A Physiologic Basis for the Evolution of Pharmacotherapy for Insomnia

Insomnia is a highly prevalent disorder with consequences for the patient’s physical and mental health, daily function, and job performance. Although the exact pathophysiology of insomnia is unknown, recent research has demonstrated that normal sleep and wakefulness are controlled by reciprocal inhibition by different brain regions. This sleep-wake control system offers multiple therapeutic targets for the treatment of insomnia; currently, most research and available hypnotic agents target γ-aminobutyric acid (GABA) on the sleep side of the switch. Historically, drugs have evolved from benzodiazepine receptor agonists to nonbenzodiazepines to, most recently, selective extrasynaptic GABA_A receptor agonists. However, these drugs have a differential impact on characteristics of sleep. Among the compounds that modulate the benzodiazepine-sensitive GABA_A receptors, benzodiazepines suppress stage 3-4 sleep, whereas nonbenzodiazepines have no substantial effect on these stages of sleep. Recently, work on GABA agonists indicates that they increase stage 3-4 sleep. This has been demonstrated via sleep-stage scoring as well as with spectral analysis. Further, this increase in stage 3-4 sleep is associated with a decrease in stage 1 sleep and arousals from sleep. Thus, the GABA agonists may not simply promote sleep, but consolidate it as well. The clinical utility of the increase in slow-wave sleep and the sleep consolidation it produces warrants further investigation.