Targeting Orexinergic and Histaminergic Wake-Promoting Circuits: Effects on Sleep and Mental Health

Abstract Purpose of Review Sleep disturbances and mental disorders are tightly and bidirectionally linked, with hyperarousal representing a shared pathophysiological mechanism. This review focuses on two major wake-promoting systems, orexin and histamine, as pharmacological targets to improve sleep and potentially ameliorate mental health disorders that are frequently associated with sleep disturbances. Recent Findings Dual and selective orexin receptor antagonists have proven effective and well tolerated in the treatment of insomnia, promoting physiological sleep by dampening wake drive. Emerging preclinical and clinical evidence suggests additional benefits on stress, anxiety, and mood-related symptoms. In parallel, modulation of the histaminergic system represents a well-established yet evolving therapeutic approach, encompassing both sedative and wake-promoting strategies, with clinical applications in insomnia and narcolepsy and emerging relevance for a broader range of mental disorders. Summary Targeting wake-promoting circuits represents a rational strategy to improve the quality of life of patients suffering from insomnia or mental disorders by stabilizing arousal and sleep-wake regulation.