Placebo Response Rates Research Articles

856 Evaluation of Paired and Separated Endoscopic Reads at Baseline and Week 14 in the Exploratory BERGAMOT Induction Cohort

INTRODUCTION: Treatment guidelines recommend that Crohn’s disease evaluation and treatment decisions should include endoscopic evaluation in conjunction with clinical and laboratory assessment. Previously, an adjudicated central read model (CRM) for evaluating Simple Endoscopic Score for Crohn's Disease (SES-CD) that included a local reader and at least 1 central reader (CR) was found to reduce placebo rates and variability and increase treatment response rates versus single reader models (1). This study explored the impact on scoring by blinded reading of paired endoscopic reads (i.e. simultaneous assessment of pre- and postinduction treatment endoscopic videos) versus unpaired reads scored by the CRM. METHODS: Patients in this analysis (n = 63) were a subset from the exploratory BERGAMOT induction cohort, who were randomized 2:2:1 to receive subcutaneous etrolizumab 105 mg every 4 weeks (n = 24); etrolizumab 210 mg at weeks 0, 2, 4, 8, and 12 (n = 24); or placebo (n = 15). Three CRs performed the paired endoscopy readings. The unpaired reads were evaluated using the CRM and included a predefined sliding threshold to trigger adjudication of discordant scores by a second CR. All readers were blinded to treatment arm, timing of the endoscopy, and the other reader’s assessments. RESULTS: In the overall population, 48% had ileocolonic disease, 30% had colonic disease, and 22% had disease restricted to the ileum. Prior treatment for Crohn’s disease included anti-TNFs (73%), oral corticosteroids (49%), or nonbiologic immunosuppressants (27%). In general, the mean baseline and week 14 SES-CD evaluated by the paired read model were higher than those assigned by the CRM. Differences between models in assigning categorical thresholds were more varied (Table 1). The placebo rates of ≥ 50% SES-CD decrease from baseline, SES-CD ≤ 4, and SES-CD ≤ 2 were similarly low (0%-6.7%) with either the unpaired CRM or the paired endoscopy model. More patients achieved ≥ 50% SES-CD decrease from baseline with etrolizumab treatment using the CRM compared with the paired read model (21% vs 13%, respectively). CONCLUSION: Based on data generated by experienced CRs in a small subset of patients, both paired and unpaired central reading of CD endoscopic videos resulted in very low placebo response rates. However, unpaired central reading resulted in increased treatment response rates compared with a paired read paradigm.

An Innovative Disease-Drug-Trial Framework to Guide Binge Eating Disorder Drug Development: A Case Study for Topiramate.

As with other psychiatric disorders, development of drugs to treat binge‐eating disorder (BED) has been hampered by high placebo response and dropout rates in randomized controlled trials (RCTs). Although not approved for use in BED, several RCTs have suggested that topiramate is efficacious for BED in obese individuals. Using data from a positive investigator‐initiated RCT of topiramate in 61 obese individuals with BED, the objective of the present study is (i) to develop a quantitative disease‐drug‐trial framework to inform future BED clinical trial designs, and (ii) to determine the optimal topiramate dose to achieve therapeutic efficacy. Disease‐drug‐trial models were developed separately for the two efficacy measures, namely, longitudinal normalized weekly binge‐eating episode frequency (BEF) and binge day frequency (BDF). Model building consisted of (i) developing a placebo effect model that describes response from the placebo group, (ii) adding a drug effect to the placebo model to describe dose‐response relationships, and (iii) developing a parametric time to event model to characterize patient dropout patterns. The placebo effect on normalized BEF and BDF over time demonstrated a maximum decrease of ~ 57% by 5 weeks. Participants had a higher dropout probability if no weight loss occurred during the trial period. The identified dose‐response relationship demonstrated a daily dose of 125 mg was needed to exhibit a marked reduction in weekly BEF. The developed comprehensive disease‐drug‐trial model will be utilized to simulate different clinical trial designs to increase the success for future BED drug development programs.

