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Molecular Psychiatry Mar 2022There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap... (Meta-Analysis)
Meta-Analysis
There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.
Topics: Depression; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Neuroimaging; Placebo Effect; Prefrontal Cortex; Transcranial Magnetic Stimulation
PubMed: 34903861
DOI: 10.1038/s41380-021-01397-3 -
Sexually Transmitted Diseases Sep 2022Active-controlled noninferiority studies are used to investigate novel agents for uncomplicated urogenital gonorrhea (uUGC) as placebo-controlled trials are unethical. A... (Meta-Analysis)
Meta-Analysis
Systematic Review and Meta-Analysis to Estimate the Treatment Effect and Inform a Noninferiority Margin for a Phase 3 Noninferiority Trial in Uncomplicated Urogenital Gonorrhea.
BACKGROUND
Active-controlled noninferiority studies are used to investigate novel agents for uncomplicated urogenital gonorrhea (uUGC) as placebo-controlled trials are unethical. A systematic literature review and meta-analysis were conducted to estimate the ceftriaxone and proxy-for-placebo microbiological treatment effect and determine an appropriate noninferiority margin for phase 3 trials.
METHODS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. To account for interstudy variability, a weighted, noniterative random-effects model was fitted using "R" software to estimate the microbiological response rate and 95% confidence intervals (CIs) for ceftriaxone and proxy-for-placebo (treatment with an antibiotic the isolate was subsequently confirmed resistant to, or spontaneous resolution without treatment). I2 , τ2 , and P values were computed and included in the meta-analysis forest plot.
RESULTS
Seventeen studies were included in the meta-analysis; 14 reported ceftriaxone response in micro-intent-to-treat and microbiologically evaluable populations, and 3 reported proxy-for-placebo treatment response in uUGC (microbiologically evaluable population only). Microbiological treatment effect was estimated by subtracting the upper end of the CI for placebo from the lower end of the CI for ceftriaxone. Overall microbiological response was 98% (95% CI, 97-99) for ceftriaxone and 44% (95% CI, 34-54) for proxy-for-placebo, resulting in a microbiological treatment effect of 43%. A noninferiority margin of 15% preserved 65% of the ceftriaxone treatment effect, exceeding the 50% recommended per US Food and Drug Administration guidance for noninferiority studies.
CONCLUSIONS
Results of this systematic literature review and meta-analysis could help inform the design, conduct, and analysis of future clinical studies in uUGC.
Topics: Anti-Bacterial Agents; Ceftriaxone; Gonorrhea; Humans; Treatment Outcome
PubMed: 35675712
DOI: 10.1097/OLQ.0000000000001657 -
Drug Safety 2009Biases in adverse effect reporting in randomized controlled trials (RCTs) [e.g. due to investigator expectations or assessment quality] can be quantified by studying the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Biases in adverse effect reporting in randomized controlled trials (RCTs) [e.g. due to investigator expectations or assessment quality] can be quantified by studying the rates of adverse events reported in the placebo arms of such trials.
OBJECTIVE
We compared the rates of adverse effects reported in the placebo arms of tricyclic antidepressant (TCA) trials and placebo arms of selective serotonin reuptake inhibitor (SSRI) trials.
METHODS
We conducted a literature search for RCTs across PUBMED, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL). Only studies allowing adverse effect analysis were included. Publication year ranged from 1981 to 2007.
RESULTS
Our systematic review and meta-analysis included 143 placebocontrolled RCTs and data from 12,742 patients. Only 21% of studies used structured and systematic adverse effect ascertainment strategies. The way in which trials recorded adverse events influenced the rate of adverse effects substantially. Systematic assessment led to higher rates than less systematic assessment. Far more adverse effects were reported in TCA-placebo groups compared with SSRI-placebo groups, e.g. dry mouth (odds ratio [OR] = 3.5; 95% CI 2.9, 4.2); drowsiness (OR = 2.7; 95%CI 2.2, 3.4); constipation (OR= 2.7; 95%CI 2.1, 3.6); sexual problems (OR =2.3; 95%CI 1.5, 3.5). Regression analyses controlling for various influencing factors confirmed the results.
CONCLUSION
Adverse effect profiles reported in clinical trials are strongly influenced by expectations from investigators and patients. This difference cannot be attributed to ascertainment methods. Adverse effect patterns of the drug group are closely related to adverse effects of the placebo group. These results question the validity of the assumption that adverse effects in placebo groups reflect the 'drug-unspecific effects'.
