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It’s More Complicated Than That: Probing the complexities of the antidepressants debate

By John Preston

Q: Recently there’s been a spate of studies and negative media stories raising questions about the effectiveness of antidepressants. As a practicing therapist, I’m not sure what clinical conclusions to draw from all this confusing information. Can you help?

A: In February 2010, the cover of Newsweek magazine declared: “Antidepressants Don’t Work.” Earlier that year, “Antidepressant Drug Effects and Depression Severity,” published by Jay Fournier and his colleagues in the Journal of the American Medical Association (JAMA), arrived at a similar conclusion: antidepressants’ effects are minimal to nonexistent in treating mild to moderate depression when compared to placebos. They corroborated the findings of Irving Kirsch and his colleagues published in “The Emperor’s New Drugs”—-the first metanalysis of data from pharmaceutical companies’ registration trials.

Registration trials are the studies pharmaceutical companies conduct to demonstrate the effectiveness of their drugs to garner FDA approval. In all cases, they must be double-blind, placebo controlled, randomized trials, with adequate sample sizes. For FDA approval, the medication must be shown to be superior to placebos to an extent that’s statistically significant.

The Kirsch metanalysis included outcomes from 38 studies, and all of the antidepressants surveyed had been approved by the FDA between 1987 and 1999. However, the conclusion from this metanalysis was that the registration studies universally showed the treatment outcomes from antidepressants to be only slightly better than those from placebos. In fact, comparing the outcomes, the active medications, on average, showed only a two-point superiority compared with placebos, as measured by standard depression rating scales. A two-point advantage, Kirsch and his colleagues argue, suggests that antidepressants aren’t effective in treating major depression. Jay Fournier and his colleagues’ conclusions were essentially the same, except that their article found that with severely depressed patients, outcomes from prescription antidepressants were significantly more effective than placebos.

Such conclusions are certainly noteworthy and a reason for concern. But before clinicians completely reject the use of antidepressants, it’s important to look more carefully at the medical treatment of depression and consider a number of issues not addressed by the Kirsch article. The first, and possibly most important, issue is that all the studies reviewed in the metanalysis involved the use of only one antidepressant compared to a placebo. In addition, all FDA antidepressant registration trials recruit subjects with a diagnosis of major unipolar depression, but they exclude subjects who have comorbidities, such as substance abuse or Axis II disorders, making the study samples unrepresentative of the types of clients most therapists see.

The largest study to date evaluating the medical treatment of depression in the kind of patients most often seen in clinical practices was the National Institute of Mental Health STAR-D study (Sequential Treatment Alternatives to Relieve Depression) in 2006. In this project, researchers recruited 2,876 patients, all of whom suffered from major, unipolar depression. Among the subjects, 80 percent suffered from chronic or recurrent major depression, 25 percent had been depressed continuously for two or more years, and 65 percent of subjects had complex psychiatric and/or medical comorbidities.

The STAR-D study began by treating all subjects with the antidepressant citalopram (Celexa). Aggressive dosing was used if necessary to bring subjects to full recovery. By seven weeks, 30 percent of those treated had reached full recovery. All subjects that hadn’t reached complete remission then moved into phase two.

This phase consisted of two treatment options: combining Celexa with another medication (Wellbutrin or BuSpar) or switching from Celexa to a different antidepressant (Effexor, Wellbutrin, or Zoloft). By the end of phase two, a total of 55 percent of the subjects had recovered.

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  • Comment Link Tuesday, 17 January 2012 11:02 posted by Lorraine Baum

    For those interested in reading in more detail the findings of the STAR*D trial I recommend Understanding Depression issue of the Special Health Report series published by Harvard Medical School. The contact for ordering this and others in the series is 877-649-9457 or online at