Balancing body and mind: selecting the optimal antipsychotic

In The Lancet, Maximilian Huhn and colleagues5 report a network meta-analysis of antipsychotic medications for the acute management of schizophrenia that includes 402 studies of 32 different antipsychotics with data for 53 463 participants (mean age 37·40 years [SD 5·96], 29 949 [56·02%] male and 23 514 [43·98%] female, mean illness duration 11·90 years [SD 5·19]). This is the largest and most comprehensive meta-analysis of antipsychotic medication for acute psychosis to date. The use of a network meta-analysis allows comparisons between agents that might not have been directly compared in clinical trials. Other strengths include consideration of the placebo response rate, study sample size, publication year, baseline severity, sponsorship, comparability of doses, and patient demographics, using both meta-regression and sensitivity analyses of excluding poorer-quality studies. None of these factors greatly altered outcomes.

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.

Objective: The high placebo response rate may hamper the discovery of antidepressants in children and adolescents with major depressive disorder (MDD). The aim of the study was to clarify the relationship between the placebo response rate and clinical trial outcomes of the use of antidepressants in children and adolescents, and distinguish main factors responsible to placebo response rate. Methods: The PubMed and Cochrane Library databases were searched for double-blind randomized placebo-controlled trials of the new-generation antidepressants for the acute treatment of MDD in children and adolescents. The response rate differences (RDs) between placebo group and treatment group under different level of placebo response rate were pooled by random-effects meta-analysis. The classification thresholds for low, medium, and high placebo response rate were set at <40%, 40%-50%, and ≥50%, respectively. Predictors of placebo response rate were explored using meta-regression. Results: The analysis included 18 trials with 4365 participants. This study found that the lower the placebo response rate, the greater the efficacy differences between antidepressants and placebo. In the high, moderate, and low placebo response rate subgroups, the response RDs (95% CI) between antidepressants and placebo were 8 (1-14)%, 10 (2-17)%, and 21 (9-32)%, respectively. The meta-regression showed that the number of study sites was the factor most associated with placebo response rate, and that response rate increased 3% with every additional 10 study sites. Conclusions: The clinical outcome was related to the placebo response rates in the clinical trials of antidepressants in children and adolescents with MDD. The efficacy differences between antidepressants and placebo will be maximized when placebo response rates are reduced. The number of study sites was the factor most associated with the placebo response rates.

Placebo Effect in Obsessive-Compulsive Disorder (OCD). Placebo Response and Placebo Responders in OCD: The Trend Over Time.

BackgroundPlacebo response appears to be increasing in antidepressant, antipsychotic and various internal medicine trials. A similar trend has been reported for OCD during 1989-1999. Placebo response is generally considered as the extent to which placebo treatment is associated with core symptom improvement. In this analysis, we used Joinpoint regression to assess the time trend of both placebo response and placebo responder rates according to the year of publication with no time restriction in OCD drug trials.MethodWe included drug and/or psychotherapy trials vs. placebo from PubMed, Embase, CINAHL, and PsycINFO retrieved through the search (placebo OR sham) AND (obsessive* OR OCD). We included studies through investigator consensus. We then performed on data of included studies log-linear joinpoint segmented regression models using a p<0.05 cutoff.ResultsWe included 113 studies from 112 published papers. Placebo mean annual response rates in OCD studies significantly increased from 1991 to 2017 with an annual percent change (APC) of 0.66%, while placebo mean annual responder rates also significantly increased from 2010 to 2017, with an APC of 5.45%. Drug mean annual response rates in OCD studies significantly increased from 1987 to 2012 with an APC of 0.72%, while the corresponding responder rates did not show statistically significant APC changes between 1984 and 2017.ConclusionWe observed a tendency for placebo to increase both measures of response in OCD clinical drug trials through the years that tend to approximate the responses shown by drugs. Changes in the type of study (moving from classical head to head comparisons to add-on studies in treatment-resistant populations) and countries involved in experimentation may partially account for some portion of these results. It appears that placebo effects are becoming more elusive and out of control.

