clozapine and Sleep-Apnea--Obstructive

Rapid eye movement (REM) sleep was discovered nearly 60 years ago. This stage of sleep accounts for approximately a quarter of total sleep time in healthy adults, and it is mostly concentrated in the second half of the sleep period. The majority of research on REM sleep has focused on neurocognition. More recently, however, there has been a growing interest in understanding whether obstructive sleep apnea (OSA) during the two main stages of sleep (REM and non-REM sleep) leads to different cardiometabolic and neurocognitive risk. In this review, we discuss the growing evidence indicating that OSA during REM sleep is a prevalent disorder that is independently associated with adverse cardiovascular, metabolic, and neurocognitive outcomes. From a therapeutic standpoint, we discuss limitations of continuous positive airway pressure (CPAP) therapy given that 3 or 4 h of CPAP use from the beginning of the sleep period would leave 75% or 60% of obstructive events during REM sleep untreated. We also review potential pharmacologic approaches to treating OSA during REM sleep. Undoubtedly, further research is needed to establish best treatment strategies in order to effectively treat REM OSA. Moreover, it is critical to understand whether treatment of REM OSA will translate into better patient outcomes.

Topics: Animals; Clozapine; Continuous Positive Airway Pressure; Dose-Response Relationship, Drug; Dronabinol; Humans; Outcome and Process Assessment, Health Care; Pharynx; Polysomnography; Randomized Controlled Trials as Topic; Risk; Sleep Apnea, Obstructive; Sleep, REM; Tongue

Topics: Animals; Clozapine; Diaphragm; Efferent Pathways; Electromyography; Facial Muscles; Hypoglossal Nerve; Motor Neurons; Rats; Rats, Wistar; Serotonin; Sleep; Sleep Apnea, Obstructive; Tongue; Wakefulness

Obstructive sleep apnea (OSA) is characterized by recurrent upper airway obstruction during sleep. OSA leads to high cardiovascular morbidity and mortality. The pathogenesis of OSA has been linked to a defect in neuromuscular control of the pharynx. There is no effective pharmacotherapy for OSA. The objective of this study was to determine whether upper airway patency can be improved using chemogenetic approach by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motorneurons. DREADD (rAAV5-hSyn-hM3(Gq)-mCherry) and control virus (rAAV5-hSyn-EGFP) were stereotactically administered to the hypoglossal nucleus of C57BL/6J mice. In 6-8 weeks genioglossus EMG and dynamic MRI of the upper airway were performed before and after administration of the DREADD ligand clozapine-N-oxide (CNO) or vehicle (saline). In DREADD-treated mice, CNO activated the genioglossus muscle and markedly dilated the pharynx, whereas saline had no effect. Control virus treated mice showed no effect of CNO. Our results suggest that chemogenetic approach can be considered as a treatment option for OSA and other motorneuron disorders.

Topics: Animals; Antipsychotic Agents; Clozapine; Dependovirus; Disease Models, Animal; Electromyography; Genes, Reporter; Genetic Vectors; Green Fluorescent Proteins; Hypoglossal Nerve; Injections, Intraventricular; Luminescent Proteins; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Neurons; Pharynx; Red Fluorescent Protein; Sleep Apnea, Obstructive; Stereotaxic Techniques

Topics: Adult; Antipsychotic Agents; Clozapine; Continuous Positive Airway Pressure; Humans; Male; Memory; Schizophrenia; Sleep Apnea, Obstructive

Topics: Antipsychotic Agents; Body Mass Index; Clozapine; Comorbidity; Female; Humans; Male; Middle Aged; Obesity; Schizophrenia; Sleep Apnea, Obstructive; Weight Gain