Circadian rhythm sleep-wake disorders and treatment. Debra J. SKENE. Chronobiology. University of Surrey, Guildford, UK.

Circadian rhythm sleep-wake disorders and treatment Debra J. SKENE Chronobiology University of Surrey, Guildford, UK d.skene@surrey.ac.uk

ICSD3, 2014 Circadian Rhythm Sleep-Wake Disorders Extrinsic Jet Lag Disorder (JLD) Shift Work Disorder (SWD) Intrinsic Delayed Sleep-Wake Phase Disorder (DPSD) Advanced Sleep-Wake Phase Disorder (ASPD) Non-24-hour Sleep-Wake Rhythm Disorder (N24SWD) Irregular Sleep-Wake Rhythm Disorder (ISWRD) Circadian Sleep-Wake Disorder Not Otherwise Specified (NOS)

Circadian rhythm sleep-wake disorders Human circadian timing system Circadian misalignment - acute - chronic health consequences Treatment strategies - chronobiotics - melatonin, light - factors affecting their efficacy

The suprachiasmatic nuclei (SCN) of the hypothalamus Site of circadian oscillator Courtesy of Dr Michael Hastings

The Clock in the Brain Hz A5 2 0 B7b 4 0 D1 3 0 G3b 4 0 24 48 72 Time (hours) Welsh, Logothetis, Meister & Reppert, Nature 1995 Courtesy of Till Roenneberg

SCN oscillation is produced by rhythmic expression of clock genes via a intracellular transcriptional/translational negative feedback loop Adapted from Green et al 2008; Cell

Central and peripheral oscillators Reppert & Weaver, 2002 Courtesy of Simon Archer

Circadian rhythms - endogenously generated - persist in constant conditions Melatonin Cortisol Rectal temperature Activity Sleep Mood Performance

Melatonin and core body temperature Cagnacci et al., J. Clin. Endocrinol.Metab. 75, 447-452 (1992)

Circadian rhythms melatonin core body temp subjective alertness task performance triacylglycerol Rajaratnam &Arendt 2001

Need a reliable marker of circadian phase Circadian rhythm disorders - for diagnosis - to optimise timing of treatment

Confounders Light/dark cycle Sleep/wake cycle Activity/exercise Drugs Food Posture Stress Menstrual cycle?

To assess circadian phase need Constant routine protocol - constant dim light (dim ~0.5 10 lux) temperature posture (semi-recumbent) - equicaloric meals (every 1-3h) - time isolation conditions - minimal physical and intellectual activities - no sleep or naps Limitations: - forced wakefulness / sleep deprivation 40 h - need controlled laboratory conditions - expensive, onerous for volunteers & researchers

Constant routine protocol versus entrained sleep/wake Czeisler & Klerman 1999 Recent Prog Horm Res 54:97-132

Melatonin as a reliable marker of circadian phase unaffected by: meals, stress, bathing, sleep dim light conditions (< 8 lux) exclude drugs control posture, exercise

Plasma melatonin (pg/ml) Melatonin rhythm n = 135 healthy volunteers 60 50 40 30 20 10 0 12 16 20 24 04 08 12 Clock Time (h) Middleton el al., unpublished

plasma melatonin (pg/ml) Markers of the melatonin rhythm used to characterise the timing of the circadian clock 80 duration 70 60 50 * acrophase (calculated peak time) 40 30 20 10 0 * 1500 1700 1900 2100 2300 100 300 500 700 900 1100 1300 1500 1700 * * * * * clock time (h) mid-range crossing 25% rise/fall onset/offset biological night Arendt & Skene, Sleep Medicine Reviews (2005) 9:25-39

Melatonin as a reliable marker of circadian phase amt6s as a reliable marker of melatonin rhythms non invasive convenient for field studies

Timed urine sampling 4 h (+ overnight) for 48 h every week of 4 weeks Calculate amt6s peak (6-sulphatoxymelatonin)

Photic entrainment Arendt, 1995

amt6s (g/hr) Intact eyes Normally entrained amt6s rhythms 3.5 3 F H J 2.5 J 2 J H F F 1.5 1 B B 0.5 0 H B F B H J B J F H J H B F F J H J B H F J H B J B F H F 6 12 18 24 6 12 18 24 6 Time (h) Lockley, Skene et al., J. Clin. Endocrinol.Metab. 81, 2980-2985 (1997)

