Circadian rhythm sleep disorders (CRSD) are a family of sleep disorders affecting (among other bodily processes) the timing of sleep. People with circadian rhythm sleep disorders are unable to go to sleep and awaken at the times commonly required for work and school as well as social needs. They are generally able to get enough sleep if allowed to sleep and wake at the times dictated by their "body clocks". The quality of their sleep is usually normal unless they also have another sleep disorder. My presentation deals with how circadian rhythm happens in human body and how alterations in circadian rhythm effects in different disorders.

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Circadian Rhythm and Related
Disorders
Guided by Presented by
Dr. Venu Talla Shivaraju Annaldas
Pharmacology & Toxicology RT/2016/601

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Contents
 Introduction
Biological markers
General Biological clock
Genetic Regulation
Disorders
Treatment
Summary

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Introduction
 The term “circadian”,(Latin) was first
coined by Franz Halberg,(1896)
 Means Approximately one day.
 Controlled by the endogenous
Biological Pacemaker, the
Suprachiasmatic Nucleus(SCN),
located in the anterior Hypothalamus.
 These are endogenous, but adjusted by
external cues called Zeitgeber.
ex. Light, temperature, exercise, eating,
drinking..etc….
Malik, Vipin. Sleep And Circadian Rhythms In The ICU, An Issue Of Critical Care Clinics. 1st ed. Elsevier Health Sciences, 2015.
Page.no.01-05

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Biological markers
.
Robert LeBlanc, Nils Schallner. "Circadian Rhythm In Stroke – The Influence Of Our Internal Cellular Clock On Cerebrovascular Events".
Journal of Clinical & Experimental Pathology 04.02 (2014): pg.05-10

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General Biological Clock
Effect of Age on Circadian rhythm:
 New born - 16 to 20h
 Child - 10 to 12h
 Age @10 - 09 to 10h
 Adolescence- 07 to 7.5h
 A gradual decline to 6.5h develops
In late adult life.
 >35years women tend to sleep
more than men.
Aksu, Murat. "Sleep And Biological Rhythms In 2015". Sleep and Biological Rhythms 13.1 (2015): 1-1..

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Why do we have to Sleep?
 Restoration intellectual function.
 Creation of long term and short term memory.
 Secretion of hormones-growth hormone.
 Impact on immunity
short-term lack of sleep – good impact
long-term lack of sleep – very bad impact
Larks Owls
Malik, Vipin. Sleep And Circadian Rhythms In The ICU, An Issue Of Critical Care Clinics. 1st ed. Elsevier Health Sciences,
2015. Page.02-08

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Genetic Regulation
 Circadian rhythms are determine genetically by a core set of clock genes,
including three Per genes (the period homolog 1 gene, Per1; the period
homolog2 gene, Per2; the period homolog 3gene, Per3)
 The circadian locomotor output cycles kaput gene, Clock; the cycle gene,
Bmal1; and two plant cryptochrome gene homologs (the cryptochrome
1gene, Cry1, and the cryptochrome 2 gene,Cry2).
Rosenwasser, Alan M. and Fred W. Turek. "Neurobiology Of Circadian Rhythm Regulation". Sleep Medicine Clinics 10.4 (2015): 403-412.
Cry1
Cry2
Per1
Per2
Per3
Nucleus
Cry/Per
Dimer
Cry 1 Protein
Cry 2 Protein
Per 1 Protein
Per 2 Protein
Per 3 Protein
Clock/Bmal1

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Circadian Rhythm Sleep Disorders
Phyllis C. Zee, Northwestern University, Circadian Rhythm Sleep Disorders, Primary Psychiatry. CLINICAL FOCUS 2006;13(8):58-67.
Delayed Sleep
Phase
Syndrome(DSPS)
Advanced Sleep
Phase
Syndrome(ASPS)
Irregular Sleep-
Wake Pattern
Non -24-
Hour Sleep-
Wake
Syndrome
Intrinsic

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Shift Work Time-Zone Change
Disorders
Extrinsic
Phyllis C. Zee, Northwestern University, Circadian Rhythm Sleep Disorders, Primary Psychiatry. CLINICAL FOCUS 2006;13(8):58-67

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Delayed Sleep Phase Syndrome
• Delayed sleep-phase disorder (DSPD) is characterized by a chronic or
recurrent inability to fall asleep and wake up at socially acceptable times,
resulting in symptoms of difficulty falling asleep and excessive daytime
sleepiness, particularly in the morning. Mostly in Adults.
• Although the exact mechanisms responsible for DSP are unknown,
• The postulated mechanisms for DSPD include
(1) increased sensitivity to the phase-delay response of evening light
and
(2) long circadian period
Treatment: Timed Bright light & Melatonin administration

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Advanced Sleep Phase Syndrome
• Characterized by early evening sleepiness and wake-up times that
are several hours earlier relative to conventional and desired times.
• ASP complaints include early-morning awakenings, sleep
maintenance insomnia, and sleepiness in the late afternoon or early
evening.
• ASPS is much more common in older individuals than in the young,
and the complaint of waking up too early in the morning may be
confused with depression.
• The current approach to treating ASPS is bright light exposure in the
evening and avoidance of light exposure (e.g. wearing dark, wrap
around sunglasses) in the morning.

