5-HT2A Inverse-Agonists for the Treatment of Insomnia

Nearly one half of the adult population in the U.S. experience some symptoms of insomnia (difficulties with getting to sleep, maintaining sleep, and/or sleep quality) on a weekly basis. Although most people with insomnia complain primarily of issues related to sleep maintenance and quality, current therapeutic approaches, including GABAA agonists, off label antidepressant use, H1 antagonists and melatonin agonists, primarily address sleep onset latency. The overall sleep architecture, especially that of the deeper stages of NREM sleep known as slow wave sleep (SWS), plays a crucial role in restorative, restful sleep. Through the 5-HT2A receptor, serotonin plays an active role in the regulation of sleep architecture. Antagonists / inverse-agonists of 5-HT2A, such as APD125, volinanserin, eplivanserin, pruvanserin and pimavanserin, are currently being investigated as therapeutics that could improve the treatment of sleep maintenance and quality in people with insomnia.