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. 2024 May 29;81(8):757–768. doi: 10.1001/jamapsychiatry.2024.0994

Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders

A Systematic Review and Meta-Analysis

Tom Bschor 1,6,✉, Lea Nagel 1,2, Josephine Unger 3, Guido Schwarzer 4, Christopher Baethge 5
PMCID: PMC11137661  PMID: 38809560

Key Points

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.

This systematic review and meta-analysis compares outcomes in placebo groups in 90 randomized clinical trials across 9 psychiatric disorders.

Abstract

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 (dav) 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 (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 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.

Introduction

Placebo is arguably the most extensively investigated therapeutic agent worldwide. In psychiatry, a placebo is deemed ethically acceptable for research in nearly all indications, serving as the sole intervention that has been studied for all psychiatric disorders.

In studies of psychiatric conditions, even patients in placebo groups typically show improvement, making it sometimes challenging to discern a verum-placebo contrast.1,2,3 Also, placebo effects have increased over the years in studies on major depression4,5,6 and schizophrenia and schizoaffective disorder.7

A genuine placebo effect, by definition, encompasses improvements induced by suggestion, hope for effective treatment, and conditioning effects through the administration of medications. However, other factors might improve psychopathology: psychiatric disorders often have episodic courses. Contextual factors, such as attentive study personnel, compassionate care, supportive conversations, and psychoeducation, can influence outcomes positively.8 Life circumstances may change during a study, and regression to the mean is a statistical factor in symptom improvement.9 Consequently, all observable changes under a placebo medication are referred to as the placebo response.

Placebo response is not equally distributed across different disorders, with limited comprehensive comparisons in psychiatry. Khan and coauthors10 compared 6 disorders in a 2005 study, which is still the most comprehensive study to date, to our knowledge; however, significant conditions, like mania or social phobia, were not included. Other reviews have focused on depressive disorders1,3,6,10,11,12,13,14,15,16 or a few other diagnoses.7,17,18,19,20

Understanding differential outcomes observed in placebo groups may enrich our knowledge of these conditions, aid clinical trial interpretation, assist treatment decisions, and improve treatments. Therefore, in this systematic review and meta-analysis, we compared placebo responses among a wide spectrum of psychiatric disorders in adults.

Methods

This study aimed to quantify differences in the change of psychopathological symptoms within placebo groups of high-quality randomized clinical trials (RCTs) across major psychiatric diagnoses. We compared pooled pre-post effect sizes of placebo groups by diagnosis. The study protocol has been registered in advance on Open-Science-Foundation (identifier: u469a). This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline.

We selected 9 prevalent and clinically significant psychiatric conditions commonly subject to pharmacological treatment: major depressive disorder (MDD; unipolar recurrent or single episode), mania, schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), panic disorder, posttraumatic stress disorder (PTSD), and social phobia. We included the 10 most recent high-quality RCTs per diagnosis due to feasibility constraints, using a 2-stage systematic selection process.

Stage 1

In stage 1, we identified the most recent high-quality systematic review pertaining to psychopharmacological acute therapy for each of the diagnoses through systematic literature searches in MEDLINE via PubMed and in the Cochrane Database of Systematic Reviews (search history as well as quality, inclusion, and exclusion criteria are provided in eAppendix 1 in Supplement 1). In this initial step, we restricted the search to 2 databases, as we intended on finding a recent high-quality systematic review rather than all systematic reviews.

Screening for and selection of reviews was carried out in duplicate and independently by 2 of the authors (T.B., L.N., J.U., and C.B.) for each diagnosis. Any discrepancies were resolved by discussion among the entire group of authors. Originally, we aimed to include 10 diagnoses; however, we could not identify a systematic review adhering to stage 1 inclusion criteria for agoraphobia.

Stage 2

In stage 2, the 10 highest-quality RCTs (lowest risk of bias [ROB]) with placebo groups were selected from each of the 9 systematic reviews,21,22,23,24,25,26,27,28,29 totaling 90 RCTs reported in 86 publications.30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115 The selection was carried out independently by 2 authors (L.N. and J.U.).

All 9 systematic reviews used the Cochrane Risk of Bias tool (first or second version)116,117 for ROB analysis of each RCT. The tool categorizes various ROB domains (sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective reporting of outcomes, and other sources of bias, eg, enriched design). RCTs with the highest number of domains rated as low ROB were included, so that the 10 RCTs per diagnosis with the highest total score were included for analysis. If this process led to more than 10 RCTs we selected the most recent RCTs. Inclusion and exclusion criteria for RCTs are provided in eAppendix 2 in Supplement 1.

