NPC Archive Item: Publication bias in studies of antidepressants?

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Turner EH, et al, Selective publication of antidepressant trials and its influence on apparent efficacy. New Engl J Med 2008;358:252-260

What is the background to this?
It is important that we are provided with a balanced and complete view of the evidence for the efficacy and harms of medicines on which to base our prescribing decisions. In the case of treatment for depression, making a rational choice of antidepressants relative to other interventions is difficult, due to many limitations in the published evidence: see Moncrieff and Kirsch (2005), which considers many of these limitations. Included among the limitations are the failure to demonstrate a clinically meaningful effect over placebo, and inappropriate categorisation of patients into responders or those in remission. Additionally, few studies demonstrate differences between individual antidepressants or consider whether or not they offer any advantages over non-drug interventions, such as psychological therapy. Things become even more uncertain when you consider the article by Turner et al (2008) in a recent issue of the New England Journal of Medicine, which infers that there is selective publication of positive studies for antidepressants by the pharmaceutical industry, while negative studies or studies that question their benefit are not published.

What does this study claim?
Turner et al (2008) identify selective reporting of publications which appear to exaggerate the benefits of antidepressant drugs. Nearly every study submitted to the Food and Drug Administration (FDA) and deemed positive by them was published in the medical literature in a way that agreed with the FDA’s judgement. By contrast, most studies deemed negative or questionable by the FDA were published in a way that conflicted with the FDA’s judgement or were not published. The authors found that, not only were positive results more likely to be published, but studies that were not positive, in their opinion, were often published in a way that conveyed a positive outcome.

The authors consider that by altering the apparent risk-benefit ratio of drugs, selective publication can lead doctors to make inappropriate prescribing decisions that may not be in the best interest of their patients and, thus, the public health.

How does this relate to other studies?
This is not the first article that demonstrates publication bias in studies of antidepressants by the pharmaceutical industry. In a review of 42 studies of selective serotonin reuptake inhibitors (SSRIs), provided to the Swedish drug regulatory authority between 1983 and 1999, Melander et al (2003) concluded that, “any attempt to recommend a specific SSRI from the publicly available data only is likely to be based on biased evidence”. Whereas 19 of the 21 studies showing significant advantages over placebo were published as stand alone publications, only six of the 21 studies not showing significant results were published as stand alone publications. Of the four studies that never reached the public domain, all showed non-significant results with respect to the primary variable.

So what?
Selective reporting biases the evidence base in favour of antidepressant drugs. As a result of the perceived inflated benefits, inappropriate prescribing decisions may be made. Selective reporting is unfair to researchers who rely on published information, and to participants of trials who put themselves forward to study these drugs.

Prescribers are reminded of NICE guidance for the management of depression (see MeReC Briefing, 2005). For mild depression, watchful-waiting and non-drug interventions, such as brief psychological therapy, may be all that is needed, and drug treatment is not recommended initially. Antidepressants are appropriate for patients with moderate to severe depression; however, they may not be suitable or preferred by all patients. Prescribers need to be aware of the limitations in the evidence for the effectiveness of antidepressants, and be mindful that published evidence may be biased in favour of their effectiveness. Rather than relying on results of evidence from individual articles, clinicians would be well advised to base their prescribing decisions on evidence-based advice from independent trusted summarised sources such as NICE, CKS, Clinical Evidence, and the National Prescribing Centre. However, as these sources largely rely on published evidence, unless public access to all clinical trials is made mandatory, even these trusted sources may not be able to give guidance based on the whole evidence-base.

Study details
Reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients were examined, and a systematic literature search carried out to identify matching publications. For trials that were reported in the literature, published outcomes were compared with the FDA outcomes. Among 74 FDA-registered studies, 31% (accounting for 3,449 study participants) were not published. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in the authors opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. From a meta-analysis, all 12 drugs included in the study looked more effective in published trials than in trials registered with the FDA. The increase in effect size varied from 11% to 69%, with a median of 32%. The authors could not determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both.

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