Two studies published last year (Turner et al., 2008; Kirsch et al., 2008) began to shake the foundation of the research that has established the efficacy and usefulness of modern antidepressant medications — those psychiatric drugs most commonly prescribed to people to treat depression. A recent commentary published in The American Journal of Psychiatry by two researchers with drug industry funding suggests these studies need to be examined within a broader context (Mathew & Charney, 2009).
The commentary authors argue that for meta-analyses to be valid, researchers must have access not only to the published research, but also the unpublished research of nonsignificant data. After agreeing that such meta-analyses such as Kirsch et al.’s are needed and valuable, they then suggest the study’s conclusions were too broad (that antidepressants are largely ineffective and no better than placebo response).
They suggest that such studies, while valuable for describing group-level differences, are useless for helping determine individual outcomes (which is a criticism of virtually any meta-analysis). Mathew and Charney also point out that another meta-analysis on antidepressants found a number needed to treat of 6.25 (“that is, approximately six patients would require treatment with an antidepressant medication to produce one response that would not have occurred had the patient been given placebo”).
Other criticisms of the Kirsch study include that the optimal clinical management of patients with major depressive disorder is simply not addressed in FDA registration trials. They also suggest there is not a lot of evidence that supports the use of psychotherapy as the preferred method of treatment for major depression over antidepressant medications. Indeed, most research shows that a combined approach of medications + psychotherapy seems to be the most effective for most patients with depression.
The commentary authors then offer three recommendations they suggest will enhance transparency and foster greater communication in the drug trial process:
“1. Industry-sponsored clinical trial protocols submitted for FDA review should include a section detailing publication strategy.” Such a strategy would be meant to address publication bias, encouraging even negative results to eventually be published. Of course the problem with this is that nobody can guarantee eventual publication in a journal, yet only such publishing would give other researchers the complete picture of the efficacy of a particular drug. Perhaps one step further would be the NIH to fund online-only, open-access journals in each major specialty area that only publishes negative and null results. This would then guarantee that every drug study is indeed published.
“2. The FDA should scrutinize the total number of trials conducted for an investigational new drug in making an initial determination of approval for new drug applications. Package inserts for new antidepressants could be required to disclose the number of placebo-controlled trials conducted for an adequate trial duration at the FDA-approved dose range, along with a summary of trial results (positive, negative, or failed). Clinicians (and patients) have a right to know, for example, that the manufacturer of a new FDA-approved antidepressant performed a total of nine placebo-controlled trials for major depressive disorder, of which only two studies beat placebo.
“3. Ultimately we need improved approaches to study depression to discover better antidepressants. This will require enhanced understanding of pathophysiological mechanisms associated with short-term therapeutic effects and mechanisms associated with long-term maintenance of benefit. Animal models for the latter are particularly needed. Personalized approaches to antidepressant trials that use biomarkers, including neurophysiological, neuroimaging, genetic, and neuropsychological techniques, are required to guide treatment. “
We think the overall efficacy of antidepressants will remain open to debate by many within the field for some years to come. It is likely the efficacy of such drugs was overstated in the original FDA clinical trials, while other independently-funded research (such as the STAR*D trial) shows that taking antidepressants eventually results in a 67% remission rate (which required changing medications and sticking with the treatment over the long-term).
There is a definite need moving forward in drug research to be far more open and transparent in all drug trials. Clinicaltrials.gov is a good start, but our efforts shouldn’t stop with simple clinical trials registration. We need to ensure that all studies — even the negative ones — eventually find a way to be published.
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT. (2008). Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5:e45.
Mathew, S.J. & Charney, D.S. (2009). Publication Bias and the Efficacy of Antidepressants. Am J Psychiatry 166:140-145. DOI 10.1176/appi.ajp.2008.08071102.
Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med, 358, 252–260.