Chronobiolgoy

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ChronobiologyOverview and its relevance in
psychiatry

• Presenter Dr. Suman Pd. Adhikari

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Chronobiological Terms
Term Definition
Biological clock Physiological mechanism that gives a time sense to every living organisms i.e., when to eat, sleep/awake etc.
Biological rhythm Cyclical, repeated variation in a biological function.
Circadian rhythm Cyclical variation in a metabolic , physiological or behavioral process with a period of about 24 hours when in constant conditions
Circannual rhythm Cyclical variation in a metabolic, physiological or behavioral process with a period of about an year.
Diurnal activity Activity performed mainly during the daytime
Endogenous Of rhythms or other forms of biological timekeeping controlled from within the organism by some kind of physiological biological clock
Entrainment Synchronization of one biological rhythm to another or to a zeitgeber cycle, e.g. circadian rhythm are often entrained to the light-dark cycle
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Term Definition
Melatonin A hormone produced rhythmically in vertebrates by the pineal gland, a pea sized organ at the center of the human brain.
Nocturnal activity Activity performed mainly at night
Oscillator Internal and therefore unseen, or endogenous oscillator (the biological clock ) that produces an overt measurable biological rhythm in the organism.
Period The length of one complete cycle of a rhythm
Phase A particular reference point in the cycle of a rhythm, e.g. the daily onset of locomotor activity, or the light-to-dark transition in a zeitgeber cycle.
Phase shift Shift in a biological rhythm along its time axis so whilst the period remains the same the time at which the rhythm occurs changes
Zeitgeber time giver Periodic environmental signal that entrains some biological rhythm , for example a natural or artificial day-night cycle for a circadian rhythm
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 zeitgeber 

• An environmental agent or event (as the
  occurrence of light or dark) that provides the
  stimulus for setting or resetting a biological
  clock of an organism
• Any external or environmental cue that entrains,
  or synchronizes, an organism's biological rhythms
  to the earth's 24-hour light/dark cycle and 12
  month cycle.
• The term "zeitgeber" (German for "time giver" or
  "synchronizer") was first used by Jurgen Aschoff
  , one of the founders of Chronobiology
• Common zeitgeber
• Temperature
• Social interactions
• Pharmacological manipulation
• Exercise
• Eating/drinking patterns

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Introduction of Chronobiology

• Study of biological time in relation with cyclic
  rotation of the earth in its axis which is
  completed within 24 hrs.
• Biological rhythm varies from milliseconds in
  ocular field potential to years
• Circadian rhythm is the most extensively studied
  and best understood biological rhythm.
• Chronobiology comes from the ancient Greek
  (chrónos, meaning "time"), and biology, which
  means the study, or science, of life

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History of Chronobiology
Date Literature/contributor Comment
4th Century BC Androsthenes (Ship captain of Alexandar the Great) Described diurnal leaf movements of the  Tamarind tree.
13th Century Noon and Midnight Manual (Chinese) Circadian or diurnal process in humans mentioned

1729 Jean-Jacques d Ortous de Mairan (French) Noted 24-hour patterns in the movement of the leaves of the plant Mimosa pudica
1751 Carlous Linneaus (Swedish Botanist and naturalist) Designed a flower clock using certain species of flowers. By arranging the selected species in a circular pattern, he designed a clock that indicated the time of day by the flowers that were open at each given hour
1896 Patrick and Gilbert Observed that during a prolonged period of sleep deprivation, sleepiness increases
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Date Literature/contributor Comment
1918 J.S. Szymanski Showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature
1959 Franz Halberg (University of Minnesota-Father of American Chronobiology) Coined the term Circadian
20th Century Auguste Forel, Oskar Wahl Circadian rhythms were noticed in the rhythmic feeding times of bees
1967 Erwin Bunning Described physiological clock in plant
1970s Ron Konopka, Seymour Benzer Isolated the first clock mutant in  Drosophila  and mapped the period" gene, the first discovered genetic component of a circadian clock
1994 Joseph Takahasi Discovered the first mammalian 'clock gene' (CLOCK) using mice
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biological rhythms
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Circadian rhythms

• Latin word circa means about and dies means
  days, which has the periodicity of one day.
• Such rhythms persist in the absence of time cues
• Self sustained biological rhythms characterized
  by a free-running period of about 24 hours
  (circa diem)
• Circadian rhythm may be
• Diurnal organisms active during daytime
• Nocturnal organisms active in the night
• Crepuscular animals primarily active during
  the dawn and dusk hours
• (ex white-tailed deer, some bats)

