August 13, 2013. A new meta-analysis examining 40 years' worth of trials of antipsychotic drugs for schizophrenia points to several factors likely to increase placebo response in trial participants. In their study published online July 30 in the American Journal of Psychiatry, Ofer Agid of the Centre for Addiction and Mental Health in Toronto, Canada, and colleagues confirm several factors associated with greater placebo response in previous studies (e.g., shorter trials and smaller placebo groups) but also point to variables in trial design and makeup of study populations that were not found in previous work, including younger age of patients, shorter duration and greater severity of illness, and greater number of trial sites, particularly if those sites were non-academic or not affiliated with the Veterans Administration.
"We think these are all tractable design and patient population factors that can be addressed in future trials," Agid and co-author Cynthia Siu wrote in an e-mail to SRF.
The trials of drug development—increasing placebo response
Strong placebo responses in clinical trials are a considerable obstacle in drug development in many fields of medicine (see Enck et al., 2013, for a review). But placebo responses are particularly vexing in trials of pain medications and of psychiatric drugs, a fact that has been recognized for some time. For example, a 1994 review found that placebo responses had occurred in 21 percent to 70 percent of patients in controlled trials of psychiatric drugs (Laporte and Figueras, 1994). However, such placebo responses appear to be increasing over time for reasons that are not fully understood (see SRF related conference story). This diminishes the significance of any meaningful drug benefit seen in treatment groups and leads to failed trials of new compounds to treat psychiatric disorders (see SRF related news story).
The new study is based on a literature review conducted over the past several years by Agid and his international collaborators. The group identified thousands of randomized controlled trials of antipsychotics conducted between 1970 and 2010, and by applying various quality and design criteria to this initial pool of records they winnowed down the dataset to 50 trials deemed suitable for meta-analysis.
Focusing just on patients receiving placebo, the researchers used a measure called standardized mean change (SMC), derived from reported scores on the Positive and Negative Symptom Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS), to capture whether symptoms improved or worsened over the course of the trials under study, with a negative SMC indicating better outcomes. Meta-regression analyses were then performed with a number of patient and study characteristics.
A shrinking difference
The researchers found considerable heterogeneity in the SMC of patients given placebo across studies ranging from -1.4 to 0.9, with a mean of 0.33. But when the studies were taken as a whole, greater improvement in symptoms in the group treated with active drug was positively correlated with a greater response in those receiving placebo. For example, in trials in which drug response reached a mean SMC of 1.3, the mean placebo response was 0.75, but in trials in which active drug treatment resulted in a poorer SMC of 0.19, the placebo response was -0.75.
As these mean SMC values indicate, in addition to the general correlation between drug response and placebo response, the difference between the drug response and placebo response—a measure crucial to a given trial’s success—was smaller in studies with a greater placebo response: The respective difference between the mean SMCs for the trials just cited, for example, are 0.55 (higher placebo response) and 0.94 (lower placebo response).
Researchers have consistently found that the placebo response is increasing over time, and the current study is no exception, showing an SMC of -0.17 for studies conducted from 1970-1989; -0.28 from 1990-1999; and -0.39 from 2000-2010. The studies themselves were found to have improved in overall quality over the same time periods, but that improvement was reflected in more consistency in SMCs among studies rather than a lowering of mean SMCs.
The placebo is in the details
The critical question for future trials is determining what drives the placebo effect. In terms of individual patient factors, Agid and colleagues report that greater placebo response was seen in studies that enrolled younger patients and patients with a shorter duration of illness and/or more severe baseline symptoms. In the realm of study design, consistent with earlier analyses, the researchers found that the placebo response was higher in shorter studies and grew with the number of study sites. They also confirmed that this effect was more pronounced if trials included non-academic centers or research sites unaffiliated with the Veterans Administration. This is a significant corroboration of earlier work, say the authors, because the median number of sites involved in trials of antipsychotics has increased from two before 1990 to 38 in the period 2005-2010.
Based on these results, the authors recommend that investigators designing future trials attempt to minimize the placebo response by conducting studies no shorter than six weeks, exercising caution when expanding the number of study sites (especially if including non-academic sites), and modifying inclusion criteria to screen out younger patients, or patients with very short duration of illness or particularly severe symptoms.—Pete Farley.
Agid O, Siu CO, Potkin SG, Kapur S, Watsky E, Vanderburg D, Zipursky RB, Remington G. Meta-regression analysis of placebo response in antipsychotic trials, 1970-2010. Am J Psychiatry. 2013 Jul 30. Abstract