Faculty Bibliography

There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder (g = 0.90, 95% CI [0.70, 1.09]), depression (g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome (g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder (d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder (d = 0.32, 95% CI [0.22, 0.41]), primary insomnia (g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged 'low' quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.

To further explore the role of different antipsychotic treatments for cardio-cerebrovascular mortality, we performed several subgroup, sensitivity and meta-regression analyses based on a large previous meta-analysis focusing on cohort studies assessing mortality relative risk (RR) for cardio-cerebrovascular disorders in people with schizophrenia, comparing antipsychotic treatment versus no antipsychotic. Quality assessment through the Newcastle-Ottawa Scale (NOS) and publication bias was measured. We meta-analyzed 53 different studies (schizophrenia patients: n = 2,513,359; controls: n = 360,504,484) to highlight the differential effects of antipsychotic treatment regimens on cardio-cerebrovascular-related mortality in incident and prevalent samples of patients with schizophrenia. We found first generation antipsychotics (FGA) to be associated with higher mortality in incident samples of schizophrenia (oral FGA [RR=2.20, 95 %CI=1.29-3.77, k = 1] and any FGA [RR=1.70, 95 %CI=1.20-2.41, k = 1]). Conversely, second generation antipsychotics (SGAs) and clozapine were associated with reduced cardio-cerebrovascular-related mortality, in prevalent samples of schizophrenia. Subgroup analyses with NOS score ≥7 (higher quality) demonstrated a significantly increased cardio-cerebrovascular disorder-related mortality, among those exposed to FGAs vs SGAs. Meta-regression analyses demonstrated a larger association between antipsychotics and decreased risk of mortality with longer follow-up, recent study year, and higher number of adjustment variables. Overall, this subanalysis of a systematic review contributes to the evolving understanding of the complex role of antipsychotic treatment for cardio-cerebrovascular mortality in schizophrenia, paving the way for more targeted interventions and improved patient outcomes.

OBJECTIVE/UNASSIGNED:Evidence on the efficacy of social skills training for adolescents with Level 1 Autism Spectrum Disorder (ASD) is unclear. METHOD/UNASSIGNED:We searched Pubmed, Scopus, and Web of Science until July 27th, 2023, for randomized controlled trials (RCTs) of social skills training for pre-adolescents and adolescents (aged 9-18) with Level 1 ASD. We then pooled data on efficacy from individual RCTs by conducting multivariate mixed-effects meta-analyses in R. We estimated possible bias in the retained RCTs using the RoB2 tool. RESULTS/UNASSIGNED:We retained 36 RCTs (encompassing 2796 participants), including 18 RCTs comparing an experimental treatment to a waiting list, and 18 RCTs comparing it to standard care/control treatment. Meta-analyses showed that experimental treatments were significantly more efficacious than waiting list or standard care/ control treatments in improving social skills (SMD = 0.3745; 95%CI = [0.2396; 0.5093]), as well as reducing behavioral symptoms (0.3154;0.1783, 0.4525) and anxious/depressive symptoms (0.2780; 0.0432, 0.5128). However, for some outcomes there was significant heterogeneity across studies and evidence of publication bias. Subgroup analyses and meta-regressions did not identify any specific clinical or demographic factors as significant predictors of outcome. The most common risk of bias across studies was related to deviations from intended interventions and measurement of the outcomes. CONCLUSIONS/UNASSIGNED:At the group level, social skills training for adolescents with Level 1 ASD is efficacious, with small-to-moderate effect size. Future research should focus on personalized medicine approaches, aimed at tailoring interventions to specific characteristics of adolescents with Level 1 ASD.

Socioeconomic status (SES) influences the risk of both physical diseases, such as asthma, and neurodevelopmental conditions, including attention-deficit/hyperactivity disorder (ADHD). Using Causal Mediation Analysis on French birth-cohort data, we found a causal pathway from SES to ADHD symptoms, in part mediated by asthma. An increase in family income at age 3 by one unit resulted in lower ADHD symptoms at age 5, by -0.37 [95% CI: -0.50, -0.24] SDQ-score-points, with additional -0.04 [95% CI: -0.08, -0.01] points reduction indirectly via asthma at age 3, both with statistical significance. Importantly, family income at age 3 exerted both direct and indirect (via asthma) negative effects on later ADHD symptoms with much higher magnitudes for the direct effect. Our findings underscore the importance of apprehending ADHD symptoms in the broader context of socioeconomic disparities, along with their comorbidities with asthma, potentially influencing public health interventions and clinical practice in managing ADHD.

