New perspectives for the treatment of disorders of sleep and arousal.

A variety of molecules with novel mechanisms of action are currently being evaluated for their potential as treatments for sleep disorders. The GABA-A receptor complex remains an important target for hypnotic drugs (eg gaboxadol, indiplon). However, drugs acting through histamine, calcium channels and serotonin receptors may also be of interest for the treatment of insomnia. In the case of the 5HT2A subtype of serotonin receptors, several molecules which improve sleep maintenance and modify sleep architecture by increasing slow wave sleep are currently being tested (eg eplivanserin). Two new drugs with efficacy in excessive sleepiness (modafinil, sodium oxybate) have improved the treatment of this condition. However, the mechanisms of action of these agents are poorly understood. The recent discovery of the hypocretin arousal system in the hypothalamus may aid the identification of additional new drugs. An agonist at receptors for the pineal hormone melatonin is available in some countries (ramelteon) but is currently used only for the treatment of insomnia associated with difficulties of sleep onset. Additional melatonin receptor agonists are being developed and may have potential for treating several conditions including circadian rhythm disorders and depression.