Dynamic Features of Placebo Effects Addressing Primary Insomnia

Background: It has been accepted knowledge that placebo effects have been significant in insomnia randomized 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 primary insomnia. Methods: We performed a comprehensive literature search for randomized, placebo-controlled, double-blind clinical trials evaluating the efficacy of therapeutic regimens addressing primary insomnia. We pooled separate effect size estimates (Hedge's g) of placebo and regimen conditions across trials for outcome measures, and multilevel mixed-effects models was used to explore potential sources of heterogeneity. Findings: The placebo effects were significant and robust to reduce the symptoms of insomnia, and subjective measures were significantly smaller than objective measures (p<0.001), but placebo response rates were nearly identical. The overall placebo effects were influenced by publication year (p = 0.015), treatment duration (p = 0.010), sample size (p<0.001), and therapeutic regimen (p<0.001). Placebo effects showed a diphasic feature within treatment duration: initial short-term increase-to-decrease status, and subsequent long-term slow increase-to-steady status. After withdrawals, placebo effects showed a sustained decline with fast-to-slow trend. In a large-scale time span, placebo effects of a new therapeutic regimen showed a slow-decline status. Interpretation: The dynamic features of placebo effects addressing primary insomnia may lead to the development and validation of dosing strategies that require less medication exposure to maintain clinical effects. Funding Statement: The authors state: There was no funding source for this study. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement was followed for this pooled analysis.

Magnitude, response, and psychological determinants of placebo effects in chronic low-back pain: a randomised, double-blinded, controlled trial.

Introduction:Denervation of the lumbar zygapophyseal joints by medial branch radiofrequency neurotomy has shown some benefit in treating chronic low-back pain. Before denervation, a diagnosis is made by one or more blinded injections on separate occasions to ascertain whether the relevant joints are contributing to the pain. Placebo injections have been advocated in a diagnostic regime that also includes local anaesthesia, with a decision to proceed to neurotomy based on response to local anaesthesia and not to placebo.Objectives:We investigated the magnitude of and response rate to placebo injections, and the roles of expectation, desire for pain relief, and anxiety as determinants of response to placebo.Methods:One hundred twenty patients were randomised to receive placebo and local anaesthetic injections on alternate occasions in a double-blind manner. A smaller control group with 2 local anaesthetic injections was also used. Responses to placebo were characterised, including magnitude and frequency.Results:This study demonstrated very large response to placebo injections, both response rate (78%) and magnitude (effect size d = 1.85). Expectation and anxiety were important modulators of response to placebo in this setting, with support given to expectation as a dynamic modulator of placebo responses. Large response to placebo (both in rate and magnitude) was observed when participants reported the belief that they were in the placebo arm.Conclusion:This study demonstrated large placebo responses in the context of injections for low-back pain and further characterised the importance of expectation and anxiety as important psychological mediators.

Review of Acute Treatment of Migraine Trial Results With the New FDA Endpoints: Design Implications for Future Trials.

BackgroundIn October 2014, the US Food and Drug Administration released a draft guidance for the development of drugs for the acute treatment of migraine. This guidance offered the option of replacing the previously required 4 co‐primary endpoints: pain freedom, freedom from nausea, freedom from photophobia, and freedom from phonophobia, all at 2 hours posttreatment, with 2 co‐primary endpoints: pain freedom and freedom from most bothersome symptom (MBS) other than pain, both at 2 hours posttreatment. At the time the new draft guidance was released, no large clinical trials had been undertaken with these 2 co‐primary endpoints, posing a challenge in determining the sample size that might be required to achieve statistical significance. As a number of trials have now been completed, we conducted a review of the observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials.MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane library for primary publications of phase 3 randomized, placebo‐controlled, double‐blind acute migraine treatment trials that used pain freedom and MBS freedom as primary or planned secondary endpoints. For each endpoint, placebo response rates were determined and used to generate estimates of sample size, assuming differences between placebo and active treatment groups of 10%, 15%, and 20%. Sample size calculations were based on 80% power using a 2‐group continuity corrected chi‐square test with a 5% 2‐sided significance level.ResultsWe identified abstracts or full‐length papers describing results of 8 clinical trials employing the new co‐primary endpoints. The mean placebo response rate for 2‐hour pain freedom was 16.75% (range 11.8‐21.3%) and treatment effect (difference in response rates between active and placebo groups) ranged from 5.0% to 27.2%. For 2‐hour MBS freedom, the mean placebo response rate was 32.8% (range 25.2‐48.1%), and the range of treatment effect was 8.9% to 25.4%. Based on a placebo response rate of 17% for pain freedom, the sample sizes that would have been required to achieve statistical significance were n = 269, n = 128, and n = 77, for treatment effect sizes of 10%, 15%, and 20%, respectively. For MBS, assuming a placebo response rate of 33%, the corresponding required sample sizes would have been n = 389, n = 181, and n = 105.ConclusionsThe observed range of placebo response and treatment effect sizes suggests that use of the newly recommended 2 co‐primary endpoints could reduce the sample sizes required to achieve significance compared with past trials using 4 primary endpoints (in which mean and median group sizes for recent trials were 375 and 362, respectively). However, the initial trials using the newly recommended co‐primary endpoints tended to treat more participants than would have been minimally required. We anticipate that with the growing body of information regarding the use of these new endpoints, samples sizes may be more aligned with treatment efficacy, enabling faster and more cost‐effective trials for acute migraine treatment.