Data Collection

Two authors (L.N. and J.U.) independently extracted predefined core data from each study into a standardized spreadsheet (Excel version 1808; Microsoft). Discrepancies were resolved through group discussion. Extracted data included quality ratings, study details (location, duration), active study group intervention, diagnosis confirmation method, and likelihood of receiving placebo. For placebo groups, initial and final participant numbers, age, gender or sex distribution, and psychopathology ratings of changes in the selected outcome or of baseline and follow-up scores, each with corresponding measures of dispersion, were extracted. Where available, Clinical Global Impression (CGI) scores were also extracted. Intention-to-treat data were prioritized (80 studies30,31,32,33,34,35,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,60,61,62,63,64,65,67,68,69,70,71,72,73,74,76,77,78,80,81,83,84,85,86,87,88,89,90,91,92,93,94,95,96,98,99,101,102,104,105,106,107,108,109,110,111,112,114,115); if not available, data from observed patients were used.36,59,66,75,79,82,97,100,103,113 Dropout rates will be presented in a separate publication.

Outcomes Per RCT

Of 90 included RCTs,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115 only placebo groups were considered. Because RCTs for the different diagnoses used various established psychopathology rating scales, standardized pre-post effect sizes118 were used to compare outcomes across diagnoses. Formulae are provided in eAppendix 3 in Supplement 1. We opted against calculating response rates, as these are directly dependent on the response definition, which varied significantly among diagnoses.

In panic disorder, most RCTs used panic attacks per time period as the main outcome. Owing to the nonparametric distribution of rate data and consistent with earlier research,10,18,19 we resorted to including RCTs presenting an established outcome scale, such as the Hamilton Anxiety Rating Scale.

Statistical Analysis

Pre-Post Effect Sizes per Diagnosis

The main outcome was pooled pre-post placebo effect sizes per diagnosis (Cohen d for within-participant designs using mean SD, dav118,119). In random-effects meta-analyses (method-of-moments-estimator DerSimonian and Laird), pooled pre-post placebo effect sizes and 95% CIs were calculated by diagnosis. With intention-to-treat data, we followed the imputation methods chosen by trial authors (eg, last observation carried forward or mixed-effects model analysis). For calculations, we used the Magnitude of Effect Size calculator, version 2 (MOTE),120 as well as Comprehensive Meta-Analysis version 4 (Biostat). Statistical significance of the difference across pooled effects of all diagnoses was set at 2-sided α = .05 and calculated in a Q test.

Small Study Effects and Heterogeneity

To find evidence of small study effects or publication bias, we used funnel plots and calculated Egger test. Heterogeneity was explored using Q statistics and I2 values, showing variance in excess of random error. Following the Cochrane Handbook,121 I2 values between 50% and 90% were classified as substantial heterogeneity and values above 75%, considerable heterogeneity. We also calculated prediction intervals, indicating the possible spread of outcomes in studies similar to those included, whereas CIs provide an estimate of the precision of dav calculated.

Secondary Outcome

In most of the included RCTs, symptom severity was also assessed with the CGI scale. Since CGI is a validated and established transdiagnostic scale, we decided post hoc to repeat our main analysis with CGI severity scores as a validation of the primary outcome. Although a meta-analysis of CGI suggests itself for calculating a nonstandardized mean change, for ease of comparison with the main analysis, we present standardized values.

Regression Analyses

We investigated potential confounders, including age, gender or sex, study duration and size, placebo randomization probability, ROB, and year of publication, in bivariable meta-regressions (considering the weights of RCTs included), with diagnoses as second factor to account for clustering by diagnoses. In multivariable meta-regression (mixed-effects, method-of-moments estimator), we included all possible confounders with P < .10 in bivariable analysis and also, on theoretical grounds, diagnosis and study duration. Data were analyzed from October 10 to December 15, 2023.

Results

Stage 1

The literature search (stage 1) was conducted on March 19, 2022, and yielded the results shown in the eTable in Supplement 1. A total of 9 high-quality systematic reviews21,22,23,24,25,26,27,28,29 were selected (Table 1).

Table 1. Systematic Reviews Identified Through the Search Process.

Diagnosis Review
Major depression Cipriani et al, 201821
Mania Kishi et al, 202122
Schizophrenia Huhn et al, 201923
Obsessive-compulsive disorder Skapinakis et al, 201624
Attention-deficit/hyperactivity disorder Elliott et al, 202025
Generalized anxiety disorder Kong et al, 202026
Social phobia Williams et al, 202027
Agoraphobia None
Panic disorder Chawla et al, 202228
Posttraumatic stress disorder Williams et al, 202229
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Stage 2

An overview of the 90 RCTs30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115 included in the meta-analysis is provided in Table 2. A total of 9985 placebo-treated study participants were included, distributed across the 9 diagnoses as follows: 1598 participants with MDD,30,31,32,33,34,35,36,37,38,39 967 participants with mania,40,41,42,43,44,45,46 888 participants with schizophrenia,47,48,49,50,51,52,53,54,55,56 803 participants with OCD,57,58,59,60,61,62,63,64,65,66 1189 participants with ADHD,67,68,69,70,71,72,73,74,75,76 1457 participants with GAD,77,78,79,80,81,82,83,84,85 1180 participants with social phobia,86,87,88,89,90,91,92,93,94,95 1248 participants with panic disorder,96,97,98,99,100,101,102,103,104,105 and 655 participants with PTSD.106,107,108,109,110,111,112,113,114,115 There was no indication of small-study effects or publication bias based on findings from a funnel plot (eFigure in Supplement 1) or from Egger test (P = .95).

