CHRONOBILOGY, CIRCADIAN RHYTHMS,

1. - Dr.V.L.N.SEKHAR
PG in Psychiatry

2.  Chronos= time; biology=study of life
 Chronobiology is a field of biology that
examines periodic(cyclic)phenomena in living
organisms and their adoptation to solar and
lunar related rhythms.
 The variation of the timing and duration of
biological activity in living organisms occur
for many essential biological processes.

3.  These occur:-
1. In animals (eating, sleeping, mating, hibernating,
migration, cellular regeneration etc.)
2. In plants (leaf movements, photosynthetic reactons
etc.)
3. In microbial organisms such as fungi and protozoa.
 The most important rhythm in chronobiology is the
circadian rhythm.

4.  Biological clock:- - the internal physiological systems
that track the environmental rhythms. Responsible
for generating biological rhythms.
 Biological rhythm:- is one or more biological events
or functions that reoccur in time in a repeated order
and with a repeated interval between occurrence.
 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.

5.  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.
 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

6.  Biological rhythm is one or more biological events
or functions that reoccur in time in a repeated
order and with a repeated interval between
occurrence.
 these are the ways that organisms adapt and live
with the environmental rhythms around them, such
as the spin of the earth, the movement of the earth
around the sun, and movement of the moon around
the earth.
 biological rhythms allow an organism to harmonize
successfully with its environment.

7.  Two types- exogenous and endogenous.
 Exogenous biological rhythms are driven directly by
the environment or another external influence.
Eg. the hopping of sparrows on a perch when a light is
turned on
 Endogenous biological rhythms are driven by internal
biological clocks and are maintained even when
environmental cues are removed.
Eg. the wake-sleep cycle and the daily body temperature
cycles.

8.  the 24-hour periodicity represents a small time domain
within the spectrum of temporal biology. A broad range
of frequencies exist , ranging from millisecond
oscillations in ocular field potentials to the 17-year
cycle of emergence seen in the periodic cicada
(Magicicada spp.).
 Ultradian rhythm: Biologic rhythm with a period shorter
than circadian (less than 20 h).
 Circadian: About 24 h. The term describes rhythms with
about 24 h ( > 20 to < 28 h) cycle length whether they
are synchronized with a 24 h periodic surrounding or
not.

9.  Infradian rhythm- Rhythm with a period longer (by
definition > 28 h) than the circadian range
eg. the annual migration ; reproduction cycles found
in certain animals ; the human menstrual cycle.
 Circaseptan: A rhythm with a period of about 7 (
± 3) days, which may or may not be synchronized
with the calendar week.
 Circadiseptan: A rhythm with a period of about 14
( ± 3) days
 Circavigintan: A rhythm with a period of about 20
( ± 3) days.
 Circatrigintan or circalunar: A rhythm with a
period of about 30 (± 5) days.
Eg. the menstrual cycle.

10.  Circaannual -A rhythm with a period of about 1 year ( ± 2
months), synchronized with or desynchronized from the
calendar year. E.g.. over-winter hibernation
 Seasonal variation -Change in a biologic system brought
about by seasonal changes of temperature, light-span, etc,
and not observed in the absence of such changes.
 Tidal rhythms - commonly observed in marine life,
which follow the roughly 12-hour transition from high to
low tide and back.
 Gene oscillations – some genes are expressed more
during certain hours of the day than during other hour

11. biological rhythms

12.  "biological clocks" - the internal physiological systems
that track the environmental rhythms. Responsible for
generating biological rhythms
 True biological clocks has 4 characteristics
1. the clock is endogenous, meaning it gives the organism
an innate ability to maintain periods of a particular
length between biological functions.
2. the clock is temperature independent—a very unusual
situation in biology but an essential characteristic to
avoid biological rhythms being governed by the weather.
3. biological clocks have the ability to be reset in order to
maintain a relationship with environmental cues.
4. biological clocks are an internal continuous monitor of
the passage of time, allowing the organism to keep track
of duration biologically.

13.  Two functions: 1.the capacity of the biological clock to
free run (operate without external cues),
2. the ability of timing signals, known as Zeitgeber
(German for "time-giver"), to synchronize the cycles to
the environmental signals.
Common zeitgebers include light, temperature, and
social cues such as clocks, sound, or physical contact.
A biological clock is said to be free running when these
external cues are removed. the average free run period
for circadian rhythms in humans is 25 hours.
Thus, if isolated from outside input, people tend to go to
sleep one hour later each day, quickly becoming out of
sync with the rest of the 24 hour-based human world.