Topics: Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Bias; Humans; Randomized Controlled Trials as Topic; Regression Analysis; Research Personnel; Research Subjects; Selective Serotonin Reuptake Inhibitors
PubMed: 19810776
DOI: 10.2165/11316580-000000000-00000 -
Critical Reviews in Food Science and... 2023Although creatine supplementation is well-known to increase exercise performance in acute high-intensity exercises, its role in aerobic performance based on VOmax is... (Meta-Analysis)
Meta-Analysis
Although creatine supplementation is well-known to increase exercise performance in acute high-intensity exercises, its role in aerobic performance based on VOmax is more controversial. Thus, we performed a systematic review and meta-analysis on the effects of creatine supplementation on VOmax. PubMed, Cochrane, Embase, and ScienceDirect were searched for randomized controlled trials (RCTs) reporting VOmax in creatine supplementation and placebo groups before and after supplementation. We computed a random-effects meta-analysis on VOmax at baseline, within groups following supplementation, on changes on VOmax between groups, and after supplementation between groups. Sensitivity analyses and meta-regression were conducted. We included 19 RCTs for a total of 424 individuals (mean age 30 years old, 82% men). VOmax did not differ at baseline between groups (creatine and placebo). Participants in both groups were engaged in exercise interventions in most studies (80%). Using changes in VOmax, VOmax increased in both groups but increased less after creatine supplementation than placebo (effect size [ES] = -0.32, 95%CI = -0.51 to -0.12, = 0.002). Comparisons after creatine supplementation confirmed a lower VOmax in the creatine group compared to the placebo group (ES= -0.20, 95%CI = -0.39 to -0.001, = 0.049). Meta-analysis after exclusion from meta-funnel resulted in similar outcomes in a subgroup of young and healthy participants. Meta-regressions on characteristics of supplementation, physical training, or sociodemographic were not statistically significant. Creatine supplementation has a negative effect on VOmax, regardless of the characteristics of training, supplementation, or population characteristics.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.2008864 .
Topics: Male; Humans; Adult; Female; Creatine; Exercise; Dietary Supplements
PubMed: 34859731
DOI: 10.1080/10408398.2021.2008864 -
PloS One 2014Cancer-related fatigue (CRF) is a common symptom affecting patients with cancer. There are an increasing number of trials examining potential treatments for CRF.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cancer-related fatigue (CRF) is a common symptom affecting patients with cancer. There are an increasing number of trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs and an up-to-date assessment of the evidence for its use is needed. Trials of methylphenidate for CRF provided inconsistent results. This meta-analysis was aimed at assessing the effect and safety of methylphenidate on CRF.
METHODS
We comprehensively searched the Pubmed, EMBASE, PSYCHInfo and the Cochrane databases in order to identify published studies on the effect of methylphenidate on CRF. Primary outcomes included fatigue. Secondary outcomes included depression, cognition and adverse effects.
FINDINGS
A meta-analysis was conducted on five randomized controlled trials and 498 patients were enrolled. Despite a large placebo effect observed in the studies included, pooled data suggested therapeutic effect of methylphenidate on CRF. Subgroup Analyses showed that the efficacy of methylphenidate on CRF is getting better with prolonging treatment duration, with a MD of -3.70 (95% CI -7.03- -0.37, p = 0.03) for long-time group and a MD of -2.49 (95% CI -6.01-1.03, p = 0.17) for short-time group. In general, there was no impact of methylphenidate on depression and cognition associated with CRF. Adverse events were similar between methylphenidate and placebo groups except that more patients reported vertigo, anxiety, anorexia and nausea in methylphenidate group compared to placebo group.
CONCLUSION
Existing trials of methylphenidate on CRF provided limited evidence for the use of methylphenidate to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF.