Table 2. Randomized Clinical Trials Included in Analyses.

Source Patients in placebo group, No. Age, mean (SD or range), y Women, % Probability of receiving placebo, % Active drugs Study duration, wk Selected outcome (psychopathology scale)
MDD
Alvarez et al,30 2012 105 42.0 (10.9) 65.7 25 Vortioxetine, venlafaxine 6 MADRS
Bakish et al,31 2014 185 42.3 (13.2) 62.4 33.3 Levomilnacipran 8 MADRS
Baldwin et al,32 2012 145 43.4 (12.5) 69.6 20 Vortioxetine, duloxetine 8 MADRS
Jain et al,33 2013 286 42.4 (12.7) 54.7 50 Vortioxetin 6 HAM-D-24
Kennedy et al,34 2006 105 42.2 (12.0) 55.2 50 Agomelatine 6 HAM-D-17
Liebowitz et al,35 2013 223 42 (13) 62 33.3 Desvenlafaxine 8 HAM-D-17
Mahableshwarkar et al,36 2015 126 46.2 (11.8) 67.5 33.3 Vortioxetine 8 MADRS
McIntyre et al,37 2014 194 45.6 (12.1) 65.8 33.3 Vortioxetine 8 MADRS
Oakes et al,38 2012 110 43.9 (11.9) 66.4 33.3 Duloxetine 8 HAM-D Maier subscale
Olie et al,39 2007 119 45.6 (11.2) 75 50 Agomelatine 6 HAM-D-17
Overall MDD, mean (SD) 159.8 (57.7) 43.6 (1.6) 64.4 (5.9) 36.2 (10.0) NA 7.2 (1.0) NA
Mania
Berwaerts et al,40 2012 115 41.0 (11.2) 45 25 Paliperidone 3 YMRS total score
Kushner et al,41 2006; cohort A 111 42 (13) 49 25 Topiramate, lithium 3 YMRS total score
Kushner et al,41 2006; cohort B 98 37 (10) 60 33.3 Topiramate 3 YMRS total score
Kushner et al,41 2006; cohort C 106 40 (11) 37 50 Topiramate 3 YMRS total score
Kushner et al,41 2006; cohort D 112 41 (12) 60 33.3 Topiramate, lithium 3 YMRS total score
Landbloom et al,42 2016 126 44.6 (11.5) 57.1 33.3 Asenapine 3 YMRS total score
Potkin et al,43 2005 65 39 (11.5) 45.5 33.3 Ziprasidone 3 MRS score
Tohen et al,44 2008 99 40.6 (12.8) 46.5 20 Olanzapine, valproate 3 YMRS total score
Vieta et al,45 2010 104 38 (10) 47 20 Paliperidone quetiapine 3 YMRS total score
Yildiz et al,46 2008 31 36a (18-54) 52 50 Tamoxifen 3 YMRS total score
Overall mania, mean (SD) 96.7 (26.6) 39.9 (2.4) 49.9 (7.0) 32.3 (10.2) NA 3.0 (0.0) NA
Schizophrenia
Coppola et al,47 2011 63 36.5 (11.6) 28.1 33.3 Paliperidone 6 PANSS total score
Egan et al,48 2013 78 36.4 (8.5) 36.1 40 Mk-8998, olanzapine 4 PANSS total score
Kane et al,49 2015 145 36.7 (11.3) 25.2 33.3 Cariprazine 6 PANSS total score
Kane et al,50 2016 93 38.8 (11.4) 38.9 20 Brexpiprazole, aripiprazole 6 PANSS total score
Litman et al,51 2014 39 40.2 (11.6) 4.9 40 Pavinetant, olanzapine 4 PANSS total score
Loebel et al,52 2016 112 40.7 (11.6) 30.4 25 Lurasidone 6 PANSS total score
Meltzer et al,53 2011 114 37 (11.3) 23 25 Lurasidone olanzapine 6 PANSS total score
Nasrallah et al,54 2013 124 38.2 (9.9) 27.4 25 Lurasidone 6 PANSS total score
Ogasa et al,55 2012 49 38.1 (9.7) 16 33.3 Lurasidone 6 BPRS score
Potkin et al,56 2015 71 41 (9.7) 23.6 20 Lurasidone, haloperidol 6 BPRS score
Overall schizophrenia, mean (SD) 88.8 (32.8) 38.4 (1.7) 25.4 (9.2) 29.5 (7.1) NA 5.6 (0.8) NA
OCD
GlaxoSmithKline,57 2005a 75 36.3 (10.7) 29.9 33.3 Paroxetine, clomipramine 12 Y-BOCS total score
Goodman et al,58 1996 78 36.6 (19-69) 50 50 Fluvoxamine 10 Y-BOCS total score
Hollander et al,59 2003a 73 43.1 (12.3) 33 25 Paroxetine 12 Y-BOCS total score
Hollander et al,60 2003b 120 36.7 (1.1b) 67 50 Fluvoxamine 12 Y-BOCS total score
Kamijima et al,61 2004 94 38.5 (12.2) 58.5 50 Paroxetine 12 Y-BOCS total score
