Cortical morphology predicts placebo response in multiple sclerosis

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

The Placebo Response in Double-Blind Randomised Trials Evaluating Regenerative Therapies for Parkinson’s Disease: A Systematic Review and Meta-Analysis

In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson’s disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson’s Disease Scale in the ‘OFF’ state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18 F-fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD.

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

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.

Genomic Effects Associated With Response to Placebo Treatment in a Randomized Trial of Irritable Bowel Syndrome

Background and Aims: Irritable bowel syndrome (IBS), a functional pain disorder of gut-brain interactions, is characterized by a high placebo response in randomized clinical trials (RCTs). Catechol-O-methyltransferase (COMT) rs4680, which encodes high-activity (val) or low-activity (met) enzyme variants, was previously associated with placebo response to sham-acupuncture in an IBS RCT. Examining COMT effects and identifying novel genomic factors that influence response to placebo pills is critical to identifying underlying mechanisms and predicting and managing placebos in RCTs.Methods: Participants with IBS (N = 188) were randomized to three placebo-related interventions, namely, double-blind placebo (DBP), open-label placebo (OLP), or simply trial enrollment without placebo treatment [no placebo (i.e., no pill) treatment control (NPC)], for 6 weeks. COMT rs4680, gene-set, and genome-wide suggestive (p < 10−5) loci effects on irritable bowel symptom severity score (IBS-SSS) across all participants were examined.Results: Participants with IBS homozygous for rs4680 met (met/met) had the greatest improvement across all arms, with significantly greater improvement compared to val/val in DBP (beta (SE), −89.4 (42.3); p = 0.04). Twelve genome-wide suggestive loci formed a gene regulatory network highly connected to EGR1, a transcription factor involved in placebo-related processes of learning, memory, and response to stress and reward. EGR1 gene expression in peripheral blood mononuclear cells (PBMC) was significantly reduced at the endpoint across all treatment arms (log fold-change, −0.15; p = 0.02). Gene-set enrichment analysis returned three genome-wide significant ontology terms (GO:0032968, GO:0070934, and GO:0070937) linked to transcription regulation and GO:0003918 associated with DNA topoisomerase regulation.Conclusion: These results suggest common molecular mechanisms in response to varying forms of placebo that may inform personalized IBS treatment and placebo response prediction.Clinical Trial Registration:ClinicalTrials.gov, Identifier: NCT0280224.

A Multi-Center Disclusion Time Reduction (DTR) Randomized Controlled Occlusal Adjustment Study Using Occlusal Force and Timing Sensors Synchronized with Muscle Physiology Sensors

Objective—To perform a Randomized Controlled Trial (RCT) Disclusion Time Reduction (DTR) study at five Dental Colleges, using intraoral sensors and muscular electrodes. Methods and Materials—One hundred students were randomly assigned to a treatment group to receive the ICAGD coronoplasty, or a control group that received tooth polishing. All subjects answered symptom questionnaires: Beck Depression Inventory-II, Functional Restrictions, and Chronic Pain Symptom and Frequency. Subjects self-reported after ICAGD or placebo at 1 week, 1 month, 3 months, and 6 months. The Student’s t-Test analyzed the measured data. The Mann–Whitney U Test analyzed the subjective data (Alpha = 0.05). Results—The Disclusion Times, BDI-II scores, and Symptom Scales were similar between groups prior to treatment (p > 0.05). At 1 week, all three measures reduced in the treatment group, continuing to decline over 6 months (p < 0.05), but not for the controls (p > 0.05). Symptom Frequency, Functional Restrictions, and Pain Frequencies were higher in the treated group (p < 0.05), but declined after ICAGD compared to the control group (p < 0.05). Conclusions—ICAGD reduced Pain, Functional Restrictions, Symptom Frequency, and Emotional Depression within 1 week, which continued for 6 months. The tooth polishing did not initiate a placebo response.

Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren’s Syndrome

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren’s syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren’s syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren’s syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren’s syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.

Reappraising Treatment Effect Heterogeneity in Schizophrenia: A Meta-analysis

Objective Determining whether individual patients differ in response to treatment ('treatment effect heterogeneity') is important as it is a prerequisite to developing personalised treatment approaches. Previous variability meta-analyses of response to antipsychotics in schizophrenia found no evidence for treatment effect heterogeneity. Conversely, individual patient data meta-analyses suggest treatment effect heterogeneity does exist. In the current paper we combine individual patient data with study level data to resolve this apparent contradiction and quantitively characterise antipsychotic treatment effect heterogeneity in schizophrenia. Method Individual patient data (IPD) was obtained from the Yale University Open Data Access (YODA) project. Clinical trials were identified in EMBASE, PsycInfo, and PubMed. Treatment effect heterogeneity was estimated from variability ratios derived from study-level data from 66 RCTs of antipsychotics in schizophrenia (N=17,202). This estimation required a correlation coefficient between placebo response and treatment effects to be estimated. We estimated this from both study level estimates of the 66 trials, and individual patient data (N=560). Results Both individual patient (r=-0.32, p=0.002) and study level (r=-0.38, p<0.001) analyses yielded a negative correlation between placebo response and treatment effect. Using these estimates we found evidence of clinically significant treatment effect heterogeneity for total symptoms (our most conservative estimate was SD = 13.5 Positive and Negative Syndrome Scale (PANSS) points). Mean treatment effects were 8.6 points which, given the estimated SD, suggests the top quartile of patients experienced beneficial treatment effects of at least 17.7 PANSS points, while the bottom quartile received no benefit as compared to placebo. Conclusions We found evidence of clinically meaningful treatment effect heterogeneity for antipsychotic treatment of schizophrenia. This suggests efforts to personalise treatment have potential for success, and demonstrates that variability meta-analyses of RCTs need to account for relationships between placebo response and treatment effects.