DAY 2 s s s s 4 6 8 10 12 14 16 18 20 22 24 26 28 24 Entrained sleep and amt6s * * * * 4 8 12 16 20 24 Time (h) Lockley et al., 1997

Arendt, 1995

amt6s (g/hr) B B B B B B B B B B J J J J J J J J J H H H H H H H H H H F F F F F F F F Time (h) Blind - no eyes Free-running amt6s rhythms 2 1.5 1 0.5 0 6 12 18 24 6 12 18 24 6 Lockley, Skene et al., J. Clin. Endocrinol.Metab. 81, 2980-2985 (1997)

Study Week 6 5 4 3 2 4 8 12 16 20 24 24 4 8 12 Time (h) NPL - bilaterally enucleated subjects n = 11 1 Lockley, Skene et al., J. Clin. Endocrinol.Metab. 81, 2980-2985 (1997)

Conclusions bilaterally enucleated subjects have free running circadian rhythms LIGHT is a major time cue in humans OCULAR light Lockley, Skene et al., J. Clin. Endocrinol.Metab. 81, 2980-2985 (1997)

Environmental light/dark cycle synchronises the biological clock to the 24 h day Synchronisation between Synchronisation between external and internal time good sleep alert during the day external and internal time

S S S S S DAY 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Abnormal circadian phase poor sleep daytime napping 24 * * * * 4 8 12 16 20 24 Time (h) Lockley et al., 1997

DAY Non 24 h sleep/wake disorder Abnormal circadian phase poor sleep daytime napping S S S S S 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 24 * * * * * 4 8 12 16 20 24 Time (h) Lockley et al., 1997

Consequences of circadian desynchrony poor sleep during waking hours: napping tiredness/fatigue reduced performance increased accident/ injury risk

Circadian Rhythm Disorders Jet Lag Shift Work eastward flight, shiftwork

Field shift work study Barnes et al., 2000

Consequences of chronic shift work - chronic sleep restriction - chronic circadian desynchrony

Long term health risks? cardiovascular risk metabolic syndrome cancer risk Increased risk of breast cancer Increased risk of prostate cancer Kawachi et al. 1995; Bøggild and Knutsson, 1999; Ellingsen et al. 2007 Karlsson et al. 2001; 2003 Sookoian et al. 2007; De Bacquer et al. 2009; Esquirol et al. 2009 Hansen, 2001; Schernhammer et al., 2001; 2003; Megdal et al., 2005; Hansen & Stevens, 2012; Knutsson et al., 2012; Sigurdardottir et al., 2012

Chronic shift work cardiovascular risk? metabolic syndrome? cancer risk? Mechanism? Multifactorial

SHIFTWORK Circadian desynchrony sleep loss Night time meals altered light exposure fatigue and stre ss reduced diet quality Reduced light at night time meals? increased inflammatory factors insulin resistance altered nutrient/ antioxidant intake Impaired postprandial metabolism TAG Cholesterol LDL - HDL impaired endothelial function reduced cardio - protection Increased CVD risk Gibbs, 2006

Circadian Rhythm Disorders Delayed Sleep Phase Insomnia DSPS Advanced Sleep Phase Insomnia ASPS - altered sleep timing DSPS ASPS ageing?

Time isolation studies - Free-running protocols t ~ 25.3 h Aschoff (1965)

Number of subjects Forced desynchrony Human circadian period (t) n = 11 young n = 13 old Sighted t = 24.18 0.02 h Czeisler et al., Science, 1999 Real life 8 7 6 n = 29 Totally blind 5 4 t = 24.50 0.04 h 3 2 1 0 23.9 24.1 24.3 24.5 24.7 24.9 Skene et al., unpublished

An altered t in entrained conditions (24 h light/dark cycle) will manifest as: extreme diurnal preference extreme morningness extreme eveningness

Lark? Intermediate? Owl?

morningness 80 n = 217 Male 70 HO score 60 50 40 eveningness morningness 30 20 10 20 30 40 50 60 70 80 80 n = 267 Age (years) Female 70 HO score 60 50 40 eveningness 30 20 10 20 30 40 50 60 70 80 Age (years) Robilliard et al., 2002 105 subjects selected (48 males, 57 females) n = 35 in each group-extreme morning; extreme evening; intermediate

