Understanding Neuronal Pathways: Novel Targets for the Management of Insomnia

treated within the United States and throughout the developed world. The 2005 Sleep in America poll, conducted by the National Sleep Foundation, revealed that more than 75% of adult Americans experience at least 1 symptom of a sleep disorder more than 1 night per week. 1 Fifty-four percent of the 1506 respondents reported experiencing at least 1 symptom of disturbed sleep, and 33% reported suffering from insomnia almost every night. The most common symptoms of insomnia were “waking up feeling unrefreshed” (38%) and “waking up a lot during the night” (32%). Other commonly reported symptoms included “difficulty falling asleep” (21%) and “waking up too early and not being able to get back to sleep” (21%). 1 The personal and societal costs of insomnia are enormous. Insomnia is associated with increased direct health care costs, as well as with indirect costs related to lost productivity and accidents. Individuals with insomnia report lower quality of life and impaired daily functioning and are more likely to develop depression. Insomnia interacts with other aspects of mental and general health. Problems with sleep initiation or maintenance can be caused or aggravated by comorbid psychiatric disorders, medical illnesses, and the medications that treat them. In turn, research suggests that insomnia substantially increases the risk of new and recurrent bouts of depression and can promote poorer outcomes in psychiatric and medical illnesses. 2 Effective management of primary and secondary insomnia, including both medication and nonpharmacologic modalities, is therefore critical. Potential therapeutic targets for the treatment of insomnia include γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter of the mammalian central nervous system (CNS), and melatonin, but most available pharmacotherapies modulate GABA receptor function. Barbiturates have been largely supplanted by benzodiazepine receptor agonists (BZRAs), which include both benzodiazepine and newer nonbenzodiazepine GABAA receptor agonists. Most recently, selective extrasynaptic GABAA agonists have been developed that may provide additional treatment options. Each of these drug classes targets the GABAA receptors within the CNS, but they modulate different receptor subunits/inhibitory pathways and, therefore, differ in their effects on a variety of CNS functions. Barbiturates decrease rapid eye movement (REM) sleep, 3 and benzodiazepines suppress stage 3‐4 sleep, known as slow-wave sleep. 4 The function of slow-wave sleep is not clearly understood, but it is hypothesized to play an important role in determining sleep quality. Several of the newer nonbenzodiazepine receptor agonists do not lead to deficits in REM sleep or slow-wave sleep. 5‐8 Given the shortcomings of available therapies, researchers continue to search for compounds that modulate GABAA receptors with increased efficacy, but with few or no adverse effects. Of experimental agents in development, gaboxadol, or THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol), has been shown to increase sleep duration through the activation of extrasynaptic GABAA receptors, increasing slow-wave sleep without altering REM sleep. 9,10