ChronobiologyOverview and it’s relevance in psychiatry презентация

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

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 rhythm.

Chronobiology comes from the ancient Greek (chrónos, meaning "time"), and biology, which means “the study, or science, of life”

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)

Circadian rhythms

genes

situated in the eye

Efferent-- Rhythmic outputs which provide insight into the clockwork of the circadian pacemaker.

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.

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 recipient animals.

SCN & light/dark cycles

, Sleep/wake - Temp

the internal clock (takes about 24 hours).

Light may participate in the triggering of some of these protein fluctuations.

How the biological clocks work

Environmental cues

Sensory
receptors

Pace-maker

Locomotion

Hormone release

Feeding

Others

Clock-setting
pathway

Clock
mechanism

Observed
behaviour

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).

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.

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.

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.

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.

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.

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

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

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.

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

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 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 1:00 am and 6:00 am, and awakens in the late morning or in the afternoon.

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.

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

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 individual’s lifetime.

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

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

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.

F=1:4
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
Alcoholism

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.

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

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

of various diseases

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.

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.

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.

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.

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 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.

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.