14.  Entrainment is the process of aligning a biological
rhythm with an environmental stimulus. There are
limits to the time periods that biological rhythms can
be entrained.
 For circadian rhythms in most animals, 18 hours is the
shortest period tolerated, with an upper limit of about
28-30 hours. If zeitgebers are provided for shorter or
longer intervals, the organism reverts back to free
running.
 A good example of entrainment is the acquisition of
the 24-hour wake-sleep schedule by human infants
after birth. Newborn circadian rhythms free run,
significantly disrupting the sleeping patterns of their
parents. However, as they mature and become
responsive to zeitgebers such as light and dark, infants
gradually adopt the 24-hour schedule of adults.

15.  Latin: circa=about; dies=day
 the most extensively studied and best
understood biological rhythms.
 Rhythms that fluctuate on a 24-hour time scale are
known as circadian rhythms.
 Physiologic or behavioral cycles with a period of 24
hrs produced by endogenous pacemaker.
 Franz Halberg who coined the word circadian, is
widely considered the "father of American
chronobiology.“
 The best-known circadian rhythms
 body temperature
 hormone secretion
 metabolism
 sleep/wake cycle

16.  Ubiquitous (cyanobacterias, plants, rodents, humans)
 Endogenous (persist in the absence of environmental cycles)
circadian rhythm can further be broken down into routine
cycles during the 24-hour day:
 Diurnal- which describes organisms active during daytime
 Nocturnal- which describes organisms active in the night
 Crepuscular- which describes animals primarily active
during the dawn and dusk hours (ex: white-tailed deer,
some bats)
 Prominent daily variations also occur in
 endocrine,
 thermoregulatory,
 cardiac,
 pulmonary,
 renal,
 gastrointestinal,
 neurobehavioral functions.

17.  Measurement of circadian phase and its changes can
be obtained through the assessment of proxy-
markers which are:
1.Core body temperature minimum(CBTM) –which
occurs approximately 2 hrs before awakening from
nocturnal sleep.
2.Dim light melatonin onset (DLMO)- the time at
which endogenous melatonin begins to climb which
takes place approximately 2-3 hr before routine
bedtime.

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

19.  Taken together, the circadian axis of mammals can
be divided into three distinct functional
components:
 (1) a master pacemaker situated in the SCN,
 (2) a photoreceptive input to the SCN that
originates in the eye, and
 (3) the myriad of rhythmic outputs that provide
insight into the clockwork of the circadian
pacemaker.

20. Anatomy
 The mammalian circadian system is
organized as a hierarchy of pacemakers.
 The SCN is the master oscillator that
orchestrates a multitude of slave oscillators.
 These slave oscillators are found in a wide
range of peripheral tissues including the
kidney, liver, lung, and other sites in the
brain.
 Most of these studies were conducted in
rodents.

21.  The SCNs are small, paired, hypothalamic
structures situated immediately dorsal to the optic
chiasm.
 They were recognized as the site of the primary
circadian pacemaker, because lesions in the ventral
hypothalamus that encompassed the SCN rendered
rodents behavioraly arrhythmic.
 Transplantation of SCN tissue from mutant
hamsters that expressed abnormally short circadian
periods into the brains of SCN-lesioned host
hamsters with normal prelesion circadian periods
resulted in a transfer of the abnormally short
period.
 SCN is a true biological pacemaker and not simply a
neural relay for a rhythm generator located
elsewhere in the brain.

22.  SCN neurons that are isolated and maintained in
culture for several days also continue to show
approximately 24-hour rhythms in action potential
frequency.
 The neurons of the SCN are among the smallest
neurons in the entire brain.
 They possess short dendrites that are not
extensively branched.
 A consequence of these cellular dimensions is the
high packing density of the nucleus.
 Virtually every neuron in the SCN is immunopositive
for the inhibitory neurotransmitter γ-aminobutyric
acid (GABA).

23.  the most obvious anatomical subdivision is the core
of the SCN, defined by the presence of calbindin-
positive neurons.
 The remainder of the SCN that surrounds the core
is considered the shell.
 Discrete functions have not been firmly assigned to
subdivisions of the SCN, but the afferent and
efferent projections to and from these subdivisions
are beginning to provide insights into their putative
functions.

24.  Retinohypothalamic tract is the primary
afferent input originating from retinal
ganglion cells innervating SCN, excitatory
glutamate is the primary NT
 Ipsilateral intergeniculate leaflet (IGL) of
the lateral geniculate complex receives
input directly from the retina, providing a
secondary indirect pathway from the retina
to the SCN. Neuropeptide Y is the
predominant NT
 Distinct serotonergic projection from the
midbrain raphe. Serotonin modulates light's
effect on SCN function.