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Normal characteristics of circadian rhythm Character Comment Normal characteristics of circadian rhythm Character Comment
Endogenous free running period The period of the rhythm in constant conditions is called the free-running period and is denoted by the Greek letter t (tau). The rhythm persist in constant conditions, (i.e., constant darkness)
Entrainable The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment The external stimulus used to entrain a rhythm is called the Zeitgeber, or "Time giver".
Exhibit temperature compensation They maintain circadian periodicity over a range of physiological temperatures
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Human circadian rhythms

• Sleep-wake cycle
• Body temperature
• Behaviour
• Food and water intake
• Hormones
• Metabolism
• Body fluids
• Expression of genes

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Pulsatile exocrine and endocrine secretions
dependent on human circadian rhythm
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functional components of circadian axis

• Master pacemaker situated in SCN
• Afferent-- Photoreceptive input situated in the
  eye
• Efferent-- Rhythmic outputs which provide insight
  into the clockwork of the circadian pacemaker.

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Scn-master pacemaker

• A group of neurons present in anterior
  hypothalamus located dorsal to the optic chiasma
• Master oscillator-- generates the mean circadian
  rhythm and orchestrates a multitudes of slave
  oscillators found in peripheral tissues like
  kidney, liver, lungs other sites of the brain.
• The neurons of the SCN are among the smallest
  neurons in the entire brain.
• They possess short dendrites that are not
  extensively branched.

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SCN light/dark cycles

• The SCN is active during the day in both diurnal
  and nocturnal animals.
• The SCN tells the animal whether its day or
  night, but not how to behave.
• Transplants of SCN establish donor rhythms in
  recipient animals.

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Zeitgeber (time givers) entrain clock
Light
Master clock SCN
Pineal Gland
EYE
Regulates Hormones , Sleep/wake - Temp
Exercise Food Social factors
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Afferent efferent and projections
Afferent Efferent
Main tract Retinohypothalamic Within the hypothalamus and to pineal gland
Primary neurotransmitter Glutamate GABA
Modulator Pituitary adenylate cyclase activating peptide(PACAP) Efferent of SCN regulate autonomic division of PVN--Sympathetic outflow to pineal gland-stimulate melatonin synthesis Efferent parvicellular neuron of PVN has the role in secretion of CRH which regulates the release of cortisol
Other tract origin Ipsilateral intergeniculate leaflet(IGL)-sub nucleus of LGN Midbrain raphe Efferent of SCN regulate autonomic division of PVN--Sympathetic outflow to pineal gland-stimulate melatonin synthesis Efferent parvicellular neuron of PVN has the role in secretion of CRH which regulates the release of cortisol
NT and receptor Neuropeptide Y, 5-HT1B Efferent of SCN regulate autonomic division of PVN--Sympathetic outflow to pineal gland-stimulate melatonin synthesis Efferent parvicellular neuron of PVN has the role in secretion of CRH which regulates the release of cortisol

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How the biological clocks work

• Oscillations of protein production and
  degradation serves as the ticking of the
  internal clock (takes about 24 hours).
• Light may participate in the triggering of some
  of these protein fluctuations.

Locomotion
Hormone release
Sensory receptors
Pace-maker
Environmental cues
Feeding
Others
Clock-setting pathway
Clock mechanism
Observed behaviour
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The Biochemistry of Circadian Rhythms

• Cortisol
• Release is highest in the morning and drops
  during the day.
• Glutamate
• Released by the retinohypothalamic tract during
  light
• Melatonin
• Released only at night (by the retina and the
  pineal gland).

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• Melatonin
• Indoleamine, a circadian regulated hormone the
  synthesis of which is regulated through the
  multisynaptic pathway from SCN to pineal gland.
• Serum level of melatonin is elevated at night and
  returns to baseline during the day.
• Light shifts the phase of melatonin synthesis and
  suppresses the elevated melatonin level.

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Molecular clockwork

• Involves interaction and coordination between the
  positive and negative transcriptional and
  translational feedback loops.
• The products of per and cry genes translocate
  back into the nucleus and repress their own
  transcription.
• Orphan nuclear receptor gene Rev-Erb alpha also
  regulates the CLOCK-BAML1 then per and cry
  genes.
• Enzymes kinase and phosphatase also act upon the
  gene products and has role in molecular clock
  work.

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In all cells, the expression of many genes
changes rhythmically over 24 hours. Specific
circadian genes such as CLOCK, BMAL1, and PER are
responsible for the main SCN clock working
machinery as well as subsidiary clocks in other
parts of the body.
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Resetting the circadian clocksensory parameters

• The mean circadian period generated by the human
  SCN is of about 24.18 hours.
• In human light is the most effective agent for
  entraining the circadian system
• Bilateral removal of eyes incapable to reset
  circadian clock, indicating that the
  photosensitive apparatus necessary for resetting
  must be ocular
• To maintain the proper phase relationship of
  behavioral and physiological process circadian
  clock should be resetted in a regular basis
  within a context of 24 hours a day.

