Final Word? Placebo Response in Depression Trials Not Rising

Megan Brooks

October 17, 2016

A new systematic review discounts the widely held belief that the placebo response rate in antidepressant treatment trials is rising.

Investigators found that average placebo response rates in antidepressant trials have held stable for more than 25 years, at about 35% to 40%.

"Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods," Andrea Cipriani, PhD, Department of Psychiatry, University of Oxford, Warneford Hospital, United Kingdom, and colleagues note.

The study was published online October 7 in Lancet Psychiatry.

Need for Nondrug Strategies

The systematic review included 252 randomized placebo-controlled trials of first- and second-generation antidepressants for the acute treatment of adults with major depression. The trials, which were conducted between 1978 and 2015, included more than 26,000 patients who received placebo.

The researchers noted a "structural break" in 1991, after which no further increase of the placebo response was seen. Since 1991, the average placebo response rate in antidepressant trials has remained constant, in the range of 35% to 40% (relative risk [RR], 1.00; 95% confidence interval [CI], 0.97 – 1.03; P = .99, for every 5-year increase), they report.

On the basis of this large dataset, "there is no doubt now that the average placebo-response rates have been staying constant since 1990s, as far as antidepressant trials in depression are concerned. These results are robust since they remained consistent in all the sensitivity analyses," the authors write.

The investigators were able to replicate the reported increase in placebo response rates before 2000, but this association was no longer significant after controlling for methodologic factors, such as shorter duration of trials and a preponderance of single-center studies, which once were common but have been used less since the 1990s.

"This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view," they write.

From a clinical perspective, an average placebo response rate of 35% to 40% remains a "high proportion of patients" and highlights the need for incorporating nondrug strategies to boost antidepressant response.

It has been shown that the expectation of improvement, classic conditioning, and the contact with a healthcare environment with supportive and therapeutic features contribute to the objective response observed in patients with major depression who are randomly assigned to receive placebo, the authors point out. Yet these nonpharmacologic aspects of care are typically not provided to the same extent in standard clinical practice.

"Clinicians should create a specific context and level of therapeutic contact, to enhance non-specific effects of treatment and gain greater treatment response," they advise.

"In terms of study design, some important factors should be reconsidered. Appropriately timed assessments and multicentre design are necessary for trials to provide results directly relevant and applicable to real-world clinical practice. Trialists need to use design characteristics to make their trials as clinically relevant as possible," the researchers write.

Final Word?

In an accompanying commentary, Paul Enck, MD, from University Hospital Tubingen in Germany, notes that the whole discussion regarding an increase in the placebo response "might come to an end with [this] very comprehensive and up-to-date systematic review.

"The remaining unanswered questions are: what caused the increase of the placebo response observed before 1991? What initiated the 'structural break' around the turn of the century? And why were these time trends and their change not observed in other medical subspecialties?"

The study had no commercial funding. Several authors have financial relationships with various pharmaceutical companies, a complete list of which is included in the original article. Dr Enck has disclosed no relevant financial relationships related to this work.

Lancet Psychiatry. Published online October 7, 2016. Abstract, Commentary

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