Efficacy of repetitive transcranial magnetic stimulation in the treatment of depression with comorbid anxiety disorders

BackgroundThe presence of comorbid anxiety is generally associated with poorer treatment outcomes in people with depression. Repetitive transcranial magnetic stimulation (rTMS) has been shown to be effective for treatment resistant depression, but there has been little research examining rTMS in depressed patients with comorbid anxiety disorders. This study aimed to investigate the efficacy of rTMS in patients with treatment resistant Major Depressive Disorder (MDD) and comorbid anxiety disorders. MethodsThis study included 248 patients with treatment resistant MDD who were treated with rTMS. Of these, 172 patients had one or more comorbid anxiety disorders, so their outcomes were compared with patients who did not have comorbid anxiety. ResultsPatients both with and without comorbid anxiety disorders showed improvement in depression ratings after rTMS treatment, with no significant difference in remission rates between groups. In those with comorbid anxiety disorders, 23.3% met criteria for remission and 39.5% met response criteria. For each anxiety disorder diagnosis, there was a significant reduction in HAM-A, HAM-D21, MADRS and ZUNG scores (p = <0.001 for all). LimitationsThis was not a sham-controlled study, so placebo response rates are not known. Patients were referred by private psychiatrists so are not representative of all patients with depression. ConclusionOur study indicates that rTMS is an effective treatment for Major Depressive Disorder in people who have comorbid anxiety disorders.

Migraine in children: presentation, disability and response to treatment.

The current review presents findings from investigations of migraine in children. The presentation of pediatric migraine, related consequences, and medication treatments are reviewed. A number of advancements have been made in the study of the presentation, disability, and treatments for migraine in children. However, recent research suggests that not all approaches are equally effective in the treatment of migraine in children. Specifically, a recent study comparing pharmacological interventions found that preventive medications were not statistically more effective than placebo in children. Consistent findings showing clinically meaningful placebo response rates, shorter duration of headaches and other characteristic features (e.g. frontal, bilateral location) have been barriers to the design of randomized clinical trials in children and adolescents with migraine. Better understanding of treatment mechanisms for medication interventions is needed. Several migraine treatments have determined to be effective for use in children but few controlled studies have evaluated the effectiveness of medication treatments. Recent research suggests that preventive medications may not be more effective than placebo. Additional research is needed to evaluate the effectiveness of medication treatment in migraine headache care.

Clinical Features at Baseline Cannot Predict Symptom Response to Placebo in Patients With Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by ≥15 eosinophils per high-power field (eos/hpf) and esophageal dysfunction.1 One confounder in the assessment of drug efficacy in clinical trials for EoE2 and other gastrointestinal diseases3,4 has been the symptomatic response to placebo. In placebo-controlled, randomized trials of EoE therapies, placebo response rates as high as 78% have been reported.2 To mitigate placebo effect, a phase 2, randomized, double-blind, placebo-controlled trial of budesonide oral suspension (BOS) was designed with a single-blind, placebo run-in to attempt to screen out placebo responders before randomization.5 The aim of this post hoc analysis was to identify clinical factors associated with a symptom response during the placebo run-in.

