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

Abstract

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 ∼ 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-HT_2A and 5-HT_2C 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-HT_2A 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.

Keywords::

• 5-HT receptor antagonist
• GABA_A agonist
• GHB
• histamine antagonist
• hypnotic
• insomnia
• melatonin
• orexin