Differential power of placebo across major psychiatric disorders: a preliminary meta-analysis and machine learning study

AbstractThe placebo effect across psychiatric disorders is still not well understood. In the present study, we conducted meta-analyses including meta-regression, and machine learning analyses to investigate whether the power of placebo effect depends on the types of psychiatric disorders. We included 108 clinical trials (32,035 participants) investigating pharmacological intervention effects on major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ). We developed measures based on clinical rating scales and Clinical Global Impression scores to compare placebo effects across these disorders. We performed meta-analysis including meta-regression using sample-size weighted bootstrapping techniques, and machine learning analysis to identify the disorder type included in a trial based on the placebo response. Consistently through multiple measures and analyses, we found differential placebo effects across the three disorders, and found lower placebo effect in SCZ compared to mood disorders. The differential placebo effects could also distinguish the condition involved in each trial between SCZ and mood disorders with machine learning. Our study indicates differential placebo effect across MDD, BD, and SCZ, which is important for future neurobiological studies of placebo effects across psychiatric disorders and may lead to potential therapeutic applications of placebo on disorders more responsive to placebo compared to other conditions.

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Systematic review and meta-analysis of the placebo effect in panic disorder: Implications for research and clinical practice

Australian & New Zealand Journal of Psychiatry ◽

10.1177/00048674211068793 ◽

2022 ◽

pp. 000486742110687

Author(s):

Masoud Ahmadzad-Asl ◽

Farnoush Davoudi ◽

Safoura Mohamadi ◽

Fatemeh Hadi ◽

Seyed Aria Nejadghaderi ◽

...

Keyword(s):

Systematic Review ◽

Clinical Practice ◽

Panic Disorder ◽

Placebo Effect ◽

Effect Size ◽

Rating Scales ◽

Data Extraction ◽

Meta Analysis ◽

Placebo Response ◽

Patient Reports

Objective: This review aimed to measure the degree of placebo response in panic disorder. Data Sources: We searched major databases up to 31 January 2021, for randomized pharmacotherapy trials published in English. Study Selection: A total of 43 studies met inclusion criteria to be in the analysis (with 174 separate outcome measurements). Data Extraction: Changes in outcome measures from baseline in the placebo group were used to estimate modified Cohen’s d effect size. Results: A total of 43 trials (2392 subjects, 174 outcomes using 27 rating scales) were included in the meta-analysis. Overall placebo effect size was 0.57 (95% confidence interval = [0.50, 0.64]), heterogeneity ( I2: 96.3%). Higher placebo effect size was observed among clinician-rated scales compared to patient reports (0.75 vs 0.35) and among general symptom and anxiety scales compared to panic symptoms and depression scales (0.92 and 0.64 vs 0.56 and 0.54, respectively). There was an upward trend in effect size over the publication period ( r = 0.02, p = 0.002) that was only significant among clinician-rated scales ( r = 0.02, p = 0.011). There was no significant publication bias, Egger’s test ( p = 0.08). Conclusion: We observed a substantial placebo effect size in panic disorder. This effect was more prominent for some aspects of panic disorder psychopathology than for others and was correlated with the source of the assessment and publication year. This finding has implications both for research design, to address the heterogeneity and diversity in placebo responses, and for clinical practice to ensure optimal quality of care. Systematic review registration number: PROSPERO, CRD42019125979.

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Emotional Intelligence and Attachment in Adulthood: A Meta-analysis

10.31234/osf.io/36zcr ◽

2021 ◽

Author(s):

Sarah A Walker ◽

Kit S Double ◽

Hannah Kunst ◽

Michael Zhang ◽

Carolyn MacCann

Keyword(s):

Emotional Intelligence ◽

Attachment Styles ◽

Rating Scales ◽

Meta Analysis ◽

Secure Attachment ◽

Emotional Experiences ◽

Anxious Attachment ◽

Avoidant Attachment ◽

Causal Direction ◽

Meta Regression

Attachment styles form during childhood emotional experiences. These experiences may be shaped by emotion-related traits such as how children interpret and regulate their own and others' emotions. These emotion-related traits appear in many emotional intelligence (EI) models, such that EI may relate to attachment styles. We conduct a meta-analysis to estimate the association between EI and attachment styles (26 studies, N = 6914). We include only non-clinical adult samples and validated psychometric assessments. We examine EI type as a moderator, comparing ability EI versus EI rating-scales using subgroups analysis and meta-regression. We find that lower anxious attachment is significantly associated with EI rating-scales (r = −0.25, k = 26) and ability EI (r = −0.16, k = 45), lower avoidant attachment is significantly associated with EI rating-scales (r = −0.36, k = 21) and ability EI (r = −0.21, k = 40), but secure attachment is significantly associated with EI rating-scales only (r = 0.31, k = 30). EI type significantly moderated the EI/avoidant attachment association only (β = −0.14, p = .01). We discuss possible mechanisms by which EI could influence early development of attachment styles (and vice-versa) while acknowledging that the causal direction underlying EI/attachment associations is unclear.