Topics: Cognition; Depression; Fatigue; Humans; Methylphenidate; Neoplasms
PubMed: 24416225
DOI: 10.1371/journal.pone.0084391 -
Pain Nov 2023Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that... (Meta-Analysis)
Meta-Analysis
Observing someone experience pain relief or exacerbation after an intervention may induce placebo hypoalgesia or nocebo hyperalgesia. Understanding the factors that contribute to these effects could help in the development of strategies for optimizing treatment of chronic pain conditions. We systematically reviewed and meta-analyzed the literature on placebo hypoalgesia and nocebo hyperalgesia induced by observational learning (OL). A systematic literature search was conducted in the databases PubMed, PsycINFO, Web of Science, ScienceDirect, PsycARTICLES, Scopus, and Academic Search Ultimate. Twenty-one studies were included in the systematic review, 17 of which were suitable for meta-analysis (18 experiments; n = 764 healthy individuals). The primary end point was the standardized mean difference (SMD) for pain following placebo cues associated during OL with low vs high pain. Observational learning had a small-to-medium effect on pain ratings (SMD 0.44; 95% confidence interval [CI] 0.21-0.68; P < 0.01) and a large effect on pain expectancy (SMD 1.11; 95% CI 0.49-2.04; P < 0.01). The type of observation (in-person vs videotaped) modulated the magnitude of placebo hypoalgesia/nocebo hyperalgesia ( P < 0.01), whereas placebo type did not ( P = 0.23). Finally, OL was more effective when observers' empathic concern (but no other empathy-related factors) was higher ( r = 0.14; 95% CI 0.01-0.27; P = 0.03). Overall, the meta-analysis demonstrates that OL can shape placebo hypoalgesia and nocebo hyperalgesia. More research is needed to identify predictors of these effects and to study them in clinical populations. In the future, OL could be an important tool to help maximize placebo hypoalgesia in clinical settings.
Topics: Humans; Hyperalgesia; Nocebo Effect; Pain; Learning; Pain Perception; Placebo Effect
PubMed: 37326688
DOI: 10.1097/j.pain.0000000000002943 -
Neurogastroenterology and Motility Feb 2023Pharmacological trials in functional dyspepsia (FD) are associated with high placebo response rates. We aimed to identify the magnitude and contributing factors to the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pharmacological trials in functional dyspepsia (FD) are associated with high placebo response rates. We aimed to identify the magnitude and contributing factors to the placebo response.
METHODS
We conducted a systematic review and meta-analysis including randomized controlled trials (RCTs) with a dichotomous outcome in adult patients with FD that compared an active pharmacotherapeutic treatment with placebo. Our main outcome was identification of the magnitude of the pooled placebo response rate for the following endpoints: symptom responder, symptom-free responder, adequate relief responder, and combined endpoint responder (i.e., the primary endpoint of each specific trial regarding treatment response). Several putative moderators (i.e., patient, disease, and trial characteristics) were examined.
KEY RESULTS
We included 26 RCTs in our analysis. The pooled placebo response rate was 39.6% (95% CI 30.1-50.0) using the symptom responder definition, 20.5% (12.8-31.0) using the symptom-free responder definition, 38.5% (33.8-43.6) using the adequate relief responder definition, and 35.5% (31.6-39.7) using the combined endpoint responder definition. A lower overall baseline symptom score was significantly associated with a higher placebo response rate. No other moderators were found to significantly impact the placebo response rate. Due to the lack of data, no analyses could be performed according to individual FD subtypes or symptoms.
CONCLUSIONS AND INFERENCES
The pooled placebo response rate in pharmacological trials in FD is about 39%, depending on which responder definitions is used. Future trials should consider applying an entry criterion based on minimal level of symptom severity to decrease the placebo response. We also suggest separate reporting of core FD symptoms pending more concrete harmonization efforts in FD trials.
Topics: Adult; Humans; Dyspepsia; Placebo Effect; Treatment Outcome
PubMed: 36168188
DOI: 10.1111/nmo.14474 -
Inflammatory Bowel Diseases Apr 2024Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Precise estimates of placebo response rates help efficient clinical trial design. In this systematic review and meta-analysis, we assessed contemporary placebo endoscopic and histological response rates in Crohn's disease (CD) clinical trials.
METHODS
MEDLINE, EMBASE, and Cochrane CENTRAL were searched from inception to April 2022 to identify placebo-controlled studies of pharmacological interventions for CD. Endoscopic response, remission, and mucosal healing rates for participants assigned to placebo in induction and maintenance studies were pooled using a random-effects model. Point estimates and associated 95% confidence intervals (CIs) were calculated.
