Orexin System

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The orexin system, also known as the hypocretin system, is a group of specialized neuropeptides produced in the hypothalamus that act as the brain’s primary arousal switch. It’s responsible for stabilizing wakefulness and preventing unintended transitions into sleep. In bipolar disorder (BD), the orexin system is increasingly studied as a key driver of the profound circadian/sleep-wake disruptions that define the illness. How it works: 

• Master switch: Orexin neurons send signals to other brain regions to promote alertness and suppress REM sleep. When orexin is high, a person is awake and motivated. When low, they fall asleep.
• Stabilizing rhythms: It acts as a bridge between the body’s internal master clock (the SCN) and the systems that control physical activity, appetite, and reward-seeking.

Research suggests that orexin dysregulation in BD creates a vulnerable internal clock that struggles to stay in sync:

• Phase shifts/instability: In people with BD, the normal diurnal cycle of orexin — which should peak during the day — is often flattened or mistimed. This contributes to fragmented sleep and BD’s common night owl patterns [see delayed sleep-wake phase disorder/DSWPD].
• Mood state-dependent levels: In depression, many studies show reduced orexin levels during depressive episodes, which correlates with excessive sleepiness (hypersomnia) and low energy. Conversely, some evidence points to elevated orexin (hyper-responsiveness) during manic phases, potentially explaining the “reduced need for sleep” and high goal-directed activity.
• Reward-arousal link: Because orexin also controls reward circuitry, its disruption in BD may explain why sleep loss often triggers a manic switch, as the brain becomes over-sensitized to dopamine and reward signals. 

Because the orexin system is central to BD, new medications called DORAs (dual orexin receptor antagonists) like suvorexant are being explored to treat insomnia in bipolar patients without triggering the hangover effects of traditional sedatives. Other BD medications like lithium also might help stabilize the orexin system.