ASPS and DSPS extrinsic - environmental and/or behavourial intrinsic - light sensitivity clock gene polymorphisms Gene Polymorphism Association Reference per2 2106 A/G ASPS Toh et al., 2001 per3 5 coding polymorphisms 1940 T/G per3 VNTR DSPS? Ebisawa et al., 2001 eveningness/ Archer et al., DSPS 2003 CKI T44A ASPS Xu et al., 2005

Diurnal preference and Per3 4/5 allele frequency 80 5/5 4/5 4/4 70 60 % 50 40 30 20 10 0 Morning Intermediate Evening DSPS Longer allele (5-repeat) associated with morningness Shorter allele (4-repeat) associated with eveningness and DSPS Archer et al., Sleep 26, 413-415, 2003.

Circadian Rhythm Disorders Affective Disorder? seasonal (SAD); non-seasonal Old Age? Alzheimer s Disease?

Circadian rhythm disorders Blindness Eastward flight, shiftwork DSPS ASPS, ageing? Westward flight, shiftwork

Treatment of Circadian Rhythm Sleep Disorders

Chronotherapy to hasten adaptation LIGHT MELATONIN Phase shift circadian rhythms

Light Melatonin shifts circadian rhythms sleep timing melatonin temperature cortisol

Arendt, 1995

Melatonin receptors in human SCN From Reppert et al, 1995

plasma melatonin (pg/ml) biological night 80 70 60 normal phase 50 40 30 20 10 0 1500 1700 1900 2100 2300 100 300 500 700 900 1100 1300 1500 1700 clock time h circadian time 7 9 11 13 15 17 19 21 23 1 3 5 7 9 Ability of melatonin and light to phase shift and the DIRECTION of the shift (advance or delay) depends on WHEN it is administered in relation to biological time PHASE RESPONSE CURVE (PRC)

Light phase response curve (PRC) advance delay Khalsa et al., J Physiol, 549, 945-952, 2003

Melatonin phase response curve (PRC) ADVANCE Lewy et al. 1998

Phase Shift with Melatonin (h) Phase Shift with Light (h) Human Phase Response Curves To Bright Light and Melatonin Delay Advance 1.0 0.5 0.0-0.5-1.0 Melatonin PRC Light PRC 3 2 1 0-1 -2-3 12 15 18 21 0 3 6 9 12 Clock Time - 9-6 - 3 0 3 6 9 12 15 Hours before and after DLMO From: Revell VL, Eastman CI. J Biol Rhythms. 2005;20:353-65 Time of Melatonin or Bright Light

plasma melatonin (pg/ml) 80 70 60 Optimal phase ADVANCE early morning light evening melatonin normal phase 50 40 30 advanced 20 10 0 1500 1700 1900 2100 2300 100 300 500 700 900 1100 1300 1500 1700 clock time h circadian time 7 9 11 13 15 17 19 21 23 1 3 5 7 9 advances advancess advances Melatonin timed to advance the clock Light timed to advance the clock

Circadian rhythm disorders Blindness Eastward flight, shiftwork DSPS ASPS, ageing? Westward flight, shiftwork

plasma melatonin (pg/ml) 80 70 60 Optimal phase DELAY evening light early morning melatonin normal phase 50 40 30 delayed 20 10 0 1500 1700 1900 2100 2300 100 300 500 700 900 1100 1300 1500 1700 clock time h circadian time 7 9 11 13 15 17 19 21 23 1 3 5 7 9 delays delays delays Light timed to delay the clock Melatonin timed to delay the clock

Circadian rhythm disorders Blindness Eastward flight, shiftwork DSPS ASPS, ageing? Westward flight, shiftwork

Light shifts circadian rhythms sleep timing melatonin, temperature cortisol acute effects increases alertness increases temperature improves performance

Melatonin shifts circadian rhythms sleep timing melatonin, temperature cortisol acute effects reduces alertness reduces temperature increases sleepiness

Acute effects of 5mg melatonin 37.2 37 Rectal Temperature 36.8 ( C) 36.6 Core body temperature 36.4 100 36.2 Alertness Subjective Alertness (%) 80 60 40 Placebo Melatonin 20 17:00 19:00 21:00 23:00 01:00 Time (h) Meal Deacon et al., 1994

Circadian Rhythm Disorders Jet Lag Shift Work Delayed Sleep Phase Insomnia (DSPS) Advanced Sleep Phase Insomnia (ASPS) Blindness Old Age? Alzheimer s disease? Affective disorders?

