Orexin receptor antagonists for sleep disturbance in attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review

Background Sleep disturbance is among the commonest and most impairing comorbidities of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Melatonin has the strongest evidence base, but its action is chronobiotic, its maintenance effect inconsistent, and adult evidence sparse. Orexin receptor antagonists reduce wake drive rather than induce sedation, a mechanistically distinct alternative. Methods Reported in accordance with PRISMA 2020. PubMed, Europe PMC, OpenAlex and ClinicalTrials.gov were searched on 23 September 2026 using three complementary concept searches with backward citation tracking; Embase and PsycINFO were not searched. Screening applied a mechanical rule, and every candidate was assessed at full text by two independent reviewers. Eligible reports described a person with diagnosed ADHD or ASD given an orexin receptor antagonist, with a sleep, behavioural, cognitive or safety outcome. Risk of bias was appraised at domain level and certainty against the GRADE domains without categorical ratings. Pooling was precluded by heterogeneity and by the absence of comparable controlled effect estimates. Results Eight reports representing seven patient groups described 41 exposed participants, 25 with ADHD and 16 with ASD. No completed trial provides peer-reviewed or registry-posted diagnosis-specific outcomes. The strongest signal is a one-month open-label study of daridorexant 50 mg in 24 adults with ADHD and insomnia, where median insomnia severity fell from 16 to 8 and actigraphic total sleep time rose by about 24 minutes, both surviving correction, and 62.5% responded; no cognitive outcome survived correction, one worsened, and the favourable attention results required excluding sleep non-responders. In ASD the evidence is case reports and small series confounded by co-medication, the only comparison-group report being null. No report provides ADHD-stratified paediatric outcomes. Of two registered trials one is recruiting and one completed, the latter’s sponsor releasing top-line data without diagnosis-stratified outcomes. Conclusion Orexin receptor antagonism is a mechanistically coherent approach to sleep disturbance in ADHD and ASD, but no appraisable, diagnosis-specific controlled evidence supports its use, and the evidence is too sparse and biased for causal inference. The signal that sleep gains may accompany attention gains requires a randomised test. Routine use cannot be recommended, and off-label prescribing requires individualised specialist assessment.