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• Photosensitive apparatus required for resetting
  the circadian clock is different from the
  photoreceptors rods or cones.
• The light intensity required to activate such
  apparatus having high threshold is of low i.e. 3
  log unit for longer duration than of visual
  system.
• Eyes may retain the function in clock resetting
  despite being useless for vision.

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Extraocular photoreception

• Photic stimulation of extraocular tissue is
  sufficient to shift the human circadian clock
• Blue light illumination of highly vascularized
  tissue like popliteal region behind the
  knee---shown to phase shift the nightly increase
  of melatonin
• Currently this is not widely accepted and further
  research is needed

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Novel class of retinal photoreceptors

• Studies in blind human and retinally degenerate
  animals photoreceptors other than rods and cones
  are likely to be involved in circadian system
• Rodent retinal ganglion cells found to be
  intrinsically photosensitive
• These cells contain Melanopsin photo pigment
  initially discovered in melanophores of tadpoles
  later identified in human retina
• Melanopsin is also localized in plasma membrane
  of cell body, axon and dendrites
• Plays important role in phase shifting of
  circadian locomotor activity

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Relevance in psychiatry

• Sleep regulation
• Seasonal affective disorders
• Non seasonal depression
• Schizophrenia

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Sleep regulation

• Regulated by two mechanisms
• Sleep homeostat
• Related to the accumulation and dissipation of
  sleep debt.
• Adenosine is supposed to be a neuromodulator of
  the sleep homeostat.
• Circadian cycle/clock
• Controls a daily rhythm in sleep propensity or
  conversely, arousal.
• Arousal steadily increases throughout the day,
  reaching a maximum immediately before the
  circadian increase in plasma melatonin.

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Circadian rhythm sleep disorders1

• Advanced sleep phase syndrome
• Delayed sleep phase syndrome
• Free-running type
• Irregular Sleep-Wake Disorder (ISWD)
• Jet lag
• Shift work type

1 Circadian Rhythm Sleep Disorders Part I, Basic
Principles, Shift Work and Jet Lag Disorders An
American Academy of Sleep Medicine Review
Robert L Sack, MD Dennis Auckley, MD R. Robert
Auger, MD Mary A. Carskadon, PhD Kenneth P.
Wright Jr, PhD Michael V. Vitiello, PhD Irina
V. Zhdanova, MD
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• Advanced sleep phase syndrome (ASPS)
• Characterized by bedtime and wake-up time much
  earlier than normal, although sleep quality is
  normal.
• People with ASPS may fall sleep at 6 or 8 p.m.
  and awaken about eight hours later. 
• An autosomal dominant familial form (FASPS) 4
  hour advance of daily sleep wake
  rhythm(730pm-430am)
• ASPS is related to the single nucleotide
  polymorphism in period gene
• Delayed sleep phase syndrome (DSPS)
• A circadian sleep disorder in which the
  individual's internal body clock is delayed with
  respect to the external day/night cycle
• Falls asleep late at night, typically between
  100 am and 600 am, and awakens in the late
  morning or in the afternoon.

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• Irregular Sleep-Wake Disorder (ISWD)
• Characterized by at least three sleep episodes
  per 24-hour period, irregularly from day to day.
• Most commonly occurs in elderly persons with
  dementia.
• Also occurs in some children with developmental
  disorders, including autism spectrum disorders.
• Can be a consequence of brain tumors or traumatic
  brain injury
• Free running/ Non-24-Hour Sleep-Wake Disorder
  (Non-24)
• Rhythms, which reflect the intrinsic oscillation
  of the circadian pacemaker when it is not
  influenced by environmental time cues.
• Circadian sleep disorder in which an individual
  falls asleep later each day.
• Generally the delay is about an hour or two,
  corresponding to a circadian cycle of 25 - 26
  hours but some individuals with Non-24 exhibit a
  much longer delay, especially those who have
  lived with Non-24 for many years.

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• Jet lag
• When a person travels through the different time
  zones there would be the phase difference.
• In jet lag the clock is slow to reset, so that
  after time zones have been crossed, the
  endogenous signals for sleep and wakefulness do
  not match the local lightdark and social
  schedules1
• Travelling from east to west will have phase
  advance while reverse would be in opposite
  direction.
• Symptoms include reduced alertness, day time
  fatigue, loss of appetite, reduced cognitive
  skills and disruption of sleep/wakefulness
• Shift work schedule
• When a person works against the natural day-night
  schedule he/she would suffer from disruption of
  circadian rhythm.

