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Sleep-Wake Systems Intersected: A New Dawn in the Treatment of Sleep Disorders

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - SLEEP 2013 - 27th Annual Meeting of the Associated Professional Sleep Societies

Baltimore, Maryland / June 1-5, 2013

Baltimore - Insomnia is a common disorder frequently accompanied by comorbidities, most commonly depression. Historically, it was believed that difficulty in falling or maintaining sleep was due to abnormalities in the sleep system. It is now recognized that insomnia is a hyperarousal disorder that will not permit sleep even when given adequate opportunity to do so. Several novel agents that selectively intercept transmitters involved in the wake system have shown considerable potential as new hypnotic agents. Work continues on another molecule that has the potential to offset excessive daytime sleepiness caused by narcolepsy and Parkinson’s disease. Together, these novel agents promise a new dawn in the armamentarium targeting sleep disorders. 

Since the designation of insomnia as a disorder, understanding what insomnia is and why it occurs has become more clear. “Everyone’s had a bad night of sleep but that’s very different from insomnia,” Dr. Thomas Roth, PhD, Director, Sleep Disorders and Research Center, Henry Ford Hospital and Professor of Psychiatry, Wayne State University, Detroit, Michigan, said at the meeting. Having difficulty sleeping is one of the symptoms of insomnia, he added.

But to be diagnosed with insomnia, lack of sleep must occur in spite of having an adequate opportunity to sleep and it must cause daytime impairment. “There also has to be a frequency and a chronicity to it,” Dr. Roth added—specifically, difficulty sleeping needs to occur at least 3 days a week and has to have lasted for at least 1 month depending on the criteria used. Using the DSM-IV criteria for insomnia, Roth et al. found that between 20 to 25% of managed health care plan subscribers reported insomnia (Biological Psychiatry 2011;69(6):592-600).  Importantly, insomnia is frequently associated with a variety of co-morbidities, depression being the most common.

Breslau et al. (Biological Psychiatry 1996;39(6):411-18)  for example found that the relative risk for new onset of major depression over the ensuing 3.5 years was 4 times higher among young adults with a history of insomnia at baseline. “Historically, we thought insomnia was secondary to depression,” Dr. Roth explained. “But we now know that insomnia is a risk factor for depression and for most people with insomnia and depression, insomnia predates the depression.” Patients with insomnia are also more sensitive to pain; are at significantly greater risk to develop hypertension and among nursing home residents, insomnia is associated with a greater risk of falls, as Dr. Roth also pointed out.

“We always think of sleep and wake as a balance of two systems,” he said. Historically, it was presumed that the defects giving rise to insomnia were in the sleep system. But in one of many investigations of the neurobiological basis of poor sleep and daytime fatigue in insomnia patients, Nofzinger et al. (Am J Psychiatry 2004;161(11):2126-8) found that patients with insomnia showed greater global cerebral glucose metabolism during sleep, than while awake, compared with healthy controls.

From these findings, they concluded that patients’ inability to fall asleep is related to a failure of arousal mechanisms to decline in activity from waking to sleep states.“Patients with insomnia often say they can’t sleep because they can’t shut their mind off,” Dr. Roth observed. “But the reason they can’t shut their mind off is because they have this increase in brain metabolism so rumination is secondary to biology. Patients can’t shut their brain off because of this biological effect.”

Insomnia: Targeting Wakefulness

Targeting systems or transmitters that are responsible for wakefulness thus makes scientific sense. Current melatonin receptor agonists do not induce sleep but if they are taken enough in advance, they can have a soporific effect at bedtime. Piromelatine is a non-specific melatonin receptor agonist which induces both chronobiotic and soporific effects. At the same time, it inhibits the wake-promoting effects of orexin neurons in the hypothalamus and appears to possess additional anti-allodynic properties. In a phase II randomized, double-blind placebo-controlled yet unpublished study, piromelatine at 20 and 50 mg brought about clinically meaningful improvements in wake after sleep onset after 4 weeks of treatment in a small group of patients with insomnia.