25.  Main efferant pathway Within the hypothalamus
and to pineal gland.for this primary
neurotransimitter GABA. Efferent of SCN
regulate autonomic division of PVN--
Sympathetic outflow to pineal gland-
stimulate melatonin synthesis.
 A second, less understood efferent pathway from
the SCN plays an important role in the control of
cortisol. Systemic cortisol levels increase in
response to stress. However, these levels also
have a strong circadian component, being
highest in the early morning in humans. Peak
cortisol levels occur at approximately 6 AM to 8
AM, just as melatonin levels approach baseline

26.  The mean circadian period generated by the
human SCN is approximately 24.18 hours.
 Like a watch that ticks 10 minutes and 48
seconds too slowly per day, an individual with
such a period gradually comes out of synchrony
with the astronomical day.
 In slightly more than 3 months, a normally
diurnal human would be in antiphase to the day–
night cycle and thus would become transiently
nocturnal.
 Therefore, a circadian clock must be reset on a
regular basis to be effective at maintaining the
proper phase relationships of behavioral and
physiological processes within the context of the
24-hour day.

27.  The circadian clock drives many rhythms, including
rhythms in behavior, core body temperature, sleep,
feeding, drinking, and hormonal levels.
 One such circadian-regulated hormone is the
indoleamine, melatonin.
 Melatonin synthesis is controlled through a
multisynaptic pathway from the SCN to the pineal
gland.
 Exposure to light elicits two distinct effects on the
daily melatonin profile.

28.  First, light acutely suppresses elevated melatonin
levels, immediately decreasing them to baseline
levels
 Second, light shifts the phase of the circadian
rhythm of melatonin synthesis.
 Because melatonin can be assayed easily, it
provides a convenient window into the state of the
circadian pacemaker.
 Any perturbation of the clock is reflected in the
melatonin profile; thus, melatonin offers an
output that can be used to study the regulation of
the central circadian pacemaker

29.  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).

30.  Growth hormone –increase during sleep;
decrease during wakeful state.
 Prolactin –resembles like growth hormone
cycle.
 Aldosterone – peaks in afternoon; declines in
evening.
 Testosterone – low in afternoon; high in night

31.  A cohort of principal clock genes has been identified in mammals
since 1997.
 Many of these molecular components were initially discovered in the
fruit fly, Drosophila melanogaster, leading to the discovery of
mammalian orthologs.
 The mammalian circadian clockwork consists of interacting positive
and negative transcriptional and translational feedback loops .
 The expression of multiple homologs of the Drosophila period gene
and cryptochrome genes are positively regulated by the binding of
CLOCK-BMAL1 (Bmal1 is also known as Mop3) heterodimers to E-box
enhancers in the promoters of these genes.
 The products of the Per and Cry genes translocate back into the
nucleus and repress their own transcription.
 This series of events constitutes the negative feedback limb of the
core oscillation.

32.  In addition to activating the transcription of the Per and Cry
genes, the CLOCK-BMAL1 complex also activates expression
of the orphan nuclear receptor gene Rev-Erbα. The gene
product of Rev-Erbα, in turn, translocates into the nucleus
and represses transcription of the Bmal1 gene through Rev-
Erb/ROR response elements in the Bmal1 gene promoter.
BMAL1 subsequently hetero-dimerizes with CLOCK and again
activates expression of the Per, Cry, and Rev-Erbα genes.
 This derepression (or activation) of the Bmal1 gene,
subsequent hetero dimerization with CLOCK, and activation
of the Per, Cry, and Rev-Erbα genes constitutes the positive
feedback limb of the core oscillator.
 Regulation: by posttranslational modifications.
eg, phosphorylation of some of the PER proteins by casein
kinase Iε or δ is important for their translocation into the
nucleus or their degradation in the cytoplasm.
Other kinases, and presumably phosphatases, are emerging
as critical regulators of the circadian molecular clockwork.
Histone acetylation or phosphorylation likely to control the
rhythmic expression and function of clock genes

33.  In humans and other mammals, light perceived through the eyes is the most
effective agent for entraining (synchronizing) the circadian system to the 24-
hour day.
 Bilateral removal of the eyes renders an individual incapable of resetting the
circadian clock, indicating that the photosensitive apparatus necessary for
resetting must be ocular.
 The photic sensitivities of the visual and circadian systems are quite different
 The visual system can be activated by intensities of light ranging from dim
starlight to bright daylight.
 This dynamic range represents approximately 14 log units of light intensity
measured in photons per second per square centimeter.
 The dynamic range of the circadian system is only 3 log units, and the
activation threshold is much higher than that of the visual system.
 Additionally, the circadian system requires light stimuli of much longer
duration to activate clock resetting than that required by the visual system to
construct images.

