Drug development in autism spectrum disorder: genetic heterogeneity, failed trials, and the case for stratified pharmacotherapy

Despite three decades of clinical trials, no pharmacological treatment has shown consistent efficacy for the core features of autism spectrum disorder (ASD), and regulatory approvals remain limited to risperidone and aripiprazole for severe irritability. This limited efficacy likely reflects a mismatch between underlying biology and broad trial designs. ASD is a clinically defined neurodevelopmental condition with marked etiologic heterogeneity, shaped by highly polygenic liability and a long tail of rare, often de novo , high-impact variants. Genomic studies implicate synaptic signaling, chromatin regulation, and excitatory-inhibitory processes, but this partial biological convergence does not support a single therapeutic target across the diagnostic spectrum. Debate over environmental risk factors, including prenatal acetaminophen exposure, also shows how weak causal inference can distort research priorities. We propose three priorities for ASD pharmacotherapy: genetically stratified mechanism-linked interventions, pharmacogenomics-informed symptomatic prescribing, and trials using validated or biomarker-informed endpoints that capture outcomes regarded as meaningful by autistic people.