BACKGROUND/UNASSIGNED:Over the last decades, the prevalence of Attention-deficit/hyperactivity disorder (ADHD) has increased. However, the underlying explanation for this increase remains unclear. We aimed to assess whether there has been a secular change in how parents perceive the impairment conferred by ADHD symptomatology. METHODS/UNASSIGNED:Data for this study were obtained from the Child and Adolescent Twin Study in Sweden, involving 27,240 individuals whose parents answered a questionnaire when the children were 9 years old. We assessed the relationship between parentally perceived impairment caused by ADHD symptoms scores over time. The analysis was performed separately for five different birth cohorts, spanning three-year periods from 1995 to 2009 and for ADHD inattention and hyperactivity/impulsivity dimensions. RESULTS/UNASSIGNED:We found a consistent upward trend of parents reporting impairment in relation to ADHD symptomatology across birth cohorts. Over a 12-year period, comparing those born 2007-2009 (assessed 2016-2018) with those born 1995-1997 (assessed 2004-2006), impairment scores increased by 27% at clinically relevant levels of ADHD symptomatology. Notably, when specifically evaluating the hyperactivity/impulsivity dimension, the disparity was even more striking, with an increase of up to 77%. CONCLUSIONS/UNASSIGNED:This study revealed a significant secular change in parental perception of impairment attributed to ADHD symptomatology over recent decades, providing new insights into the increased prevalence of ADHD. It underscores the need to better understand the factors that have contributed to the increased perception of impairment related to ADHD symptoms.

Despite decades of clinical use and a large body of evidence, the WHO continues to exclude methylphenidate for attention-deficit/hyperactivity disorder (ADHD) from its EML.¹ The exclusion of methylphenidate has dire implications for millions of individuals with ADHD worldwide, especially those living in low and low-middle income countries (LMIC), where governmental decisions to make medicines available are contingent on EML listing.

The increasing administrative prevalence of Attention-Deficit Hyperactivity Disorder (ADHD) over recent years has correspondingly escalated the prescriptions of pharmacological treatments for ADHD, particularly methylphenidate (MPH), which remains the most extensively prescribed medication for this condition. In light of this trend, evaluating the long-term risks associated with using MPH is important. This article aims to present findings from studies concerning the long-term use of MPH, derived from a literature review of the past decade, primarily focusing on data sourced from PubMed to assess these risks. Our review has drawn on a diverse range of studies, including cohort studies, meta-analyses, and database reviews from various global regions, reflecting a comprehensive international perspective on the long-term safety of MPH. Our review highlights several key aspects. Initial worries about the adverse psychiatric effects of MPH did not find strong support in subsequent studies. Rather, the current body of literature suggests that MPH may have a protective effect against depression and substance use disorders. We found no significant increase in the likelihood of suicide or psychotic disorders among long-term users of MPH. In fact, studies indicate that MPH treatment might reduce the incidence of depression. Moreover, contrary to concerns that stimulant treatment might predispose individuals to SUDs, recent longitudinal studies have generally shown no increased risk of substance misuse. Some studies have even suggested a lower incidence of substance misuse among patients treated with MPH. The review also delved into cardiovascular risks, which have been a notable concern with long-term MPH usage. While short-term studies typically showed minimal cardiovascular risks, results on longer-term effects suggest potential increases in hypertension and other arterial diseases for a higher dosage, highlighting the necessity for careful cardiovascular monitoring in patients undergoing long-term treatment. No elevated risk was described concerning other cardiovascular diseases. Results regarding the impact on growth have been mixed. Some studies suggest a temporary reduction in growth velocity that normalizes over time. This pattern suggests a delayed, rather than permanently stunted, growth trajectory in children treated with MPH over the long term. Lastly, our review did not find any risk of testicular dysfunction in patients treated with MPH. The collective findings from the reviewed studies offer reassurance regarding several of the initial concerns about the long-term use of MPH. While there are concerns about potential hypertension and arterial disease risks and uncertainties regarding growth, it is important to regularly monitoring for patients using MPH. These findings should be communicated transparently to patients and their families, helping to inform shared decision-making about the initiation and continuation of MPH therapy for ADHD. As research continues to evolve, it is imperative to keep updating our understanding of the safety of MPH safety profile to optimize treatment strategies and ensure that patients receive the most effective and safe care possible.