Kobak et al,62 2005 30 38.38 (10.6) 43.3 50 St. John’s wort 12 Y-BOCS total score
Kronig et al,63 1999 79 38.1 (12.0) 47 50 Sertraline 12 Y-BOCS total score
Montgomery et al,64 1993 56 36.3 (11.2) 41.1 25 Fluoxetine 8 Y-BOCS total score
Montgomery et al,65 2001 101 38.6 (12.1) 50.1 25 Citalopram 12 Y-BOCS total score
Stein et al,66 2007 97 37.6 (11.8) 55.3 25 Escitalopram, paroxetine 12 Y-BOCS total score
Overall OCD, mean (SD) 80.3 (23.8) 38.0 (1.9) 47.5 (10.7) 38.3 (11.9) NA 11.4 (1.3) NA
ADHD
Adler et al,67 2013 75 34.9 (11.0) 46.3 50 Lisdexamfetamine 10 BRIEF-A GEC
Casas et al,68 2013 97 35.5 (8.8) 46.4 33.3 Methylphenidate 13 CAARS-O:SV
Frick et al,69 2020 103 35.6 (9.8) 44.2 25 Triple-bead mixed amphetamine salts 6 ADHD-RS-IV total score
Goodman et al,70 2017 172 34.7 (11.6) 45.1 50 Methylphenidate 6 AISRS
Goto et al,71 2017 195 31.7 (7.8) 51.3 50 Atomoxetine 10 CAARS-Inv:SV total score
Huss et al,72 2014 161 36.8 (12.2) 44.2 25 Methylphenidate 9 DSM-IV ADHD RS
Medori et al,73 2008 95 34.5a (32.5-36.4c) 38.5 25 Methylphenidate 5 CAARS:O-SV
Takahashi et al,74 2014 140 34.1 (9.0) 51.8 50 Methylphenidate 8 CAARS-O:SV DSM-IV symptom score
Weisler et al,75 2012 65 33.4 (10.3) 41.1 16.67 Bavisant, atomoxetine 6 ADHD-RS-IV total score
Weisler et al,76 2017 86 34.5 (10.8) 52.8 33.3 Triple-bead mixed amphetamine salts 4 ADHD-RS-AP total score
Overall ADHD, mean (SD) 118.9 (42.5) 34.6 (1.3) 46.2 (4.4) 35.8 (12.4) NA 7.7 (2.6) NA
GAD
Bidzan et al,77 2012 148 45.3 (13.5) 61.6 50 Vortioxetine 8 HAM-A total score
Kasper et al,78 2014 135 44.6 (12.3) 73.3 25 Lavender oil extract, paroxetine 10 HAM-A total score
Mahableshwarkar et al,79 2014 120 36.8 (12.1) 65 20 Vortioxetine, duloxetine 8 HAM-A total score
Nicolini et al,80 2009 163 42.8 (NA) 57.1 28.6 Duloxetine, venlafaxine 10 HAM-A total score
Pollack et al,81 2008; cohort 2 226 39.9 (12) 61 50 Tiagabine 10 HAM-A total score
Pollack et al,81 2008; cohort 3 223 40.8 (11.5) 58 50 Tiagabine 10 HAM-A total score
Rothschild et al,82 2012 113 41.4 (12.8) 63.8 50 Vortioxetine 8 HAM-A total score
Stein et al,83 2008 58 41.7 (6.9) 68.8 50 Agomelatine 12 HAM-A total score
Stein et al,84 2014 131 43 (12.2) 71.8 33.3 Agomelatine escitalopram 12 HAM-A total score
Stein et al,85 2017 140 44.1 (13.1) 63.4 33.3 Agomelatine 12 HAM-A total score
Overall GAD, mean (SD) 145.7 (47.4) 42.0 (2.4) 64.4 (5.2) 39.0 (11.6) NA 10.0 (1.6) NA
Social phobia
Allgulander et al,86 2004 132 38.9 (10.6) 62 33.3 Venlafaxine, paroxetine 12 LSAS total score
Asakura et al,87 2016 196 33 (18-63) 55.6 33.3 Escitalopram 12 LSAS-J total score
Baldwin et al,88 1999 151 37.3 (11.4) 54.3 50 Paroxetine 12 LSAS total score
Davidson et al,89 1993 33 37.3 (9.5) 42 50 Clonazepam 10 LSAS total score
Davidson et al,90 2004 126 37.2 (0.9b) 31 50 Fluvoxamine 12 LSAS total score
Lepola et al,91 2004 184 39 (11.5) 47 50 Paroxetine 12 LSAS total score
Schneier et al,92 1998 37 34.1 (8.2) 32.4 50 Moclobemide 8 LSPDS overall severity
Stein et al,93 1998 92 36.7 (18-76) 60.2 50 Paroxetine 12 LSAS total score
Stein et al,94 2005 126 37.7 (11.9) 43 33.3 Venlafaxine 28 LSAS total score
Stein et al,95 2010 103 35.8 (11.9) 35.8 50 Levetiracetam 12 LSAS total score
Overall social phobia, mean (SD) 118 (51.5) 36.7 (1.8) 46.3 (10.8) 45.0 (7.7) NA 13.0 (5.2) NA
Panic disorder
