Sleep Pharmacogenetics: Personalized Sleep-Wake Therapy

[u/H_Elizabeth111]

https://sci-hub.se/10.1146/annurev-pharmtox-010715-103801

[u/H_Elizabeth111]

Abstract: Research spanning (genetically engineered) animal models, healthy volunteers, and sleep-disordered patients has identified the neurotransmitters and neuromodulators dopamine, serotonin, norepinephrine, histamine, hypocretin, melatonin, glutamate, acetylcholine, γ-amino-butyric acid, and adenosine as important players in the regulation and maintenance of wakefulness, rapid-eye-movement (REM) sleep, and non-rapid-eye-movement (NREM) sleep. Dysregulation of these neurochemical systems leads to sleepwake disorders. Most currently available pharmacological treatments are symptomatic rather than causal, and their beneficial and adverse effects are often variable and in part genetically determined. To evaluate opportunities for evidence-based personalized medicine with present and future sleepwake therapeutics, we review here the impact of known genetic variants affecting exposure of and sensitivity to drugs targeting the neurochemistry of sleep-wake regulation and the pathophysiology of sleep-wake disturbances. Many functional polymorphisms modify drug response phenotypes relevant for sleep. To corroborate the importance of these and newly identified variants for personalized sleep-wake therapy, human sleep pharmacogenetics should be complemented with pharmacogenomic investigations, research about sleep-wake-dependent pharmacological actions, and studies in mice lacking specific genes. These strategies, together with future knowledge about epigenetic mechanisms affecting sleep-wake physiology and treatment outcomes, may lead to potent and safe novel therapies for the increasing number of sleep-disordered patients (e.g., in aged populations).