34.  The different sensory demands of the circadian
and visual systems raise the possibility that a
novel photoreceptive apparatus subserves light-
mediated entrainment of the circadian system
to the day–night cycle.
 Visually blind rodents that have a genetically
induced loss of rods and cones remain capable
of light-mediated circadian clock resetting.
 A similar situation has been observed in blind
humans. A subset of blind individuals retains
the ability to photically regulate the rhythmic
synthesis of melatonin.

35.  It has been suggested that photic stimulation of
extra ocular tissues is sufficient to shift the human
circadian clock.
 Specifically, blue light illumination of highly
vascularized tissue, such as the popliteal region
behind the knee, was shown to phase shift the
nightly increase of melatonin.
 Many studies were done but none of them have
given a conclusive evidence.

36.  The findings from retinally degenerate animal models
and blind humans indicate that photoreceptors other
than rods and cones are likely to be involved in the
photoregulation of the circadian axis
 A small subset of rodent retinal ganglion cells
recently has been shown to be intrinsically
photosensitive. The spectral sensitivity of these cells
matches the spectral sensitivity of the circadian
system
 Intrinsically photosensitive retinal ganglion cells
project directly to the SCN. They also project to the
IGL and the olivary pretectal nuclei, other brain
structures involved in the interpretation of
illuminance information.

37.  The intrinsically photosensitive cells contain
melanopsin, a photopigment initially discovered
in the pigmented skin cells (melanophores) of
tadpoles and subsequently identified in human
and mouse retinas
 The melanopsin-containing ganglion cells are
significantly less sensitive to light compared to
the rod and cone photoreceptors of the visual
system, and they require light stimuli of
relatively long duration to be activated.
 Finally, these cells are maximally sensitive to
wavelengths of light similar to those required to
acutely suppress nocturnal melatonin levels in
humans.

38. Function:
 Although the anatomy and physiology of melanopsin
retinal ganglion cells are highly suggestive that these
cells function as circadian photoreceptors, recent
studies provide the most compelling evidence.
 Mice with a targeted disruption of both copies of the
melanopsin gene show profound deficits in their ability
to phase-shift circadian loco motor rhythms in
response to pulses of light.
 These deficits were observed at all irradiances tested
 Thus, the photopigment melanopsin and, presumably,
the retinal ganglion cells containing melanopsin are
required for normal photic regulation of circadian
rhythms.

39.  Restful consolidated sleep is most appreciated
when sleep disturbances are experienced.
 Sleep is the integrated product of two oscillatory
processes.
 The first process, frequently referred to as the
sleep homeostat, is an oscillation that stems from
the accumulation and dissipation of sleep debt.
 The biological substrates encoding sleep debt are
not known, although adenosine is emerging as a
primary candidate neuromodulator of the sleep
homeostat.

40.  The second oscillatory process is governed by the circadian clock
and controls a daily rhythm in sleep propensity or, conversely,
arousal.
 The circadian cycle in arousal (wakefulness) steadily increases
throughout the day, reaching a maximum immediately before the
circadian increase in plasma melatonin.
 Arousal subsequently decreases to coincide with the circadian
trough in core body temperature.
 Experiments imposing forced sleep schedules throughout the
circadian day have shown that an uninterrupted 8-hour bout of
sleep can only be obtained if sleep is initiated approximately 6
hours before the temperature nadir.
 This nadir typically occurs at approximately 5:00 AM to 6:00 AM.
 In healthy individuals, initiating sleep between 11:00 PM and 12:00
AM affords the highest probability of getting 8 solid hours of sleep.

41.  Diurnal preference varies among individuals as a
function of age, endogenous circadian periods, and
other factors.
 Clinically, diurnal preference can be quantified
using the Horne–Östberg (HO) questionnaire.
 In qualitative terms, morning people or morning
larks tend to awaken earlier and experience the
core body temperature minimum at an earlier
clock time relative to night people or night owls.

42.  Adult short sleepers habitually get 5-6 or fewer
hours of sleep per 24 hours, without impairment
in daytime functioning. Their sleep is typically
unbroken and, although short, is not a result of
voluntarily restricted sleep.In children, short
sleepers are those who get three hours or less
than the norm for their age group.
 A “long sleeper” is an individual who sleep
longer than average, but feels well and functions
without impairment. Long sleep is different from
idiopathic hypersomnia where a person sleeps
long hours but still does not feel refreshed. Long
sleepers are adults who typically sleep 9-10
hours (or more) when not previously sleep-
deprived, and children who sleep 2 hours more
than the age-appropriate norm.