Nutraceuticals for major depressive disorder- more is not merrier: An 8-week double-blind, randomised, controlled trial

BackgroundOne of the most pressing questions in “Nutritional Psychiatry” is whether using combinations of different nutraceuticals with putative antidepressant activity may provide an enhanced synergistic antidepressant effect. MethodsA phase II/III, Australian multi-site, 8-week, double-blind, RCT involving 158 outpatients with a DSM-5 diagnosis of MDD. The intervention consisted of a nutraceutical combination: S-adenosyl methionine; Folinic acid; Omega-3 fatty acids; 5-HTP, Zinc picolinate, and relevant co-factors versus placebo. The primary outcome was change in MADRS score. Hypothesis-driven analyses of potential moderators of response involving key SNPs, and BDNF were also conducted. ResultsPlacebo was superior to the nutraceutical combination in reducing MADRS score (differential reduction -1.75 points), however a mixed linear model revealed a non-significant Group X Time interaction (p = 0.33). Response rates were 40% for the active intervention and 51% for the placebo; remission rates were 34% and 43% for active and placebo groups, respectively. No significant differences were found between groups on any other secondary depression, anxiety, psychosocial, or sleep outcome measures. Key SNPs and BDNF did not significantly moderate response. No significant differences occurred between groups for total adverse effects, aside from more nausea in the active group. LimitationsVery high placebo response rates suggest a placebo run-in design may have been valuable. InterpretationThe adoption of a nutraceutical ‘shotgun’ approach to treating MDD was not supported, and appeared to be less effective than adding placebo to treatment as usual.

A double-blind, randomized, placebo-controlled clinical trial evaluating the safety and efficacy of autologous muscle derived cells in female subjects with stress urinary incontinence.

The purpose of the study was to assess safety and efficacy of autologous muscle derived cells for urinary sphincter repair (AMDC-USR) in female subjects with predominant stress urinary incontinence. A randomized, double-blind, multicenter trial examined intra-sphincteric injection of 150 × 106 AMDC-USR versus placebo in female subjects with stress or stress predominant, mixed urinary incontinence. AMDC-USR products were generated from vastus lateralis needle biopsies. Subjects were randomized 2:1 to receive AMDC-USR or placebo and 1:1 to receive 1 or 2 treatments (6months after the first). Primary outcome was composite of ≥ 50% reduction in stress incontinence episode frequency (IEF), 24-h or in-office pad weight tests at 12months. Other outcome data included validated subject-recorded questionnaires. Subjects randomized to placebo could elect to receive open-label AMDC-USR treatment after 12months. Subject follow-up was up to 2years. AMDC-USR was safe and well-tolerated with no product-related serious adverse events or discontinuations due to adverse events. Interim analysis revealed an unexpectedly high placebo response rate (90%) using the composite primary outcome which prevented assessment of treatment effect as designed and thus enrollment was halted at 61% of planned subjects. Post hoc analyses suggested that more stringent endpoints lowered placebo response rates and revealed a possible treatment effect. Although the primary efficacy finding was inconclusive, these results inform future trial design of AMDC-USR to identify clinically meaningful efficacy endpoints based on IEF reduction, understanding of placebo response rate, and refinement of subject selection criteria to more appropriately align with AMDC-USR's proposed mechanism of action.

The efficacy of adjunctive N-acetylcysteine in acute bipolar depression: A randomized placebo-controlled study

ObjectiveTo investigate the efficacy of adjunctive N-acetylcysteine (NAC) for the treatment of acute bipolar depression. MethodA randomized, double-blind, multicentre, placebo-controlled trial including adult subjects diagnosed with bipolar disorder, currently experiencing a depressive episode. Participants were treated with 3 g/day NAC or placebo as an adjunctive to standard treatment for 20 weeks, followed by a 4-week washout where the blinding was maintained. The primary outcome was the mean change in the Montgomery Asberg Depression Rating Scale (MADRS) score over the 20-week treatment phase. Linear Mixed Effects Repeated Measures (LMERM) was used for analysing the primary outcome. ResultsA total of 80 subjects were included. The mean MADRS score at baseline was 30.1 and 28.8 in participants randomized to NAC and placebo, respectively. Regarding the primary outcome measure, the between-group difference (NAC vs. placebo) was 0.5, which was statistically non-significant (95% CI: -7.0-5.9;p = 0.88). All findings regarding secondary outcomes were statistically or clinically insignificant. LimitationsThe study had a placebo response rate of 55.6% - high placebo response rates are associated with failure to separate from placebo. ConclusionsBased on our primary outcome measure, we could not confirm previous studies showing a therapeutic effect of adjunctive NAC treatment on acute bipolar depression. Further studies with larger samples are needed to elucidate if specific subgroups could benefit from adjunctive NAC treatment.

