Antidepressants versus placebo in major depression: an overview

Abstract

Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non-profit agencies. This narrowing of the drug-placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM-III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant-placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive.

Keywords: Major depression; antidepressants; clinical trials; drug development regulators; expectation bias; placebo.

Figure 1

Mean percentage symptom reduction in unblinded and blinded treatment arms from published depression trials compared to data from pivotal registration depression trials as reported by the U.S. Food and Drug Administration (FDA) (adapted from 13). Striped bars represent unblinded trial arms; black bars represent blinded trial arms; the grey bar represents placebo control arms from published non-registration trials; checkered bars represent data from pivotal registration trials. The mean percentage symptom reduction was weighted by the number of assigned patients. Error bars represent 95% confidence intervals