Placebo Response Rates Research Articles

Placebo Effects in Antidepressant Trials Across Four Decades: A Comparison of Binary and Continuous Outcomes

Background: Previous work suggested placebo response rate in antidepressant trials to be stable since the 1970s. The present analysis aimed to compare placebo response with placebo remission (both binary outcomes) and placebo efficacy (continuous outcome, based on the Hamilton Depression Scale), thereby considering previously suggested (but not assessed) nonlinear time trends and accounting for previously suggested (but not properly adjusted for) small-study effects (SSE). Methods: Random-effects meta-regression was conducted to estimate the effects of study year. Potential nonlinear effects of study year were modeled using restricted cubic splines (RCS). Relative importance of SSE compared to other trial-level covariates (study centers, dosing schedule, study length) was assessed using multimodel averaging. Findings: Multimodel averaging suggested any nonlinear time trends in placebo response (0·07 [-0·05-0·18] 95% CI) and remission (0·00 [-0·01-0·02] 95% CI) to be sufficiently explained by SSE and other trial-level covariates, with between-trial heterogeneity being reduced to I2 =55%/672%, respectively. This suggested stable rates across years, in line with previous work. By contrast, efficacy (continuous) showed an increasing trend from 1979 to 2914 (0·11 [0·02-0·21] 95% CI) with substantial between-trial heterogeneity being unexplained (I2 =85%). Interpretation: The present analysis reports differences in the time trends between binary and continuous placebo outcomes across decades. The findings are discussed regarding their clinical relevance because increasing placebo effects have been suspected of contributing to so-called failed antidepressant trials. Funding Statement: The authors stated: No funding. Declaration of Interests: The author declares no competing interests. Ethics Approval Statement: The authors declared: Not applicable.

Dynamic features of placebo effects addressing persistent insomnia disorder: A meta-analysis of placebo-controlled randomized clinical trials.

It has been accepted knowledge that placebo effects have been significant in insomnia clinical trials. However, the dynamic features of placebo effects have not been clarified. Our aim was therefore to conduct a meta-analysis of placebo-controlled randomized clinical trials to characterize the dynamic features of placebo effects addressing persistent insomnia disorder. We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of therapeutic regimens addressing persistent insomnia disorder. We pooled separate effect size estimates (Hedge's g) of placebo and regimen conditions across trials for outcome measures, and multilevel mixed-effects models were used to explore potential sources of heterogeneity. The placebo effects were significant and robust to improve the symptoms of insomnia, and subjective measures were significantly smaller than objective measures (p<.001), but placebo response rates were nearly identical between subjective and objective measures. The overall placebo effects were influenced by publication year (p=.015), treatment duration (p=.010), sample size (p<.001) and therapeutic regimen (p<.001). Placebo effects showed a diphasic feature within treatment duration: initially a decrease and subsequently being stable; a sustained decline trend after withdrawals; and a steady-to-upward trend for a mixed therapeutic regimens in a large-scale period over decades. The dynamic features of placebo effects addressing persistent insomnia disorder may lead to the development and validation of dosing strategies that require less medication exposure to maintain clinical effects.

What affects the placebo effect?

ObjectiveTo determine whether electronic bladder diaries are associated with a larger placebo effect than paper diaries in studies of overactive bladder (OAB). To identify any other factors in study design that may influence the placebo effect. Study designThis is a secondary analysis of a previous systematic review and network meta-analysis on the efficacy and tolerability of mirabegron. Each study was analysed and placebo response rate (PRR) was calculated. Statistical analysis was used to look for associations with different factors and PRR. ResultsThe PRR was considerable in the studies analysed (10.5 % when calculated for change in number of micturitions over 24 h and 41.2 % for change in urgency urinary incontinence episodes over 24 h). Paper bladder diaries were associated with a significantly larger placebo response rate than electronic (10.76 % vs 10.22 %), although this may be clinically small. The size of study had a moderate positive correlation with PRR. Length of bladder diary was not associated with increased PRR. ConclusionsThe PRR in studies of OAB is varied and significant. It is clear that it can be affected by factors in study design including type of bladder diary. When designing clinical studies this should be borne in mind. Equally, when attempting to optimise patient care, the benefit of the therapeutic encounter should be remembered.

