JMIR Publications

ABSTRACT

Background:

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition emerging in early childhood, characterized by core features such as socio-communicative deficits and repetitive, rigid behaviors, interests, and activities. In addition to these, disruptive behaviors (DB), including aggression, self-injury, and severe tantrums, are frequently observed in pediatric patients with ASD. The atypical antipsychotics risperidone and aripiprazole, currently the only Food and Drug Admnistration-approved treatments for severe DB in ASD patients, often encounter therapeutic failure or intolerance. Given this, exploring pharmacological alternatives for more effective management of DB associated with ASD is essential. Clozapine, noted for its unique anti-aggressive effects in schizophrenia and in various treatment-resistant neuropsychiatric disorders, independent from its antipsychotic efficacy, remains under-explored in youths with ASD facing severe and persistent DB.

Objective:

This study aims to evaluate the efficacy, tolerability, and safety of clozapine for treatment-resistant DB in youths with ASD.

Methods:

This is a prospective, single-center, non-controlled, open-label trial. After a cross-titration phase, an estimated sample of 30 patients with ASD aged from 10 to 17 years and with treatment-resistant DB will receive a flexible dosage regime of clozapine (up to 600 mg/day) for 12 weeks. Standardized instruments will be applied before, during, and after the treatment, and rigorous clinical monitoring will be performed weekly. The primary outcome will be assessed utilizing the Irritability Subscale of the Aberrant Behavior Checklist (ABC-I). Other efficacy measures include the Clinical Global Impression Severity and Improvement (CGI-S and CGI-I), the Swanson, Nolan, and Pelham questionnaire (SNAP-IV), the Childhood Autism Rating Scale (CARS-BR), and the Vineland Adaptive Behavior Scale (VABS-3). Safety and tolerability measures will comprise adverse events, vital signs, electrocardiography, laboratory tests, physical measurements, and extrapyramidal symptoms with the Simpsons-Angus Scale (SAS). Statistical analysis will include Chi-square tests with Monte Carlo simulation for categorical variables, paired t-tests or Wilcoxon tests for continuous variables, and multivariate linear mixed models to evaluate the primary outcome, adjusting for confounders.

Results:

Recruitment commenced in February 2023. Data collection was concluded by April 2024, with analysis completion by November 2024 and study publication anticipated by April 2025.

Conclusions:

The urgent need for effective pharmacological therapies in mitigating treatment-resistant DB in pediatric patients with ASD underscores the importance of this research. Our study represents the first open-label trial to explore the anti-aggressive effects of clozapine in this specific demographic, marking a pioneering step in clinical investigation. Adopting a pragmatic approach, this trial protocol aims to mirror real-world clinical settings, thereby enhancing the applicability and relevance of our findings. The preliminary findings from this research have the potential to pave the way for more robust studies and emphasize the need for continued innovation in ASD treatment. Clinical Trial: Brazilian Clinical Trials Registry RBR-54j3726; https://ensaiosclinicos.gov.br/rg/RBR-54j3726