Asnis et al,96 2001 92 36.7 (9.8) 64.1 50 Fluvoxamine 8 CAS item 7
Ballenger et al,97 1988 234 37.5 (10.2) 68 50 Alprazolam 8 HAM-A total score
Ballenger et al,98 1998 69 37.3 (10.4) 68.1 25 Paroxetine 10 HAM-A total score
Caillard et al,99 1999 51 37 (10) 58.8 33.3 Clomipramine 8 HAM-A total score
Liebowitz et al,100 2009 105 36.7 (12.0) 59 50 Venlafaxine 10 HAM-A total score
Michelson et al,101 1998 74 37.9 (11.5) 67.9 33.3 Fluoxetine 10 HAM-A total score
Noyes et al,102 1996 79 36.6 (10.5) 65.2 33.3 Alprazolam, diazepam 8 HAM-A total score
Pohl et al,103 1998 73 37.5 (11.5) 57 50 Sertraline 10 Multicenter Panic Anxiety Scale
Pollack et al,104 1998 87 34.9 (9.6) 61 50 Sertraline 10 HAM-A total score
Sheehan et al,105 2005 384 37.8 (10.6) 56.4 50 Paroxetine 10 HAM-A total score
Overall panic disorder, mean (SD) 124.8 (99.0) 37.0 (0.8) 62.6 (4.4) 42.5 (9.5) NA 9.2 (1.0) NA
PTSD
Connor et al,106 1999 26 38 (33-41d) 93 50 Fluoxetine 12 Duke Global Rating for PTSD
Davidson et al,107 2006 168 40.5 (13.0) 53 50 Venlafaxine 24 CAPS-SX17 score
Davis et al,108 2008 41 55.2 (6.8) 2 50 Divalproex 8 CAPS total
Davis,109 2017 44 36.6 (10.5) 8.7 50 Nepicastat 6 CAPS total
Davis et al,110 2020 34 38.1 (9.5) 7.7 50 Mirtazapine 8 SIP
Friedman et al,111 2007 82 37.8 (8.4) 19.3 50 Sertraline 12 CAPS-2 total score
Li et al,112 2017 36 44.9 (5.8) 11.1 50 Sertraline 12 IES-R
Raskind et al,113 2018 136 51.4 (13.8) 0.7 50 Prazosin 10 CAPS total
Rasmusson et al,114 2017 50 37.7 (10.9) 17 50 Ganaxolone 6 CAPS total
Villarreal et al,115 2016 38 54 (10) 3 50 Quetiapine 12 CAPS total
Overall PTSD, mean (SD) 65.5 (46.1) 43.4 (7.0) 21.5 (27.8) 50.0 (0.0) NA 11.0 (4.9) NA
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Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ADHD-RS-AP, ADHD Rating Scale with Adult Prompts; ADHD-RS-IV, ADHD Rating Scale, version IV; AISRS, Adult ADHD Investigator Symptom Rating Scale; BPRS, Brief Psychiatric Rating Scale; BRIEF-A GEC, Behavior Rating Inventory of Executive Function–Adult Version, Global Executive Composite; CAARS-Inv:SV, Conners’ Adult ADHD Rating Scale-Investigator Rated: Screening Version; CAARS-O:SV, Conners’ Adult ADHD Rating Scales–Observer: Screening Version; CAPS, Clinician-Administered PTSD Scale for DSM-5; CAPS-2, Part 2 of the Clinician-Administered PTSD Scale; CAPS-SX17, Clinician-Administered PTSD Scale, abbreviated 1-Week Symptom Status Version; CAS, Clinical Anxiety Scale; DSM-5, Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition); DSM-IV, Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition); GAD, generalized anxiety disorder; HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; HAM-D-17, Hamilton Depression Rating Scale, 17-item version; HAM-D-24, Hamilton Depression Rating Scale, 24-item version; IES-R, Impact of Event Scale–Revised; LSAS, Liebowitz Social Anxiety Scale; LSAS-J, Liebowitz Social Anxiety Scale, Japanese version; LSPDS, Liebowitz Social Phobic Disorders Scale–Severity; MADRS, Montgomery-Åsberg Depression Rating Scale; MRS, Mania Rating Scale; NA, not applicable; OCD, obsessive-compulsive disorder; PANSS, Positive and Negative Syndrome Scale for Schizophrenia; SIP, Structured Interview for PTSD; Y-BOCS, Yale-Brown Obsessive Compulsive Scale; YMRS, Young Mania Rating Scale.