P463 Induction of endoscopic response: a network meta-analysis of induction studies comparing ontamalimab with other treatments for moderate-to-severe ulcerative colitis

Abstract Background Clinicians, patients, payers and policymakers require relevant, high-quality evidence to support decision-making regarding the treatment of ulcerative colitis (UC). In the absence of head-to-head trials, network meta-analysis (NMA) can be used to compare treatments. We conducted an NMA to compare the efficacy of ontamalimab (anti-MAdCAM-1) using its phase 2 data, with all biologics and novel small molecules for which induction study data on endoscopic response were available. Methods A systematic literature review was conducted in November 2017 to identify published randomised controlled trials of induction treatment in patients with moderate-to-severe UC. An NMA of the identified studies was performed using random-effects models and methods based on NICE guidance. Odds ratios and 95% credible intervals were calculated to describe the relative differences between treatments and placebo in terms of efficacy in inducing endoscopic response. Results were examined by anti-TNF status (naïve vs. experienced). Results In total, 15 phase 2 and phase 3 induction studies of the following agents were available and included: adalimumab (160/80mg), etrolizumab (100mg and 300mg), golimumab (200/100mg), infliximab (5mg), ontamalimab (22.5mg and 75mg), ozanimod (0.5mg and 1mg), tofacitinib (10mg) and vedolizumab (300mg). The definition of endoscopic response (improvement) in all trials was a Mayo endoscopic subscore of ≤1. Homogeneity between studies was good, enabling pooling of results. Figure 1 shows odds ratios for induction of endoscopic response with treatments relative to placebo in anti-TNF-naïve and -experienced patients. All treatments performed significantly better than placebo in anti-TNF-naïve patients, with the exception of both doses of etrolizumab and ozanimod 0.5 mg. Significant differences between some treatments were observed; specifically, ontamalimab 22.5 mg (p = 0.0277), tofacitinib 10 mg (p = 0.0233) and infliximab 5 mg (p = 0.0047) were all superior to adalimumab 160/80 mg. Conclusion This study suggests that ontamalimab, infliximab and tofacitinib could be superior to adalimumab in inducing endoscopic healing, although it was conducted before any large-scale head-to-head trials of these drugs. Furthermore, large variances due to differing endpoint timings, the combination of phase 2 and phase 3 data, and lack of control for placebo response rates preclude firm conclusions being drawn.

Enrichment designs using placebo nonresponders.

Enrichment designs that select placebo nonresponders have gained much attention during the last years in areas with high placebo response rates, eg, in depression. Proposals were made that re-randomize patients who did not respond to placebo during a first study phase as the sequential parallel design (SPD). This design uses in a second phase an enriched patient population where the treatment effect is expected to be more pronounced. This may be problematic if an effect in the overall population is claimed. Proposals were made to combine the treatment effects in the overall population from study phase 1 and the enriched population from study phase 2, alleviating but not solving the issue of a potential selection bias. This paper shows how this bias corresponding to the effect difference between the overall population and the enriched population depends on the variability of a potential subject-by-treatment interaction. Sample sizes are given, which lead to a significant result in the combining test with a given probability if actually the average effect in the overall population is zero. If, on the other hand, no subject-by-treatment interaction is given, the enrichment is shown to be inefficient. We conclude that enrichment designs using placebo nonresponders are not able to claim a positive average effect in the overall population if a subject-by-treatment interaction cannot be excluded. It cannot be used to demonstrate positive efficacy in the overall population in a pivotal phase III trial but may be used in early phases to demonstrate varying treatment effects between patients.

Placebo responses in Parkinson's disease.

Parkinson's disease (PD) patients exhibit strong placebo responses in clinical trials. Patient characteristics that affect placebo include patients' expectations of good outcomes, genetic variants, and personality. The presence of motor fluctuation and high baseline UPDRS motor scores predicted placebo response. However, gender, age, duration of PD, religion, or level of education do not correlate with placebo response. PD patients who are preconditioned with active treatment such as apomorphine have more robust placebo effects. Studies that focused on patients with motor fluctuations, surgical intervention, or higher probability of placebo assignment had higher rates of placebo response. Patients view participating in placebo-controlled trials positively. Placebo effect can be measured objectively using neuroimaging and neurophysiological techniques. PET studies show that placebo-induced improvement is associated with dopamine release in the dorsal striatum and that the expectation of receiving the reward, not the reward itself, increased dopamine release in the ventral striatum. Expectations of benefitting from repetitive transcranial magnetic stimulation also induced dopamine release. Expectations of receiving a dopaminergic drug induced changes in fMRI in a reward-learning task. Single cell recordings demonstrate that placebo response is associated with changes of single neuronal activities in the basal ganglia circuit. These studies demonstrate that placebo effects are genuine biological responses to the administration of placebo. In clinical trials, we can use several approaches to minimize placebo responses. In clinical practice, we can use approaches to harness the power of placebo and minimize nocebo effects to improve patients' outcome.

