Placebo Effects Are Small on Average in the 7.5% CO2 Inhalational Model of Generalized Anxiety.

BACKGROUND: Anxiety disorders are highly prevalent and socio-economically costly. Novel pharmacological treatments for these disorders are needed because many patients do not respond to current agents or experience unwanted side effects. However, a barrier to treatment development is the variable and large placebo response rate seen in trials of novel anxiolytics. Despite this, the mechanisms that drive placebo responses in anxiety disorders have been little investigated, possibly due to low availability of convenient experimental paradigms. We aimed to develop and test a novel protocol for inducing placebo anxiolysis in the 7.5% CO2 inhalational model of generalized anxiety in healthy volunteers. METHODS: Following a baseline 20-minute CO2 challenge, 32 healthy volunteers were administered a placebo intranasal spray labelled as either the anxiolytic "lorazepam" or "saline." Following this, participants surreptitiously underwent a 20-minute inhalation of normal air. Post-conditioning, a second dose of the placebo was administered, after which participants completed another CO2 challenge. RESULTS: Participants administered sham "lorazepam" reported significant positive expectations of reduced anxiety (P = .001), but there was no group-level placebo effect on anxiety following CO2 challenge post-conditioning (Ps > .350). Surprisingly, we found many participants exhibited unexpected worsening of anxiety, despite positive expectations. CONCLUSIONS: Contrary to our hypothesis, our novel paradigm did not induce a placebo response, on average. It is possible that effects of 7.5% CO2 inhalation on prefrontal cortex function or behavior in line with a Bayesian predictive coding framework attenuated the effect of expectations on subsequent placebo response. Future studies are needed to explore these possibilities.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

Comparison of low-level laser therapy and standard treatment for temporomandibular disorders: An assessment of therapeutic and placebo effects.

BACKGROUND: Despite extensive research on the use of low-power lasers for TMD treatment, the extent of their effectiveness remains uncertain. OBJECTIVE: This study aimed to investigate the therapeutic or placebo effect of LLLT for TMD, and to compare it with standard treatment methods. A unique aspect of this study was the inclusion of a control group that received only standard treatment, allowing for an assessment of the placebo effect of LLLT. METHODS: A total of 42 patients with TMD were referred to Kerman Dental School Pain Clinic and were randomly assigned to three groups: group A received LLLT, group B was a placebo group and group C was a control group that received only standard treatment. The laser groups received gallium-aluminium-arsenide laser treatment twice a week for 10 sessions. Patients' jaw movement rate indicators and VAS index were evaluated at the start of treatment, and indicators were re-recorded every week for 5 weeks. SPSS 21 was used for statistical analysis, including ANOVA and Tukey's post hoc tests for inter-group comparisons. The repeated measurement test was used to analyse the data. RESULTS: All groups showed significant improvement in VAS indicators (p = .0001), lateral jaw movements (p = .0001), forward jaw movement (p = .007) but not for maximum mouth opening. No significant difference was observed between the groups at the end of the study (p = .000). CONCLUSION: Our study provides insights into LLLT's effectiveness for TMD, suggesting it cannot replace standard treatment alone. These findings contribute to the literature and emphasise the importance of including a control group in future studies to assess the placebo effect of LLLT.

