Antidepressants: Are They Effective or Just a Placebo?
By Maia Szalavitz, courtesy of TIME
In the early 1990s, everyone was listening to Prozac — right up until they weren’t anymore. By the middle of that decade, the media had begun spotlighting disasters involving the life-changing wonder drug — cases of suicide, even mass murder, apparently spurred by Prozac and similar medications. And by 2005, the Food and Drug Administration had mandated a black-box warning on all antidepressants, cautioning against an increase in suicide risk in certain patients.
Since then, a small but vocal minority of researchers have also questioned whether the mood-enhancing benefit of antidepressants amounts to anything more than a psychological artifact. They point to studies that suggest the drugs’ seemingly powerful effects are the same as those of a sugar pill. Most recently, a headline-grabbing Journal of the American Medical Association (JAMA) paper published in January found that antidepressants worked no better than a placebo in patients with mild or moderate depression (but the study did conclude that medication helped the most persistent and severe cases). For some observers, however, the judgment was sealed. That month, Newsweek ran a cover story bemoaning "The Depressing News About Antidepressants."
But how can the same drug be at once poison, panacea and placebo? With about 7% of the American population estimated to suffer from depression at any given time, and some 67 million prescriptions written for the top three antidepressants alone in 2009, the answer is of wide public-health and economic interest.
The Placebo Studies
Less emphasized than the study’s findings was that fact that the January paper in JAMA was a meta-analysis — not an original clinical trial, but a review of the combined results of multiple previous studies. Although meta-analyses can be useful for summarizing large amounts of data, they can sometimes be misleading. For one thing, such papers are only as good as the studies on which they rely, and in cases like this, in which individual responses to a class of medication vary widely — some people improve dramatically, while others get much worse — the particular studies the authors decide to include can sway the results.
The JAMA meta-analysis wound up including just six studies — out of the more than 2,000 the authors considered — on only two drugs, the selective serotonin uptake inhibitor (SSRI) Paxil and an older tricyclic drug called imipramine, though there are dozens of antidepressants on the market. (Paxil happens to be the most controversial of all SSRIs; it is most strongly associated with negative side effects that many similar medications do not have, such as weight gain, withdrawal symptoms and possibly even birth defects.) The meta-analysis also did not include studies that had a "placebo washout period" — those that start all patients on placebo before introducing the antidepressant, in order to identify and eliminate people who get better on their own. While drug companies argue that these studies help them gauge the real effects of the drug, critics say they give antidepressants an advantage that doesn’t reflect clinical practice — either way, eliminating these studies strengthens the placebo effect in a meta-analysis.
Further, when data are aggregated, patients’ opposing responses to antidepressants can cancel each other out. If one patient’s depression score drops 20 points while taking medication, and another’s increases by the same amount, in aggregate there has been no effect. "You can have an overall slightly significant change in active treatment vs. placebo, but what you may see when you look at the figures on a patient-by-patient level is that there are dramatic differences," says Richard Tranter, a psychiatrist and consultant with the North West Wales NHS Trust in the U.K., who was not involved in the JAMA study.
Overall, the scientific evidence confirms that not all patients respond the same way to antidepressants, and not all antidepressants — even those in the same class — work the same way in any given individual. One drug can, in fact, have profoundly different effects in the same patient at different times in his or her life.
Yet even with its narrow selection of studies, the JAMA review still showed improvement in people with severe depression and those whose illness was mild but chronic. And the troublesome data from placebo-controlled antidepressant trials is not unique to this type of drug. Notably, about half of all clinical trials of opioid painkillers like OxyContin, which are powerful and known to work, show the drug to be no more effective than placebo, according to Dr. Gavril Pasternak, an opioid expert at Memorial Sloan-Kettering Cancer Center. Again, it’s not because the medication is ineffective, but because of the huge variance in individual response and metabolism of the drug.
In practice, only about one-third of patients with depression will be helped by the first drug they try. Many people improve on their own or with talk therapy. About 8% to 14% patients will respond badly to medication, experiencing increased thoughts of suicide after taking it, a response that appears with equal frequency in placebo takers. So the question becomes not whether antidepressants work better than placebo, but how they will work, in whom and under what conditions.
This Is Your Brain on Drugs
Aimee Hunter, a research psychologist at the University of California, Los Angeles, has long studied individual responses to antidepressants. Being skeptical of the true effectiveness of the drugs, she says she was originally interested in researching the impact of placebos. But over the years, her own data began convincing her otherwise. "I’ve come to see now, by doing the research myself and spending hours looking at numbers, that the medication is absolutely doing something," Hunter says.
In their most recent paper, Hunter and her colleagues looked at the relatively rare but serious side effect of suicidal ideation during depression treatment. The goal of their study, published in April in the journal Acta Psychiatrica Scandinavica, was to use patterns of brain activity to identify the subgroup of patients who might be at risk — a finding that could help doctors steer patients toward the most beneficial medication early in treatment.
