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      • Record: found
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      Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms

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          Highlights

          • •

            Most totally blind individuals have Non-24-Hour Sleep–Wake Disorder (N24HSWD).

          • •

            Optimal treatment should reset the underlying non-entrained circadian pacemaker.

          • •

            We tested daily caffeine treatment (150 mg, 10 a.m.) in three blind patients with N24HSWD.

          • •

            Caffeine treatment improved daytime alertness at adverse circadian phases.

          • •

            Caffeine treatment was unable to entrain the circadian clock.

          Abstract

          Objective/Background

          Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep–wake disorder.

          Patients/Methods

          Three totally blind males (63.0 ± 7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48 h every 1–2 weeks. Participants completed daily sleep–wake logs, and rated their alertness and mood using nine-point scales every ~2–4 h while awake on urine sampling days. Caffeine capsules (150 mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period τ and compared to placebo ( n = 2) or no treatment ( n = 1) in a single-masked manner.

          Results

          Non-24-h aMT6s rhythms were confirmed in all three participants ( τ range = 24.32–24.57 h). Daily administration of 150 mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases ( p <  0.0001) but did not decrease the occurrence of daytime naps compared with placebo.

          Conclusions

          Although caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep–Wake Disorder in the blind appropriately.

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          Most cited references19

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          Comparison between subjective and actigraphic measurement of sleep and sleep rhythms.

          Debra J. Skene, Wayne Arendt, Steven Lockley (1999)
          Sleep is often assessed in circadian rhythm studies and long-term monitoring is required to detect any changes in sleep over time. The present study aims to investigate the ability of the two most commonly employed methods, actigraphy and sleep logs, to identify circadian sleep/wake disorders and measure changes in sleep patterns over time. In addition, the study assesses whether sleep measured by both methods shows the same relationship with an established circadian phase marker, urinary 6-sulphatoxymelatonin. A total of 49 registered blind subjects with different types of circadian rhythms were studied daily for at least four weeks. Grouped analysis of all study days for all subjects was performed for all sleep parameters (1062-1150 days data per sleep parameter). Good correlations were observed when comparing the measurement of sleep timing and duration (sleep onset, sleep offset, night sleep duration, day-time nap duration). However, the methods were poorly correlated in their assessment of transitions between sleep and wake states (sleep latency, number and duration of night awakenings, number of day-time naps). There were also large and inconsistent differences in the measurement of the absolute sleep parameters. Overall, actigraphs recorded a shorter sleep latency, advanced onset time, increased number and duration of night awakenings, delayed offset, increased night sleep duration and increased number and duration of naps compared with the subjective sleep logs. Despite this, there was good agreement between the methods for measuring changes in sleep patterns over time. In particular, the methods agreed when assessing changes in sleep in relation to a circadian phase marker (the 6-sulphatoxymelatonin (aMT6s) rhythm) in both entrained (n = 30) and free-running (n = 4) subjects.
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            Human phase response curve to a 1 h pulse of bright white light.

            Melissa A. St. Hilaire, Joshua Gooley, Sat Bir S. Khalsa … (2012)
            The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting.
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              Entrainment of free-running circadian rhythms by melatonin in blind people.

              Alfred Lewy, Jonathan Sack, Arnd Brandes … (2000)
              Most totally blind people have circadian rhythms that are "free-running" (i.e., that are not synchronized to environmental time cues and that oscillate on a cycle slightly longer than 24 hours). This condition causes recurrent insomnia and daytime sleepiness when the rhythms drift out of phase with the normal 24-hour cycle. We investigated whether a daily dose of melatonin could entrain their circadian rhythms to a normal 24-hour cycle. We performed a crossover study involving seven totally blind subjects who had free-running circadian rhythms. The subjects were given 10 mg of melatonin or placebo daily, one hour before their preferred bedtime, for three to nine weeks. They were then given the other treatment. The timing of the production of endogenous melatonin was measured as a marker of the circadian time (phase), and sleep was monitored by polysomnography. At base line, the subjects had free-running circadian rhythms with distinct and predictable cycles averaging 24.5 hours (range, 24.2 to 24.9). These rhythms were unaffected by the administration of placebo. In six of the seven subjects the rhythm was entrained to a 24.0-hour cycle during melatonin treatment (P<0.001). After entrainment, the subjects spent less time awake after the initial onset of sleep (P=0.05) and the efficiency of sleep was higher (P=0.06). Three subjects subsequently participated in a trial in which a 10-mg dose of melatonin was given daily until entrainment was achieved. The dose was then reduced to 0.5 mg per day over a period of three months; the entrainment persisted, even at the lowest dose. Administration of melatonin can entrain circadian rhythms in most blind people who have free-running rhythms.
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                Author and article information

                Contributors
                Steven W. Lockley
                Journal
                Journal ID (nlm-ta): Sleep Med
                Journal ID (iso-abbrev): Sleep Med
                Title: Sleep Medicine
                Publisher: Elsevier Science
                ISSN (Print): 1389-9457
                ISSN (Electronic): 1878-5506
                Publication date PMC-release: 1 June 2015
                Publication date (Print): June 2015
                Volume: 16
                Issue: 6
                Pages: 800-804
                Affiliations
                [a ]Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA
                [b ]Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA
                [c ]Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
                Author notes
                [* ]Corresponding author. Circadian Physiology Program, Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA. Tel.: +1 617 732 4977; fax: +1 617 732 4013. slockley@ 123456hms.harvard.edu
                Article
                Publisher ID: S1389-9457(15)00088-X
                DOI: 10.1016/j.sleep.2015.01.018
                PMC ID: 4465963
                PubMed ID: 25891543
                SO-VID: 1fb8e132-301f-4ea6-a60d-3395203550db
                Copyright © © 2015 The Authors
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 15 September 2014
                Date revision received : 31 December 2014
                Date accepted : 26 January 2015
                Categories
                Subject: Brief Communication

                ScienceOpen disciplines: Medicine
                Keywords: blindness,non-24-hour sleep–wake disorder,caffeine,circadian,entrainment,alertness
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: blindness, non-24-hour sleep–wake disorder, caffeine, circadian, entrainment, alertness

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