title: Caffeine does not entrain the circadian clock but improves daytime alertness in blind patients with non-24-hour rhythms.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: St Hilaire
authors.affiliation: Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA; Division of Sleep Medicine, Department of Medicine, Harvard Medical School, Boston, MA, USA; Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK. Electronic address: slockley@hms.harvard.edu.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lockley
mesh_terms: D000339:Affect / Q000187:drug effects; D000368:Aged; D001143:Arousal / Q000187:drug effects*; D001766:Blindness / Q000523:psychology* / Q000652:urine; D002110:Caffeine / Q000008:administration & dosage*; D057906:Circadian Clocks / Q000187:drug effects*; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives / Q000652:urine; D008875:Middle Aged; D017286:Polysomnography; D020178:Sleep Disorders, Circadian Rhythm / Q000188:drug therapy* / Q000652:urine
chemical_list: C054513:6-sulfatoxymelatonin; D002110:Caffeine; D008550:Melatonin
keywords: Alertness; Blindness; Caffeine; Circadian; Entrainment; Non-24-hour sleep–wake disorder