1 The New England Journal of Medicine Jet Lag
Robert L. Sack, M.D. N Engl J Med 3625 February
4, 2010
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Seasonal affective disorders

• Seasonal affective disorder(SAD) is a form of a
  recurrent major depressive episodes followed by
  periods of remissions that occurs in seasonal
  basis.
• In DSM-IV, it is not categorized as a distinct
  mood disorder but as the seasonal pattern
  specifiers.
• Full remissions(or a change from depression to
  mania or hypomania) also occur at a
  characteristic time of the year.
• Two major depressive episodes meeting criteria A
  and B have occurred in the last 2 yrs and no non
  seasonal episodes have occurred in the same
  period.
• Seasonal major depressive episodes substantially
  outnumber the non seasonal episodes over the
  individuals lifetime.

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SAD Mechanisms

• Phase Shift Hypothesis 1
• Phase delay in body
• Melatonin Dysregulation 2
• Secretion is longer than normal in winter
• Serotonin Deficiency
• L-tryptophan is a precursor of serotonin
• Genetic Abnormalities
• Based on epidemiology studies serotonin
  transporter or clock gene defects

1. Samir Malhotra, Girish Sawhney, Promila Pandhi
   (2004) The Therapeutic Potential of Melatonin A
   Review of the Science. MedGenMed. 6 (2) 46
2. Alfred J. Lewy, Bryan J. Lefler, Jonathan S.
   Emens, and Vance K. Bauer.(2006) The circadian
   basis of winter depression. PNAS 103 7414-7419

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Winter SAD

• Called as winter depression or winter blues.
• Onset in the late fall and early winter and
  remits in the late winter and early summer.
• Symptoms may be atypical to major depression
• Significant increase in weight
• Increase rather than decrease in sleep
• Hyperphagia
• Heightened sensitivity to interpersonal rejection
  
• Leaden feeling in the extremities.

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• Incidence
• 4-9 of total population
• 20 of population may have sub syndromal
  features.
• M F14
• Runs in families showing genetic or environmental
  influences
• Serum level of melatonin is considered as
  causative condition.
• Treatment
• Light therapy
• High irradiance(5,000 -10,000 lux) for about 45
  90 minutes.
• Early morning or evening pattern of exposure.
• Pharmacotherapy
• MAO inhibitors.
• Cognitive behavioral therapy
• Comorbidity
• Bulimia nervosa
• Premenstrual dysphoric disorder

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Non seasonal depression

• Depression causes the phase delay while mania
  causes phase advance in sleep cycle.
• Sleep disturbances can contribute to the
  pathogenesis of disease.
• Total sleep deprivation provides a transient
  antidepressant effect in a majority (60)of
  depressed patient.
• No difference is observed in the efficacy of such
  treatment with or without medicine.
• Relapse occurs after the following night sleep
  even day time short napping among which early
  morning is critical.

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• With regard to MDD, almost all patients present
  with sleep disturbances and altered circadian
  rhythms including hormonal secretion, cardiac
  function, and body temperature.
• Sleep disruption is a major symptom in
  depression, with over 90 of patients showing
  sleep complaints that affect daytime functioning
• There may be delayed sleep onset, terminal
  insomnia, decreased N3-N4 sleep, increased phasic
  REM density, decreased REM latency, fragmented
  sleep and day time napping
• Insomnia often appears before the onset of mood
  disorder symptoms and may persist into clinical
  remission
• Sleep difficulties are often are the key factor
  that causes depressed patients to seek medical
  help

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schizophrenia

• Sleep-onset and maintenance insomnia is a common
  symptom regardless of either their medication
  status (previously treated) or the phase of the
  clinical course (acute or chronic).
• Regarding sleep architecture, NREM-N3 sleep and
  REM sleep onset latency are reduced whereas REM
  sleep duration tends to remain unchanged.
• Many of these sleep disturbances are caused by
  abnormalities of the circadian system as
  indicated by misalignments of the endogenous
  circadian cycle and the sleep wake cycle.
• Circadian disruption, sleep onset insomnia and
  difficulties in maintaining sleep could be partly
  related to a presumed hyperactivity of the
  dopaminergic system and dysfunction of the
  GABAergic system

Sleep and circadian rhythm dysregulation in
schizophrenia Progress in Neuro-Psychopharmacology
Biological Psychiatry, Elsevier 2013
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Relevance in medical conditions

• Obesity and metabolic dysfunction
• Cancer
• Effect of aging

The circadian pattern of various diseases
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Obesity and metabolic dysfunction

• Experimental studies showed the relation between
  blood lipid, glucose, and insulin level with the
  circadian rhythm.
• Shift workers have more incidence of having
  metabolic syndrome characterized by
• Hyperglycemia
• Hypoinsulinemia
• Dyslipidemia
• Visceral obesity and the complications following
  such conditions.