Treatment of non-24 h sleep/wake disorder? blindness

Non 24 h sleep/wake disorder blindness Melatonin = the drug of choice Lockley et al., J Endocrinol, 2000 Hack et al., J Biol Rhythms, 2003

J Endocrinol. 164, R1-R6 (2000)

ENTRAINED - 5 mg melatonin S17 Study day 2 10 18 26 34 42 50 58 66 74 82 90 98 106 114 122 130 138 146 154 162 170 178 186 24 M P 24.00 ± 0.06 h 24.30 ± 0.06 h 24.27 ± 0.08 h 12 24 12 24 12 24 Time of day (h) S31 2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 24 P M P 24.03 ± 0.20 h 24.57 ± 0.23 h 24.57 ± 0.24 h 12 24 12 24 Time of day (h) amt6s m cortisol Lockley et al., 2000

FREE-RUNNING - 5 mg melatonin S18 Study day 9 8 2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 94 24 P M P 24.70 ± 0.56 h 24.96 ± 0.61 h 24.72 ± 0.84 h Time of day (h) 12 24 12 24 12 24 12 S51 2 10 18 26 34 42 50 58 66 74 82 90 98 106 114 122 130 138 146 154 162 170 178 186 P M 24.53 ± 0.09 h 24.49 ± 0.12 h 24.52 ± 2.24 h 24 12 24 12 24 12 24 12 24 12 24 Time of day (h) amt6s m cortisol Lockley et al., 2000

Entrained vs not entrained? age visual disease presence of intact eyes congenital/ acquired duration mel admin time of year amt6s concs/ amt6s amplitude tau circadian time when melatonin treatment began

IMPORTANCE OF TIMING MELATONIN PRC ADVANCE ENTRAINMENT FREE-RUNNING Lewy et al. 1998 Lockley et al., 2000

CROSSOVER STUDY Entrained 2 0 10 10 18 P CT 3 24.53 ± 0.09 24.58 ± 0.04 26 20 CT 7 34 30 S51 Study day Not entrained 42 50 58 66 74 82 90 98 106 114 122 130 138 146 154 162 170 178 186 P M 24.52 ± 2.24 24 12 24 12 24 12 24 12 24 12 24 Lockley, Arendt, Skene, unpublished 40 50 60 70 80 90 100 110 120 130 140 150 M Time of day (h) 24.01 ± 0.11 f = 9.8 ± 1.0 24 12 24 12 24 12 24

Optimise effect on clock MELATONIN dose? formulation time of administration

Is a lower dose effective? 0.5 mg melatonin J. Biol. Rhythms (2003) 18:420-429

S70 ENTRAINED - 0.5 mg melatonin 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 Placebo m m m m 24.35 ± 0.06 h Melatonin Placebo 24.33 ± 0.09 h m 23.99 ± 0.19 h m m m 24.31 ± 0.08 h m 24.43 ± 0.13 h m m m m 250 0 12 24 36 48 60 72 84 Time (h) CT 10 amt6s m cortisol Hack et al., JBR, 2003

Study day S51 0 10 20 30 CT 22 40 50 CT 10 60 70 80 90 100 110 P 24.69 ± 1.88 h 24.73 ± 0.35 h M P ENTRAINED AFTER LAG - 0.5 mg melatonin 24.58 ± 1.57 h (n=3) 18 days 24.02 ± 0.16 h (n=5) 24.36 ± 0.84 h 120 24 12 24 12 24 12 24 Time (h) Hack et al., JBR, 2003

Entrainment by ADVANCE presumed phase shifts Rapid entrainment Entrainment after a lag period Free-running Free-running 10 10 20 20 Entrained 30 Entrained 24 12 Time (h) Melatonin daily at same clock time Period of melatonin secretion: biological night 12 24 12 Time (h) Arendt & Skene, 2005

