Orexin receptor antagonists for sleep disturbance in attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review
- 1School of Human and Health Sciences, University of Huddersfield
- 2Department of Health Sciences, School of Life and Health Sciences, University of Nicosia
Abstract
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.
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BibTeX
@article{adamou2026orexin,
title = {{Orexin receptor antagonists for sleep disturbance in attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review}},
author = {Marios Adamou and Christos Petrou},
journal = {Frontiers in Psychiatry},
year = {2026},
month = nov,
doi = {10.3389/fpsyt.2026.1969750},
url = {https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1969750/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Orexin receptor antagonists for sleep disturbance in attention-deficit/hyperactivity disorder and autism spectrum disorder: a systematic review
AU - Marios Adamou
AU - Christos Petrou
PY - 2026
DA - 2026/11/09
JO - Frontiers in Psychiatry
DO - 10.3389/fpsyt.2026.1969750
UR - https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1969750/full
AB - 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.
SN - 1664-0640
ER -