Statistical methods in handling placebo effect.

A critical issue facing the therapeutic area of neurological diseases is the large number of failed randomized clinical trials, especially when moving from promising Phase 2 trials to failed Phase 3 trials. A common cited reason for these failures is a high placebo response rate that thereby reduces the observed treatment effect. Explanations for this higher than anticipated placebo response include small sample sizes, inadequate study designs and/or analytic methods, baseline characteristics of the trial sample, possible investigator bias and a participant's own expectations and conditional learning. Several innovative study designs and new methodological approaches to statistical analyses have been proposed to handle placebo effects anticipated or observed in double blind, randomized clinical trials (RCT's). This chapter examines current study designs being used to reduce the observed placebo response and statistical analysis methods being employed for addressing this problem in neuroscience clinical trials.

Clinical response rates, placebo response rates, and significantly associated covariates are dependent on choice of outcome measure in hidradenitis suppurativa: A post hoc analysis of PIONEER 1 and 2 individual patient data

The hidradenitis suppurativa clinical response (HiSCR) is the gold standard primary outcome measure for hidradenitis suppurativa clinical trials; however, it does not assess the presence of draining tunnels, a common finding in advanced disease. It is unclear what the effect of the presence or absence of draining tunnels has on the efficacy of adalimumab therapy in moderate and advanced disease. We evaluated the efficacy of adalimumab versus placebo using the International Hidradenitis Suppurativa Severity Scoring System (IHS4). Additionally, we assessed the effect of draining tunnels on therapeutic response as measured by both the HiSCR and change in nodule counts. Reanalysis was conducted with the IHS4 and PIONEER 1 and 2 individual patient data. Both binary outcomes (achieving HiSCR and achieving change in IHS4 severity category) and continuous outcomes (nodule counts and IHS4 score) were calculated with R. Regression modeling was undertaken to assess the effect of draining tunnels and other variables. P<.05 was considered statistically significant. The significance of adalimumab therapy depended on the outcome measure used. Placebo response rates were highest when binary outcome measures were used. Draining tunnels, smoking, antibiotics, and body mass index influenced HiSCR response in PIONEER 2. Significant differences in disease severity were observed between PIONEER 1 and 2 data sets. Elevated placebo response rates in PIONEER 1 and 2 are partially attributable to the use of binary outcome measures. Draining tunnels influence clinical response as measured by HiSCR and nodule counts in PIONEER 2. Further investigation into the effect of body mass index on clinical response is required.

Sequential parallel comparison design with two coprimary endpoints.

A placebo-controlled randomized clinical trial is required to demonstrate that an experimental treatment is superior to its corresponding placebo on multiple coprimary endpoints. This is particularly true in the field of neurology. In fact, clinical trials for neurological disorders need to show the superiority of an experimental treatment over a placebo in two coprimary endpoints. Unfortunately, these trials often fail to detect a true treatment effect for the experimental treatment versus the placebo owing to an unexpectedly high placebo response rate. Sequential parallel comparison design (SPCD) can be used to address this problem. However, the SPCD has not yet been discussed in relation to clinical trials with coprimary endpoints. In this article, our aim was to develop a hypothesis-testing method and a method for calculating the corresponding sample size for the SPCD with two coprimary endpoints. In a simulation, we show that the proposed hypothesis-testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy. In addition, the usefulness of our methods is confirmed by returning to an SPCD trial with a single primary endpoint of Alzheimer disease-related agitation.

Oral medicinal cannabinoids to relieve symptom burden in the palliative care of patients with advanced cancer: a double-blind, placebo controlled, randomised clinical trial of efficacy and safety of cannabidiol (CBD)

BackgroundDespite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care.Methods and designThis study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians.DiscussionA major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms.Trial registration numberALCTRN12618001220257 Registered 20/07/2018.

