Sleep Initiation and Maintenance Disorders: Klerman EB

Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB. · Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA. · Lancet. · Pubmed #19054552 No free full text.

Abstract: BACKGROUND: Circadian rhythm sleep disorders are common causes of insomnia for millions of individuals. We did a phase II study to establish efficacy and physiological mechanism, and a phase III study to confirm efficacy of the melatonin agonist tasimelteon (VEC-162) for treatment of transient insomnia associated with shifted sleep and wake time. METHODS: We undertook phase II and phase III randomised, double-blind, placebo-controlled, parallel-group studies. In a phase II study, 39 healthy individuals from two US sites were randomly assigned to tasimelteon (10 [n=9], 20 [n=8], 50 [n=7], or 100 mg [n=7]) or placebo (n=8). We monitored individuals for 7 nights: 3 at baseline, 3 after a 5-h advance of sleep-wake schedule with treatment before sleep, and 1 after treatment; we measured plasma melatonin concentration for circadian phase assessment. In a phase III study, 411 healthy individuals from 19 US sites, who had transient insomnia induced in a sleep clinic by a 5-h advance of the sleep-wake schedule and a first-night effect in a sleep clinic, were given tasimelteon (20 [n=100], 50 [n=102], or 100 mg [n=106]) or placebo (n=103) 30 min before bedtime. Prespecified primary efficacy outcomes were polysomnographic sleep efficiency (phase II study), latency to persistent sleep (phase III study), and circadian phase shifting (phase II study). Analysis was by intention to treat. Safety was assessed in both studies. These trials are registered with ClinicalTrials.gov, numbers NCT00490945 and NCT00291187. FINDINGS: In the phase II study, tasimelteon reduced sleep latency and increased sleep efficiency compared with placebo. The shift in plasma melatonin rhythm to an earlier hour was dose dependent. In the phase III study, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (ie, sleep maintenance). The frequency of adverse events was similar between tasimelteon and placebo. INTERPRETATION: After an abrupt advance in sleep time, tasimelteon improved sleep initiation and maintenance concurrently with a shift in endogenous circadian rhythms. Tasimelteon may have therapeutic potential for transient insomnia in circadian rhythm sleep disorders.

Klerman EB, Dijk DJ. · Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. · Curr Biol. · Pubmed #18656358 links to  free full text

Abstract: Sleep changes markedly across the life span and complaints about insomnia are prevalent in older people [1]. Whether age-related alterations in sleep are due to modifications in social factors, circadian physiology, homeostatic drive, or the ability to sleep remains unresolved. We assessed habitual sleep duration at home and then quantified daytime sleep propensity, sleep duration, and sleep structure in an inpatient protocol that included extended sleep opportunities covering 2/3 of the circadian cycle (12 hr at night and 4 hr in the afternoon) for 3-7 days in 18 older and 35 younger healthy men and women. At baseline, older subjects had less daytime sleep propensity than did younger subjects. Total daily sleep duration, which was initially longer than habitual sleep duration, declined during the experiment to asymptotic values that were 1.5 hr shorter in older (7.4 +/- 0.4 SEM, hour) than in younger subjects (8.9 +/- 0.4). Rapid-eye-movement sleep and non-rapid-eye-movement sleep contributed about equally to this reduction. Thus, in the absence of social and circadian constraints, both daytime sleep propensity and the maximal capacity for sleep are reduced in older people. These data have important implications for understanding age-related insomnia.