A new cure for insomnia?

Edit: Looks like Merck's DORA drug in on the brink of approval from the FDA. Exciting!

Many a nights I’ve tossed and turned, willing my brain to STFU and let me sleep. I’m not alone in this battle. 10-15% of adults suffer from insomnia, and up to a third take prescription sleeping pills to bring on the snooze – for a heavy cognitive price.

Current sleeping drugs, such as Ambien and Lunesta, target a type of receptor called GABAAR in the brain. GABAAR is not only implicated in sleep; it also regulates mood, learning and cognition, and works to increase inhibitory synaptic transmission. Targeting GABAAR with Ambien is almost like bringing a hammer to the head: it slows down the brain enough to bring on sleep, but at the same time disrupts normal cognition, attention, learning and memory the next day, leading to “hypnotic hangovers” that are hard to shake off. Even worse, GABAA-modulators don’t really mimic the physiological sleep state, and can bring on some seriously weird behaviors, such as walking, eating and even driving while the person is asleep.

Is it time for a new target?

Jason M. Uslaner et. al. (2013) Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition. Science Translational Medicine 5, 179ra44

The authors in this study have their eyes on the orexinergic system. Along with its role in appetite and energy regulation, orexin (aka hypocretin) is also a predominant arousal signal to parts of the brain controlling the sleep/wake cycle. It is a protein synthesized almost exclusively at the lateral hypothalamus, the brain’s major sleep/wake control centre, and acts to promote wakefulness and vigilance. Unlike the promiscuous GABAAR, orexin’s receptors are scattered in brain areas primarily involved in sleep. Previous studies have shown that blocking orexin can induce sleep, but haven’t looked at potential cognitive side effects. Here, the authors developed a new orexin receptor antagonist called DORA-22, and pitted it against the traditional hypnotics, Valium (diazepam), Ambien (zolpidem) and Lunesta (eszopiclone).

By feeding the drugs to rats and rhesus monkeys, the authors first discovered that at higher doses, DORA-22 was just as effective as GABA-modulating drugs in bringing on the zzzs, while at lower doses it was even more effective than current drugs on the market. (How do you tell when an animal is asleep? Here the authors fitted their test subjects with devices for ECGs to measure their brain waves. A less objective way is to flip a rat over and see if it flips back. Either way, sleepy rats make cute subjects. Not so sure about sleepy monkeys). So DORA-22 seems to work as hypothesized, but what about side effects? The authors went on to test DORA-22’s effect on three aspects of cognition: episodic-like memory, the ability to remember things and events; working memory, the ability to keep information in mind and manipulate it towards a goal; and attention, the ability to focus and keep track.

After inducing sleep with the drugs, researchers rudely awakened their subjects and started the tests. They presented rats with a new object, which the rats eagerly explored. They then took the object away, and returned it one hour later, along with a new object. If the rats remembered the first object, they would explore the newer one more vigorously. This is called the “object recognition task”, and is a measure of memory. Valium, Ambien and Lunesta all disrupted object recognition memory. In fact, the minimum dose that did so was ½ to 1/10 the minimum dose that increased sleep in rats! This means that GABAA modulators induce memory failure BEFORE sleep. In stark contrast, while DORA-22 also decreased memory at high doses, the minimum dose required was 30-fold greater than the dose that increased sleep. In other words, DORA-22 had a much greater therapeutic window. The same trend was observed for the other two tasks: monkeys on GABAA modulators performed much worse on tasks measuring working memory and attention than controls, while those given DORA-22 did just as well.

This is very exciting and encouraging, as DORA-22 signifies an entirely new class of hypnotics. Not every drug works for everyone, and those that do work tend to be less effective over time as tolerance develops. The lack of negative effects on short-term cognition is also a major plus.

HOWEVER, due to the experimental design, it is impossible to tell whether manipulating the orexin system will cause next day “hypnotic hangover”. The conditions used in this study corresponds to situations where the patient is awakened from a short stretch of DORA-22-induced sleep and expected to perform tasks that demands attention, memory and mental flexibility. Think a student popping a pill to power nap for an hour, before being wakened by the alarm to immediately go take an exam. From the available data we don’t know if cognition is disrupted the next day after a full sleep period. We also don’t know if DORA-22 influences the composition of sleep, as in the relative percentage of rapid-eye movement (REM), non-REM and slow-wave sleep. Since each stage of sleep has its own distinct function, maintaining a physiological sleep make-up is crucial. Along the same lines, sleep generally occurs in 90-min cycles, and disrupting the cycle can impair memory processes such as memory reconsolidation. At the moment we also don’t know whether DORA-22 influences cycle duration and/or total sleep time. There is also no information on long-term usage. And finally, while orexin receptors are more specifically distributed than GABAARs, orexins DO have roles outside managing wakefulness, such as increasing food intake and energy expenditure. Whether DORA-22 (and its sons and daughters) will affect these biological processes is anybody’s guess.

Although I wouldn’t call DORA-22 a “drug that can overcome insomnia without leaving users feeling hungover the following day” or “the perfect hypnotic” just yet, overall, targeting the orexin system seems to be a promising strategy for bringing sleep to insomniacs without the cognitive side-effects.

Finally, if you haven’t seen Mike Birbiglia’s “Sleepwalk with me” yet, I highly recommend it. From Wikipedia: Sleepwalk with Me is a comedy written by, directed by and starring comedian Mike Birbiglia, based on a true story he told in his one-man off-Broadway show and his first book. The film follows the journey of an aspiring comedian in denial about his girlfriend, his career, and, most significantly, his REM Sleep Behavior Disorder. The more he fails to express his true feelings, the more his anxiety comes out in increasingly funny and dangerous sleepwalking incidents.

Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT, Binns J, Cannon CE, Garson SL, Yao L, Hodgson R, Stevens J, Bowlby MR, Tannenbaum PL, Brunner J, McDonald TP, Gotter AL, Kuduk SD, Coleman PJ, Winrow CJ, & Renger JJ (2013). Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Science translational medicine, 5 (179) PMID: 23552372