Magnitude of The Placebo Response Across Treatment Modalities Used For Treatment-Resistant Depression in Adults A Systematic Review and Meta-Analysis

Original Investigation | Psychiatry
Magnitude of the Placebo Response Across Treatment Modalities

Used for Treatment-Resistant Depression in Adults
A Systematic Review and Meta-analysis
Brett D. M. Jones, MD, MSc; Lais B. Razza, BSc; Cory R. Weissman, MD; Jewel Karbi, MD; Tya Vine, HBSc; Louise S. Mulsant, BASc; Andre R. Brunoni, MD, PhD;
M. Ishrat Husain, MBBS, MD; Benoit H. Mulsant, MD, MSc; Daniel M. Blumberger, MD, MSc; Zafiris J. Daskalakis, MD, PhD
Abstract Key Points

Question What is the placebo effect
IMPORTANCE The placebo effect in depression clinical trials is a substantial factor associated with
magnitude in different treatment
failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the
modalities used for management of
placebo effect and whether it differs across treatment modalities in treatment-resistant depression
patients with treatment-resistant
(TRD) is unclear.
depression?
OBJECTIVE To examine the magnitude of the placebo effect in patients with TRD across different Findings In this systematic review and
treatment modalities and its possible moderators. meta-analysis of 3228 patients with
treatment-resistant depression in 50
DATA SOURCES Searches were conducted on MEDLINE, Web of Science, and PsychInfo from randomized clinical trials, the placebo
inception to June 21, 2021. effect size was large and consistent
across treatment modalities. Response
STUDY SELECTION Randomized clinical trials (RCTs) were included if they recruited patients with and remission rates associated with
TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or placebo effect were comparable across
psychotherapy arm. modalities.
Meaning The findings of this study

DATA EXTRACTION AND SYNTHESIS Independent reviewers used standard forms for data
suggest a placebo effect size benchmark
extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses
may be used to interpret the findings of
were performed.
past and future clinical trials.
MAIN OUTCOMES AND MEASURES The primary outcome was the Hedges g value for the reported
depression scales. Secondary outcomes included moderators assessed via meta-regression and + Invited Commentary
2
response and remission rates. Heterogeneity was assessed with the I test, and publication bias was
evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to
+ Supplemental content
Author affiliations and article information are
estimate risks.
listed at the end of this article.
RESULTS Fifty RCTs were included involving various types of placebo or sham interventions with a
total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled
placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in
RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission
rates associated with placebo were comparable across modalities. Heterogeneity was large. Three
variables were associated with a larger placebo effect size: open-label prospective treatment before
double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of
publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95%
CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability
a smaller placebo effect size (β = −0.12; 95% CI, −0.23 to −0.01, P = .03). The Egger test result was
not significant for small studies’ effects.
(continued)
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 (Reprinted) September 24, 2021 1/18
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JAMA Network Open | Psychiatry Magnitude of the Placebo Response Across Treatment-Resistant Depression in Adults
Abstract (continued)
CONCLUSIONS AND RELEVANCE This analysis may provide a benchmark for past and future
clinical RCTs that recruit patients with TRD standardizing an expected placebo effect size.
JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531
Introduction
Major depressive disorder (MDD) is a relapsing and remitting illness, and many patients do not
respond to available treatments.1,2 The standard to evaluate a new intervention for MDD uses a
randomized clinical trial (RCT) with placebo as the control design that can distinguish the benefit of
an active treatment compared with the nonspecific benefit of the placebo response. The placebo
response is defined as the therapeutic effect produced by a placebo or sham intervention that is not
due to any inherent properties of the placebo. Several novel or repurposed treatments have not been
able to establish efficacy in the context of large placebo effects.3 This phenomenon is a challenge for
researchers; however, attention has begun to focus on trying to understand and quantify the
magnitude of the placebo response.1,2
In RCTs of non–treatment-resistant depression (non-TRD) in patients with MDD,4-14 the placebo
effect has been found to have a large magnitude and to be associated with several factors, although
with some inconsistent findings. These factors have included later publication years, number of trial
arms, multicenter setting, dosing schedule, increased length of the trial, sham device placement, the
magnitude of active response, early score fluctuations, and inflation of baseline severity.4-14 A large
meta-analysis evaluating the placebo effect in depression (256 RCTs; n = 26 324) found placebo-
response rates of about 35% to 40%.13 However, this analysis included only RCTs of antidepressant
drugs in patients without TRD.13 Treatment-resistant depression is commonly defined as the lack of
response to 2 separate antidepressant trials of adequate dose and duration. Previous meta-
analyses have suggested that TRD is associated with a smaller placebo effect than non-TRD
(repetitive transcranial magnetic stimulation [rTMS] and escitalopram trials).15,16 Nonetheless, to our
knowledge, no analysis has assessed the placebo effect in patients with TRD receiving other
treatment modalities.
Patients with TRD often receive multiple treatment modalities and have lower rates of response
and remission; thus, one would expect them to experience less benefit from the nonspecific effects
of treatment. This lack of response highlights the importance of quantifying the placebo effect in
TRD, how it may differ across treatment modalities, and what may contribute to it. An appreciation
of the expected placebo effect of specific treatment modalities in TRD would provide a benchmark to
inform interpretation of past and future RCTs. We therefore conducted a systematic review and
meta-analysis to quantify the placebo effect across treatment modalities in TRD. We explored the
methodological, demographic, and clinical variables that may contribute to placebo effect. This
quantitative analysis is needed to interpret previous RCTs and emerging treatments as well as
potentially identifying the beneficial aspect of the placebo effect.
Methods
Searches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21,
2021 (eAppendix 2 in the Supplement). In addition, references from relevant reviews were
searched.15,17-21 Figure 1 provides an overview of the number of studies screened and full texts
reviewed. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-
analyses (PRISMA) reporting guideline. The protocol was developed a priori and was published and
registered22,23 (trial registration: PROSPERO Identifier: CRD42020190465).

