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Autistic adults are highly vulnerable to mental health problems and yet, our understanding of co-occurring psychiatric disorders in this population is limited. Anxiety is one of the most pervasive psychiatric disorders that affects autistic adults. Here, we investigated the association between anxiety, restricted and repeated behaviors and interests (RRB), and challenges in social communication and interaction (CSCI) as a post-hoc analysis of a large Phase 3 clinical trial (NCT03504917). The study enrolled 322 adults (64 females, age 27 ± 10) assessed at baseline and weeks 12, 24, 36, and 52, with the Hamilton Anxiety Rating Scale, the Repetitive Behaviors Scale – Revised, and the Vineland-II for CSCI. All analyses were blind to treatment assignment as the primary study analysis had found no treatment effects. Anxiety levels were significantly correlated with RRB and CSCI at baseline (RRB: r  = 0.19, P  < 10 –3 ; CSCI=–0.13, P  = 0.02) and across the entire study (RRB: r  = 0.22, P  < 10 –3 ; CSCI=–0.16, P  < 0.01). However, a mediation analysis revealed that the effect of CSCI on anxiety was fully explained by RRB ( P  = 0.17). While no causal relationship between both symptom domains has been established yet, our findings suggest that anxiety symptoms are associated with increased RRB, warranting further exploration of a potential causal association and implications for treatment. Clinical trial registration : The research presented is registered at ClinicalTrials.gov with the code NCT03504917.

High rates of placebo response are increasingly implicated in failed autism spectrum disorder (ASD) clinical trials. Despite this, there are limited investigations of placebo response in ASD. We sought to identify baseline predictors of placebo response and quantify their influence on clinical scales of interest for three harmonized randomized clinical trials of balovaptan, a V1a receptor antagonist. We employed a two-step approach to identify predictors of placebo response on the Vineland-II two-domain composite (2DC) (primary outcome and a caregiver measure) and Clinical Global Impression (CGI) scale (secondary outcome and a clinician measure). The initial candidate predictor set of variables pertained to participant-level, site-specific, and protocol-related factors. Step 1 aimed to identify influential predictors of placebo response using Least Absolute Shrinkage and Selection Operator (LASSO) regression, while Step 2 quantified the influence of predictors via linear regression. Results were validated through statistical bootstrapping approaches with 500 replications of the analysis dataset. The pooled participant-level dataset included individuals with ASD aged 5 to 62 years (mean age 21 [SD 10]), among which 263 and 172 participants received placebo at Weeks 12 and 24, respectively. Although no influential predictors were identified for CGI, findings for Vineland-II 2DC are robust and informative. Decreased placebo response was predicted by higher baseline Vineland-II 2DC (i.e., more advanced adaptive function), longer trial duration, and European (vs United States) sites, while increased placebo response was predicted by commercial (vs academic) sites, attention deficit hyperactivity disorder and depression. Identification of these factors may be useful in anticipating and mitigating placebo response in drug development efforts in ASD and across developmental and psychiatric conditions.