At 50 mg, the same molecule improved total time in non-REM sleep and total sleep time. It was also shown to be effective against hyperarousal in insomnia patients, an effect that is quite unique to this particular molecule and which is in contrast to the benzodiazepines. Early findings suggest it is also safe and well-tolerated.

Clinical and genetic studies have demonstrated that orexin neuron activity promotes wakefulness (Lancet 2000;355:39-40). Unlike widely used treatments for insomnia that increase the action of GABA—a global CNS inhibitory neurotransmitter—orexin receptor antagonists (ORAs) act on a highly localized nexus of neurons located in the hypothalamus and nowhere else in the brain. Pre-clinical studies have confirmed that selective binding to these neurons leaves memory and other forms of cognition intact. 

As the first in its class of ORAs, suvorexant blocks the wake-promoting signal of orexin, facilitating transition to sleep. A pooled analysis of two phase III trials evaluating two doses of suvorexant versus placebo confirmed the efficacy of this new ORA in primary insomnia (abstract 0553). Both studies had a nearly identical design where non-elderly and elderly patients with a DSM-IV diagnosis of insomnia were randomized to pharmacokinetically-equivalent (PK) doses of the ORA at either 40 mg or 20 mg a day for the non-elderly and 30 mg or 15 mg for the elderly. Since non-elderly and elderly patients were matched in terms of PK exposure to the drug, both age groups were combined for this pooled analysis. A total of 755 patients were in the high-dose group; 494 in the low-dose group and 772 were randomized to placebo. At the end of the 3-month trial, there was a reduction in time to sleep onset of about 30 minutes in the high-dose group and 20 to 25 minutes in the low-dose group compared to a baseline mean of 70 to 75 minutes. At study end point, total sleep time improved by about 1 hour in the high-dose group and by about 50 minutes in the low-dose group from approximately 5 ¼ hours at baseline.

A safety analysis of 3 pooled phase III studies also presented here (abstract 0647) found that the most frequently reported adverse events associated with chronic use of suvorexant were somnolence at between 7 and 10% and fatigue at 2 to 3% for the low and high-dose therapy, respectively.

Opposingly: Treating Sleepiness

Another innovative molecule under evaluation – this time to heighten wakefulness – is the H3-receptor inverse agonist, pitolisant. As noted by John et al. (abstract 737), narcolepsy is linked to the loss of hypocretin or orexin neurons. Histamine is also known to be released in waking and has thus been proposed to mediate the arousal produced by hypocretin. In a number of clinical trials (Br J Pharmacol 2011;163(4):713-21), pitolisant, an H3-receptor inverse agonist, was shown to improve excessive daytime sleepiness in narcolepsy. In a small pilot study in teenagers who developed narcolepsy in childhood, Inocente et al. (Clin Neuropharmacol. 2012;35:55-60) concluded that pitolisant may constitute an acceptable alternative for the treatment of refractory sleepiness in teenagers with narcolepsy. The same molecule has also been shown to significantly improve excessive daytime sleepiness in Parkinson’s disease (PD) and it may have partial synergy with the dopamine system as PD patients treated with the novel agonist were able to reduce their daily dose of levodopa, as speakers here indicated.

Findings indicate that the histamine system constitutes a brain-activating system; that its deficiency causes somnolence, and that the H3-receptor inverse agonists may offer a more specific treatment for somnolence, simultaneously improving cognition, in the treatment of sleep-wake disorders such as narcolepsy.


Historically, hypnotics have been non-selective affecting GABA in many regions of the brain and thus functions other than sleep. Having identified novel transmitters involved in the wake system, researchers have been able to target neurons localized to one small part of the brain and intercept wakefulness. Clinical studies show this mechanism is highly effective in inducing and maintaining sleep. Agonism of histamine pathways in turn has the potential to promote wakefulness and offset excessive daytime sleepiness associated with a number of disorders. 


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