Study designs were limited to parallel-arm, double-blind placebo-controlled RCTs or the first
phase of randomized crossover trials that exclusively recruited patients with TRD and randomized
them to at least 1 placebo arm, as specified in the protocol.22 Included active interventions were
pharmacologic and somatic treatments (Maudsley Treatment Inventory) and psychotherapeutic
interventions from the National Institute for Health and Care Excellence (NICE) guidelines.24,25 A
placebo arm was defined as an inert pill placebo, parenteral placebo, sham device, or sham therapy
that does not include any theoretical active property to induce the proposed therapeutic effect. Wait
list or treatment as usual were not included as placebo interventions. Randomized clinical trials that
used an open-label prospective antidepressant treatment phase to establish treatment resistance
before randomization were included. Exclusion criteria were studies in which more than 15% of
participants had bipolar depression, included patients with other psychiatric disorders, had sample
sizes of less than 10 participants (5 per treatment arm), or used a noninert placebo arm.
Data were extracted by 3 of us (L.B.R., J.K., L.S.M.) and discrepancies were resolved by
consensus. Data were confirmed by 1 of us (B.D.M.J.). Variables extracted included demographic
characteristics, methodologic data, clinical/outcome data, and placebo-specific data. The
demographic characteristics were age and sex. Methodological data included treatment strategy
(augmentation vs monotherapy), multicenter setting, length of the trial (calculated as number of
days for double-blind treatment), number of treatment arms, year of publication, trial design (ie,
whether the trial used open-label prospective treatment to determine treatment resistance before
double-blind randomization), and whether the trial was industry sponsored (defined as being
sponsored by a pharmaceutical company or a medical device manufacturer). Randomized clinical
trials funded by the US Department of Veterans Affairs; government agencies, such as the Canadian
Institutes of Health Research or National Institute of Mental Health; nonprofit foundations, such as
National Alliance for Research on Schizophrenia & Depression, or Brain & Behavior Research
Foundation; or hospitals or universities were not considered to be industry sponsored. Clinical/
outcome data comprised treatment modality, sample size, mean (SD) scores of depression rating
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses Flow Diagram for Inclusion
of Studies
20 757 Records identified through 73 Additional records identified

database searching through other sources
11 236 Records after duplicates removed
11 236 Records screened
10 650 Records excluded
586 Full-text articles assessed for eligibility
536 Full-text articles excluded

244 Not meeting criteria for TRD
118 Wrong patient population
78 Wrong study design
60 Inappropriate placebo
26 Duplicate study
10 Pooled analysis of included primary
papers already screened
50 Studies included in qualitative synthesis
50 Studies included in quantitative

synthesis (meta-analysis)

scales at baseline and end point in both the placebo and active groups, number of responders/
remitters (as defined by the individual studies), number of failed antidepressant trials, past
depressive episodes, and length of the current episode. Placebo-specific data included route (eg, oral
vs parenteral) of administration and number of days receiving placebo. This variable was calculated
by determining how many days during the trial period participants would receive placebo or sham
intervention.
If the mean (SD) scores of the depression rating scales were not reported in the study, the
corresponding author was contacted by email. If no reply was obtained, we extracted the data from
the study graphs. Moreover, when only the SD of the change was reported, we imputed the data as
recommended by the Cochrane group.26 For studies that included an open-label prospective (run-in)
treatment phase, effect size was calculated from the start of the double-blind randomized phase.
The quality of the studies was assessed independently by 2 of us (B.D.M.J. and C.R.W.) and
recorded using the Cochrane Risk of Bias tool.27 Thus, 5 bias domains were assessed: selection
(randomization and allocation concealment), performance (blinding of participants and personnel),
attrition (incomplete outcome data), detection (blinding of outcome assessment), and reporting
(selective outcome reporting). For a judgment of the overall risk of bias, we followed the Cochrane
recommendation: low risk of bias (low risk for all domains or some concerns of bias for 1 domain),
unclear risk of bias (2 or 3 domains were rated as presenting some cause for concern), and high risk of
bias (>3 domains with some bias concerns and/or ⱖ1domain with high risk of bias).
The analyses were performed using Stata, version 17 (StataCorp LLC) software. Considering that
most studies have small samples, we used the Hedges g to estimate the effect size of the placebo
response. The effect size was computed based on the baseline and end point sample sizes and means
(SDs) of the primary depression score scales of the placebo group of each study. A random-effects
model (restricted maximum-likelihood method instead of fixed-effect models was used considering
that study heterogeneity would be high). The model provides wider 95% CIs compared with fixed-
effects models, thereby providing a more conservative estimation of summary effect size.28 The
model assumes that the effect sizes of the studies are different from each other and represent a
random sample from a larger population of studies.29 The components of the random-effects model
applied in this meta-analysis are described in eAppendix 1 in the Supplement. Heterogeneity among
studies was assessed with I2 analysis and was considered high when presenting a value greater than
or equal to 50% as suggested elsewhere.30 Small studies effects were assessed using the Begg
modified funnel plot, the Duval and Tweedie trim-and-fill procedure, and the Egger regression
intercept. The Egger test was considered significant for small studies’ effects when presenting
findings significant at P < .05.
Meta-regression and subgroup analyses were applied to explore potential moderators of the
placebo effect. To increase overall sample size, treatment modalities were pooled for the meta-
regression. Meta-regressions were conducted using only 1 variable at a time. Subgroup analysis was
conducted to compare the effect size of the placebo response among treatment modalities. Values
were considered statistically significant when presenting findings at P < .05 for both meta-regression
and subgroup analysis. The mean of the percentage of responders and remitters for each treatment
modality was also assessed. In addition, a sensitivity analysis was conducted looking at low risk
of bias.
Results
Our search yielded 11 236 studies that were screened; full texts of 605 articles were reviewed and 50
RCTs (N = 3228) were included.31-80 the mean (SD) age of the participants was 45.8 (6.0) years, and
the mean (SD) proportion of women was 54.8% (20.7%) (Figure 1 and Table 1). Additional clinical
characteristics are described in eTable 3 in the Supplement. Sixteen RCTs were classified to have a
low risk of bias; 19, an unclear risk of bias, and 16, a high risk (eTable 1 in the Supplement). No
psychotherapy RCTs met our eligibility criteria. Placebo or sham interventions were categorized as