Эффективность и безопасность таргетных лекарственных препаратов в терапии взрослых пациентов со среднетяжелым и тяжелым вульгарным псориазом в Российской Федерации

Multiple randomised controlled trials (RCTs) have compared the efficacy of targeted therapies for the treatment of moderate-to-severe plaque psoriasis with placebo. However, the relative effectiveness of these treatments is not studied sufficiently. The aim of this study was to compare the effectiveness and safety of targeted drugs (netakimab, ixekizumab, guselkumab, secukinumab, ustekinumab, certolizumab, infliximab, adalimumab, etanercept, tofacitinib and apremilast) in adult patients with moderate-to-severe plaque psoriasis using such outcomes as PASI 75/90/100, PGA/IGA, DLQI, AEs, SAEs and withdrawals due to AEs. Material and methods. We performed a systematic literature review in PubMed database and in the CENTRAL section of Cochrane library (Embase filter) to identify relevant RCTs. The primary outcome was Psoriasis Area and Severity Index (PASI) 75 response at week 12 of treatment. Other analyzed outcomes: PASI 90/100, Physician’s Global Assessment (PGA) /IGA, Dermatology Life Quality Index (DLQI), number of patients suffering from at least one adverse event (AE) / severe AE and number of patient withdrawals from the study due to AE during initial 12 weeks of treatment. For each outcome we conducted network meta-analyses (NMAs) and univariate meta-regression analyses to adjust for baseline risk differences and cross-trial differences. Results. We selected 35 RCTs. We conducted several types of NMAs for each outcome to avoid bias in research. In most cases random effects NMAs adjusted to differences in placebo response rate provided the best model fit statistics and were selected for interpretation. Pairwise indirect comparisons from most NMAs suggested IL-17 inhibitors (netakimab and ixekizumab) along with IL-23 inhibitor guselkumab have superior effectiveness and favorable safety profile compared to other targeted therapies used to treat adults with moderate-to-severe plaque psoriasis during initial 12 weeks of therapy based on PASI 75/90/100, PGA/IGA, and DLQI.

Early score fluctuation and placebo response in a study of major depressive disorder

Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints.We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404.A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.

New Somatic Treatments for Child and Adolescent Depression.

Depression is a common clinical problem in youth, with prevalence increasing significantly during the adolescent period. Although several evidence-based treatments are currently available for treating depression in adults, only a subset of these have been investigated in a pediatric sample. Unfortunately, even well-established, first-line interventions do not lead to sufficient treatment response for many children and adolescents suffering from depression. However, recent research has been conducted in the area of somatic treatments for youth with depression. This review focuses on current (past three years, including published results and ongoing studies) research on somatic treatments for adolescent depression in the following categories: psychopharmacology, nutraceuticals, interventions implicating motor and sensory systems, and neuromodulation. Results from recent randomized, controlled trials testing psychopharmacological options suggest that while antidepressants that have been recently approved for adult patients are safe and tolerable in children and adolescents, none have yet outperformed performed placebo in efficacy. Nutraceuticals, motor-sensory interventions, and neuromodulation techniques, present safe and promising results, but few have been tested against controls to support effectiveness over current treatment options. This review of research on pediatric depression treatment from the past 3 years highlights some disappointments (negative results following some of the well-designed clinical trials) and gaps (preliminary studies in need of follow up with robust methodology) but also some promising directions in research of the efficacyof these treatments in a pediatric sample. We offer suggestions for future research including consideration of treatment timing, sequencing, the role of symptom severity in directing treatment selection, the potential value of combined treatments, consideration of how to best account for high placebo response rates, and the incorporation of neurobiological assessments to examine mechanisms and biomarker predictors of treatment response.

S-Adenosylmethionine (SAMe) monotherapy for depression: an 8-week double-blind, randomised, controlled trial.

