Emerging drugs for insomnia: new frontiers for old and novel targets

Background: Insomnia is the most prevalent sleep disorder, with up to 50% of the US adult population reporting symptoms of insomnia on a weekly basis and similar to 12% with insomnia disorder. Comorbid conditions such as depression and anxiety are frequent. Insomnia is more common with older age, female gender and socioeconomic status. Traditionally, therapy has focused on GABA(A) receptor agonists, and off-label antidepressant and antihistamine use. Objective: With increased understanding of complex neural networks involved in sleep and wake, hypnotics are being developed to target a broader variety of receptors with increasing selectivity. This review summarizes promising compounds in Phase II and III trials with evidence supporting efficacy for treatment of insomnia. Methods: 5-HT2A and 5-HT2C antagonists, melatonergic (MT1/MT2) agonists, orexin receptor (OX1/OX2) antagonists, as well as GABA(A) receptor agonists are reviewed and summarized. Data are collected from PubMed and Pharmaprojects database searches, company websites, recent scientific meeting presentations and abstracts. Results/conclusions: A variety of drugs targeting several pathways, including GABA(A) agonism, MT1/MT2 agonism, 5-HT2A antagonism, OX1/OX2 antagonism and others, are in Phase II and III trials. More work should be done to understand the impact of these drugs in certain populations and in the context of comorbid conditions.