Table 1. Demographic, Clinical, and Methodological Characteristics of Included Studies in the Systematic Review and Meta-analysis
Demographic characteristics Methodologic characteristics Placebo characteristics

Total days Times
Age, Depression receiving placebo was Overall risk
Source No. Women No. (%) mean (SD), y score Design Augmentation Treatment Placebo route placebo measured of bias
Bakim et al,31 2012 12 11 (91.7) 44.4 (10.2) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 30 6 Unclear
prospective, 3 stimulation
treatment arms,
42 d
Barbee et al,32 2011 48 33 (68.8) 45.8 (11) MADRS MC, prospective Yes Lamotrigine Oral 70 6 Low
treatment, 2 arms,
70 d
Bauer et al,75 2019 441 302 (68.5) 46.4 (12.1) MADRS MC, prospective Yes Brexiprazol Oral 168 9 High
JAMA Network Open | Psychiatry
treatment, 2 arms,
168 d
Bennabi et al,74 2015 12 5 (45.5) 59.9 (15.4) HDRS-21 SC, treatment not Yes tDCS Noninvasive brain 5 3 Unclear
prospective, 2 arms, stimulation
35 d
Berman et al,73 2007 176 113 (64.2) 44.2 (10.9) MADRS MC, prospective Yes Aripiprazole Oral 42 6 Low
treatment, 2 arms,
42 d
Berman et al,33 2009 172 117 (68.0) 45.6 (11.3) MADRS MC, prospective Yes Aripiprazole Oral 42 6 Unclear
treatment, 2 arms,
42 d
Blumberger et al,35 2012 22 14 (70.0) 45.8 (13.4) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 30 6 Low
42 d
Blumberger et al,34 2012 11 10 (90.9) 49.7 (9.4) HDRS-17 SC, treatment not Yes tDCS Noninvasive brain 15 2 Low
21 d
Blumberger et al,36 2016 41 24 (59.0) 48.1 (12.0) HAMD-17 SC, treatment not Yes rTMS Noninvasive brain 30 2 Low
42 d
JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 (Reprinted)

Boutros et al,37 2002 9 1 (11.0) 52 (7) HDRS-25 SC, treatment not Yes rTMS Noninvasive brain 10 5 Low

14 d
Chen et al,38 2013 10 4 (40.0) 47.3 (3.5) HAMD-17 SC, treatment not Yes rTMS Noninvasive brain 10 2 High
14 d
Coenen et al,72 2019 8 3 (37.5) 49.9 (12) MADRS SC, treatment not Yes DBS Invasive brain 1 4 High
56 d
Concerto et al,39 2015 15 7 (46.7) 53 (6.7) HDRS SC, treatment not Yes rTMS Noninvasive brain 20 1 High
28 d
Dougherty et al,40 2015 14 5 (35.7) 48.9 (8.9) MADRS MC, treatment not Yes DBS Invasive brain 1 6 Low
112 d
Fava et al,77 2015 85 56 (65.9) 45.9 (10.6) MADRS MC, prospective Yes nAChR antagonist Oral 42 5 High
treatment, 2 arms,
42 d
Fava et al,41 2018 81 61 (75.3) 45.2 (10.2) MADRS MC, prospective Yes Cariprazine Oral 56 5 Low
treatment, 3 arms,
56 d
Fitzgerald et al,42 2012 20 8 (40.0) 44.9 (15.7) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 15 1 High
September 24, 2021

21 d
(continued)
Magnitude of the Placebo Response Across Treatment-Resistant Depression in Adults
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Table 1. Demographic, Clinical, and Methodological Characteristics of Included Studies in the Systematic Review and Meta-analysis (continued)

Total days Times
43
Garcia-Toro et al, 2001 18 8 (44.4) 50 (11) HDRS-21 SC, treatment not Yes rTMS Noninvasive brain 10 2 Unclear
14
Garcia-Toro et al,76 2006 10 7 (70.0) 47.2 (11.8) HDRS-21 SC, treatment not Yes rTMS Noninvasive brain 10 2 Unclear
14
Heresco-Levy et al,44 2013 13 8 (61.5) 53 (10.2) HDRS-21 MC, treatment not Yes D-cycloserine Oral 42 3 Low
prospective, 2 arms,
42 d
Hobart et al,45 2018 206 144 (71.3) 41.8 (11.7) MADRS MC, prospective Yes Brexiprazol Oral 42 Low
treatment, 3 arms,
42 d
Hobart et al,71 2018 202 149 (72.3) 42.7 (12.5) MADRS MC, prospective Yes Brexiprazol Oral 42 6 Unclear
treatment, 2 arms,
42
Holtzheimer et al.46 2004 8 3 (42.9) 45.4 (4.9) HDRS-17 SC, treatment not No rTMS Noninvasive brain 10 2 Unclear
prospective, 2 arms stimulation
14 d
Holtzheimer et al,70 2017 30 17 (57.0) 48.7 (0.6) MADRS MC, treatment not Yes DBS Invasive brain 1 2 Low
183 d
Husain et al,69 2017 20 11 (55.0) 34.9 (2.5) HDRS-17 MC, treatment not Yes MiNocycline Oral 84 3 Unclear
84 d
Ionescu et al,68 2019 13 3 (23.0) 45.3 (11.7) HAMD-28 SC, treatment not Yes Ketamine Parenteral 6 6 Low
21 d

Kamijima et al,66 2013 195 80 (41.0) 38.7 (9.2) MADRS MC, prospective Yes Aripiprazole Oral 42 6 Unclear
treatment, 3 arms,