a

Expressed as median instead of mean.

b

Expressed as SE.

c

Expressed as 95% CI.

d

Expressed as quartiles.

There was an overrepresentation of women in depression, GAD, and panic disorder studies and an underrepresentation of women in schizophrenia and PTSD studies, whereas age, on the study level, varied only moderately. The duration of the studies also differed based on the diagnosis, with a relatively long duration of up to 12 weeks for OCD, social phobia, and GAD, and a shorter duration of 3 weeks for mania (Table 2).

Main Outcome

In all diagnoses, there were improvements in symptom severity during placebo treatment (ie, the lower limit of the 95% CIs of the pooled pre-post placebo effect sizes were >0). As indicated by the Q test, the pooled pre-post placebo effect sizes differed statistically significantly among the disorders (Q = 88.5; df = 8; P ≤ .001) (Figure 1). The largest effect size was observed in MDD (dav = 1.40; 95% CI, 1.24 to 1.56), followed by GAD (dav = 1.23; 95% CI, 1.06 to 1.41). Schizophrenia had the smallest effect size (dav = 0.59; 95% CI, 0.41 to 0.76) and OCD had the second weakest (dav = 0.65; 95% CI, 0.51 to 0.78). There were no overlaps of the 95% CIs of GAD and depression with the 95% CIs of panic disorder, ADHD, social phobia, mania, OCD, and schizophrenia (Figure 1).

Figure 1. Random-Effects Meta-Analysis Estimates of Pooled Pre-Post Placebo Effect Sizes.

Figure 1.

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Random-effects meta-analysis estimates of Cohen dav pooled pre-post placebo effect sizes (ES) and 95% CIs of placebo groups in randomized clinical trials by diagnosis (90 studies; 10 for each diagnosis). ADHD indicates attention-deficit/hyperactivity disorder; GAD, generalized anxiety disorder; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; and PTSD, posttraumatic stress disorder.

The placebo response varied substantially from study to study, as indicated by heterogeneity values (I2>75% for GAD, mania, MDD, PTSD, and schizophrenia) (Figure 1). The prediction intervals were 0.84 to 1.96 for MDD, 0.60 to 1.87 for GAD, 0.60 to 1.23 for GAD, −0.31 to 1.99 for PTSD, 0.29 to 1.15 for social phobia, 0.06 to 1.30 for mania, 0.19 to 1.10 for OCD, and −0.02 to 1.19 for schizophrenia. For ADHD, a prediction interval was not assessed due to uniform effect sizes (I2 = 0); thus, there was no difference between CI and prediction interval results.

Clinical Global Impression

In 47 studies,32,33,34,35,37,39,42,43,44,46,48,49,50,52,53,54,55,56,57,60,64,70,73,78,79,82,83,84,85,86,87,88,89,90,91,96,98,99,100,104,105,107,108,110,111,112,115 CGI severity score (CGI-S) results allowed a transdiagnostic comparison on the same scale. Results of standardized comparisons corroborated main analysis findings, highlighting pronounced placebo responses in GAD, panic disorder, and MDD (Figure 2). Diagnoses differed significantly (Q = 71.2; df = 8; P < .001). Again, substantial heterogeneity across studies was apparent (I2>75%), except for MDD (I2 = 5%) and OCD (I2 = 0%). Summary outcomes based on mean differences, as opposed to standardized mean differences, of CGI-S supported standardized-based results for both the CGI-S–related and the primary analyses.

Figure 2. CGI Severity Score Based Random-Effects Meta-Analysis Estimates of Pooled Pre-Post Placebo Effect Sizes.

Figure 2.

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Pooled pre-post effect sizes (Cohen dav), 95% CIs, and 95% prediction intervals (PIs) in random-effects meta-analysis in randomized clinical trials of 9 different psychiatric diagnoses. Q = 71.2; df = 8; P < .001. ADHD indicates attention-deficit/hyperactivity disorder; GAD, generalized anxiety disorder; MDD, major depressive disorder; NA, not assessed (all studies share a common effect size; thus I2 was very low and there was no difference between CI and PI); ND, not done (number of studies too small for valid determination [ie, <3 studies]); OCD, obsessive-compulsive disorder; and PTSD, posttraumatic stress disorder.