Dysregulation of the one carbon cycle is documented in depression. Thereby, S-adenosylmethionine (SAMe), a one-carbon cycle nutraceutical compound with a favourable side effect profile, has a theoretical rationale for efficacy. However, further controlled studies are required to confirm SAMe's efficacy. To test the efficacy of SAMe versus placebo in unmedicated DSM-5 diagnosed (major depressive disorder) (MDD) patients with mild-to-moderate levels of depressive symptoms. We conducted an 8-week, double-blind, randomised controlled trial testing 800mg/day of SAMe monotherapy versus placebo in 49 patients with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score 14-25) who were not currently taking antidepressants. One-carbon cycle biomarkers, brain-derived neurotropic factor (BDNF), and relevant single nucleotide polymorphisms (SNPs) were analysed as potential treatment moderators. A clinically relevant differential reduction from baseline to week 8 of 3.76 points occurred on the primary outcome (MADRS) in favour of SAMe. This however was not significant (p = 0.13) on an adjusted linear mixed model, notwithstanding a medium to large effect size of 0.72. A high placebo response rate of 53% occurred (>50% reduction on MADRS). Exploratory analyses showed that SAMe was however effective in reducing depression amongst participants with milder depression severity (MADRS ≤ 22, p = 0.045). Response was not moderated by BDNF, SNPs, or one-carbon cycle biomarkers, although increased folate concentrations were correlated with improved symptoms in the SAMe group (r = - 0.57, p = 0.026). The treatment was safe and well tolerated. Although a differential reduction in depression symptoms between groups was observed in favour of SAMe, the results of this pilot study were not statistically significant. ANZCTR-Australian New Zealand Clinical Trials Registry; No.: ACTRN12613001299796; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364900.

Acute Treatment of Migraine in Children and Adolescents.

The management of headaches with juvenile onset presents several problems, related not only to appropriate drug selection but also to the specific features distinguishing headache disorders in children and adolescents: a child is not a "little adult". Many age-related factors influence the clinical expression of headache and these should be taken into account not only in the treatment, but also in the diagnosis, of juvenile headache. Few randomised placebo-controlled clinical trials of acute or preventive drugs have been conducted in paediatric headache patients, and those that have show a high placebo response rate in children (e.g. up to 55% for prophylactic drugs and up to 69% for symptomatic ones). The available data on symptomatic drugs are presented and discussed, focusing, in particular, on mechanisms of action, evidence of efficacy, and tolerability.

Efficacy of oral midazolam for minimal and moderate sedation in pediatric patients: A systematic review.

One of the most widely used options for minimal/moderate sedation in pediatric patients is oral midazolam, as it presents an alternative to less well‐accepted routes of administration (eg, intravenous or intranasal) of this well‐known efficacious and well‐tolerated short‐acting benzodiazepine. A systematic review of the literature was conducted in order to identify clinical studies evaluating the effectiveness of oral midazolam for sedation in pediatric patients in the context of premedication before anesthesia or during diagnostic/treatment procedures. The percentage of responders (response rate) after single administration of oral midazolam was evaluated and compared versus placebo in a subset of placebo‐controlled studies. The range of oral midazolam doses providing effective sedation in the different pediatric age subsets was analyzed in order to assess optimum dosing strategies. A total of 25 pediatric clinical studies, utilizing a variety of measures of sedation effectiveness, were selected. These studies included a total of 1472 patients (aged 4 months‐18 years) treated with midazolam (0.25‐1.5 mg/kg) and 138 patients treated with placebo. The response rates [95% confidence interval] with oral midazolam ranged from 36.7% [21.6%, 54.9%] to 97.8% [86.1%, 99.7%], while with placebo response rates ranged from 4.0% [0.6%, 23.5%] to 41.0% [29.4%, 53.6%]. When considering the 4 placebo‐controlled studies, the odds ratios [95% confidence interval] for the comparison of midazolam vs. placebo ranged from 13.4 [5.0, 36.0] to 25.9 [6.7, 100.6]. The analysis of subgroups by context of sedation showed response rates [95% confidence interval] with oral midazolam ranging from 36.7% [21.6%, 54.9%] to 97.0% [94.8%, 98.3%] for anesthetic premedication and from 56.1% [43.1%, 68.4] to 97.8% [86.1%, 99.7%] for medical procedures. The efficacy of midazolam for pediatric minimal/moderate sedation from a dose of 0.25 mg/kg and above was demonstrated. The probability of occurrence of adverse events and over‐sedation increases with increasing doses.

Re: "The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder" by Li Y, Huang J, He Y, Yang J, Lv Y, Liu H, Liang L, Zheng Q, and Li L (J Child Adolesc Psychopharmacol 29:712-720, 2019).