Asymptotic and exact interval estimators of the common odds ratio under the sequential parallel comparison design.

When studying treatments for psychiatric or mental diseases in a placebo-controlled trial, we may consider use of the sequential parallel comparison design to reduce the number of patients needed through the reduction of the high placebo response rate. Under the assumption that the odds ratio of responses is constant between phases in the sequential parallel comparison design, we derive the conditional maximum likelihood estimator for the odds ratio. On the basis of the conditional likelihood, we further derive three asymptotic interval and an exact interval estimators for the odds ratio of responses. We employ Monte Carlo simulation to evaluate the performance of these interval estimators in a variety of situations. We find that the asymptotic interval and exact interval estimators developed here can all perform well. We use the double-blind, placebo-controlled study assessing the efficacy of a low dose of aripiprazole adjunctive to antidepressant therapy for treating patients with major depressive disorder to illustrate the use of these estimators.

Evolution of Clinical Trials in Inflammatory Bowel Diseases.

Since the first clinical trial of cortisone in ulcerative colitis in 1955, remarkable progress has been made in the design and conduct of clinical trials in inflammatory bowel diseases (IBD). In this review article, we will discuss evolution of clinical trials in IBD over the last 3-5years. Recognizing limitations intrinsic to clinical disease activity indices in IBD, regulatory authorities have recommended evaluating co-primary endpoints of patient-reported outcomes and endoscopic disease activity in clinical trials. Biomarker-enriched trial enrolment and central endoscopy reading have emerged as critical events in trial recruitment and outcome assessment and have driven placebo response rates down. While trials of novel biologic therapies and advanced small molecules continue at an accelerated pace, pragmatic comparative efficacy trials of treatment strategy aimed at optimizing current therapies (such as early combined immunosuppression [REACT], tight disease control [CALM], therapeutic drug monitoring [TAXIT, TAILORIX]) have directly informed clinical practice. With emphasis on value-based care and population health management, multi-pronged remote monitoring, self-management, and telemedicine approaches in the era of smartphones have re-emerged with promise. Non-conventional therapies such as fecal microbiota transplantation, though still experimental, have provided insight into disease pathogenesis and offered hope for microbial manipulation strategies for treating these complex diseases. Clinical trials have rapidly evolved over the last 5years not only focusing on novel therapies but also optimizing existing treatment approaches and population health management. Over the next decade, these trials will continue to advance the field, and be readily translatable into clinical practice.

Neurobiology of placebo effect in Parkinson's disease: What we have learned and where we are going

The placebo effect is a phenomenon produced when an inert substance administered like a regular treatment improves the clinical outcome. Parkinson's disease (PD) is one of the main clinical disorders for which the placebo response rates are high. The first evidence of the neurobiological mechanisms underlying the placebo effect in PD stems from 2001, when de la Fuente-Fernandez and colleagues demonstrated that a placebo injection led to the release of dopamine in the striatal nuclei of PD measured with positron emission tomography technology. Since then, several studies have been conducted to investigate the neurobiological underpinnings of placebo responses. This article presents a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Of an initial yield of 143 papers, 19 were included. The lessons learned from these studies are threefold: (i) motor improvement is dependent on the activation of the entire nigrostriatal pathway induced by dopamine release in the dorsal striatum; (ii) the magnitude of placebo-induced effects is modulated by an expectancy of improvement, which is in turn related to the release of dopamine within the ventral striatum; (iii) the functioning of the neural pathways underlying the placebo response can be tuned by prior exposure and learning strategies. In conclusion, although the neural network underlying the placebo effect in PD has been largely confirmed and accepted, what remains to be established is how, when, and where the expectation of reward (mediated by the ventral striatum) interacts with the primary motor system (mediated by the dorsal striatum) to induce clinical improvement in motor symptoms. © 2018 International Parkinson and Movement Disorder Society.

Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents.

Autism spectrum disorder is defined by two core symptoms: a deficit in social communication and the presence of repetitive behaviors and/or restricted interests. Currently, there is no US Food and Drug Administration-approved drug for these core symptoms. This article reviews the biological origins of the social function deficit associated with autism spectrum disorder and the drug therapies with the potential to treat this deficit. A review of the history of autism demonstrates that a deficit in social interaction has been the defining feature of the concept of autism from its conception. Abnormalities identified in early social skill development and an overview of the pathophysiology abnormalities associated with autism spectrum disorder are discussed as are the abnormalities in brain circuits associated with the social function deficit. Previous and ongoing clinical trials examining agents that have the potential to improve social deficits associated with autism spectrum disorder are discussed in detail. This discussion reveals that agents such as oxytocin and propranolol are particularly promising and undergoing active investigation, while other agents such as vasopressin agonists and antagonists are being activity investigated but have limited published evidence at this time. In addition, agents such as bumetanide and manipulation of the enteric microbiome using microbiota transfer therapy appear to have promising effects on core autism spectrum disorder symptoms including social function. Other pertinent issues associated with developing treatments in autism spectrum disorder, such as disease heterogeneity, high placebo response rates, trial design, and the most appropriate way of assessing effects on social skills (outcome measures), are also discussed.

Update on Randomized Placebo-Controlled Trials in the Past Decade for Treatment of Major Depressive Disorder in Child and Adolescent Patients: A Systematic Review.

Objectives: Antidepressant treatment for major depressive disorder (MDD) has been a topic of continued interest with a number of placebo randomized-controlled trials (RCTs) being published in the past decade. We review the updated literature since the 2007 Bridge meta-analysis, and reassess safety data looking at signals of treatment-emergent suicidality with the Columbia Suicide Severity Rating Scale (CSSR-S). Methods: PubMed literature review was performed searching for RCTs published since the 2007 article and supplemented with manual search. Results: Findings from seven trials (five industry sponsored, one NIMH funded, and one other) were included in this systematic review, which showed high medication and placebo response rates, with only fluoxetine and escitalopram treatment reaching statistical significance. Fluoxetine was also shown to prevent relapse of MDD with continued treatment with an odds ratio of 3.2 for prevention of relapse compared with placebo. There were no increases in treatment-emergent suicidality associated with antidepressant medication in any trial measuring suicidality systematically using the CSSR-S. Conclusions: Depressed pediatric patients respond similarly in these trials to antidepressant intervention and placebo, with recent studies showing that newer agents did not clearly demonstrate benefit above placebo. The evidence continues to support fluoxetine and escitalopram as first-line treatment and demonstrated effect to prevent relapse. Use of newer rating scales reveals similar rates of treatment-emergent suicidality in patients on antidepressants as placebo, in contrast to increased suicide signal suggested by past research using adverse events data. Antidepressant treatment is generally safe and well tolerated in this age group.

Characterizing the Placebo Response in Adults With ADHD

Objective: Several ADHD pharmacological trials reported high placebo response (PR) rates. This study aims to characterize the PR in adult ADHD. Method: A retrospective cohort analysis of the placebo arm (140 adults with ADHD, 18-55 yrs, M:F 46.4%-53.6%) of a 6-week randomized, multicenter, double-blind metadoxine study, using Conners’ Adult ADHD Rating Scale (CAARS) and the Adult ADHD Self-Report Scale (ASRS), was conducted. Results: Pre–post changes in placebo-treated adults were significant for both the CAARS and ASRS, F(2.9, 404.5) = 61.2, p < .00001, F(2.8, 383.0) = 43.1, p < .00001, respectively. Less than half of the participants had a PR which began early in treatment and persisted; almost 50% had a variable, inconsistent PR. Conclusion: In the current sample, PR in adult ADHD was prominent on both symptom scales and the investigator–rater instrument. Therefore, using investigator ratings as a primary endpoint does not necessarily attenuate PR. Of note, about half of the PR is variable, suggesting unreliable determination of efficacy.