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Placebo response in treatment resistant depression: a systematic review and meta-analysis of multiple treatment modalities

BJPsych Open ◽

10.1192/bjo.2021.697 ◽

2021 ◽

Vol 7 (S1) ◽

pp. S261-S262

Author(s):

Brett D M Jones ◽

Cory R. Weissman ◽

Jewel Karbi ◽

Tya Vine ◽

Louise S. Mulsant ◽

...

Keyword(s):

Systematic Review ◽

Brain Stimulation ◽

Placebo Effect ◽

Meta Analysis ◽

Specific Treatment ◽

Placebo Response ◽

Treatment Modalities ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression

AimsThe placebo response in depression clinical trials is a major contributing factor for failure to establish the efficacy of novel and repurposed treatments. However, it is not clear as to what the placebo response in treatment-resistant depression (TRD) patients is or whether it differs across treatment modalities. Our objective was to conduct a systematic review and meta-analysis of the magnitude of the placebo response in TRD patients across different treatment modalities and its possible moderators.MethodSearches were conducted on MEDLINE and PsychInfo from inception to January 24, 2020. Only studies that recruited TRD patients and randomization to a placebo (or sham) arm in a pharmacotherapy, brain stimulation, or psychotherapy study were included (PROSPERO 2020 CRD42020190465). The primary outcome was the Hedges’ g for the reported depression scale using a random-effects model. Secondary outcomes included moderators assessed via meta-regression and response and remission rate. Heterogeneity was evaluated using the Egger's Test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks.Result46 studies met our inclusion criteria involving a total of 3083 participants (mean (SD) age: 45.7 (6.2); female: 52.4%). The pooled placebo effect for all modalities was large (N = 3083, g = 1.08 ,95% CI [0.95-1.20)I 2 = 0.1). The placebo effect in studies of specific treatment modalities did not significantly differ: oral medications g = 1.14 (95%CI:0.99-1.29); parenteral medications g = 1.32 (95%CI:0.59-2.04); ayahuasca g = 0.47 (95%CI:-0.28-1.17); rTMS g = 0.93 (95%CI:0.63-1.23); tDCS g = 1.32 (95%CI:0.52-2.11); invasive brain stimulation g = 1.06 (95%CI:0.64-1.47). There were no psychotherapy trials that met our eligibility criteria. Similarly, response and remission rates were comparable across modalities. Heterogeneity was large. Two variables predicted a lager placebo effect: open-label prospective design (B:0.32, 95%CI: 0.05-0.58; p:0.02) and sponsoring by a pharmaceutical or medical device company (B:0.39, 95%CI:0.13-0.65, p:0.004)). No risk of publication bias was found.ConclusionThe overall placebo effect in TRD studies was large (g = 1.08) and did not differ among treatment modalities. A better understanding of the placebo response in TRD will require: standardizing the definition of TRD, head-to-head comparisons of treatment modalities, an assessment of patient expectations and experiences, and standardized reporting of outcomes.

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Choice and the Placebo Effect: A Meta-analysis

Annals of Behavioral Medicine ◽

10.1093/abm/kaab111 ◽

2022 ◽

Author(s):

Biya Tang ◽

Kirsten Barnes ◽

Andrew Geers ◽

Evan Livesey ◽

Ben Colagiuri

Keyword(s):

Placebo Effect ◽

Effect Size ◽

Meta Analysis ◽

Placebo Treatment ◽

Placebo Effects ◽

Sleep Difficulty ◽

Clinical Scenarios ◽

Health Related ◽

Choice Frequency ◽

Improve Patient

Abstract Background Choice has been proposed as a method of enhancing placebo effects. However, there have been no attempts to systematically evaluate the magnitude, reliability, and moderators of the influence of choice on the placebo effect. Purpose To estimate the effect size of choice on the placebo effect and identify any moderators of this effect. Methods Web of Science, PsycINFO, EMBASE, and PubMed were systematically searched from inception to May 2021 for studies comparing placebo treatment with any form of choice over its administration (e.g., type, timing) to placebo treatment without choice, on any health-related outcome. Random-effects meta-analysis was then used to estimate the effect size associated with the influence of choice on the placebo effect. Meta-regression was subsequently employed to determine the moderating effect of factors such as type of choice, frequency of choice, and size of the placebo effect without choice. Results Fifteen independent studies (N = 1,506) assessing a range of conditions, including pain, discomfort, sleep difficulty, and anxiety, met inclusion criteria. Meta-analysis revealed that choice did significantly enhance the placebo effect (Hedges’ g = 0.298). Size of the placebo effect without choice was the only reliable moderator of this effect, whereby a greater effect of choice was associated with smaller placebo effects without choice. Conclusions Treatment choice can effectively facilitate the placebo effect, but this effect appears more pronounced in contexts where the placebo effect without choice is weaker. Because most evidence to date is experimental, translational studies are needed to test whether providing choice in clinical scenarios where placebo effects are weaker may help boost the placebo effect and thereby improve patient outcomes.

