Volume 742013Supplement 1

Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System

3 Understanding the Sleep-Wake Cycle: Sleep, Insomnia, and the Orexin System

Clinical Points
  • The Sleep-Wake Cycle and the Roles of GABA and Orexin in Sleep and Insomnia
  • The sleep-wake cycle is regulated by homeostatic and circadian processes and competing neurobiological structures that tip the balance from sleep to wake.
  • Possible mechanisms of insomnia are diminished GABA and elevated orexin levels; more research is needed to clarify these relationships.
  • Insomnia Treatments: Current Options and Ongoing Unmet Needs
  • Psychological and behavioral therapies, such as CBT, should be considered as a first-line treatment for insomnia, either alone or in combination with pharmacotherapy.
  • Over-the-counter treatments for insomnia may have some short-term use for sleep latency or sleep maintenance, but their efficacy is not established in controlled trials.
  • Benzodiazepines and BZRAs share similar efficacy for insomnia symptoms, with the BZRAs showing better safety and tolerability over benzodiazepines.
  • Off-label use of antidepressants and antipsychotics for insomnia treatment is not recommended as first-line treatment due to their adverse effects and limited effectiveness for primary insomnia, but may be useful for insomnia comorbid with psychiatric disorders.
  • Mechanism of Action of Insomnia Treatments: GABA Agonists Versus Orexin Antagonists
  • The GABAergic system has been the focus of hypnotics until the orexin system became a treatment target.
  • Benzodiazepines and BZRAs both act on the GABAA receptor, although their shorter half-lives and the specificity of BZRAs for subunits on the GABAA receptor provide better tolerability profiles than the benzodiazepines.
  • The orexin system has provided a new mechanism of action for hypnotics; at certain doses, antagonists may improve sleep without some of the adverse effects associated with benzodiazepines and BZRAs.

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