42 d
Kamijima et al,67 2018 203 72 (35.5) 39.5 (11.8) MADRS MC, prospective Yes Aripiprazole Oral 42 6 Low
treatment, 2 arms,
42 d
Kauffmann et al,47 2004 5 4 (91.7) 51.7 (17.2) HDRS-21 SC, treatment not Yes rTMS Noninvasive brain 10 2 Unclear
14 d
Li et al,48 2014 15 11 (73.3) 46.9 (NA) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 10 2 Unclear
14 d
Marcus et al,49 2008 190 128 (67.4) 44.4 (10.7) MADRS 42 Yes Aripiprazole Oral 42 6 High
McAllister-Williams et al,50 82 52 (63.0) 45.2 (10.4) MADRS MC, treatment not Yes Metyrapone Oral 21 2 Low
2016 prospective, 2 arms,
35 d
Chen et al,65 2019 16 13 (81.3) 49.9 (8.1) MADRS SC, treatment not Yes Ketamine Parenteral 1 1 High
3d
Nierenberg et al,64 2003 17 7 (41.2) 39.7 (11.9) HSRD-17 42 Yes Lithium Oral 42 3 Unclear
Palhano-Fontes et al.63 2019 15 10 (66.7) 44.2 (12.0) HDRS-17 SC, treatment not No Ayahuasca Oral 1 3 Unclear
7d
September 24, 2021

(continued)
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Table 1. Demographic, Clinical, and Methodological Characteristics of Included Studies in the Systematic Review and Meta-analysis (continued)

Total days Times
51
Pallanti et al, 2010 20 12 (60.0) 47.9 (9.1) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 15 3 High
21 d
Santos et al,52 2008 17 11 (65.0) 29 (NA) MADRS SC, treatment not Yes Lamotrigine Oral 56 4 High
56 d
Shelton et al,53 2001 10 NA NA MADRS SC, prospective Yes Olanzapine Oral 56 8 High
treatment, 3 arms,
56 d
Su et al,62 2017 24 15 (62.5) 48.6 (8.2) HDRS-17 SC, treatment not Yes Ketamine Parenteral 1 8 Unclear
5d
Thase et al,54 2015 191 137 (71.6) 45.2 (11.3) MADRS MC, prospective Yes Brexpiprazole Oral 42 6 High
treatment, 2 arms,
42 d
Thase et al,55 2015 221 146 (66.1) 46.6 (11) MADRS MC, prospective Yes Brexpiprazole Oral 42 6 High
treatment, 3 arms,
42 d
Theleritis et al,56 2017 20 10 (50) 38 (9.9) HDRS-17 SC, treatment not No rTMS Noninvasive brain 15 3 Unclear
21 d
Theleritis et al,56 2017 24 10 (31.6) 39.4 (8.9) HDRS-17 SC, treatment not No rTMS Noninvasive brain 15 3 Unclear
21 d
Triggs et al,57 2010 7 2 (28.6) 41.9 (14.1) HAMD-24 SC, treatment not Yes rTMS Noninvasive brain 10 2 Unclear
(left sham) prospective, 4 arms, stimulation
14 d

Triggs et al,57 2010 7 4 (57.1) 46.6 (20.2) HAMD-24 SC, treatment not Yes rTMS Invasive Brain 10 2 Unclear
(right sham) prospective, 4 arms, Stimulation

14 d
Yesavage et al,61 2018 83 18 (21.7) 54.8 (12.6) HSRD-24 MC, treatment not Yes rTMS Noninvasive brain 30 3 Low
42 d
Zheng et al,60 2010 15 5 (33.3) 26.7 (4.3) HAMD-17 SC, treatment not Yes rTMS Noninvasive brain 20 1 High
28 d
Palm et al,59 2012 11 8 (72) 58 (12) HAMD-24 SC, treatment not Yes tCDS Noninvasive brain 10 2 Low
14 d
van Eijndhoven et al,58 2020 16 13 (81) 49.7 (11) HDRS-17 SC, treatment not Yes rTMS Noninvasive brain 35 5 Unclear
prospective, 2 arms, 20 stimulation
Rush et al,79 2005 110 73 (66) 45.9 (9) HAMD-24 MC, treatment not Yes Vagus nerve Invasive brain 70 7 High
prospective, 2 arms, stimulation stimulation
70 d
Baeken et al,80 2013 11 5 (45) 47.3 (13.6) HDRS SC, treatment not No rTMS Noninvasive brain 4 1 High
7d
Padberg et al,78 1999 6 4 (66.6) 43.3 (11.6) HDRS SC, treatment not Yes rTMS Noninvasive brain 5 2 Unclear
5d
September 24, 2021