Melatonin and effect on sleep Improves sleep in blind subjects with freerunning circadian rhythms 5 mg 7subjects/11 trials placebo controlled no. & duration of daytime naps sleep duration

15 S21 S27 33 39 45 51 57 S63 S69 75 81 87 93 99 S105 S111 117 123 129 135 141 S147 S153 3 9 159 165 171 177 183 24 S17-5 mg melatonin treatment * * * * * * * * 4 8 12 16 20 24 Time (h) 0 Mel P 0

5 mg melatonin entrainment of sleep/wake cycle CT 11 S62

Conclusions non-24 h sleep/wake disorder 0.5 & 5 mg melatonin improves subjective sleep/reduces naps If timed appropriately to phase advance ( CT 6-18) entrains free-running circadian rhythms including sleep/wake

FUTURE Optimise melatonin s effect time of administration (clock & circadian time) lowest effective dose? most appropriate formulation? treatment regime (daily?) length of treatment dosing schedule (set or staggered)? EACH circadian rhythm disorder

plasma melatonin (pg/ml) Delayed Sleep Phase Insomnia (DSPS) Melatonin advances circadian clock and sleep in DSPS patients 0.3-5 mg 2-6 weeks 80 70 60 50 40 30 20 advanced normal phase 10 5-7 h before sleep onset 3-5 h before DLMO 0 15 17 19 21 23 01 03 05 07 09 11 13 15 17 clock time h circadian time 7 9 11 13 15 17 19 21 Melatonin timed to advance the clock

plasma melatonin (pg/ml) IMPORTANCE OF TIMING Melatonin and DSPS Melatonin (0.3 or 3.0 mg) or placebo - 4 weeks 3-fold difference in efficacy 6.5 h before DLMO >> 1.5 h before DLMO 80 70 60 50 40 30 20 advanced normal phase 3 h advance vs 1 h advance 0 10 15 17 19 21 23 01 03 05 07 09 11 13 15 17 DLMO Mundey et al., Sleep 28:1271-1278, 2006

Optimise effect on clock LIGHT intensity duration wavelength time of administration previous light history MELATONIN dose formulation time of administration

Illuminance response curve (IRC) white light Zeitzer et al., J Physiol, 526, 695-702, 2000

Optimise effect on clock LIGHT intensity duration wavelength time of administration previous light history MELATONIN dose formulation time of administration

Spectral sensitivity?

Plasma melatonin (pg/ml) Spectral sensitivity of light-induced melatonin suppression Suppression by short wavelength light 140 120 100 80 60 40 O O O O O O O O O 424 nm 16 W/cm 2 O 472 nm 36 W/cm 2 20 0 23:00 23:30 0:00 0:30 1:00 1:30 2:00 Clock time (hours) Thapan, Arendt & Skene, J Physiol, 535, 261-67, 2001

Melatonin suppression (%) 70 60 50 40 30 Melatonin suppression as a function of wavelength and irradiance 20 10 0 1E+11 1E+12 1E+13 1E+14 1E+15 5E+15 Photons/cm 2 /sec Thapan, Arendt & Skene, J Physiol, 535, 261-267, 2001 424 nm 456 nm 472 nm 496 nm 520 nm 548 nm

% relative sensitivity Short wavelength sensitivity compared with scotopic and photopic visual systems 100 80 60 40 Scotopic luminosity curve max 505 nm Photopic luminosity curve max 555 nm Melatonin action spectrum (uncorrected) 20 0 400 450 500 550 600 650 700 Wavelength (nm) Thapan, Arendt & Skene, J Physiol, 535, 261-267, 2001

Short wavelength light is most effective J Physiol 535, 261-267, 2001 Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor. Brainard GC et al. J Neurosci 21, 6405-6412, 2001

Melanopsin opsin/vitamina based photopigment λ max ~ 480 nm Xenopus Melanophores Iris Brain Horizontal cells PE Mammals Ganglion cells Other places? expressed within putative photoreceptive structures

Melanopsin expressed in photosensitive ganglion cells acts as a sensory photopigment Melyan et al., Nature 433, 741-745, 2005 Qiu et al., Nature 433, 745-749, 2005 Panda et al., Science 307, 600-604, 2005