43.  Defined as an alteration of the phase relationship
between the intrinsic circadian system & the
extrinsic light-dark cycle resulting in an
unconventional or abnormal sleep-wake pattern
 leads to symptoms of insomnia ,excessive sleepiness
or impairment of occupational/academic/social
functioning.
 Included in sleep disorders but differ from others as
the defect is in the circadian clock and the
circadian rhythm of sleep-wake cycle.

44.  Alteration of endogenous
circadian system
 Delayed sleep phase
Syndrome
 Advanced sleep phase
syndrome
 Non 24hr sleep-wake
syndrome
 Irregular sleep-wake
rhythm
Change in timing of
environmental light-dark
or social activity
cycles(circadian
desynchrony)
 Shift work sleep disorder
 Jet lag disorder

45.  Advanced sleep phase syndrome (ASPS) is a
pathological extreme of the morning lark phenotype.
 An autosomal-dominant familial form of ASPS (FASPS)
recently has been genetically characterized.
 Afflicted family members exhibit a striking 4-hour
advance of the daily sleep–wake rhythm.
 They typically fall asleep at approximately 7:30 PM
and spontaneously awaken at approximately 4:30 AM.
 Affected individuals have a single nucleotide
polymorphism in the gene encoding hPER2, the human
homolog of the mouse Per2 clock gene.

46.  Functional impairment occur in the late
afternoon & evening when sleepiness begins.
 Diagnosis include confirmation of advanced
timing of sleep period with a sleep log for 7
days with exclusion of other causes.
 Prevalence is about 1 % in middle aged
individuals ,appears more common with
advancing age.
 Elderly vulnerable to reduction of light
transmission due to various eye conditions
like cataracts , glaucoma , senile miosis

47.  Light therapy used in the evening to delay the circadian
phase eg. 4000 lux artificial light source over 12
consecutive days from 7 – 9 pm resulted in decreased
awakenings and phase advancement.
 Only drawback is compliance with usage of bright light
boxes in older subjects
 Melatonin taken in the morning delays the sleep
schedule but side effects may limit this use.
 Most efficacious is chronotherapy in which sleep onset is
advanced 3 hrs at a time to an interval of 2 days until
desired sleep-wake cycle timing is obtained.

48.  A circadan sleep disorder in which the individual ‘s
internal body clock is delayed with respect to external
day/night cycle.
 Falls asleep late at night,typically betwwen 1:00am and
6:00am and awakens in the late morning or in the
afternoon.
 Delayed sleep phase syndrome (DSPS) has been shown to
be influenced by genetics. A length polymorphism in a
repeat region of the hPER3 gene appears to be associated
with diurnal preference in DSPS patients, the shorter
allele being associated with evening preference.
 Functional impairment is seen in daytime if total
sleep time is reduced.

49.  Diagnosis by stable sleep delay in at least 1
week of sleep log along with delay in CBTM &
DLMO with exclusion of other causes.
 Prevalence of 5-10% and more common in
adolescents & young adults.
 Unusually long endogenous circadian period
that maintains its entrainment may be the
underlying patho-physiology

50.  Light therapy for 2 wks with 2500 lux given for 2 hrs b/w 6 – 9 am
with evening light restriction showed an improvement in multiple
sleep latencies.
 Melatonin given at night time at a dose of 5 mg for 6 wks 5 hrs
before the mean sleep onset time.
 Vit B12 has been reported as effective in advancing sleep phase.
 Avoidance of napping to enhance homeostatic drive to sleep during
the night and avoidance of bright light exposure in evening hrs.
 Addressing concurrent stressors is also part of treatment.

51.  Circadian rhythm that free runs at a period of its endogenous
circadian clock even in the presence of time cues. So, sleep wake
period gradually shifts to later in day as time advances.
 Hallmark is the episodic symptom presentation depending on the
phase of patient’s clock at any given time. If the phase is out of
sync with the desired sleep-wake cycle ,symptoms are maximum
but if phase identical, then symptoms are not present at all.
 Diagnosis by progressively delayed sleep-wake times with a period
of greater than 24 hrs for 7 days in sleep log.
 Most common in blind because light signals fail to transmit to
SCN.In sighted, secondary to diminished sensitivity to light as an
entraining agent or exceedingly long intrinsic circadian rhythm.
 Melatonin dosed at 0.5 mg-10mg at night within an hr of bed time
over 1-3 wks in the blind. In sighted. artificial light given may be
effective in slowing down the clock.
 Vitamin B12 has been reported to be effective.

