ChronobiologyOverview and it’s relevance in psychiatry

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Chronobiology Overview and it’s relevance in psychiatry Presenter: Dr. Suman Pd. Adhikari

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Chronobiological Terms

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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 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 (chronos, meaning "time"), and biology, which means “the study, or science, of life”

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History of Chronobiology

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biological rhythms

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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) Circadian rhythms

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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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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 recipient animals. SCN & light/dark cycles

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Light Exercise Food Social factors EYE Master clock: SCN “Zeitgeber” (time givers) “entrain” clock Pineal Gland Regulates Hormones , Sleep/wake - Temp

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Afferent efferent and projections

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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 the biological clocks work Environmental cues Sensory receptors Pace-maker Locomotion Hormone release 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 clock sensory 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(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.

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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 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

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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 individual’s 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 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

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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: 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

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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

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Terminologies related to chronotherapeutics

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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 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.

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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.

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