Bivariable and Multivariable Meta-Regressions

Bivariable meta-regressions indicated potential associations of pre-post effect sizes with gender or sex (slope point estimate, 0.0084; 95% CI, 0.0036 to 0.0133), study duration (slope point estimate, 0.0202; 95% CI, 0.0002 to 0.0402), and probability of placebo assignment (slope point estimate, −0.0047; 95% CI, −0.0103 to 0.0008). In multivariable analysis, apart from diagnosis, only gender or sex remained statistically significantly associated with pooled pre-post effect sizes (slope point estimate, 0.0076; 95% CI, 0.0026 to 0.0126; P = .003), indicating that with each percentage point of women in the study, the effect size increased by 0.0076, or by 0.19 with 25% more women (R2 = 51%; goodness of fit [residual heterogeneity]: Q = 354.97; df = 78; P < .001). Bivariable and multivariable analyses based on CGI-S supported this finding.

Discussion

This systematic review and meta-analysis of placebo groups of RCTs for 9 psychiatric diagnoses had 5 main findings. First, symptom improvement occurred in all conditions under placebo treatment. Second, the improvements were of considerable magnitude. Third, improvement varied significantly among disorders and was particularly strong in MDD and GAD, while schizophrenia, OCD, and mania had comparatively modest improvements. Fourth, for most diagnoses, there was substantial or considerable variability in the improvements across RCTs. Fifth, alongside diagnoses, an increasing proportion of women was associated with larger improvements in placebo groups.

First, symptom improvement in all disorders is in line with previous studies,10,13,19,20 but our study expands insight toward a broader range of diagnoses. A secondary CGI-S analysis supported our findings. Second, even without systematic treatment, such as psychotherapy, meaningful improvements were evident. The more pronounced the improvement in the placebo groups, the more the treatment could at least initially be justified by the omission of medication. The significant improvements under placebo treatment justify placebo controls in psychiatric research. Of note, pre-post effect sizes, whether for placebo or active treatments, are in a different order of magnitude than effect sizes resulting from the comparison of an intervention group with a control group, at least in psychiatry.

Third, previous studies have already reported a particularly large effect of placebo in MDD4,6,11,12,14,15,16 and GAD,10,19 with a comparatively smaller effect in OCD.13,17,18,19,20 Schizophrenia,7 mania,17,20 ADHD, and PTSD have been comparatively less studied.

To date, depression studies have been investigated the most extensively. Some investigators submit that more than three-quarters122 or two-thirds6 of the positive outcomes observed under a treatment with an antidepressant may be attributed to nonspecific and placebo effects, although it should be noted that the diagnosis of depression encompasses a wide range of disorders, rather than being a specific entity.123 This appears counterintuitive, given depression’s impact on hope and confidence. However, affective disorders commonly follow an episodic course. Additionally, interpersonal support, psychoeducation, inspiring of hope, and the conveyance of medical concepts constitute fundamental components of antidepressant psychotherapy but are also often evident in placebo groups.

The large and robust improvements observed in ADHD studies have not been reported to our knowledge. Notable differences among anxiety disorders exist. GAD studies presented the largest improvements, and social phobia studies presented relatively modest improvements. Panic disorder again showed a moderate effect size, and OCD, often classified as an anxiety disorder, showed relatively small improvements in the placebo group.

We found that patients with schizophrenia had the least benefit associated with placebo treatment, possibly due to episodic relapses and an unfavorable prognosis.124 Impaired interpersonal functioning might reduce the impact of personal attention and nonspecific effects in placebo groups. Distorted reality perception and limited insight into illness may hinder the development of hope and belief in effective treatment. However, these hypotheses cannot be proven with our approach. Furthermore, the relatively small improvement observed in mania studies is reasonable with regard to impaired illness awareness and little desire for treatment.

Uncontrolled studies often gauge treatment effectiveness using pre-post findings or historical control comparisons. In this regard, our analyses highlight the importance of understanding symptom trajectories without specific treatment, underscoring the crucial role of placebo controls, especially for diagnoses with substantial placebo effects.

Fourth, the high heterogeneity, with I2 values greater than 75% for MDD, GAD, PTSD, mania, and schizophrenia, indicates significant variation within diagnoses across RCTs. This suggest prudence in drawing conclusions but is also unsurprising, considering internal and external influences, like study design and illness characteristics. Notably, active treatment group pre-post effect sizes also vary, such as in MDD studies.122 Meta-analyses of single study groups typically exhibit greater between-study heterogeneity than pairwise analyses under the same conditions.125 In multivariable meta-regression, we found no association of pre-post effect sizes with study duration or the likelihood of receiving placebo. This latter differs from previous analyses of depression studies.126 Overall, diagnosis differences in our study were not solely explained by study design variations.