Abbreviations: DBS, deep brain stimulation; HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; MC, multicenter; SC, single-center; rTMS, repetitive transcranial magnetic stimulation;
tDCS, transcranial direct current stimulation.
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pill placebo, liquid placebo (trials in this analysis used ayahuasca, a South American psychoactive
brew), parenteral placebo, sham rTMS, sham transcranial direct current stimulation (tDCS), or sham
invasive brain stimulation.
Studies were pooled based on treatment modality to maintain sufficient similarity in the
pairwise analysis. The effect sizes for each treatment modality were pill placebo, g = 1.14 (95% CI,
0.99 to 1.30; I2 = 80.25%); parenteral placebo, g = 1.33 (95% CI, 0.63 to 2.04; I2 = 62.28%); liquid
placebo, g = 0.45 (95% CI, −0.26 to 1.15; I2 = 0%); rTMS, g = 0.89 (95% CI, 0.63 to 1.15; I2 = 62.14%);
tDCS, g = 1.32 (95% CI, 0.53 to 2.11; I2 = 52.57%); and invasive brain stimulation, g = 0.86 (95% CI,
0.58 to 1.14; I2 = 15.48%). The pooled effect size for all treatment modalities was g = 1.05 (95% CI,
0.91 to 1.18) with an overall I2 = 76.19% (Figure 2 and Figure 3).
The funnel plot of the primary outcome showed a symmetrical distribution among the included
studies (eFigure 1 in the Supplement). The Egger test corroborated this finding (z = 1.18; P = .23). We
also applied the trim-and-fill method to deeply investigate any asymmetry of the funnel plot
(eFigure 2 in the Supplement) and its analysis showed the presence of 5 unpublished studies.
Considering these studies in the pooled analyses, the overall effect size was adjusted to g = 1.14 (95%
CI, 1.00 to 1.29). The overall placebo effect size remained large when considering only studies with a
low risk of bias (g = 1.18; 95% CI, 0.98 to 1.38) (eFigure 3 in the Supplement).
For a subset of RCTs that reported response rates (n = 42) and remission rates (n = 25), the
pooled mean (SD) response rate was 21.2% (14.6%) and the pooled remission rate was 13.0%
(9.05%). Modality-specific response and remission rates are described in Table 2.
Figure 2. Main Placebo Effect Size of Included Pill and tDCS Studies
Favors
Baseline End point
active Favors
Source No. Mean (SD) No. Mean (SD) Hedges g (95% CI) treatment placebo Weight, %
Pill
Barbee et al,32 2011 48 26.63 (4.88) 31 17.37 (8.62) 1.39 (0.89 to 1.89) 2.24
Bauer et al,75 2019 441 25.8 (4.1) 381 12.41 (11.07) 1.65 (1.49 to 1.81) 3.16
Berman et al,73 2007 176 25.9 (6.5) 160 20.1 (2.9) 1.13 (0.90 to 1.36) 3.01
Berman et al,33 2009 172 27.1 (5.8) 149 20.7 (5.3) 1.15 (0.91 to 1.38) 2.99
Fava et al,77 2015 85 29.1 (5.5) 63 20.8 (6.46) 1.39 (1.03 to 1.75) 2.65
Fava et al,41 2018 81 26.4 (6.3) 72 18.4 (2.89) 1.59 (1.23 to 1.96) 2.64
Heresco-Levy et al,44 2013 13 27.2 (4.9) 12 23.3 (9.6) 0.50 (–0.27 to 1.27) 1.54
Hobart et al,45 2018 202 26.2 (6.2) 96 18.1 (3.53) 1.47 (1.20 to 1.74) 2.91
Hobart et al,71 2018 206 25.4 (5.2) 186 20.8 (5.7) 0.84 (0.64 to 1.05) 3.06
Husain et al,69 2017 20 32.6 (10.1) 18 32 (11.8) 0.05 (–0.57 to 0.68) 1.89
Kamijima et al,66 2013 195 25.5 (7.4) 183 18.1 (6.8) 1.04 (0.82 to 1.25) 3.04
Kamijima et al,67 2018 203 25.2 (6.5) 183 18 (6.8) 1.08 (0.87 to 1.30) 3.05
Marcus et al,49 2008 190 27 (5.5) 162 21.3 (3.93) 1.17 (0.95 to 1.40) 3.02
McAllister-Williams et al,50 2016 82 28.1 (5.4) 74 22.6 (10.3) 0.68 (0.35 to 1.00) 2.76
Nierenberg et al,64 2003 17 21.7 (4.2) 15 15.1 (5.3) 1.36 (0.60 to 2.11) 1.58
Santos et al,52 2008 17 28.4 (7.7) 13 21.2 (11.3) 0.74 (0.02 to 1.47) 1.64
Shelton et al,53 2001 10 27.7 (4.2) 7 20.8 (6.8) 1.21 (0.21 to 2.22) 1.13
Thase et al,54 2015 191 27.1 (5.6) 178 21.95 (3.56) 1.09 (0.87 to 1.31) 3.03
Thase et al,55 2015 221 26.3 (5.3) 203 20 (3.69) 1.37 (1.16 to 1.58) 3.05
Heterogeneity: τ2 = 0.08; I2 = 80.25%; H2 = 5.06 1.14 (0.99 to 1.30)
Test of θi = θj: Q18 = 87.80; P <.001
tDCS
Bennabi et al,74 2015 12 24.2 (5.6) 11 13.17 (4.97) 2.00 (1.02 to 2.98) 1.17
Blumberger et al,35 2012 11 24.1 (2.9) 7 18.1 (5.5) 1.40 (0.39 to 2.41) 1.11
Palm et al,59 2012 11 34.6 (5.4) 10 30.2 (7.4) 0.66 (–0.19 to 1.50) 1.39
Test of θi = θj: Q2 = 4.23; P = .12)
–2 –1 0 1 2 3 4
Hedges g (95% CI)
Studies were grouped by treatment modality and pooled. tDCS indicates transcranial direct current stimulation.