52.  Lack of clearly distinct sleep-wake cycles resulting
in symptoms of insomnia or sleepiness.
 Nighttime sleep is truncated and shows poor
consolidation,daytime has frequent,irregualar
napping.
 Total amount of sleep over 24 hrs is normal ,but
sleep tends to be divided into among 3 or more
erratic sleep periods
 Sleep logs shows at least three irregular sleep bouts
during 24-hr period over a week.
 M/c in institutionalised patients with dementia & in
children with MR

53.  Desynchrony between and among the SCN and the various
oscillators in peripheral tissues result in circadian-associated
maladies.
 Travel across multiple time zones (jet-lag) and shift work are the
most common causes of circadian desynchrony.
 Cardiovascular disease risk factors such as obesity, low high-density
lipoprotein (HDL) cholesterol levels, and high triglycerides are more
prevalent among shift workers than day workers. Furthermore,
many of these associations increase in aged shift workers.
 Epidemiological studies have shown that women working night
shifts have a significantly elevated risk of breast cancer.

54.  Jet lag is the condition of one's circadian clock being
desynchronized from the local time resulting from rapid long-
distance trans meridian (east–west or west–east) travel, as on a jet
plane.
 The condition of jet lag may last several days, and a recovery rate
of one day per time zone crossed is a fair guideline .
 It is not linked to the length of flight, but to the trans-meridian
(west–east) distance traveled.
 Eg: A ten-hour flight from Europe to southern Africa does not cause
jet lag, as travel is primarily north–south. A five-hour flight from
the east to the west coast of the United States may well result in
jet lag.
 Air travellers who fly west typically complain of difficulty
maintaining sleep & early morning awakenings whereas those flying
east have difficulty with initiating sleep.
 Symptom severity dependent on number of time zones crossed.

55.  Symptoms include headaches , fatigue , irregular sleep patterns,
insomnia , disorientation , grogginess, irritability , mild depression
, constipation or diarrhea.
 the guide for calculating jet lag is the number of time zones
crossed, and the maximum possible disruption is plus or minus 12
hours.
 for most people, traveling west to east is more disruptive. This may
be because most people have a circadian period which is a bit
longer than 24 hours, making it easier to stay up later than to get
up earlier.
 It may also be that flights to the east are more likely to require
people to stay awake more than one full night in order to adjust to
the local time zone.
 To catch up with local time upon eastward travel, a phase advance
must occur whereas a phase delay occurs in westward travel. Since
phase advances are more difficult than phase delays , eastward
travel is more difficult.

56. Before the flight- 1. to visit the doctor to plan a coping strategy for
medical conditions that require monitoring & regarding meds.
2.attempt to partially adapt to the destination time zone in advance
by starting the daily routine one hour before or after one normally
does during the week before departure.
During the flight- not to take alcoholic beverages and caffeine, as
caffeine disrupts sleeping schedules & to drink plenty of water.2. to
break the trip into smaller segments if it is too long and stay overnight
in some city. Also, to adjust sleeping times in plane to destination
time.
Upon arrival- to adapt to the local time and eat accordingly. Also,
exposure to sunlight during the day is helpful.[
 the recommended dose of melatonin is 0.3–0.5 mg, to be taken the
first day of traveling.
 Light therapy can speed up to one hour per time zone when used at
the correct time, combined with avoiding light during specific
periods.[1

57.  Artificial lighting has permitted the manufacturing and service industries
to work around the clock. As a result, shift workers are constantly
experiencing the effects of circadian desynchrony as they try to entrain
to an ever-changing light–dark cycle.
 Deleterious effects of shift work include elevated stress, deficits in
alertness, decreased cognitive function, and gastric distress. Prevalence
of about 10% in night shift workers.
 Diagnostic criteria include either insomnia or excessive sleepiness ,
temporal relationship with work , present for at least 1 month,7-day
sleep log or actigraph revealing disturbed sleep circadian/sleep
alignment.
 Total sleep time is reduced, reporting 10 fewer sleep hrs/week.Shift
workers fail to delay their circadian rhythm b’cos of exposure to bright
light in morning.
 At increased risk of development of disease in other organ systems.

