In a recent interview on 60 Minutes, Harvard psychologist Irving Kirsch, PhD, commented, “the difference between the effect of a placebo and the effect of an antidepressant is minimal for most people.” 1 However, a newly published “panoramic overview” of 127 meta-analyses challenges that asser-tion by demonstrating how psychiatric drugs, including antidepressants, are as efficacious as drugs used to treat general medical conditions.2
“Our study puts the effectiveness of psychiatric drugs and general medical drugs into perspective,” lead author Stefan Leucht, MD, Assistant Professor in the Department of Psychiatry and Psychology at Munich Technical University in Germany, said in a press announcement. “There is a deep mistrust of psychiatry, fostered by reports suggesting that the efficacy of psychiatric drugs is very small. Psychiatrists, patients, carers, and the media are often unsettled by these findings, and some may think that psychiatric medication is not worth the bother.”
In CBS’s 60 Minutes segment, Kirsch, Associate Director of the Harvard-wide Program in Placebo Studies and the Therapeutic Encounter and Lecturer on Medicine at Beth Israel/Deaconess Medical Center, said his research, which analyzed both published and unpublished trials of antidepressants, challenges the effectiveness claims for antidepressants.
“If they [patients on antidepressants] were mildly or moderately depressed, you don’t see any real difference at all. The only place where you get a clinically meaningful difference is at these very extreme levels of depression,” Kirsch said.
He went on to explain that the reason most people who are taking antidepressants get better relates to the placebo effect and “not because of the chemicals in the drug.”
Later, in a 60 Minutes Overtime show, interviewer Lesley Stahl acknowledged that her husband has taken antidepressants for years, and she noted, “we know they work.” She found the placebo-effect discussion very “confusing” and worried about Americans discontinuing their antidepressants without consulting their physician.
John Davis, MD, a coauthor of the meta-analyses review and Research Professor in the Department of Psychiatry at the University of Illinois at Chicago, urged health care professionals, journalists, and others to “do their homework” before mak-ing pronouncements about placebo effects and efficacy of psychiatric drugs, because the consequences can be deadly.
“I personally know of patients who have quit taking their medications and ended up back in the hospital,” he said. “And I know of others who went off their meds, had a recurrence of depression and committed suicide.”
Davis likened the controversy over the efficacy of psychiatric medications to the widespread scare linking the vaccine for measles, mumps, and rubella to autism. There is, he said, a similar anatomy—lack of credible evidence tying the vaccine to autism; extreme opinions; sensationalism in the press; and health professionals and patients seeking fame by promoting the link as a cause clbre. All of this has led to children not being immunized, unnecessary mortality and morbidity, and possible loss of herd immunity in some countries.
The meta-analyses review, Davis said, is particularly important for primary care and other physicians who may “think that psychiatric drugs are not efficacious, may not prescribe them, and may discourage their patients from taking them. Such perceptions and actions,” he noted, “can cause great harm to patients.”
Davis added he has tried for years in his lectures to make psychiatrists aware that the effect sizes of the psychiatric drugs are in “the ballpark with most of the internal medicine drugs” and that “most medical drugs were not the breakthroughs they [psychiatrists] thought they were.”
“With this review,” he told Psychiatric Times, “we finally got it done.”
In a commentary published in BMC Medicine, Seemuller and colleagues3 from the Department of Psychiatry and Psychotherapy at the Ludwig-Maximilian University of Munich described the review as “a milestone in destigmatizing psychiatry and its pharmacological treatments.” They described Leucht as “an experienced member of the Cochrane collaboration” who is very familiar with the pitfalls of meta-analyses.
Similarly, Davis is highly experienced with meta-analyses. “I wrote the first ones in psychiatry in 1975 and 1976, even before they were called meta-analyses,” he said.4,5
For their article, Leucht and colleagues searched Medline and the Cochrane Library for systematic reviews on the efficacy of drugs compared with placebo and then systematically presented the effect sizes for primary efficacy outcomes. They included 94 meta-analyses of 48 drugs in 20 medical diseases (eg, cardiovascular disease, hypertension, rheumatoid arthritis, chronic asthma, type 2 diabetes mellitus, and hepatitis C) and 33 meta-analyses of 16 drugs in 8 psychiatric disorders (eg, schizophrenia, bipolar disorder, MDD, obsessive-compulsive disorder, ADHD, and Alzheimer disease). They excluded meta-analyses of subgroup studies and, if available, chose reviews of classes of drugs rather than single drugs.
“To be up to date, we also chose more recent studies,” he said. “And when there were several meta-analyses on the same topic, we looked to see if they agreed or not; if they disagreed, we called the authors to find out why. So there is extensive information in the fine print.”
