead to a new diagnosis of “bipolar disorder” and treatment with a “mood stabilizer,” such as Depokote (an anticonvulsant) plus one of the newer antipsychotic drugs. And so on.
Some patients take as many as six psychoactive drugs daily. One well- respected researcher, Nancy Andreasen, and her colleagues published evidence that the use of antipsychotic drugs is associated with shrinkage of the brain, and that the effect is directly related to the dose and duration of treatment. As Andreasen explained to The New York Times, “The prefrontal cortex doesn’t get the input it needs and is being shut down by drugs. That reduces the psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy.”*
Getting off the drugs is exceedingly difficult, according to Whitaker, because when they are withdrawn the compensatory mechanisms are left unopposed. When Celexa is withdrawn, serotonin levels fall precipitously because the presynaptic neurons are not releasing normal amounts and the postsynaptic neurons no longer have enough receptors for it. Similarly, when an antipsychotic is withdrawn, dopamine levels may skyrocket. The symptoms produced by withdrawing psychoactive drugs are often confused with relapses of the original disorder, which can lead psychiatrists to resume drug treatment, perhaps at higher doses.
Unlike the cool Kirsch, Whitaker is outraged by what he sees as an iatrogenic (i.e., inadvertent and medically introduced) epidemic of brain dysfunction, particularly that caused by the widespread use of the newer (“atypical”) antipsychotics, such as Zyprexa, which cause serious side effects. Here is what he calls his “quick thought experiment”:
Imagine that a virus suddenly appears in our society that makes people sleep twelve, fourteen hours a day. Those infected with it move about somewhat slowly and seem emotionally disengaged. Many gain huge amounts of weight—twenty, forty, sixty, and even one hundred pounds. Often their blood sugar levels soar, and so do their cholesterol levels. A number of those struck by the mysterious illness—including young children and teenagers—become diabetic in fairly short order…. The federal government gives hundreds of millions of dollars to scientists at the best universities to decipher the inner workings of this virus, and they report that the reason it causes such global dysfunction is that it blocks a multitude of neurotransmitter receptors in the brain—dopaminergic, serotonergic, muscarinic, adrenergic, and histaminergic. All of those neuronal pathways in the brain are compromised. Meanwhile, MRI studies find that over a period of several years, the virus shrinks the cerebral cortex, and this shrinkage is tied to cognitive decline. A terrified public clamors for a cure.
* See Claudia Dreifus, "Using Imaging to Look at Changes in the Brain," The New York Times, September 15, 2008. ↩
See Claudia Dreifus, "Using Imaging to Look at Changes in the Brain," The New York Times, September 15, 2008. ↩