Response and Adverse Event Rates With Placebo in Gastroparesis: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Multiple drugs have been used to treat gastroparesis symptoms, yet their therapeutic benefits are poorly understood partly due to lack of insight into response and adverse event rates with placebo in randomized controlled trials (RCTs). We evaluated these issues systematically in drug trials for gastroparesis. METHODS: We searched the medical literature through August 2, 2022 to identify RCTs comparing active drug with placebo in patients with gastroparesis. We assessed placebo response rates according to at least one of the following endpoints: improvement according to a composite outcome, nausea, vomiting, abdominal pain, bloating, or fullness, as well as total adverse events, and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses with dropouts assumed to be treatment failures. We pooled placebo response and adverse event rates using a random effects model and expressed as proportions with 95% confidence intervals (CIs). RESULTS: Thirty-five studies were eligible. Among 23 trials reporting a composite endpoint of improvement, the pooled placebo response rate was 29.3% (95% CI, 23.7%-35.2%). Pooled placebo response rates were higher in idiopathic compared with diabetic gastroparesis (34.2% vs 28.1%), among trials that did not use validated symptom questionnaires (31.2% vs 27.4%), and in RCTs of shorter duration (<4 weeks, 32.6% vs ≥9 weeks, 23.2%). Adverse events occurred in 33.8% (95% CI, 26.4%-41.8%) of patients with placebo, in 27 trials, and were less common in idiopathic compared with diabetic gastroparesis (17.9% vs 43.4%), trials of shorter duration (<4 weeks, 33.7% vs ≥9 weeks, 40.7%), and trials with lower randomization ratios of active drug to placebo (1:1, 26.7% vs 3:1, 50.5%). CONCLUSIONS: This meta-analysis assessed placebo response and adverse event rates in gastroparesis. To accurately assess therapeutic gain, future trials should be a minimum of 8 weeks duration, use validated questionnaires, and distinguish gastroparesis subtypes.

Usefulness of the placebo lead-in design for clinical trials with binary outcomes.

BACKGROUND: In placebo-controlled clinical trials to develop new drugs for the treatment of psychiatric or neurological disorders, a high and sometimes greater-than-expected placebo response makes it difficult to show the superiority of an investigational drug over a corresponding placebo. To avoid such difficulty, a placebo lead-in design has been presented, but its usefulness has been open to discussion. Although the statistical properties of the placebo lead-in design are investigated in the context of continuous outcomes, whether these properties can be generalized for binary or ordinal cases remains unclear. METHODS: We investigate whether the placebo lead-in design is useful in clinical trials with binary outcomes through mathematical formulae and a numerical investigation. Specifically, we compare the proportion of placebo responders, the drug-placebo difference, and the effect size between two populations: one enriched for placebo nonresponders and the other comprising the all-comers. RESULTS: Under positive correlation of the data between the lead-in stage and the randomized stage for both treatment groups, we mathematically show that the proportion of responders in the population enriched for placebo nonresponders is less than that in the all-comers population, and whether the placebo lead-in design increases the drug-placebo difference depends on the variances of outcomes in both treatment groups as well as the correlations of the outcomes between two stages. Further, through a numerical investigation, we show that whether the placebo lead-in design increases the effect size strongly depends on the magnitude of the correlations and their difference. CONCLUSION: If the correlation of the placebo-placebo group is much higher than that of the placebo-drug group, the placebo lead-in design is advantageous in most cases but has an impact on an estimand in placebo nonresponders. Therefore, we do not recommend using the placebo lead-in design for clinical trials with binary outcomes.

The temporal trend of placebo response in migraine prevention from 1990 to 2021: a systematic literature review and meta-analysis with regression.

BACKGROUND: Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. METHODS: We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. RESULTS: A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. CONCLUSION: Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

Functional Neuroimaging Correlates of Placebo Response in Patients With Depressive or Anxiety Disorders: A Systematic Review.

BACKGROUND: The mechanisms underlying placebo effects of psychotropic drugs remain poorly understood. We carried out the first, to our knowledge, systematic review of functional neuroimaging correlates of placebo response in adults with anxiety/depressive disorders. METHODS: We systematically searched a large set of databases up to February 2021 based on a pre-registered protocol (PROSPERO CRD42019156911). We extracted neuroimaging data related to clinical improvement following placebo or related to placebo mechanisms. We did not perform a meta-analysis due to the small number of included studies and significant heterogeneity in study design and outcome measures. RESULTS: We found 12 relevant studies for depressive disorders and 4 for anxiety disorders. Activity in the ventral striatum, rostral anterior cingulate cortex and other default mode network regions, orbitofrontal cortex, and dorsolateral prefrontal cortex correlated with placebo antidepressant responses. Activity in regions of the default mode network, including posterior cingulate cortex, was associated with placebo anxiolysis. There was also evidence for possible involvement of the endogenous opioid, dopamine, and serotonin systems in placebo antidepressant and anxiolytic effects. CONCLUSIONS: Several brain regions and molecular systems may be involved in these placebo effects. Further adequately powered studies exploring causality and controlling for confounders are required.

