Preclinical models of insomnia: advances, limitations, and future directions for drug discovery.

Abstract

Introduction: Insomnia is a highly prevalent and clinically burdensome disorder that profoundly affects cognition, emotional regulation, cardiometabolic health, and neurodegenerative progression. Despite advances in understanding its neurobiology, current animal models fail to capture the chronic, heterogeneous, and comorbid nature of human insomnia, impeding progress in translational drug discovery.

Areas covered: This narrative review critically appraises genetic, environmental, pharmacological, and circuit-level models of insomnia, focusing on their translational relevance to drug discovery and is based on literature searches using PubMed and Scopus (2000-2025) where key systematic reviews were identified. The author also discusses how oversimplified paradigms and limited modeling of comorbidity constrain clinical applicability and highlight emerging tools - optogenetics, chemogenetics, CRISPR, wearable EEG, and AI - that enable high-resolution mapping of sleep - wake mechanisms.

Expert opinion: A paradigm shift toward integrated, multidimensional models is urgently needed to reflect the complexity of chronic insomnia better. Embedding these models into translational pipelines - through precision genetics, circuit manipulation, and AI-enhanced analytics - will accelerate mechanism-based drug discovery and support the development of durable, personalized treatments for this disabling and multifactorial disorder.