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Cancer

• Experimental studies showed the increased
  incidence of carcinomas in jet-laged-radiation
  exposed animals.
• Shift working females and airhostess crossing the
  meridians were found to be increased risk of
  breast cancer.
• Supposed to be inhibition of melatonin which
  augments estrogen effect.

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Aging

• Experimental studies showed that phase shifting
  has effect in survival of aged mice in which
  phase delay increased the survival but phase
  advance decreased the survival.
• During aging circadian period shortens with phase
  advance resulting in earlier bedtime and waking.

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Pharmacological agents affecting circadian rhythm
Drug Effect on rhythm
TCA Decreases elevated nocturnal body temperature in depressive patients
SSRI Decreases elevated nocturnal body temperature in depressive patients, augment diurnal activities.
Lithium Inhibit glycogen synthase kinase 3b which stabilizes the negative clockwork stabilizer REV-ERBa---lengthens circadian period
Benzodiazepines Brotizolam Act via GABA receptors in SCN induces circadian phase advances Reduced expression of clock genes
MDMA Methylenedioxymethamphetamine Phase shift in circadian locomotor activity
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Terminologies related to chronotherapeutics
Terminology Comment
Chronopathology It is the study of biological rhythms in disease processes and morbid and mortal events.
Chronopharmacology It is the study of manner and extent to which the kinetics and dynamics of medications are directly affected by endogenous biological rhythms, and also how the dosing time affect biological rhythms
Chronopharmacokinetics This term includes both rhythmic changes in the drug bioavailability, and its excretion
Chronopharmacodynamics Refers to dosing time, i.e., rhythm-dependent, differences in the effects of medications.
Chronotoxicology Refers specifically to dosing-time, i.e., rhythm-dependent, differences in the manifestation and severity of adverse effects and thus intolerance of patients to medications
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chronotherapeutics
Therapy Mechanism Comment
Chronotherapeutics is medical treatment administered according to a schedule that corresponds to a persons daily, monthly, seasonal or yearly biological clock to maximize health benefits and minimize adverse effects Chronotherapeutics is medical treatment administered according to a schedule that corresponds to a persons daily, monthly, seasonal or yearly biological clock to maximize health benefits and minimize adverse effects Chronotherapeutics is medical treatment administered according to a schedule that corresponds to a persons daily, monthly, seasonal or yearly biological clock to maximize health benefits and minimize adverse effects
Light therapy Light therapy emerged as the first successful treatment in psychiatry based on neurobiological principles and is now established as the treatment of choice for SAD
Wake therapy Total sleep deprivation Improvement in depressed patients occur with total sleep deprivation
Dark therapy Focuses on darkness, particularly in bipolar patients Keeping acutely manic patients in dark rooms during the night has been shown to improve symptoms and immediately stop rapid cycling.
Melatonin Agomelatine Ramelteon Tasimelteon If rhythms are out of sync, as in depression, melatonin is secreted at the wrong time and the sleep disturbance is accentuated.
Modafinil Used for excessive sleepiness associated with shift work sleep disorder
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Future advances

• Identification of coupling factors responsible
  for communicating phase information among
  biological oscillators would resolve the issues
  of circadian desynchrony.
• This would give insight for pharmacological as
  well as behavioral means to resolve the problems
  due to circadian desynchrony.
• Impact of circadian system on the effectiveness
  of pharmacological treatments would develop the
  field of chronotherapy.

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Summary

• Biological rhythms are the events and activities
  which happen in a cyclical way in the influence
  of rotation of the earth in its axis.
• Most well studied biological rhythm is the
  circadian rhythm having day night cycle.
• SCN is the master pacemaker which orchestrates
  other oscilators of the body.
• Melatonin is the hormone secreted by pineal gland
  having role in circadian rhythm.

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• Zeitgeber is the external cue which regulates and
  resets the circadian rhythm and the luminance is
  a Zeitgeber.
• There are genetic events which act as work clock.
• There is definite role of circadian rhythm in
  causation, course and outcome of various
  psychiatric and medical conditions.
• Aging is a process which affects circadian rhythm
  of an individual.
• There is significant interaction between
  pharmacological agents and circadian rhythm.