58.  Exposure to bright light during nighttime work shift has been
efficacious.Light exposure between 7000 & 12000 lux during night
and complete darkness during day on subjects for 1 week.
 Intermittent exposure to light of 20 min/hr appears to be effective
in producing desired phase shifts in night workers.
 Exogenous melatonin is used by shift workers during the morning to
improve the timing & quality of sleep.
 Modafinil (wakefulness promoting agent)is approved for shift work
disorder and is useful to improve alertness at desired times without
adversely affecting daytime sleep when taken at beginning of night
shift
 Caffeine at 250 mg to 400mg may aid in increasing alertness.

59.  M/C monthly cycle in humans is the menstrual cycle linked with
changes in the mental state.
 Premenstrual syndrome : recurrence of symptoms in the pre –
menstruum 5-10 days (luteal phase) with absence in the post-
menstruum (follicular phase). Seen in 30-80% of reproductive
women.
 Psychological symptoms : disabling tension , severe & sudden mood
swings , suicidal depression and incapacitating lethergy
 Physical symptoms : headache , bloated feeling , loss of energy ,
cyclic acne
 It is the timing rather than the nature of symptoms that indicates
the diagnosis. To establish a pattern, keep a prospective record of
her symptoms on a calendar for at least two menstrual cycles. PMS
has increased risk for clinical depression.
 PMDD: severe form of PMS with predominant mood symptoms and
disruption of personal relationships. Seen in 3-8% women.

60.  Supportive therapy includes evaluation, reassurance, and
informational counseling.
 Healthy lifestyle: Reduction of caffeine, sugar, and sodium intake
and increase of fiber, adequate rest and sleep with aerobic
exercise. Dietary intervention studies indicate that calcium
supplementation, vitamin E (400 IU/d) has shown some
effectiveness along with Vitamin B6, magnesium, manganese and
tryptophan.
 SSRIs can be used to treat severe PMS ,medication taken only on
the days when symptoms are expected to occur.
 Spironolactone has been shown to be useful for water retention.
 NSAIDs; e.g., ibuprofen have been used to treat pain.
 Evening primrose oil, which contains gamma-Linolenic acid
(GLA),phenyl alanine and chasteberry are found helpful

61.  Early morning awakening & mood most depressed in
morning d/t phase advance of sleep wake cycle.
 REM sleep occurs earlier in the night in depression
along with changes of body temperature & cortisol
levels.
 Travel from east to west a/w depression and from
west to east a/w hypomania.
 Shortened rhythm of less than 24 hrs seen in long
term schizophrenia
 Abnormal circadian rhythms in anorexia nervosa

62.  The Earth's axis is tilted 23.45 degrees from
the plane of its own orbit around the sun
(the ecliptic).
 As a result, the relative proportion of
daytime to nighttime within the 24-hour
astronomical day varies as the Earth
proceeds through its orbit of the sun.
 Many organisms are capable of synchronizing
physiology to the seasonal cycle to maximize
survival.

63.  Large mammals that typically have long
gestation periods, such as sheep, conceive in the
fall when the nights are long and the days are
short, so birth occurs during the relatively mild
season of spring. These animals are referred to
as short-day breeders.
 Conversely, mammals with gestation periods of
only a few weeks, such as hamsters, conceive
and give birth during spring and summer, when
the days are long and the nights are short.
Hence, these animals are referred to as long-day
breeders

64.  The most reliable environmental parameter providing a
faithful representation of the solar day is the day–night
cycle.
 In seasonally breeding animals, day length is
physiologically encoded through the melatonin profile.
 A long night, such as that experienced during the short
day lengths of winter, results in an elevated melatonin
profile of a relatively long duration.
 A short summer night, by contrast, results in a short
duration of elevated melatonin. This seasonal signal is
interpreted by the reproductive axis, resulting in an
appropriate reproductive response

65.  Reproductive responses to changing day length can be
dramatic.
 A male Siberian hamster (Phodopus sungorus)
maintained in long days is reproductively competent
and typically has a testicular weight of approximately
250 mg per testis.
 Under short days, however, the testes regress to
approximately 15 mg per testis, representing a 94
percent decrease in testicular mass.
 The same degree of regression is observed in
response to melatonin infusions that mimic short
days.

66.  Whether humans are truly seasonal is still a
point of considerable debate.
 Several lines of evidence exist that suggest the
presence of a residual tendency toward
seasonality.
 A peak in the rate of suicide occurs in the
summer; this peak is cross-cultural.
 Birth rates also tend to show a seasonal
variation; a small but distinguishable peak in the
rate of births occurs in spring and summer.

67.  SAD is the most overt manifestation of
seasonality in humans.
 It is characterized by recurrent major
depressive episodes followed by periods of
remission that occur on a seasonal basis.
 In DSM IV, it is not categorized as a distinct
mood disorder but as the seasonal pattern
specifiers.