Pooled meta-regression analysis revealed that industry-sponsored studies (β = 0.34; 95% CI,
0.09 to 0.59; P = .007), year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and studies
that used an open-label prospective treatment phase before double-blind randomization (β = 0.35;
95% CI, 0.11 to 0.59; P = .004) had a significantly higher placebo effect. The number of failed
interventions during the current episode was associated with a smaller placebo effect (β = −0.12;
95% CI, −0.23 to −0.01; P = .03) (Table 3).
Figure 3. Main Placebo Effect Size of Included rTMS, Invasive Brain Stimulation, Parenteral, Ayahuasca, and Overall Studies
Favors
Baseline End point
active Favors
Source No. Mean (SD) No. Mean (SD) Hedges g (95% CI) treatment placebo Weight, %
rTMS
Baeken et al,80 2013 11 26.45 (8.71) 11 22.36 (10.01) 0.42 (–0.39 to 1.23) 1.46
Bakim et al,31 2012 12 25.58 (3.82) 12 19.5 (7.83) 0.95 (0.13 to 1.77) 1.45
Boutros et al,37 2002 9 31.7 (4.9) 7 26.4 (12.4) 0.56 (–0.39 to 1.52) 1.20
Chen et al,38 2013 10 24.9 (6.3) 10 12.3 (4.7) 2.17 (1.10 to 3.25) 1.03
Concerto et al,39 2015 15 21 (5) 15 20 (7) 0.16 (–0.54 to 0.86) 1.71
Fitzgerald et al,42 2012 20 22.9 (2.1) 17 22.6 (5) 0.08 (–0.55 to 0.71) 1.87
Garcia-Toro et al,43 2001 18 25.6 (4.92) 16 23.83 (3.78) 0.39 (–0.27 to 1.05) 1.79
Garcia-Toro et al,76 2006 10 25.1 (7.28) 10 23.6 (7.79) 0.19 (–0.65 to 1.03) 1.40
Holtzheimer et al,46 2004 8 20.8 (6.3) 7 15.3 (3) 1.02 (0.00 to 2.05) 1.10
Kauffmann et al,47 2004 5 18.2 (4.9) 5 11.8 (4.3) 1.25 (0.01 to 2.50) 0.83
Li et al,48 2014 15 23.8 (3.2) 15 19.66 (3.2) 1.26 (0.49 to 2.02) 1.56
Padberg et al,78 1999 6 22.2 (8.8) 6 23.5 (10.4) –0.12 (–1.17 to 0.92) 1.07
Pallanti et al,51 2010 20 29.05 (3.54) 20 26.38 (3.4) 0.75 (0.12 to 1.38) 1.88
Theleritis et al,56 2017 20 29.4 (3.2) 18 25.4 (5.3) 0.91 (0.25 to 1.56) 1.81
Theleritis et al,56 2017 24 30.3 (3.6) 21 27 (4) 0.86 (0.25 to 1.46) 1.95
Triggs et al,57 2010 (left sham) 7 27.7 (3.5) 7 22 (11.6) 0.62 (–0.38 to 1.63) 1.12
Triggs et al,57 2010 (right sham) 7 27.3 (2.7) 7 13.4 (7.4) 2.34 (1.03 to 3.64) 0.77
Yesavage et al,61 2018 83 27.5 (5.1) 68 14.4 (8.6) 1.89 (1.51 to 2.27) 2.58
Zheng et al,60 2010 15 24.6 (2.8) 15 22.9 (3.4) 0.53 (–0.18 to 1.24) 1.68
van Eijndhoven et al,58 2020 16 22.7 (3.8) 16 18.6 (4.2) 1.00 (0.28 to 1.72) 1.66
Test of θi = θj: Q21 = 63.57; P = .001
Invasive brain stimulation
Coenen et al,72 2019 8 29.6 (4) 8 21.46 (5.37) 1.63 (0.54 to 2.71) 1.01
Dougherty et al,40 2015 (3.3) 14 27.4 (10.5) 1.12 (0.35 to 1.90) 1.53
Holtzheimer et al,70 2017 30 37.3 (3.8) 29 30 (10.6) 0.91 (0.38 to 1.44) 2.15
Rush et al,79 2005 110 29.7 (5.2) 110 25.1 (7.6) 0.70 (0.43 to 0.98) 2.90
Test of θi = θj: Q3 = 3.52; P = .32
Parenteral
Ionescu et al,68 2019 13 26.3 (4.8) 10 20 (10.7) 0.77 (–0.06 to 1.59) 1.43
Chen et al,65 2019 16 34 (4.7) 16 26.1 (8) 1.17 (0.44 to 1.91) 1.63
Su et al,62 2017 24 23.3 (4.1) 24 13.78 (5.3) 1.98 (1.29 to 2.66) 1.75
Test of θi = θj: Q2 = 5.34; P = .07
Ayahuasca
Palhano-Fontes et al,63 2019 15 19.73 (4.59) 15 16.92 (7.36) 0.45 (–0.26 to 1.15) 1.69
Heterogeneity: τ2 = 0.00; I2 = x%; H2 = x 0.45 (–0.26 to 1.15)
Test of θi = θj: Q0 = 0.00; P = x
Overall
Test of θi = θj: Q51 = 185.86; P <.001
Test of group differences: Qb5 = 8.58; P = .13
–2 –1 0 1 2 3 4
Hedges g (95% CI)
Studies were grouped by treatment modality and pooled. Ayahuasca is a South American psychoactive brew. rTMS indicates repetitive transcranial magnetic stimulation.

Subgroup analysis found no significant differences in placebo effect among treatment

modalities (eTable 2 in the Supplement). Owing to the high heterogeneity between studies, no other
subgroup analysis was completed.
Discussion
In this meta-analysis, we report on the placebo effect in TRD across multiple treatment modalities.
We synthesized data from 50 RCTs including 3228 participants who received either pill placebo,
parenteral placebo, liquid placebo, sham rTMS, sham tDCS, or sham invasive brain stimulation. The
combined placebo effect size for all interventions was large (g = 1.05) and the placebo effect sizes for
each treatment modality did not significantly differ. This finding is consistent with prior analyses that
have shown that placebo in MDD (non-TRD) has a large effect size, seen with RCTs of antidepressants
(Cohen d = 1.69), rTMS (g = 0.8), or tDCS (g = 1.0914,15,81). Studies in other psychiatric populations
have also shown a high placebo effect size, such as negative symptoms in schizophrenia (Cohen
d = 2.91) and response rate (39.2%) in bipolar depression.82,83 Although all of these analyses
reported a large effect size, the effect size found in RCTs involving patients with TRD is numerically
smaller for pill placebo and numerically larger for sham stimulation than the effect sizes reported in
these RCTs involving patients without TRD.14,15,81
In our secondary analysis, we assessed response and remission rates as reported in the
individual RCTs. The pooled response rate across all treatment modalities was 23.5% and the
remission rate was 15.5%. These low rates did not differ significantly across treatment modalities. A
large meta-analysis in patients without TRD reported a response rate of placebo to be 35% to 40%,
which is numerically higher than our rate of 21.2%.13 Another meta-analysis reported a remission rate
Table 2. Modality-Specific Response and Remission Rates
Response Remission
Modality No. of studies % Rate (SD) No. of studies % Rate (SD)
Pill 17 21.9 (8.2) 13 16.6 (6.1)
tDCS 2 18.2 (12.8) 2 4.5 (6.4)
rTMS 16 20.8 (21.4) 7 11.2 (13.2)
Invasive brain stimulation 4 19.1 (11.0) 1 7.0 (0)
Parenteral 2 22.8 (14.5) 1 8 (0) Abbreviations: rTMS, repetitive transcranial magnetic
stimulation; tDCS, transcranial direct current
Liquid (Ayahuasca) 1 27 (0) 1 7 (0)
stimulation.
Table 3. Meta-regression for Placebo Effect
Variable No. Coefficient β (95% CI) P value