Placebo Response and Its Predictors in Attention Deficit Hyperactivity Disorder: A Meta-Analysis and Comparison of Meta-Regression and MetaForest.

BACKGROUND: High placebo response in attention deficit hyperactivity disorder (ADHD) can reduce medication-placebo differences, jeopardizing the development of new medicines. This research aims to (1) determine placebo response in ADHD, (2) compare the accuracy of meta-regression and MetaForest in predicting placebo response, and (3) determine the covariates associated with placebo response. METHODS: A systematic review with meta-analysis of randomized, placebo-controlled clinical trial investigating pharmacological interventions for ADHD was performed. Placebo response was defined as the change from baseline in ADHD symptom severity assessed according to the 18-item, clinician-rated, DSM-based rating scale. The effect of study design-, intervention-, and patient-related covariates in predicting placebo response was studied by means of meta-regression and MetaForest. RESULTS: Ninety-four studies including 6614 patients randomized to placebo were analyzed. Overall, placebo response was -8.9 points, representing a 23.1% reduction in the severity of ADHD symptoms. Cross-validated accuracy metrics for meta-regression were R2 = 0.0012 and root mean squared error = 3.3219 for meta-regression and 0.0382 and 3.2599 for MetaForest. Placebo response among ADHD patients increased by 63% between 2001 and 2020 and was larger in the United States than in other regions of the world. CONCLUSIONS: Strong placebo response was found in ADHD patients. Both meta-regression and MetaForest showed poor performance in predicting placebo response. ADHD symptom improvement with placebo has markedly increased over the last 2 decades and is greater in the United States than the rest of the world.

Exploration of baseline and early changes in neurocognitive characteristics as predictors of treatment response to bupropion, sertraline, and placebo in the EMBARC clinical trial.

BACKGROUND: Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner. METHODS: In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16. RESULTS: Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline. CONCLUSION: These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

Assessing treatment benefit in the presence of placebo response using the sequential parallel comparison design.

In clinical trials, placebo response is considered a beneficial effect arising from multiple factors, including the patient's expectations for the treatment. Its presence makes the classical parallel study design suboptimal and can bias the inference. The sequential parallel comparison design (SPCD), a two-stage design where the first stage is a classical parallel study design, followed by another parallel design among placebo subjects from the first stage, was proposed to address the shortcomings of the classical design. In SPCD, in lieu of treatment effect, a weighted average of the mean treatment difference in Stage I among all randomized subjects and the mean treatment difference in Stage II among placebo non-responders was proposed as the efficacy measure. However, by linking two possibly different populations, this weighted average lacks interpretability, and the choice of weight remains controversial. In this work, under the principal stratification framework, we propose a causal estimand for the treatment effect under each of three clinically important principal strata: Always Responders, Never Responders, and Drug-only Responders. To make the stratum treatment effect identifiable, we introduce a set of assumptions and two sensitivity parameters. By further considering the strata as latent characteristics, the sensitivity parameters can be estimated. An extensive simulation study is conducted to evaluate the operating characteristics of the proposed method. Finally, we apply our method on the ADAPT-A study data to assess the benefit of low-dose aripiprazole adjunctive to antidepressant therapy treatment.

The role of placebo response in the efficacy outcome assessment in viloxazine extended-release pivotal trials in paediatric subjects with attention-deficit/hyperactivity disorder.

AIMS: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended-release in the treatment of attention-deficit/hyperactivity disorder (ADHD). The primary efficacy objective-change from baseline in ADHD Rating Scale-5 (ADHD-RS-5) Total score at end of study (EOS)-was not met in one of the studies (812P304). A band-pass analysis was performed to evaluate the impact of placebo response on the results. METHODS: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD-RS-5 Total score were used as boundaries for the band-pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band-pass filtered populations. RESULTS: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band-pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600-mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405-9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [-0.3332-7.4844]). The outcome of the analysis indicated that the impact of the band-pass adjustment is greater when placebo response is higher. CONCLUSION: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band-pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study.

