While many effective pharmacologic and behavioral treatments for insomnia are available and can be individualized in numerous ways, true precision therapy for sleep disturbances remains largely in the realm of research. This is true, in part, because there are many primary and secondary causes of insomnia, with many comorbidities that may impact sleep. The deep mechanistic, molecular, and physiologic understanding of each type of insomnia that would guide diagnosis and personalized treatment does not yet exist to the degree that it does for other conditions. Nonetheless, progress is being made in understanding the molecular aspects of insomnia, particularly in insomnias that stem from disruption of the circadian clock. These are not the most common types of insomnia, but we now recognize, to the molecular genetic level, many of the mechanisms that lead to changes in the timing of circadian control of sleep.

Today’s treatments range from cognitive behavioral therapy to pharmacotherapies that act on differing neurotransmitter systems. Available medications have distinct side-effect profiles, with differing half-lives, and treatment can be geared toward problems with sleep onset, sleep maintenance, or both. The gamma-aminobutyric acid (GABA) system is the major inhibitory neurotransmitter in the central nervous system (CNS), and the side-effect profiles of GABA-based drugs are fairly broad, including tolerance, withdrawal symptoms, and dependence. Orexin receptor antagonists are relatively recent additions to the landscape, with phase 3 clinical trials reporting favorable efficacy and safety profiles for both suvorexant and lemborexant. While having broad importance to brain function, the orexin system involves a relatively small number of neurons that produce the orexin neuropeptide. With orexin inhibitors, you are going from a set of compounds that impact a large fraction of the CNS (ie, the GABA system) to a set of compounds that have a more discrete effect on the CNS. That in and of itself has theoretical advantages. Further, given that most therapeutics for insomnia have been in the GABA-based class for quite a long time, having an additional option that is effective and safe gives clinicians another tool in their toolkit to address insomnia.

However, to achieve the goal of more personalized treatment of insomnia, a better understanding of the differing phenotypes and molecular bases for commonly encountered forms of insomnia is needed. One of the more promising steps toward this goal is the recent work aimed at developing a simple blood test that could be administered in the doctor’s office to assess physiological time using transcriptional biomarkers. Theoretically, such testing might improve the diagnosis of circadian disorders and optimize the delivery of treatments. I think that this type of precision approach might be more broadly applicable once we start to define the underlying physiological disruption, at the level of gene expression. Other research is being conducted in areas such as metabolomics and proteomics; these approaches are expected to bear fruit in terms of further characterizing the very complex and multifactorial causes of insomnia. They may be the key to solving this puzzle pipeline from diagnosis to therapeutics.