Recently, a number of articles have suggested that antidepressants are no more effective than placebos. Just last month, in an essay in The New York Review of Books, Marcia Angell-Relman, former interim editor in chief of The New England Journal of Medicine, favorably entertained the premise that “psychoactive drugs are useless.”
Earlier, a USA Today piece about a study done by the psychologist Robert DeRubeis had the headline, “Antidepressant lift may be all in your head,” and shortly after, a Newsweek cover piece discussed research by the psychologist Irving Kirsch arguing that the drugs were no more effective than a placebo.
To address the controversy surrounding the effectiveness of antidepressants used in Americans, Peter D. Kramer, a clinical professor of psychiatry at Brown University, wrote an article in the New York Times, “defending antidepressants.”
In Defense of Antidepressants
Kramer starts out by asserting that, “antidepressants work — ordinarily well, on a par with other medications doctors prescribe.” He noted that, “certain researchers who have questioned their efficacy in particular areas,” have done so “on the basis of shaky data.”
The problem with these researchers using shaky data is that the notion that antidepressants “aren’t effective in general is influencing treatment.”
Kramer first offers support that antidepressants work from a study in France of more than 100 people with a particular kind of stroke. Along with physiotherapy, half received Prozac, and half a placebo. Members of the Prozac group recovered more of their mobility. Antidepressants are good at treating post-stroke depression and good at preventing it. They also help protect memory. In stroke patients, antidepressants look like a tonic for brain health.
What was surprising to Kramer was that a friend of his, who suffered from a stroke, was not put on antidepressants until after Kramer himself emailed his friend’s doctor. And even then, he learned from his friend, Robert G. Robinson at the University of Iowa’s department of psychiatry, that neurologists say they “don’t use an antidepressant unless a patient is suffering very serious depression” because “they’re influenced by reports that say that’s all antidepressants are good for.”
Kramer asserts that, “the serious dispute about antidepressant efficacy has a limited focus. Do they work for the core symptoms (such as despair, low energy and feelings of worthlessness) of isolated episodes of mild or moderate depression? The claim that antidepressants do nothing for this common condition — that they are merely placebos with side effects — is based on studies that have probably received more ink than they deserve.”
Kramer points out that the most widely publicized debunking research — the basis for the Newsweek and New York Review pieces — is drawn from data submitted to the Food and Drug Administration (FDA) in the late 1980s and the 1990s by companies seeking approval for new drugs. This research led to its share of scandal when a study in The New England Journal of Medicine found that the trials had been published selectively. Papers showing that antidepressants work had found their way into print; unfavorable findings had not.
In his book “The Emperor’s New Drugs: Exploding the Antidepressant Myth,” Dr. Kirsch, a psychologist at the University of Hull in England, analyzed all the data. He found that while the drugs outperformed the placebos for mild and moderate depression, the benefits were small. The problem with the Kirsch analysis — and none of the major press reports considered this shortcoming — is that the FDA material is ill suited to answer questions about mild depression.
Kramer explained that as a condition for drug approval, the FDA requires drug companies to demonstrate a medicine’s efficacy in at least two trials. Trials in which neither the new drug nor an older, established drug is distinguishable from a placebo are deemed “failed” and are disregarded or weighed lightly in the evaluation. Consequently, companies rushing to get medications to market have had an incentive to run quick, sloppy trials.
Often subjects who don’t really have depression are included — and (no surprise) weeks down the road they are not depressed. People may exaggerate their symptoms to get free care or incentive payments offered in trials. Other, perfectly honest subjects participate when they are at their worst and then spontaneously return to their usual, lower, level of depression. Kramer explained that these problems are an “artifact of the recruitment process.” As a result, he noted that if many subjects labeled mildly depressed in the FDA data don’t have depression, this would explain why they might respond to placebos as readily as to antidepressants.
Kramer explained how there are two sorts of studies that are done on drugs: broad trials and narrow trials. Broad trials, like those done to evaluate new drugs, can be difficult these days, because many antidepressants are available as generics.