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Placebo response in trials of drug treatments for cancer-related fatigue: a systematic review, meta-analysis and meta-regression

BMJ Supportive & Palliative Care ◽

10.1136/bmjspcare-2019-002163 ◽

2020 ◽

Vol 10 (4) ◽

pp. 385-394 ◽

Cited By ~ 1

Author(s):

Rocio Roji ◽

Patrick Stone ◽

Federico Ricciardi ◽

Bridget Candy

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Placebo Response ◽

Risk Of Bias ◽

Small Samples ◽

Contributing Factors ◽

Cancer Related Fatigue ◽

Study Results ◽

Meta Regression ◽

Multiple Drugs

BackgroundCancer-related fatigue (CRF) is one of the most distressing symptoms experienced by patients. There is no gold standard treatment, although multiple drugs have been tested with little evidence of efficacy. Randomised controlled trials (RCTs) of these drugs have commented on the existence or size of the placebo response (PR). The objective of this systematic review was to establish the magnitude of the PR in RCTs of drugs to relieve CRF and to identify contributing factors.MethodRCTs were included in which the objective was to treat CRF. A meta-analysis was conducted using the standardised mean change (SMC) between baseline and final measurement in the placebo group. To explore factors that may be associated with the PR (eg, population or drug), a meta-regression was undertaken. Risk of bias was assessed using the revised Cochrane tool.ResultsFrom 3916 citations, 30 relevant RCTs were identified. All had limitations that increased their risk of bias. The pooled SMC in reduction in fatigue status in placebo groups was −0.23 (95% confidence intervals −0.42 to −0.04). None of the variables analysed in the meta-regression were statistically significant related to PR.ConclusionThere is some evidence, based on trials with small samples, that the PR in trials testing drugs for CRF is non-trivial in size and statistically significant. We recommend that researchers planning drug studies in CRF should consider implementing alternative trial designs to better account for PR and decrease impact on the study results.

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Hidden Assumptions and the Placebo Effect

Acupuncture in Medicine ◽

10.1136/aim.2009.000711 ◽

2009 ◽

Vol 27 (2) ◽

pp. 68-69 ◽

Cited By ~ 3

Author(s):

Anthony Campbell

Keyword(s):

Placebo Effect ◽

Folk Psychology ◽

Placebo Response ◽

Placebo Effects ◽

Cartesian Dualism ◽

Reading Research ◽

Philosophical Assumption ◽

Acupuncture Effects ◽

The Brain

Whether, or how far, acupuncture effects can be explained as due to the placebo response is clearly an important issue, but there is an underlying philosophical assumption implicit in much of the debate, which is often ignored. Much of the argument is cast in terms which suggest that there is an immaterial mind hovering above the brain and giving rise to spurious effects. This model derives from Cartesian dualism which would probably be rejected by nearly all those involved, but it is characteristic of “folk psychology” and seems to have an unconscious influence on much of the terminology that is used. The majority of philosophers today reject dualism and this is also the dominant trend in science. Placebo effects, on this view, must be brain effects. It is important for modern acupuncture practitioners to keep this in mind when reading research on the placebo question.

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Paracetamol and the Placebo Effect in Osteoarthritis Trials: A Missing Link?

Pain Research and Treatment ◽

10.1155/2011/696791 ◽

2011 ◽

Vol 2011 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Henning Zeidler

Keyword(s):

Placebo Effect ◽

Rescue Medication ◽

Meta Analysis ◽

Symptom Relief ◽

Placebo Response ◽

Potential Contribution ◽

Missing Link ◽

Starting Dose ◽

Positive Effect

This paper addresses the role of paracetamol in placebo-controlled osteoarthritis (OA) trials and the potential contribution to the large placebo response in such trials. Paracetamol is used as rescue medication in nearly all OA placebo-controlled trials. Triggered by the discussion about the placebo effect in general and because of the lack of systematic reviews of placebo effect in OA trials, a recent meta-analysis examined the placebo effect and its potential determinants in the treatment of OA, as the main result came out that placebo is very effective in the treatment of OA, especially for pain, stiffness, and self-reported function. However, mostly limited data are available from published OA trials on the starting dose, final dose, dose over time of paracetamol use, and the percentage of patients who used rescue medication during the study. Paracetamol may be an important additional simulated effect of placebo administration mimicking the true placebo effect and thus a missing link contributing partially to the large placebo response in OA trials. Therefore, the positive effect of paracetamol on symptom relief as well as the need for standardized recording of rescue medication should be taken into account when designing, executing, and interpreting placebo-controlled OA studies.

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