68.  Regular temporal relationship between the onset of major
depressive episodes and a particular time of the year
(unrelated to obvious season-related psychosocial
stressors).
 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 years, and no non seasonal
episodes have occurred in the same period.
 Seasonal major depressive episodes substantially
outnumber the nonseasonal episodes over the individual's
lifetime.

69.  Also called Winter depression, or the Winter blues.
 The most prevalent form of SAD has an onset in the
late fall and early winter and remits in the late spring
and early summer
 Symptoms atypical of major depression can present
with winter SAD.
 These include, but are not restricted to,
1. significant increase in weight,
2. hyperphagia,
3. an increase rather than decrease in sleep,
4. a heightened sensitivity to interpersonal rejection,
5. and a leaden feeling in the extremities.
 Most distinct, however, is a craving for carbohydrates.

70.  Prevalence of winter SAD among the general
population to be between 4 and 9 percent.
Women are four times as likely as men to be
affected.
 The gold standard treatment for winter SAD
is light therapy.
 A typical prescription for light therapy
involves 45 to 90 minutes daily exposure to a
broad spectrum, ultraviolet-filtered, white
light source of relatively high irradiance
(5,000 to 10,000 lux).

71.  Recent studies have suggested that a
combination treatment of light therapy in
conjunction with cognitive-behavioral
therapy may be more efficacious than light
therapy alone.
 Monoamine oxidase inhibitors (MAOIs) have
also been used successfully to treat winter
SAD.
 In some winter SAD patients, bright light
administered during the evening is also
antidepressant.

72.  Aberrations in the timing and amount of sleep
are frequently part of the symptomology of
depression, including nonseasonal depression.
 For example, the circadian phase angle of sleep
onset can vary in bipolar I disorder, depending on
the state; depression causes a phase delay,
whereas mania results in a phase advance.
 In addition, sleep disturbances can contribute to
the pathogenesis of the disease

73.  A curious phenomenon related to depression and
sleep is that total sleep deprivation can provide a
transient antidepressant effect in a majority
(approximately 60 percent) of depressed patients.
 Relapse occurs after the following night of sleep.
Even short, daytime naps can cause relapse.
 This tendency of nap-induced relapse varies as a
function of the time of day during which the nap is
taken.
 Early morning appears to be a critical time during
which naps have a high tendency of causing relapse

74.  A peak in the rate of suicide occurs in the summer
 Birth rates also tend to show a small but
distinguishable peak in spring and summer.
 In schizophrenia , patients show an excess of birth
dates in the winter months in northern & southern
hemispheres.
 Higher rate of psychiatric admissions in summer
months
 Depression and ECT more in spring & autumn.
 Female manic patients peak admissions in Aug &
Sep.

75.  Metabolic syndrome is characterized by
hyperglycemia, hypoinsulinemia,
dyslipidemia, and visceral obesity.
Furthermore, it is frequently associated with
cardiovascular disease.
 Shift workers may also suffer a greater risk
of metabolic syndrome.
 Obesity has been linked to reduced sleep,
suggesting a role for the circadian clock.
 This has also been demonstrated in mutated
mice too.

76.  Female flight attendants suffer an increased
incidence of breast cancer.
 In several studies, cancer patients with
altered daily rhythms had poor survival
relative to those patients with nearly normal
24-hour rhythms.
 Long-term shift work also has been shown to
be correlated with increased incidence of
colorectal and breast cancer.
 Supposed to be inhibition of melatonin
which augments estrogen effect

77.  In general, as humans age, circadian period
shortens, circadian phase advances resulting
in earlier waking times and bedtimes, the
amplitudes of most circadian rhythms
decrease, and dramatic phase shifts such as
those caused by jet-lag are less tolerated.

78.  Circadian rhythmicity can be affected by
drugs, and conversely, the circadian clock
can modulate the efficacy of drugs
throughout the course of the day.
 Some of the best-studied interactions
between medications and the circadian clock
have included the circadian effects of
antidepressants.
 Elevated nocturnal body temperature is a
common feature among depressed patients.

79. 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 clock work
stabilizer REV-ERBa—lengthens the
cercarion period.
BENZODIZEPINE
S(short acting)
triazolam or
brotizolam
Act via GABA receptors in SCN- induces
circadian phase advances
Brotizolam has been shown to reduce the
light-induced expression of clock genes
Per1 and Per2 in the SCN

80. 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
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

81.  Kaplan & Sodock’s Comprehensive Textbook
of Psychiatry
 Sims Symptoms of mind
 Pubmed
 Google images