Using a technique called quantitative electroencephalography (QEEG), in which patients’ brain activity is recorded through a cap of electrodes placed on the scalp (the data is then amassed and organized into a map of brain activity), Hunter studied 72 depressed patients. They were given one of two widely prescribed SSRIs — fluoxetine (Prozac) or venlafaxine (Effexor) — or placebo for eight weeks.
Each patient was brought in five times over the course of the study for QEEG measurements and mood questionnaires, starting 48 hours after taking the first pill. Previous work by Hunter had already pinpointed a specific region of the brain, the midline/right frontal (MRF) area, where activity diverged between patients taking antidepressants and those taking placebos. In the antidepressant group, MRF activity was found to drop, while increasing slightly in placebo takers.
In the new study, Hunter found a similar yet surprising effect: depressed patients who developed suicidal thoughts while taking an antidepressant had a decrease in MRF activity six times larger than that seen in the placebo group, just 48 hours after starting the drug. This pattern was not seen even in placebo-taking patients who had begun having suicidal thoughts. "It was really dramatic, and the magnitude of the change was really impressive," says Hunter.
The fact that the changes occurred after just two days makes the result potentially useful in clinical practice as well. If Hunter’s finding holds up, it could mean that a noninvasive, relatively cheap test — QEEG machines are not prohibitively expensive as far as medical equipment goes — could be used to determine whether a patient is at risk for a potentially deadly side effect of treatment. And because such side effects typically appear long before the benefits kick in, this would give physicians an advantage in helping patients find the most effective medication as quickly as possible.
"It’s an awfully interesting [study]," says David Healy, a psychiatrist and author of Let Them Eat Prozac, a critique of the $9.9 billion antidepressant industry. "It will be interesting to see how things pan out when more people try to replicate it."
Predicting a Prozac Effect
In an earlier study that Hunter published in 2009, she and her team used the same QEEG technique on 58 patients, who were given a placebo daily for one week before being randomized to take either placebo or an active drug. Researchers found distinct patterns of brain activity in the patients; not everyone responded to the placebo the same way. "We found that changes in brain function occurring during the first week of placebo predicted who will do well on medication," she says.
The region where changes were recorded — in the prefrontal lobe — is thought to be involved in generating expectations. A common explanation for the placebo effect is that the mere anticipation of improvement begets real benefit. But in the case of Hunter’s patients, the changes in brain activity predicted actual response to the antidepressant, not to placebo.
Intriguingly, in patients who showed the specific brain response associated with antidepressant-related recovery, the most significant improvement was seen in what psychologists call interpersonal sensitivity — how people respond to either positive or negative social events. When suffering from depression, patients tend to become inured to positive social cues and oversensitized to negative ones. They may interpret a passerby’s frown as being directed at them, for instance, and some research has found that depressed people are more likely to misidentify smiling faces as conveying neutral or negative emotions. The patients who improved with medication in Hunter’s study "were less sensitive to rejection and more comfortable with others," she says.
Reducing emotional sensitivity — not treating depression per se — is what medications like Prozac, which affect the levels of serotonin in the brain, do best, according to Healy. If that entire class of drugs had been studied and marketed as pills to reduce emotional reactivity rather than depression, he says, "the placebo response would be very small compared to the drug."
Still, treating a patient’s oversensitivity does not necessarily help depression. For some people whose illness is marked by social dread and misperceived rejections, reducing that anxiety could be critical. But for someone whose depression is primarily experienced as deep sadness and inability to feel pleasure, blunting emotional sensitivity may do little good. These differences further explain why the drugs may produce such varied individual responses.
The Myth of Overmedication
As many as 50% of cases of depression will lift over time with no treatment, according to some studies — a fact that contributes to the persistent perception that antidepressants are overprescribed. Such data suggests that it makes sense to start with non-drug therapies like exercise and psychotherapy, at least to treat people with first-time mild or moderate depression and especially those whose sadness is directly caused by a recent setback or personal loss.
Indeed, a larger, less publicized study, which appeared in the Archives of General Psychiatry in the same month as the JAMA meta-analysis, suggests that the fear of overmedication may be more media obsession than reality. The research, which involved a survey of nearly 16,000 Americans in their homes, found that a bare majority of 51% whose symptoms qualified as major depression received any treatment at all. Among depressed patients, more received psychotherapy (44%) than medication (34%).
Troublingly, most people who sought help did not receive high-quality care. Among those surveyed, just 21% of those in psychotherapy received care consistent with medical guidelines for best practices; only 8% of those who took antidepressants received guideline-concordant care; and about one-third of patients who got combination therapy were given appropriate treatment. Poor treatment and no treatment were most common among Latinos and African Americans.
The real problem with mental health care in the U.S., then, is not that everyone is popping antidepressants, but that effective treatment is severely lacking for large swaths of the population. Certainly, some people have been prescribed medication unnecessarily, but the problem is dwarfed by that of patients who get no help at all. Evidence suggests that about 80% of people with depression can be helped by drugs, talk therapy or a combination of the two, so although it is critical to figure out which treatments work for which patients, the larger question remains: Why aren’t most patients getting good care, and why do we continue to insist that so many of those taking antidepressants don’t really need them?