Publication year 52 0.03 (0.003 to 0.05) .03
No. of treatment arms 52 0.02 (−0.20 to 0.23) .89
Prospective treatment 52 0.35 (0.11 to 0.59) .004
Industry sponsored 52 0.34 (0.09 to 0.58) .007
Baseline depression severity 52 −0.006 (−0.04 to 0.03) .74
Total study length, d 52 0.002 (−0.001 to 0.006) .17
Total days of placebo 52 0.002 (−0.001 to 0.005) .22
Multicenter 52 0.21 (−0.05 to 0.46) .11
Augmentation treatment 52 0.35 (−0.13 to 0.83) .15
Age 51 0.02 (−0.001 to 0.05) .06
Female % 52 0.001 (−0.006 to 0.009) .72
Length of current episode 32 0.0003 (−0.004 to 0.005) .90
Past episodes 24 −0.03 (−0.15 to 0.1) .68
Effect size of active arm 51 0.08 (−0.08 to 0.25) .31
No. of failed trials 17 −0.12 (−0.23 to −0.01) .03

of 22%, which is numerically higher than our finding of 13.0%.84 Earlier studies of placebo effect that
have included participants with TRD have found that TRD was associated with a lower placebo
response, which may explain why our response and remission rates appear to be lower than in
studies involving patients without TRD.15
Our meta-regression found that RCTs that used an open-label prospective treatment phase
before double-blind randomization, a more recent year of publication, and those that were industry
sponsored had a larger placebo effect. A meta-analysis of placebo response in negative symptoms of
schizophrenia also reported that placebo response was higher in industry-sponsored clinical trials
(Cohen d = 6.72) compared with academic-funded trials (Cohen d = 1.01).82 Only pill placebo RCTs
used an open-label prospective treatment phase and only 1 small rTMS RCT was industry sponsored.
Previous research has also suggested that, in populations without treatment-resistant MDD, a higher
placebo response was associated with more recent year of publication.85 Other studies have
suggested that finding may reflect methodological changes, such as an increased number of
multicenter studies.86 Placebo effect has been shown to be associated with expectancy of active
treatment and increased activity in reward circuitry.6,87 Industry-sponsored RCTs are often
investigating novel agents, which may lead to increased expectations of efficacy by participants,
although we are unable to confirm this possibility with available data. Another potential contributing
factor to the higher placebo effect in the prospective open-label treatment trials is that of delayed
antidepressant response. In these studies, patients are continuing the recently started
antidepressant from the prospective open-label treatment phase in combination with placebo or
another active agent, which may be contributing to a delayed response. The number of failed trials
was also significantly associated with a smaller placebo effect. Although only 17 of 50 studies
reported on this variable, this finding is consistent with previous literature showing that a higher level
of treatment resistance is associated with a smaller placebo effect.15
Our analysis did not find that the placebo effect was significantly different across treatment
modalities. This finding is consistent with trials comparing rTMS with escitalopram.16 The large
placebo effect in TRD does not change substantially based on modality. This lack of effect supports
the notion that the nonspecific factors contributing to the placebo effect in TRD are prevalent in any
clinical trial. Our findings suggest that the invasiveness of the intervention (eg, pill vs invasive brain
stimulation) does not substantially affect the placebo effect in TRD. Given the consistency of the
placebo effect across treatment modalities in TRD, neurobiological and common psychological
factors need to be further investigated.
Our primary finding that the placebo effect in TRD is large (g = 1.05) and that it is consistent
across treatment modalities may help to interpret the results of past and future RCTs. Researchers
who conduct clinical trials may now compare their results with a benchmark for expected placebo
effect in TRD. For instance, a placebo-controlled RCT that reports negative findings but had a placebo
effect size greater than g = 1.05 could be interpreted as a false-negative; conversely, an RCT that
reports positive findings with a placebo effect size less than g = 1.05 could be a false-positive. Our
results also provide a context for noninferiority trials that do not use a placebo or sham control
intervention. Treatments that differentiate from this benchmark (g = 1.05) by a predetermined
margin would be expected to be superior to placebo.
Limitations
This study has limitations. Although we were able to include several different treatment modalities
in our analysis, no psychotherapy RCTs met our eligibility criteria. Psychotherapy trials in TRD were
either open-label, single arm, had an active comparator, or used treatment as usual or a wait-list
condition. There were also no RCTs of electroconvulsive therapy or magnetic seizure therapy that
used sham versions of these procedures in a TRD population. Another limitation is the definition of
TRD. Although we used the most common definition, there is no standard TRD definition. A large
proportion of studies that were excluded reported including patients with TRD even though they
defined TRD based on only one failed antidepressant trial. For this reason, we were unable to include