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Irregular Sleep Wake Pattern
• This disorder is more prevalent in older adults with dementia and
in patients with developmental disorders.
• The most likely mechanisms include central degeneration of SCN
neurons and decreased exposure or input of external
synchronizing agents, such as light and activity that result in a
weakened central circadian oscillation and temporal
disorganization of circadian rhythms.
• Treatment consists of a gradual decrease in the number and
duration of daily naps. Increase in activity levels and social
interaction is recommended to facilitate the process.

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Non 24h Sleep Wake Syndrome
• characterized by a chronic or recurrent pattern of sleep and wake cycles
that are not synchronized to the 24-hour environment.
• The etiology of N 24 HSWD in blind people is clearly a marked decrease
or absence of light perception.
• Other postulated mechanisms:
(1) alteration and reduction of social cues because of psychiatric
illness induced social withdrawal.
(2) desynchrony between the melatonin and sleep rhythms.
• Treatment focuses on entraining the circadian rhythm to a 24-hour day
through social interaction, exposure to light, and melatonin.
• Melatonin has been successful in treating this disorder in blind
individuals.

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Shift Work
• Characterized by excessive sleepiness that occur in relation to work
hours that are scheduled during the usual sleep period.
• It has been estimated that 20% of the workforce in industrialized
countries is employed in a job that requires shift work.
• Individual tolerance to shift work varies considerably and may involve
differences in the degree of circadian adaptation, sleep homeostatic
influences, age, the type of shift schedule, and family/social support.
Treatment:
• These include optimizing the sleep environment (eg, darkened room,
comfortable temperature, noise reduction), adherence to good sleep
habits (eg, maintain a regular sleep and wake schedule, avoid excessive
caffeine), patient and family education.

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2008 2010 2012 2015
DeathRate(%)
years
Shift work Driving Accidents
100
80
60
40
20
Lee, Michael L. et al. "High Risk Of Near-Crash Driving Events Following Night-Shift Work". Proceedings of the National Academy of Sciences
113.1 (2015): 176-181. Web.

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Time Zone Change Disorder

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• Jet lag occurs with rapid travel across time zones, resulting in a
misalignment between the timing of circadian rhythms with that of the
external physical environment.
• Symptoms of jet lag typically consist of general malaise, daytime
sleepiness, difficulty sleeping, impaired performance, and
gastrointestinal complaints.
• A study using zolpidem 10 mg given for three consecutive nights
starting with the first night sleep after travel was shown to improve
sleep in some seasoned travelers, use of a short acting hypnotic
during the flight and for the first few days after arrival is a reasonable
approach.
Cont………

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Other Disorders
• Obesity
• Diabetes
• Depression
• Bipolar disorders
• Seasonal Affective Disorders(SAD).
Banks, Faye D. et al. "Associations Between Circadian Rhythm Instability, Appraisal Style And Mood In Bipolar Disorder". Journal
of Affective Disorders 203 (2016): 166-175.

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Inflammatory Disorders & Cancer
o In humans, even acute circadian misalignment reduces circulating
cortisol levels and increases inflammatory cytokines.
o Constant light exposure during the night disturbs circadian
pacemaker activity in the mammalian SCN. This ultimately disrupts
circadian rhythms throughout the body.
o This hormone has oncostatic activity in experimental animals with
mammary tumor's, and also in human breast cancer cells in culture.
o Night-time light exposure can also happen as a result of loss of
rhythmic behavior, such as in SCN- lesioned animals. This both
increases the risk of tumor formation and enhances progression of
pre-existing tumor's.
Blakeman et al. Breast Cancer Research (2016) 18:89, Circadian clocks and breast cancer Biomed Central, Open Access, Pg.no 2-6

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Age Related Cataract
o Ocular aging leads to gradually loss of retinal illumination caused by
decreasing crystalline lens transmittance and pupillary area.
o Recent studies found that glaucoma might do damage to the ipRGCs,
which could possibly be harmful to the circadian system.
o With age, the crystalline lens gradually increases in thickness and
weight.
o As a result, the transparency and refractive index of the lens are
changed. These changes block the transmission of blue light to retina,
thereby reducing the blue light absorbed by ipRGCs.
o Thus, cataract may possibly lead to decreased circadian photo
entrainment.
Yan SS, Wang W. The effect of lens aging and cataract surgery on circadian rhythm, Int J Opthalmol 2016;9(7):1066-1074.

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Treatment
 Behavior therapy or advice about sleep hygiene.
 Avoid naps, caffeine, and other stimulants.
 Blue blocking glasses therapy
 Medications such as melatonin and modafinil (Provigil)
 Sleep phase chronotherapy.
 In sleep phase chronotherapy, an attempt is made to move bedtime and
rising time later and later each day, around the clock, until the person is
sleeping on a normal schedule.
Nannapaneni, Srikant and Kannan Ramar. "CPAP Compliance Study And Circadian Rhythm Disorders". Journal of Clinical Sleep
Medicine (2013): 15-20

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Non Pharmacological Treatment
Nannapaneni, Srikant and Kannan Ramar. "CPAP Compliance Study And Circadian Rhythm Disorders". Journal of Clinical Sleep Medicine
(2013): 20-25

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Summary
 CRSD’s are complex, Coordinated, Multiple, Chronic or Acute
Disorders.
 A misalignment between the endogenous circadian timing
system and the external environment constitutes the basis for
most of these disorders.
 All are Preventable, Sleep Hygiene is important.

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