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.

Different symptomatic improvement pattern revealed by factor analysis between placebo response and response to Esketamine in treatment resistant depression.

AIMS: The aim of this study is to determine whether there is difference in the change in each symptom of depression and in symptomatic improvement pattern between placebo and antidepressant responses. METHODS: Using data from a randomized, double-blind (DB), placebo-controlled trial of esketamine (ESK) in patients with treatment-resistant depression (TRD), we conducted exploratory analyses. To determine differences in the change in each depressive symptom on the MADRS subscale between placebo and antidepressant responses, a two-way factorial analysis was conducted using the amount of change on Day 2 and 28 of treatment. In addition, exploratory and confirmatory factor analyses were conducted on the MADRS subtotal variables on Day 2 and 28 of treatment to determine symptomatic improvement pattern between placebo response and antidepressant responses. RESULTS: We found that as well as MADRS total score, each subscale of MADRS score did not significantly differ between esketamine and placebo at Day 2 and 28. On the other hand, factor analysis revealed that the factor structure of the response was different between esketamine and placebo at the 2nd day. There was no difference in the factor structure between esketamine and placebo in response on Day 28 of treatment. CONCLUSION: Factor analysis revealed different patterns of symptom improvement in the early phase of the intervention between esketamine and placebo. This finding suggests that a data driven approach may provide detailed efficacy information in clinical trials for antidepressants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318. Registered: 28 September 2016.

The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: A systematic review of clinical trials of preventative pharmacological migraine treatments.

OBJECTIVE: To evaluate the association between the degree of response to placebo in migraine studies and the observed difference between drug and placebo across studies of preventative treatments for migraine. METHODS: A systematic review was performed using MEDLINE and the Cochrane Central Register of Controlled Clinical Trials from January 1988 to June 2019. Randomized, double-blind, parallel-group, placebo-controlled trials on oral or injection preventative treatments for migraine were included. Single- and multi-variable linear regression analyses were performed on the placebo-subtracted response rate (i.e. placebo responders subtracted from active responders), and the proportion of placebo responders. Fisher's exact tests were performed on the level of placebo response and the success in meeting the study's primary endpoint. RESULTS: After adjusting for route of administration and number of randomized subjects, there was a statistically significant association between the proportion of patients who were placebo responders and the placebo-subtracted response rate (b = -0.27, p = 0.02). There was a statistically significant difference in trial success rate (60%) between studies with ≤20% placebo responders and studies with > 30% placebo responders (p = 0.03). CONCLUSION: Considering the detrimental impact that high placebo response can have on clinical trials, it is imperative to find effective solutions to decrease the placebo response and increase assay sensitivity.

Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.

BACKGROUND: There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no "spontaneous improvement" prior to treatment initiation (high-severity population) than in a mild-severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. METHODS: We conducted a systematic literature review on placebo-controlled RCTs for AD.We assigned retained RCTs to high- or mild-severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta-regression analysis. RESULTS: Among the 19 retained RCTs (comprising 1996 placebo-treated patients), 11 trials were high-severity and 8 were mild-severity RCTs. The between-study variability in AR was lower in the high-severity than in the mild-severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity (p = 0.004) and treatment duration (p = 0.017) and was lower in the high-severity studies (16.8% at 3 months) than the mild-severity studies (36.7% at 3 months). CONCLUSIONS: Pharmacological RCTs for AD should select high-severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.

Sociability-based fitness approach in Parkinson's disease: Comparison with conventional rehabilitation.

