Placebo Response Rates Vary Across Psychiatric Disorders

TRANSLATING RESEARCH INTO PRACTICE

Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor

A monthly column dedicated to reviewing the literature and sharing clinical implications.

Placebo is the most studied therapeutic agent globally and is ethically accepted as a comparator to active medications for psychiatric research across nearly all indications. It is also the sole intervention that is studied for all psychiatric disorders, and placebo groups often show improvements when compared with active agents in some studies. Available evidence indicates that placebo effects have increased over time in studies on major depressive disorder (MDD), schizophrenia, and schizoaffective disorder. A true placebo effect includes improvements from suggestion, hope, and conditioning. Other factors like episodic courses, attentive personnel, compassionate care, supportive conversations, psychoeducation, changing life circumstances, and regression to the mean also contribute to symptom improvement. All observable changes under placebo are termed placebo response, which varies across disorders. Understanding these differential outcomes can enhance knowledge of conditions, aid trial interpretation, inform treatment decisions, and guide future research. This systematic review and meta-analysis compared placebo responses across 9 common adult psychiatric disorders.

The Study

Bschor T, Nagel L, Unger J, et al. Differential outcomes of placebo treatment across 9 psychiatric disorders: a systematic review and meta-analysis. JAMA Psychiatry. 2024;81(8):757-768.

Study Funding

This study received no specific grant.

Study Objectives

To compare outcomes in placebo groups across a wide range of psychiatric disorders in adults using data from high-quality randomized clinical trials.

Methodology

This systematic review and meta-analysis quantified psychopathological symptom changes within placebo groups of high-quality randomized clinical trials (RCTs) across major psychiatric diagnoses. The study protocol was registered on Open-Science-Foundation (u469a) and followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Researchers selected 9 prevalent and clinically important psychiatric conditions: MDD, mania, schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), panic disorder, posttraumatic stress disorder (PTSD), and social phobia. The 10 most recent high-quality RCTs per diagnosis (totaling 90 RCTs from 86 publications) were then selected. Selection involved a 2-stage systematic approach: identifying recent high-quality systematic reviews for psychopharmacological acute therapy (MEDLINE, Cochrane Database) and then selecting the 10 highest-quality RCTs with placebo groups from each. All systematic reviews used the Cochrane Risk of Bias (ROB) tool. Two authors independently extracted data (quality, study details, intervention, diagnosis method, placebo likelihood; for placebo groups: participant numbers, age, gender, psychopathology ratings, dispersion measures), resolving discrepancies through discussion. Intention-to-treat protocols were prioritized. Statistical analysis used Cohen d for pre-post effect sizes (d_av). Pooled pre-post placebo effect sizes and 95% CIs were calculated by diagnosis using random effects meta-analyses, with a Q test for significance across diagnoses. Small study effects and heterogeneity were explored using funnel plots, Egger test, Q statistics, and I² values. Secondary outcomes included clinical global impression scale assessment. Regression analyses investigated confounders like age, gender, study duration/size, placebo randomization probability, ROB, and publication year.

Study Results

The systematic review and meta-analysis included a total of 9985 adult participants from 90 randomized clinical trials that included 9 psychiatric diagnoses. The investigators focused on placebo group outcomes, and there were no active treatment comparisons. Across the psychiatric diagnoses examined, there was a statistically significant difference between the pooled pre-post placebo effect sizes indicated by the Q test (Q = 88.5; d_f = 8; P ≤ .001). Cohen dav was used as a measurement for standardized pre-post effect sizes. The largest Cohen d_av effect sizes were seen in MDD (d_av = 1.40; 95% CI, 1.24-1.56) and GAD (d_av = 1.23; 95% CI, 1.06-1.41). Intermediate effect sizes were seen in panic disorder, ADHD, PTSD, social phobia, and mania, with Cohen dav ranging from 0.68 to 0.92. The smallest effect size was seen in schizophrenia (d_av = 0.59; 95% CI, 0.41-0.76) followed by OCD (d_av = 0.65; 95% CI, 0.51-0.78).

The investigators acknowledged that the placebo response varied depending on the study, with heterogeneity values of I² > 75% for GAD, mania, MDD, PTSD, and schizophrenia. Clinical global impression scores were also calculated, showing pronounced placebo response in GAD (d_av = 1.63; 95% CI, 1.01-2.24), panic disorder (d_av = 1.09; 95% CI, 0.89-1.29), and MDD (d_av = 1.08; 95% CI, 1.01-1.16). Multivariable analysis demonstrated a statistically significant association between gender and placebo effect size (slope point estimate, 0.0076; 95% CI, 0.0026-0.0126; P = .003).

Conclusions

This systematic review and meta-analysis demonstrated that placebo responses in randomized control trials among individuals with psychiatric disorders showed significant symptom improvement in all 9 psychiatric disorders studied. However, the magnitude of the effect sizes varied between disorders, with the largest effects observed in MDD and GAD. More modest improvements were seen in studies of schizophrenia and OCD. These results suggest that while factors that contribute to the placebo effect can play a role in symptom improvement, their impact is limited by the underlying pathology of an illness.

Practical Applications

This paper highlights the importance of contextual and nonspecific treatment factors, such as therapeutic environment and patient expectations, that contribute to the placebo effect. These treatment factors may be especially prominent in MDD and GAD. Understanding of the placebo effects can enhance treatment planning as well as interpretation of clinical trials. There is potential to replicate placebo-like treatment through interventions such as psychoeducation, interpersonal support, and instilling hope.

Bottom Line

The authors of the paper found placebo treatments can yield clinically meaningful improvements across psychiatric disorders, with the strongest effects seen in MDD and GAD and the weakest effects seen in schizophrenia and OCD. These findings illustrate the importance of considering the full spectrum of treatment options in psychiatry.

Dr Impallaria is a second-year psychiatry resident at Creighton University in Omaha, Nebraska. Dr Sakr is a first-year psychiatry resident at Creighton University. Dr Schuster is a fourth-year psychiatry resident at Creighton University. Dr Mullen is an assistant professor of psychiatry at St Louis University School of Medicine in St Louis, Missouri. Dr Tampi is professor and chair of the Department of Psychiatry at Creighton University School of Medicine and Catholic Health Initiatives Health Behavioral Health Services. He is also an adjunct professor of psychiatry at Yale School of Medicine in New Haven, Connecticut, and a member of the Psychiatric Times editorial board.

Reference

Bschor T, Nagel L, Unger J, et al. Differential outcomes of placebo treatment across 9 psychiatric disorders: a systematic review and meta-analysis. JAMA Psychiatry. 2024;81(8):757-768.