While the review paper “covers all our important findings,” Davis explained, the team made available some 55 pages of Tables and Figures online at bjp.rcpsych.org “for individuals interested in all the data that lie behind the analysis.”
According to the research team, an effect size of 0.2 is considered significant but low, while an effect size of 0.8 or above is considered high. The median of all effect sizes was 0.40.
There was a lot of variability in effect size for medical conditions, Davis said. For example, there was a high effect size (1.39) for proton pump inhibitors to treat reflux esophagitis and a high effect size (2.27) for interferon to treat chronic hepatitis C. But many commonly used general medicine drugs, such as statins and aspirin in cardiovascular disease and stroke, had small effect sizes (0.12 for aspirin for secondary prevention of cardiovascular events and 0.15 for statins for cardiovascular events).
“As a generalization, the effect sizes of psychiatric drugs are right in the middle of most of the drugs used in internal medicine,” Davis said.
Antidepressants used as “maintenance treatment” to prevent a relapse of MDD had an effect size of 0.64; antipsychotics used to prevent relapse in schizophrenia had an effect size of 0.92. Less pronounced was the effect size of 0.26 for cholinesterase inhibitors for dementia. In between were atypical antipsychotics and haloperidol, with an effect size of 0.44 for acute mania in bipolar disorder.
In the discussion section of their review, Leucht and colleagues commented on several controversial issues, including outcomes measures, duration of studies in a meta-analysis, and decrease of drug efficacy over the decades.
Psychiatry is often criticized, they wrote, for using “soft outcomes,” such as rating scales, whereas medicine uses “hard” outcomes, such as death or major events (eg, heart attack). Still, they wrote, there are examples in general medicine (eg, asthma, diabetes) for which intermediate outcomes may improve but mortal-ity increases, as well as other examples (esophagitis and migraine) for which the reductions of symptoms and suffering are regarded as primary outcomes.
“Therefore, reduction of disease severity (eg, degree of delusions and hallucinations in schizophrenia) and prevention of further episodes are primary outcomes, and it is not entirely appropriate to criticize psychiatry for using ‘soft’ outcomes. This said, there is considerable room for improvement in psychiatric outcome measures, and death or suicide should always be reported. The example of lithium shows that some psychiatric drugs may reduce suicide rates.”
Some of the most important outcomes take years to develop, and you can’t measure them with double-blind studies that are often only 6 to 8 weeks long, Davis added. “We have to look at other methodologies.”
Regarding the duration of studies, Leucht and associates noted that studies of many years’ duration would be necessary to obtain large differences in mortality, “but such studies are almost impossible to conduct for many reasons,” so shorter studies are performed, which show only small differences.
“In this context, many psychiatric drugs not only improve the acute episode but also prevent further episodes. Patients with severe, recurrent depression might have 20 episodes in their lifetime, which could be reduced by medication to 10,” they wrote.
The authors also acknowledged that earlier meta-analyses in psychiatry yielded higher effect sizes than recent meta-analyses. In a paper published last year, Davis and coworkers6 wrote that the antidepressant drug-placebo difference is larger in the more severely depressed subgroups and in older studies. They explained that in the early double-blind studies involving antidepressants, for example, there were severely ill and drug-naive patients referred to clinical trials by their physicians.
Davis said that many severely ill and suicidal patients are excluded from recent drug trials because of ethical concerns, that a lack of “fresh” (drug-naive) patients exists, and that there is an increase in advertisements offering free medications to clinical trial participants—all of which can influence the placebo response.
Also, pharmaceutical companies have, on occasion, suppressed data on negative trials, Davis said.
“The complaints against the drug companies hiding studies and heavily promoting drugs are often quite legitimate, but it doesn’t mean the drugs are worthless,” he said.
Results of all controlled studies—including failed studies—should be published, Davis believes. He points to some pharmaceutical companies that are sharing information on both published and unpublished studies. One example, he said, is a recent article of which he is a coauthor.7 The article is a reanalysis of the randomized placebo-controlled studies of fluoxetine and venlafaxine that used complete longitudinal person-level data from a large set of published and unpublished studies. The reanalysis found that the drugs decreased suicidal thoughts and behavior for adult and geriatric patients and that the “protective effect was mediated by decreases in depressive symptoms with treatment.”
Davis stressed the need for everyone—physicians and patients alike—to examine the data on psychiatric drugs and efficacy and to understand the problems.
“It’s much harder,” he said, “to think through the issues than to come to snap judgments.”
References1. Treating depression: is there a placebo effect? [transcript]. 60 Minutes. CBS television. February 19, 2012. http://www.cbsnews.com/8301-18560_162-57380893/treating-depression-is-there-a-placebo-effect/?tag=contentMain;cbsCarousel. Accessed February 29, 2012.