2 large industry-sponsored trials for rTMS.88,89 Future research would benefit from an improved and
consistent definition of TRD. Current definitions of TRD are homogeneous and do not consistently
account for a number of important factors, such as specific treatments failed (eg, psychotherapy vs
brain stimulation vs selective serotonin reuptake inhibitor vs serotonin and norepinephrine reuptake
inhibitor) and psychosocial factors. Although we aimed to compare the placebo effect across
treatment modalities, our results are limited by the absence of direct comparison of 2 placebo
modalities (ie, sham brain stimulation vs pill placebo).
Conclusions
The present systematic review and meta-analysis compared the placebo effect in TRD across
different treatment modalities. Our main finding was that the placebo effect in TRD appears to be
large and consistent across treatment modalities. The effect size in the studies included in our
analysis (g = 1.05) may serve as a benchmark to assess placebo effect in future TRD RCTs. Factors
that increase the placebo effect appear to include using an open-label, prospective treatment phase
and industry sponsorship. To better understand the placebo effect, the following improvements are
needed: more consistent reporting of data, an agreement on a standard definition of TRD and its
possible subgroups, and further assessment and reporting of participants’ expectations and
experiences within a clinical trial.
ARTICLE INFORMATION
Accepted for Publication: July 15, 2021.
Published: September 24, 2021. doi:10.1001/jamanetworkopen.2021.25531
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Jones BDM
et al. JAMA Network Open.
Corresponding Author: Zafiris J. Daskalakis, MD, PhD, Department of Psychiatry, University of California
San Diego, 9500 Gilman Dr, La Jolla, CA 92093 (zdaskalakis@health.ucsd.edu).
Author Affiliations: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Jones, Weissman,
Karbi, Husain, B. H. Mulsant, Blumberger); Department of Internal Medicine, Faculty of Medicine, University of Sao
Paulo, Sao Paulo, Brazil (Razza, Brunoni); Laboratory of Neurosciences, Instituto Nacional de Biomarcadores em
Neuropsiquiatria, Department and Institute of Psychiatry, Faculdade de Medicina, University of Sao Paulo, Sao
Paulo, Brazil (Razza, Brunoni); Centre for Addiction and Mental Health, Toronto, Ontario, Canada (Weissman,
Husain, B. H. Mulsant, Blumberger); Michael G. Degroote School of Medicine, McMaster University, Hamilton,
Ontario, Canada (Vine); Nova Scotia Health, Halifax, Nova Scotia, Canada (L. S. Mulsant); Department of Psychiatry,
University of California San Diego (Daskalakis).
Author Contributions: Dr Jones and Ms Razza are co-first authors and had full access to all of the data in the study
and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Jones, Weissman, Brunoni, Husain, Daskalakis.
Acquisition, analysis, or interpretation of data: Jones, Razza, Weissman, Karbi, Vine, L. Mulsant, B. Mulsant,
Blumberger, Daskalakis.
Drafting of the manuscript: Jones, Weissman, Husain, Daskalakis.
Critical revision of the manuscript for important intellectual content: Jones, Razza, Weissman, Karbi, Vine, L.
Mulsant, Brunoni, Husain, B. Mulsant, Blumberger.
Statistical analysis: Jones, Razza, Brunoni, Daskalakis.
Obtained funding: Jones, Daskalakis.
Administrative, technical, or material support: Jones, Weissman, Daskalakis.
Supervision: Jones, Weissman, Brunoni, Husain, B. Mulsant, Blumberger, Daskalakis.
Conflict of Interest Disclosures: Dr Blumberger has received research support from the Canadian Institutes of
Health Research, the National Institutes of Health (NIH), Brain Canada, and the Temerty Family through the Centre
for Addiction and Mental Health (CAMH) Foundation and the Campbell Research Institute. He received research

support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd, and he is the site
principal investigator for 3 sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support
from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated
trial from Indivior. Dr Mulsant holds and receives support from the Labatt Family Chair in Biology of Depression in
Late-Life Adults at the University of Toronto; he also currently receives research support from Brain Canada, the
Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute
(PCORI), the NIH, Capital Solution Design LLC (software used in a study funded by the CAMH Foundation), and
HAPPYneuron (software used in a study founded by Brain Canada). Within the past 5 years he has also received
research support (medications or matching placebo pills for NIH-funded clinical trials) from Bristol-Myers Squibb,
Eli Lilly, and Pfizer. Dr Brunoni receives grants from the National Council for Scientific and Technological
Development (CNPQ, PQ-1B), the Program of Academic Productivity of the University of São Paulo Medical School,
and from the São Paulo Research Foudation. Dr Brunoni is chief medical advisor of Flow and has a small equity of
the company. The LIM-27 Laboratory of Neuroscience receives grants from the Associação Beneficente Alzira
Denise Hertzog da Silva. Dr Husain reports receiving grants from Stanley Medical Research Institute during the
conduct of the study, personal fees from COMPASS Pathways Limited, grants from the PSI Foundation, and grants
from Brain and Behavior Research Foundation outside the submitted work, and was previously appointed a
member of the board of trustees of Pakistan Institute of Living and Learning. Ms Razza is supported by São Paulo
Research Foundation. Dr Husain reported grants from COMPASS Pathways Limited, grants from University of
Toronto, grants from PSI Foundation, grants from Brain and Behavior Research Foundation, and grants from CAMH
Foundation outside the submitted work. Dr B. Mulsant reported he holds, and receives support from, the Labatt
Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives
research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, PCORI,
the US NIH, Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and
HAPPYneuron (software used in a study founded by Brain Canada). Within the past 3 years, he has also received
research support from Eli Lilly (medications for an NIH-funded clinical trial) and Pfizer (medications for an
NIH-funded clinical trial). He has been an unpaid consultant to Myriad Neuroscience. Dr Blumberger reported
nonfinancial support from Magventure, in-kind equipment support for investigator-initiated research, other
support from Brainsway Site PI for sponsored clinical trials, and other support from Janssen One advisory board
meeting outside the submitted work. Dr Daskalakis reported grants from Brainsway Inc, nonfinancial support from
Magventure Inc, and nonfinancial support from Brainsway during the conduct of the study. No other disclosures
were reported.
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SUPPLEMENT.
eTable 1. Risk of Bias
eTable 2. Subgroup Analysis of Treatment Modalities
eTable 3. Clinical Characteristics
eAppendix 1. Components of the Randomized Effect Model Used for Our Analyses
eAppendix 2. Search Strategy
eFigure 1. Funnel Plot of Included Studies
eFigure 2. Trim and Fill Funnel Plot
eFigure 3. Forest Plot of Main Placebo Effect Size Grouped by Risk of Bias

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Original Investigation | Psychiatry

Magnitude of the Placebo Response Across Treatment Modalities

Abstract Key Points

Meaning The findings of this study

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JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531

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20 757 Records identified through 73 Additional records identified

11 236 Records after duplicates removed

11 236 Records screened

10 650 Records excluded

586 Full-text articles assessed for eligibility

536 Full-text articles excluded

50 Studies included in qualitative synthesis

50 Studies included in quantitative

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Demographic characteristics Methodologic characteristics Placebo characteristics

JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 (Reprinted)

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September 24, 2021

Demographic characteristics Methodologic characteristics Placebo characteristics

JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 (Reprinted)

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September 24, 2021

Demographic characteristics Methodologic characteristics Placebo characteristics

JAMA Network Open. 2021;4(9):e2125531. doi:10.1001/jamanetworkopen.2021.25531 (Reprinted)

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September 24, 2021

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Subgroup analysis found no significant differences in placebo effect among treatment

Table 2. Modality-Specific Response and Remission Rates

Table 3. Meta-regression for Placebo Effect

Variable No. Coefficient β (95% CI) P value

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