BACKGROUND AND PURPOSE: The effect of a sociability-based fitness approach on parkinsonian disability in patients with Parkinson's disease (PD) was assessed. METHODS: Eighty patients diagnosed with PD were randomly assigned to either the group-based rehabilitation (GBR) group (n = 40) or the individual-based rehabilitation (IBR) group (n = 40). The primary outcome was the difference between the two groups in the mean change from baseline to post-training in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS). The secondary outcomes included the change in mental status and the difference in the mean change from baseline to month 3 and month 6 in the total score on the UPDRS. RESULTS: The mean (±SD) UPDRS scores were 72.0 ± 21.0 in the GBR group and 72.1 ± 18.6 in the IBR group. The UPDRS scores from baseline to post-training were 22.8 ± 13.5 in the GBR group and 10.9 ± 8.8 in the IBR group (difference 11.8 points; 95% confidence interval [CI] 5.0-18.6; p = 0.001). The difference between the groups from baseline to month 3 (difference 10.06 points; 95% CI 3.3-16.8) and the difference between the groups from baseline to month 6 (difference 11.7 points; 95% CI 4.9-18.5) were also significant (p = 0.004 and p = 0.001, respectively). The scores of cognitive function and depression had not changed significantly. CONCLUSIONS: Patients receiving GBR demonstrated significant improvements in parkinsonian symptoms, suggesting that the sociability-based fitness can be applied to clinical treatment by sustaining the motivation in PD.

Placebo Response in Phase 3 Trials of Systemic Therapies for Moderate-to-Severe Plaque Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: Wide fluctuations in placebo responses have been reported in phase 3 trials of systemic therapies for moderate-to-severe plaque psoriasis. METHODS: In this systematic review and meta-analysis, we assessed placebo responses in phase 3 trials of systemic therapies for moderate-to-severe plaque psoriasis. The medical databases PubMed Medline, Embase, and Web of Science were searched for studies reporting on phase 3 psoriasis trials. A proportion meta-analysis determined the proportion of placebo-treated psoriasis patients obtaining a 75, 90, or 100% reduction in Psoriasis Area and Severity Index (PASI), that is, PASI75, PASI90, or PASI100, respectively, at week 12. In the assessment of PASI75 response, 44 trials with a total number of 7,972 patients were included. CONCLUSION: In pooled analyses, 5.2% (95% CI 4.7-5.7%) obtained PASI75, 2.1% (95% CI 1.7-2.4%) obtained PASI90, and 0.3% (95% CI 0.1-0.5%) obtained PASI100 among placebo receivers. No temporal changes were observed. The overall proportion of placebo responders in phase 3 psoriasis trials is low and does not appear to be increasing in recent years.

Patient Expectancy Does Not Predict Success or Failure of Thermal Neurotomy for Persistent Zygapophysial and Sacroiliac Joint Pain.

OBJECTIVE: The placebo effect is important in determining the outcome of the treatment of pain for which expectancy and context are the main contributors. The variable success of thermal neurotomy spinal pain procedures is often seen as evidence of the placebo effect. Conversely, proponents of pain procedures explain poorer outcomes by technical procedure deficiencies, including inadequate diagnosis. This cohort study set out to determine whether patient expectancy is a contributing factor in the outcome of thermal neurotomy to the cervical, thoracic, and lumbar zygapophysial and sacroiliac joints. DESIGN: This single-practitioner, single-site retrospective analysis of prospectively gathered cohort data of 549 patients evaluated the impact of patient preprocedure expectancy (rated on a simple 0-10 or 0-4 numerical rating scale) on outcomes in a large consecutive series of patients who had undergone thermal neurotomy treatment between 2009 and 2019. In addition, a portion of patients were asked to what extent they hoped for or desired a good outcome. RESULTS: Successful pain relief (≥75% reduction from baseline) was not associated with a higher preprocedure expectancy than were failed procedures. Hope and desire demonstrated no impact on the positive or negative impact of the procedure. CONCLUSIONS: Altogether, patient expectation of outcome, hope, and desire are not associated with the outcome of effective pain relief by thermal neurotomy that has been performed to the appropriate and commonly available technical standards. Further work is needed to determine the influence of patient expectation across a range of pain intervention modalities.