Photoreceptive net in the mouse inner retina A single melanopsin-positive RGC Melanopsin expressed in the dendrites of a subset of retinal ganglion cells Arrows show 2 plexuses of immunoreactive dendrites Provencio et al., 2002

VISUAL AND NON-VISUAL RETINAL PATHWAYS Geniculate Nucleus Visual Cortex Superior Colliculus PERCEPTUAL VISION Olfactory Tubercule Preoptic SCN Habenula IGL LH, RCh OPN Melanopsin retinal ganglion cells (RGCs) A blue light pathway NON-VISUAL RESPONSES TO LIGHT Circadian rhythms Sleep wake cycle Pupillary reflex Seasonal reproduction Mood Alertness heart rate, temperature Courtesy of Dr Howard Cooper

Short wavelength light is most effective 420-480 nm

Work environment lighting Design lights to affect biology OR NOT tungsten fluorescent LEDs

Relative spectral sensitivity Blue- enriched Control Colour temperature (K) 17000 4000 Irradiance ( µ W/cm 2 ) 141 131 P h oton density (photons/cm 2 /s) 3.57x10 14 3.67x10 14 Lu x 343 450 5 4 3 2 1 17000 K 4000 K 0 400 500 600 700 Wavelength (nm) Distance to the eyes: 60 cm Lederle et al., unpublished

Field studies in the elderly Effect of blue-enriched white light on sleep quality and daytime alertness in older people? - in the community - in care homes EU FP6 Marie Curie RTN ESRC New Dynamics of Ageing/Philips Lighting

Light frames Light units 17000 K lights 4000 K lights

Why light supplementation for older people? Age-related ocular changes Reduced sensitivity to blue light ** Reduced environmental light exposure - reduced mobility - homes poorly lit Older people require 3-5 times more light ** Herljevic et al., 2005; Jud et al., 2009; Sletten et al., 2009

Age-related changes in the eye increased lens density reduced transmission of light 25 years 47 years 60 years 70 years 82 years 91 years Lerman, 1980

Why blue light supplementation for older people? Laboratory studies reduced responsiveness to short wavelength blue light Exp Gerontol 40, 237-242, 2005

Individual response to light Depends on: age chronotype clock gene polymorphisms (PER3 VNTR)? previous light history - season - sleep/wake pattern - outdoor light exposure

Photic history More melatonin suppression after dim light Hebert et al., 2002 Smith et al., 2004; Jasser et al., 2006

Using Light Environment: Design lighting to maximise biological effects or not Individual: Appropriately time light exposure and avoidance of light (sunglasses; blue-light blockers)

Predicting biological effects of light Work/home lighting - intensity; spectral composition Work schedule - day work; rotating shifts; days off; night breaks Individual - age, chronotype, sleep history, photic history COMPLEX

Acknowledgements LIGHT Kavita Thapan Victoria Revell Mirela Herljevic Tracey Sletten Helen Thorne Katharina Lederle Benita Middleton Lloyd Morgan Samantha Hopkins Daniel Barrett Katrin Ackermann Shelagh Hampton MELATONIN Steven Lockley Lisa Hack Josephine Arendt

Acknowledgements Current and recent funding EU Marie Curie RTN EU FP6 IP ESRC New Dynamics of Ageing STOCKGRAND LTD STOCKGRAND LTD Past funding BHF, EU Biomed, EU FP5, MRC, Pfizer, Servier R & D, Wellcome Trust

References 1. Arendt, J. and Skene, D.J. Melatonin as a chronobiotic. Sleep Medicine Reviews (2005) 9, 25-39. 2. Burgess H. J., Sharkey, K. M. and Eastman, C. I. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Medicine Reviews (2002) 6, 407-420. 3. Rajaratnam, S.M. and Arendt, J. Health in a 24-h society. Lancet (2001) 22;358, 999-1005. Review. 4. Skene, D.J. and Arendt, J. Human circadian rhythms: Physiological and therapeutic relevance of light and melatonin. Ann. Clin. Biochem. (2006) 43, 344-353. 5. Skene, D.J. and Arendt, J. Circadian rhythm sleep disorders in the blind and their treatment with melatonin. Sleep Medicine (2007) 8, 651-655.