Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis

Question  Which psychiatric disorder exhibits the strongest improvement associated with placebo treatment in randomized clinical trials (RCTs)?

Findings  This systematic review and meta-analysis of 90 high-quality RCTs with 9985 participants found significant improvement under placebo treatment for all 9 disorders, but the degree of improvement varied significantly among diagnoses. Patients with major depressive disorder experienced the greatest improvement, followed by those with generalized anxiety disorder, panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, mania, and OCD, while patients with schizophrenia benefited the least.

Meaning  These findings may inform planning of RCTs, interpreting of uncontrolled studies, and advising patients for or against a specific treatment.

Importance  Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking.

Objective  To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients.

Data Sources  MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses.

Study Selection  Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria.

Data Extraction and Synthesis  Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.

Main Outcome and Measure  The primary outcome, pooled pre-post placebo effect sizes (d_av) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate.

Results  A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (d_av = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (d_av = 1.23; 95% CI, 1.06-1.41) exhibiting the largest d_av. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed d_av between 0.68 and 0.92, followed by OCD (d_av = 0.65; 95% CI, 0.51-0.78) and schizophrenia (d_av = 0.59; 95% CI, 0.41-0.76).

Conclusion and Relevance  This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.