RESULTS
In total, 16 studies (11 induction, 3 maintenance, 2 induction and maintenance) that randomized 1646 participants to placebo were eligible. For induction trials, the pooled placebo endoscopic response, endoscopic remission, and mucosal healing rates in participants assigned to placebo were 13% (95% CI, 10-16; I2 = 14.1%; P = .14), 6% (95% CI, 3-11; I2 = 74.7%; P < .001), and 6% (95% CI, 4-9; I2 = 26.9%; P = .29), respectively. The pooled endoscopic remission rate in patients who were bio-naïve was 10% (95% CI, 4-23) compared with only 4% (95% CI, 3-7) in bio-experienced patients. For maintenance trials, the pooled endoscopic response, remission, and mucosal healing rates were 7% (95% CI, 1-31; I2 = 78.2%; P = .004), 11% (95% CI, 4-27; I2 = 70.8%; P = .06), and 7% (95% CI, 3-15; I2 = 29.7; P = .23), respectively. Only 3 trials assessed histological outcomes.
CONCLUSIONS
Endoscopic placebo rates vary according to trial phase and prior biologic exposure. These contemporary data will serve to inform CD trial design, sample size calculation, and end point selection for future trials.
Topics: Humans; Crohn Disease; Endoscopy; Remission Induction; Placebo Effect; Randomized Controlled Trials as Topic
PubMed: 37002875
DOI: 10.1093/ibd/izad052 -
The American Journal of Gastroenterology Dec 2019Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Chronic idiopathic constipation (CIC), like other functional gastrointestinal disorders, has been associated with a high placebo response rate. However, the placebo response in randomized controlled trials has not been described.
METHODS
We conducted a search of the medical literature following the protocol outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement using MEDLINE, EMBASE and EMBASE Classic, Web of Science, and the Cochrane Central Register of Controlled Trials for all drugs used for the treatment of CIC. Two independent reviewers performed eligibility assessment and data extraction. The mean response rate was examined for the following 2 responder endpoints: (i) greater than or equal to 3 complete spontaneous bowel movements (CSBMs)/wk (≥3 CSBMs/wk responders) and (ii) mean increase of ≥1 CSBM/wk compared with baseline (increase in ≥1 CSBM/wk responders).
RESULTS
A total of 23 placebo-controlled trials met our inclusion criteria and were included in this meta-analysis. The placebo response in CIC trials ranged from 4% to 44%. The magnitude of the placebo response was 13% (95% confidence interval 11%-16%) with the ≥3 CSBM/wk responder endpoint and 28% (95% confidence interval 21%-30%) with the increase of ≥1 in the CSBM responder endpoint. Higher baseline CSBM, older age, and trials with more male participants were significantly associated with a stronger placebo response for both the ≥3 CSBMs/wk endpoint and increase in the ≥1 CSBM/wk endpoint. Trial characteristics such as location (Europe vs Asia/United States) and laxative class (prokinetic vs secretagogue) revealed key differences in the placebo response for both endpoints. The placebo response was not significantly affected by the number of study visits, study duration, year of publication, number of drop outs, or likelihood of receiving active drug.
DISCUSSION
The placebo response in CIC trials ranges from 4% to 44% depending on the endpoint. Modifying factors of the placebo response include multiple subject and trial characteristics.
Topics: Age Factors; Chronic Disease; Constipation; Humans; Placebo Effect; Randomized Controlled Trials as Topic; Sex Factors
PubMed: 31592782
DOI: 10.14309/ajg.0000000000000399 -
Pain Mar 2023Placebo effects are ubiquitous yet highly variable between individuals and therefore strongly affect clinical trial outcomes such as pain relief. It is unclear whether... (Meta-Analysis)
Meta-Analysis
Placebo effects are ubiquitous yet highly variable between individuals and therefore strongly affect clinical trial outcomes such as pain relief. It is unclear whether dispositional psychological traits influence responsiveness to placebo. This preregistered meta-analysis and systematic review synthesized the literature investigating the association between personality traits and placebo effects. Based on 21 studies with 798 participants, we performed formal meta-analyses for 10 different personality traits, including behavioral inhibition, fun seeking, goal-drive persistence, reward responsiveness, empathic concern, empathic fantasy, perspective-taking, personal distress, optimism, and anxiety. We did not find evidence of associations between any of these traits and magnitude of placebo effects, which was supported by equivalence tests. Furthermore, we did not find evidence for moderating factors such as placebo manipulation type (conditioning or nonconditioning) or condition (pain or nonpain). These findings challenge the notion that personality influences responsiveness to placebos and contradict its utility for identifying placebo "responders" and "nonresponders."
Topics: Humans; Placebo Effect; Personality; Empathy; Pain; Pain Management
PubMed: 35947877
DOI: 10.1097/j.pain.0000000000002753