Table 1.
Summary of recent findings on orexin receptor antagonists for the treatment of sleep disorders.
| Manipulation and target | Subjects | Findings | References |
|---|---|---|---|
|
Filorexant (MK-6096) DORA |
Rats and dogs | Dose-dependently reduced locomotor activity and increased sleep in rats and dogs. | Winrow et al. [151] |
| Mice | Stabilized sleep and improved sleep-dependent memory function. | Li et al. [50] | |
| Patients (18–65 years old) with primary insomnia | Increased SE, decreased WASO, and decreased the latency to persistent sleep onset. | Connor et al. [61] | |
|
Suvorexant (MK-4305) DORA |
Rats, dogs, and rhesus monkeys | Reduced locomotor activity and promoted sleep in rats, dogs, and rhesus monkeys. | Winrow et al. [47] |
| Mice | Disturbed sleep architecture by selectively increasing REM sleep and decreasing wake time. | Hoyer et al. [48] | |
| Type 2 diabetic db/db mice | Increased NREM sleep and improved impairment in glucose tolerance in db/db mice. | Tsuneki et al. [49] | |
| Non-elderly patients with primary insomnia | Increased SE, decreased LPS, and decreased WASO | Herring et al. [152] | |
| Patients with primary insomnia | Showed greater efficacy than placebo in improving subjective TST and subjective TSO; was generally safe and well tolerated over 1 year of nightly treatment. | Michelson et al. [64] | |
| Nonelderly and elderly patients with insomnia. | Improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated. | Herring et al. [57] | |
| Patients with insomnia | Increased TST (average increase ≤ 3.9% in REM sleep) and reduced REM sleep latency. | Snyder et al. [66] | |
| Elderly patients with insomnia | Generally improved sleep maintenance and onset over 3 months of nightly treatment and was well-tolerated. | Herring et al. [56] | |
| Elderly and nonelderly insomnia patients | Generally effective and well tolerated in both women and men with insomnia. | Herring et al. [59] | |
| Psychiatric inpatients with insomnia | Overall improvement in the quality of sleep and the severity of anxiety and depression. | Nakamura et al. [89] | |
| Adolescent patients with insomnia | Improved sleep quality in adolescent insomnia. | Kawabe et al. [62] | |
| Japanese elderly patients with chronic insomnia | Appeared to be more cost-effective than the alternative zolpidem in a virtual cohort. | Nishimura and Nakao [153] | |
| Elderly and non-elderly insomnia patients | Improved sleep to a greater extent than placebo as assessed by the ISI. | Herring et al. [63] | |
| Insomnia patients | Reduced WASO by reducing the number and time spent in long wake bouts. | Svetnik et al. [154] | |
| Healthy young men (18–45 years old) | Decreased LPS and wake after sleep onset time and increased SE; did not affect EEG frequency bands. | Sun et al. [60] | |
| Patients with primary insomnia | Limited effects on EEG power spectral density compared with placebo. | Ma et al. [65] | |
| Alzheimer’s disease patients with insomnia | Adequate efficacy for the treatment of insomnia in patients with Alzheimer’s disease. | Hamuro et al. [69] | |
| Patients with type 2 diabetes mellitus and insomnia | Increased TST and SE and decreased glucose levels. | Toi et al. [70] | |
| COPD patients | Did not have an overt respiratory depressant effect. | Sun et al. [76] | |
| Healthy adult men and women | Lacked clinically important respiratory effects during sleep. | Uemura et al. [74] | |
| Patients (18–65 years old) with OSA | Did not appear to have clinically important respiratory effects during sleep. | Sun et al. [75] | |
|
Almorexant (ACT-078573) DORA |
Healthy male participants | Equivalent to zolpidem with regard to subjectively assessed alertness. | Hoever et al. [155] |
| Mice | Increased REM and NREM sleep in wild-type mice but not in OX2R-knockout mice. | Mang et al. [43] | |
| Mice | Promoted sleep and exacerbated cataplexy in a mouse model of narcolepsy. | Black et al. [156] | |
| Rats | Promoted sleep without impairing memory performance. | Morairty et al. [157] | |
| Rats | Promoted sleep but was permissive for the activation of wake-promoting systems. | Parks et al. [51] | |
| Male and female adult patients with primary insomnia | Decreased subjective WASO, decreased objective and subjective LPS, decreased the latency to sleep onset, and increased objective and subjective TST. | Black et al. [158] | |
| Elderly patients with primary insomnia | Increased TST, decreased WASO, and decreased LPS. | Roth et al. [159] | |
|
SB-649868 DORA |
Healthy male volunteers | Increased TST and REM sleep duration, decreased WASO and LPS, and decreased the latency to REM sleep; did not affect SWS or EEG power spectra in NREM sleep. | Bettica et al. [67] |
| Male patients with primary insomnia | Decreased LPS, decreased WASO, increased TST, increased REM sleep, and decreased REM sleep latency. | Bettica et al. [68] | |
|
Lemborexant (E2006) DORA |
Mice | Efficacy demonstrated in an in vivo study that used objective sleep parameter measurements. | Yoshida et al. [160] |
| Adults and elderly subjects with insomnia | Improved SE and subjective SE, decreased LPS and subjective sleep onset latency, and decreased WASO and subjective WASO. | Murphy et al. [26] | |
|
Seltorexant (JNJ-42847922 and MIN 202) SORA2 |
Rats, mice, and healthy humans | Reduced latency to NREM sleep and prolonged NREM sleep duration in rats but not in OX2R-knockout mice; increased somnolence in healthy humans. | Bonaventure et al. [102] |
| Individuals with insomnia | Increased TST, decreased LPS, and decreased WASO in individuals with insomnia without psychiatric comorbidity. | De Boer et al. [78] | |
| MDD patients with persistent insomnia | Decreased LPS and increased TST and SE, accompanied by a tendency to subjectively improved mood in antidepressant-treated MDD patients with persistent insomnia. | Brooks et al. [77] | |
|
MK-1064 SORA2 |
Rats, dogs, and healthy humans | Increased NREM and REM sleep. | Gotter et al. [42] |
|
JNJ-54717793 SORA1 |
Rats and mice | Minimal effects on spontaneous sleep in rats and wild-type mice; selectively promoted REM sleep in OX2R-knockout mice. | Bonaventure et al. [45] |
|
IPSU SORA2 |
Mice | Influenced sleep only during the active phase and induced sleep by increasing NREM sleep. | Hoyer et al. [48] |
|
Compound 5 DORA |
Rats | Decreased locomotor activity and the time awake and increased REM sleep and delta sleep. | Whitman et al. [161] |
|
3,9-diazabicyclo[4.2.1]nonanes DORA |
Rats | Better oral bioavailability and exerted sleep-promoting activity in a rat EEG model. | Coleman et al. [162] |
COPD, chronic obstructive pulmonary disease; DORA, dual orexin receptor 1/2 antagonist; E2006, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide; EEG, electroencephalogram; IPSU, 2-([1H-Indol-3-yl]methyl)9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one; ISI, Insomnia Severity Index; LPS, latency to persistent sleep; MDD, major depressive disorder; NREM, non-rapid-eye-movement; OSA, obstructive sleep apnea; OX1R, orexin type 1 receptor; OX2R, orexin type 2 receptor; REM, rapid-eye-movement; SE, sleep efficiency; SORA1, selective orexin receptor 1 antagonist; SORA2, selective orexin receptor 2 antagonist; TSO, time to sleep onset; TST, total sleep time; WASO, wake after sleep onset.