Narrow studies, done on those with specific disorders, tend to be more reliable. Recruitment of subjects is straightforward; no one’s walking off the street to enter a trial for stroke patients. Narrow studies have identified many specific indications for antidepressants, such as depression in neurological disorders, including multiple sclerosis and epilepsy; depression caused by interferon, a medication used to treat hepatitis and melanoma; and anxiety disorders in children.
New ones regularly emerge. The June issue of Surgery Today features a study in which elderly female cardiac patients who had had emergency operations and were given antidepressants experienced less depression, shorter hospital stays and fewer deaths in the hospital.
Broad studies tend to be most trustworthy when they look at patients with sustained illness. A reliable finding is that antidepressants work for chronic and recurrent mild depression, the condition called dysthymia. More than half of patients on medicine get better, compared to less than a third taking a placebo. (This level of efficacy — far from ideal — is typical across a range of conditions in which antidepressants outperform placebos.) Similarly, even the analyses that doubt the usefulness of antidepressants find that they help with severe depression.
In fact, antidepressants appear to have effects across the depressive spectrum. Scattered studies suggest that antidepressants bolster confidence or diminish emotional vulnerability — for people with depression but also for healthy people. In the depressed, the decrease in what is called neuroticism seems to protect against further episodes. Because neuroticism is not a core symptom of depression, most outcome trials don’t measure this change, but we can see why patients and doctors might consider it beneficial.
Similarly, in rodent and primate trials, antidepressants have broad effects on both healthy animals and animals with conditions that resemble mood disruptions in humans.
One reason the FDA manages to identify useful medicines is that it looks at a range of evidence. It encourages companies to submit “maintenance studies.” In these trials, researchers take patients who are doing well on medication and switch some to dummy pills. If the drugs are acting as placebos, switching should do nothing. In an analysis that looked at maintenance studies for 4,410 patients with a range of severity levels, antidepressants cut the odds of relapse by 70 percent. These results, rarely referenced in the antidepressant-as-placebo literature, hardly suggest that the usefulness of the drugs is all in patients’ heads.
The other round of media articles questioning antidepressants came in response to a seemingly minor study engineered to highlight placebo responses. One effort to mute the placebo effect in drug trials involves using a “washout period” during which all subjects get a dummy pill for up to two weeks. Those who report prompt relief are dropped; the study proceeds with those who remain symptomatic, with half getting the active medication. In light of subject recruitment problems, this approach has obvious appeal.
Consequently, Kramer explained how a study conducted by Dr. DeRubeis, an authority on cognitive behavioral psychotherapy, was problematic because it was built around his own research. Overall, the medications looked best for very severe depression and had only slight benefits for mild depression — but this study, looking at weak treatments and intentionally maximized placebo effects, could not quite meet the scientific standard for a firm conclusion. And yet, the publication of the no-washout paper produced a new round of news reports that antidepressants were placebos.
In the end, Kramer asserted that, “the much heralded overview analyses look to be editorials with numbers attached. The intent, presumably to right the balance between psychotherapy and medication in the treatment of mild depression, may be admirable, but the data bearing on the question is messy.”
As for the news media’s uncritical embrace of debunking studies, Kramer suggested that this trend is based on a number of forces, including, “misdeeds — from hiding study results to paying off doctors — that have made Big Pharma an inviting and, frankly, an appropriate target.
That said, the result that the debunking analyses propose remains implausible: antidepressants help in severe depression, depressive subtypes, chronic minor depression, social unease and a range of conditions modeled in mice and monkeys — but uniquely not in isolated episodes of mild depression in humans.
Accordingly, Kramer noted that better-designed research may tell us whether there is a point on the continuum of mood disorder where antidepressants cease to work. Nevertheless, he recognized that “it is dangerous for the press to hammer away at the theme that antidepressants are placebos” because they are not, and to give the impression that they are is to cause needless suffering.
As far as other products, the effort that goes into researching a prescription product or medical device is amazing. Perhaps some of that effort should be considered when judging products.