Fifth, the positive association of response and proportion of women participants cannot be explained by higher female participation in MDD and GAD studies alone and requires further investigation. Our study cannot determine whether this signifies a generally better prognosis in women, as seen in schizophrenia,127,128 or if women particularly benefit from nonspecific factors in clinical studies.

Limitations

This study has several limitations. Our analysis cannot precisely attribute measured changes to the placebo effect in the strict sense. Assessments would require studies with a group receiving no study medication or treatment at all, a rarity in psychiatry. A 2023 review provides an overview of contextual effects in general medicine.129 A 1998 depression study indirectly compared placebo groups with psychotherapy waiting-list groups, estimating the placebo effect’s contribution to the overall improvement with an antidepressant to be approximately 50%.122 However, the study did not account for potential nocebo effects associated with waiting-list assignment.130

Our study, limited to adults, encountered variations in study designs both among and within diagnostic groups, affecting multiple factors, like study duration and placebo likelihood. Reassuringly, regression analyses yielded no positive signal regarding these potential confounders. Nevertheless, the heterogeneity in most disorders suggests prudence in drawing firm conclusions at this point. We see the association of gender or sex and placebo response found in our multivariable analyses as preliminary. These analyses are hypothesis generating and must be interpreted with caution. For example, this association is prone to an ecological fallacy, and individual patient data are necessary to uncover a true association.

Furthermore, it was not possible to analyze all placebo-controlled studies conducted on the 9 disorders, but our sample is reliable, systematically including high-quality and current RCTs through a preregistered protocol. Excluding low-quality RCTs (ie, high ROB) is particularly relevant in the analysis of placebo effects, which strongly depend, for example, on the success of blinding.131 However, ROB primarily pertains to comparing different treatment groups within a study and can only indirectly be applied to the pre-post analysis of just 1 study group (placebo). Variability in psychopathology scales used for placebo group effects measurement might limit comparability. Comparing pre-post effect sizes is the best statistical approach for this purpose, as seen in prior analyses across diagnoses.10,19 Using the CGI-S, we were able to confirm our results with a transdiagnostic scale. However, this was possible for only slightly more than half of the RCTs.

Conclusions

This systematic review and meta-analysis of placebo groups from high-quality RCTs covering a spectrum of 9 core psychiatric disorders found considerable improvements, with significant interdisorder differences not primarily linked to study design variations. Insights into the course of illness under placebo may aid in judging the urgency of specific treatments and help to understand the illness course in the absence of a specific intervention. A better understanding of placebo responses may improve treatments, especially in psychiatric disorders where confidence, conditioning, and belief play a significant role. Our findings could inform the interpretation of placebo-controlled trials, where the medication-placebo difference typically is the primary outcome.

For all disorders in our analysis, a multifactorial etiology encompassing psychogenic and biological determinants, intricately linked and interactive, is postulated. Over the past decades, diverse research paradigms, including genetic examinations and functional imaging, have been diligently used to assess individual factors.132 Comparing the courses of different disorders under placebo indirectly may assist in understanding disease etiology, possibly providing insights into the proportionate influence of organic and psychogenic factors.10 Conditions with presumed substantial hereditary and biological components, such as schizophrenia,133 exhibited modest placebo responses in our analysis. Conversely, disorders with potentially less biological contribution, eg, depression and GAD, showed stronger responses. Our study may serve as an initial framework for incorporating the comprehensive insights derived from placebo groups of controlled trials into the etiopathogenetic exploration of mental illnesses.

Supplement 1.

eAppendix 1. Search Strings and Quality, Inclusion, and Exclusion Criteria for a Systematic Literature Search for Systematic Reviews on 10 Psychiatric Disorders

eAppendix 2. Inclusion and Exclusion Criteria for RCTs

eAppendix 3. Formulae Used to Calculate Standardized Pre-Post Effect Sizes per RCT

eTable. Number of Hits in an Online Search for High-Quality Systematic Reviews

eFigure. Funnel Plot by Effect Sizes

jamapsychiatry-e240994-s001.pdf (311.5KB, pdf)
Supplement 2.

Data Sharing Statement

jamapsychiatry-e240994-s002.pdf (12.9KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eAppendix 1. Search Strings and Quality, Inclusion, and Exclusion Criteria for a Systematic Literature Search for Systematic Reviews on 10 Psychiatric Disorders

eAppendix 2. Inclusion and Exclusion Criteria for RCTs

eAppendix 3. Formulae Used to Calculate Standardized Pre-Post Effect Sizes per RCT

eTable. Number of Hits in an Online Search for High-Quality Systematic Reviews

eFigure. Funnel Plot by Effect Sizes

jamapsychiatry-e240994-s001.pdf (311.5KB, pdf)
Supplement 2.

Data Sharing Statement

jamapsychiatry-e240994-s002.pdf (12.9KB, pdf)

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