The Problem of the Placebo Response in Clinical Trials for Psychiatric Disorders: Culprits, Possible Remedies, and a Novel Study Design Approach

Abstract

The placebo response is a major issue in clinical trials for psychiatric disorders. Possible contributing factors to this problem include diagnostic misclassification, issues concerning inclusion/exclusion criteria, outcome measures’ lack of sensitivity to change, measurement errors, poor quality of data entry and verification, waxing and waning of the natural course of illness, regression toward the mean phenomenon, patient and clinician expectations about the trial, study design issues, non-specific therapeutic effects, and high attrition. Over the past few decades, researchers have attempted to reduce the placebo effect in a variety of ways. Unfortunately, approaches with very little or no benefit have included restricting enrollment to selected populations, rater training, requirement of same rater, and placebo lead-in phases. Some benefits, although often marginal, have been derived from standardizing diagnostic procedures, managing clinicians’ overestimation of change, simplification of study visits and assessments, minimizing non-specific, therapeutic effects, extending trial duration, reducing number of sites, increasing the sensitivity of outcome measures, and reducing the number of treatment arms. Thus far, there has been no attempt to develop new study designs aimed at reducing the placebo effect. We are proposing a novel study design, called ‘Sequential Parallel Comparison Design’, suitable for double-blind, placebo-controlled trials in psychiatric disorders. This design is aimed at reducing both the overall placebo response rate and the sample size required for such trials. Its usefulness in clinical research needs to be tested empirically. If this study design were to be found to meet its stated goals, this could markedly facilitate the process of clinical development of new compounds for the treatment of psychiatric disorders.

Lessons learned from placebo groups in antidepressant trials

“…In order to understand the mechanisms of non-specific treatment effects, it is necessary to assess those effects with structured assessment methods. Since clinicians tend to overestimate changes in patients, clinician bias has to be managed through the addition of self-report measures, the administration of both clinician-and patient-rated measures, and systematic rater training [22].…”

A Novel Methodology to Estimate the Treatment Effect in Presence of Highly Variable Placebo Response

“…These strategies included study designs with increased sample size, increased symptom severity at baseline, innovative study designs, enhanced inter-rater reliability programs, surveillance of within-study data to identify measurement error, site-independent subject validation to minimize site-biases, and enhanced patient education to minimize expectancy effects (Fava et al, 2003;Kobak et al, 2007;Targum et al, 2008;Targum et al, 2012).…”

“…Among the different approaches for optimizing RCTs, the sequential parallel comparison design (SPCD) was proposed to reduce both placebo response and sample size (Fava et al, 2003;Papakostas et al, 2014). The SPCD involves two double-blind stages of treatment, with stage 2 commencing immediately at the conclusion of stage 1.…”

How can we make measures of psychotic depression symptoms more clinically useful?

“…Finally, one of the challenges that clinical researchers have faced over the past couple of decades is the progressive increase in placebo responses in clinical trials of psychiatric patients (12), which has led to the reduced ability to detect signals of effective therapeutic interventions. For example, half of the studies of approved pharmacological treatments for depression have failed to detect a significant effect over placebo, and the effect sizes have typically been quite modest on average (12).…”

“…For example, half of the studies of approved pharmacological treatments for depression have failed to detect a significant effect over placebo, and the effect sizes have typically been quite modest on average (12). There is good evidence that unidimensional scales such as the HAM-D6 lead to larger effect sizes in controlled studies than multidimensional scales such as the HAM-D-17 (7).…”