Journal of Child and Adolescent PsychopharmacologyVol. 30, No. 1 Letter to the EditorRe: “The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder” by Li Y, Huang J, He Y, Yang J, Lv Y, Liu H, Liang L, Zheng Q, and Li L (J Child Adolesc Psychopharmacol 29:712–720, 2019)Irving KirschIrving KirschAddress correspondence to: Irving Kirsch, PhD, 144 Medford Street, Arlington, MA 02474 E-mail Address: irvkirsch@gmail.comProgram in Placebo Studies, Harvard Medical School, Boston, Massachusetts.Search for more papers by this authorPublished Online:30 Jan 2020https://doi.org/10.1089/cap.2019.0127AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Re: “The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder” by Li Y, Huang J, He Y, Yang J, Lv Y, Liu H, Liang L, Zheng Q, and Li L (J Child Adolesc Psychopharmacol 29:712–720, 2019)." Journal of Child and Adolescent Psychopharmacology, 30(1), pp. 55–56FiguresReferencesRelatedDetails Volume 30Issue 1Feb 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Irving Kirsch.Re: “The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder” by Li Y, Huang J, He Y, Yang J, Lv Y, Liu H, Liang L, Zheng Q, and Li L (J Child Adolesc Psychopharmacol 29:712–720, 2019).Journal of Child and Adolescent Psychopharmacology.Feb 2020.55-56.http://doi.org/10.1089/cap.2019.0127Published in Volume: 30 Issue 1: January 30, 2020Online Ahead of Print:October 11, 2019PDF download

Placebo Response in Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

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. 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). 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. 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.

Meta-Analysis of Placebo Response in Adult Antidepressant Trials.

Roughly 80% of the symptom improvement experienced on antidepressants in clinical trials is also observed in the placebo comparison group. Understanding the correlates of placebo improvement and response is important to designing efficient and successful trials of future antidepressants. The objective of this meta-analysis was to investigate the magnitude of placebo symptom improvement and placebo response rates in second-generation antidepressant trials of depression, anxiety, and obsessive-compulsive disorder. We searched PubMed on 10 June, 2016, with no date or language limits, to identify randomized placebo-controlled trials of second-generation antidepressants in adults with depression, anxiety, or obsessive-compulsive disorder. We used a random-effects meta-analysis to examine the magnitude of placebo symptom improvement using standardized mean difference and placebo response rate. Stratified subgroup analysis and meta-regression were utilized to examine the effect of diagnostic indication and correlates of placebo symptom improvement. The meta-analysis included 164 trials involving 19,591 participants. Magnitude of placebo improvement and placebo response rates varied significantly between diagnostic indications. The magnitude of placebo improvement was much lower in obsessive-compulsive disorder (standardized mean difference = 0.58, 95% confidence interval 0.36-0.79) than in depression (standardized mean difference = 1.22, 95% confidence interval 1.12-1.32) or anxiety (standardized mean difference = 1.01, 95% confidence interval 0.90-1.12) trials. There was a large amount of heterogeneity in placebo improvement between studies (Q = 899, df = 110, p < 0.001, I2 = 88%). A greater number of study sites and a later publication year were associated with a greater magnitude of placebo improvement and response rate. Presence of a placebo lead-in and absence of non-US sites were associated with a reduced magnitude of placebo improvement. Trial duration was positively associated with the magnitude of placebo improvement in depression trials but negatively associated with the magnitude of placebo improvement in anxiety and obsessive-compulsive disorder trials. Magnitude of placebo symptom improvement differed significantly based on diagnostic indication with improvement being significantly less in obsessive-compulsive disorder than anxiety and depression. Some trial characteristics were associated with a greater magnitude of placebo improvement in trials across disorders but others were disorder specific.

10.3 PHARMACOLOGICAL TREATMENT OF TRICHOTILLOMANIA

Trichotillomania, or hair-pulling disorder, is a functionally impairing, often overlooked disorder, with no US FDA-approved medications for its treatment. Several pharmacological studies, however, have offered promise for those with trichotillomania, but the ability of clinical trials to detect beneficial effects of active treatment in trichotillomania has been hampered by a lack of understanding of the possible subtypes of trichotillomania and the unusually high placebo response rate.