Overview and it’srelevancein psychiatry
Presenter: Dr. Suman Pd. Adhikari
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
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
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
Periodic environmental signal that entrains some biological rhythm , for
example a natural or artificial day-night cycle for a circadian rhythm
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
The term "zeitgeber" (German for "time giver" or "synchronizer") was first
used by Jurgen Aschoff , one of the founders of Chronobiology
Introduction of Chronobiology
Study of biological time in relation with cyclic rotation of the earth in it’s 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
Chronobiology comes from the ancient Greek (chrónos, meaning "time"),
and biology, which means “the study, or science, of life”
History of Chronobiology
Date Literature/contributor Comment
(Ship captain of Alexandar the Great)
Described diurnal leaf movements of the
Century Noon and Midnight Manual
Circadian or diurnal process in humans
1729 Jean-Jacques d Ortous de
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
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
Coined the term “Circadian”
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
1994 Joseph Takahasi Discovered the first mammalian 'clock gene'
(CLOCK) using mice
Latin word circa means about and dies means days, which has the periodicity of one
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)
Normal characteristics of circadian rhythm
The period of the rhythm in constant conditions is called the free-
running period and is denoted by the Greek letter τ (tau).
The rhythm persist in constant conditions, (i.e., constant
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".
They maintain circadian periodicity over a range of physiological
Human circadian rhythms
Food and water intake
Expression of genes
Pulsatile exocrine and endocrine secretions
dependent on human circadian rhythm
functional componentsof 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
A group of neurons present in anterior
hypothalamus located dorsal to the optic
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
The SCN is active during the day in both
diurnal and nocturnal animals.
The SCN tells the animal whether it’s day or
night, but not how to behave.
Transplants of SCN establish donor rhythms in
SCN & light/dark cycles
Afferent efferent and projections
Main tract Retinohypothalamic Within the hypothalamus and to
Modulator Pituitary adenylate cyclase
Efferent of SCN regulate autonomic
division of PVN--Sympathetic outflow to
pineal gland-stimulate melatonin
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
NT and receptor Neuropeptide Y, 5-HT1B
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.
How thebiological clockswork
TheBiochemistry of Circadian Rhythms
Release is highest in the morning and
drops during the day.
Released by the retinohypothalamic tract
Released only at night (by the retina and
the pineal gland).
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
Involves interaction and coordination
between the positive and negative
transcriptional and translational feedback
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.
Dimerization of PER, CRY
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.
Resetting thecircadian clock
The mean circadian period generated by the human SCN is of about 24.18
In human light is the most effective agent for entraining the circadian
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.
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
Photic stimulation of extraocular tissue is sufficient to shift the human
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
Novel classof 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
Plays important role in phase shifting of circadian locomotor activity
Regulated by two mechanisms
Related to the accumulation and
dissipation of sleep debt.
Adenosine is supposed to be a
neuromodulator of the sleep
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.
Circadian rhythm sleep disorders1
Advanced sleep phase syndrome
Delayed sleep phase syndrome
Irregular Sleep-Wake Disorder (ISWD)
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,
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(7:30pm-4:30am)
ASPS is related to the single nucleotide polymorphism in period
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 1:00 am and 6:00 am,
and awakens in the late morning or in the afternoon.
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
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.
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 light–dark 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 362;5 February 4, 2010
Seasonal affective disorder(SAD) is a form of a recurrent major
depressive episodes followed by periods of remissions that occurs in
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
Seasonal major depressive episodes substantially outnumber the non
seasonal episodes over the individual’s lifetime.
Phase Shift Hypothesis 1
Phase delay in body
Melatonin Dysregulation 2
Secretion is longer than normal in winter
L-tryptophan is a precursor of serotonin
Based on epidemiology studies; serotonin transporter or clock gene
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
Called as winter depression or winter blues.
Onset in the late fall and early winter and remits in the late winter and
Symptoms may be atypical to major depression
Significant increase in weight
Increase rather than decrease in sleep
Heightened sensitivity to interpersonal rejection
Leaden feeling in the extremities.
4-9% of total population
20% of population may have sub syndromal features.
Runs in families showing genetic or environmental influences
Serum level of melatonin is considered as causative condition.
High irradiance(5,000 -10,000 lux) for about 45 – 90 minutes.
Early morning or evening pattern of exposure.
Cognitive behavioral therapy
Premenstrual dysphoric disorder
Non seasonal depression
Depression causes the phase delay while mania causes phase advance in
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
Relapse occurs after the following night sleep even day time short
napping among which early morning is critical.
With regard to MDD, almost all patients present with sleep disturbances and
altered circadian rhythms including hormonal secretion, cardiac function, and
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
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
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
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
Relevancein medical conditions
Effect of aging
The circadian pattern of various diseases
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
Visceral obesity and the complications following such conditions.
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.
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.
Pharmacological agentsaffecting circadian
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
Act via GABA receptors in SCN– induces circadian phase advances
Reduced expression of clock genes
Phase shift in circadian locomotor activity
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
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
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
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.
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
Identification of coupling factors responsible for
communicating phase information among
biological oscillators would resolve the issues of
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.
Biological rhythms are the events and activities which happen in a cyclical
way in the influence of rotation of the earth in it’s axis.
Most well studied biological rhythm is the circadian rhythm having day
SCN is the master pacemaker which orchestrates other oscilators of the
Melatonin is the hormone secreted by pineal gland having role in
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