Runaway Vigilance Hormone Linked to Panic Attacks

/ Author:  / Reviewed by: Joseph V. Madia, MD

A study has linked panic disorder to a wayward hormone in a brain circuit that regulates vigilance.
While too little of this hormone, orexin, is known to underlie narcolepsy, the new study suggests too much of it may lead to panic attacks, which afflict 6 million adults in the U.S.

"Targeting the brain's orexin system may hold promise for a new generation of anti-anxiety treatments," said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This is a good example of how translational experiments in rats and humans can potentially yield clinical benefits."

NIMH grantee Anantha Shekhar, M.B., Ph.D., and colleagues at Indiana University and Lund University, reported on their findings in late December in Nature Medicine. They showed that blocking orexin gene expression or its receptor prevented panic attack-like responses in rats. The study also revealed  panic disorder patients have excess levels of the hormone.

Orexin, also called hypocretin, is secreted exclusively in a circuit emanating from the brain's hypothalamus, known to regulate arousal, wakefulness and reward.

Panic attacks can be experimentally induced by infusing susceptible humans with the normally innocuous salt sodium lactate. The salt similarly triggers panic-like anxiety behaviors in susceptible rat strains, suggesting something is altered in their arousal circuit. Since sodium lactate activated orexin-secreting neurons in panic-prone rats but not in control rats, the researchers hypothesized that something might be orexin.

The investigators first discovered that increased gene expression in orexin-secreting neurons correlated with increases in anxiety-like behavior in panic-prone rats following sodium lactate infusions. Using a technique called RNA interference, they then protected the panic-prone rats from developing anxiety behaviors following the infusions by first injecting them with a genetically-engineered agent that prevented orexin genes from turning on. Blocking orexin receptors with a drug that specifically binds to it also blocked the anxiety-like behavior following the infusions. This mirrored effects, seen in both rats and humans, of benzodiazepine medications used to treat panic disorder.

The excess sleepiness of narcolepsy, traced a decade ago to loss of orexin-secreting neurons in the arousal circuit, might seem to be an opposite state of a panic attack. However, the researchers demonstrated in rats that such sedation could not account for orexin's effects on anxiety. Also in rats, they traced orexin neurons to their end target to pinpoint the specific brain site that accounts for the anxiety effects, disentangled from cardiorespiratory components of the panic response.

Finally, by measuring orexin in cerebrospinal fluid of 53 patients, the researchers showed those patients with just panic disorder had higher levels of orexin than those patients with both panic disorder and depression.

Taken together, these results and other evidence suggest a critical role for an overactive orexin system in producing panic attacks, say the researchers. Medications that block the orexin receptor may provide a new therapeutic approach for the treatment of panic disorder, they add.

The research was also supported, in part, by the NIH's National Center for Research Resources.

Jules Asher

Reviewed by: 
Review Date: 
September 21, 2010