Chronobiology C hrono=time biology = science of life Chronobiology is a field of science that examines periodic (cyclic) phenomena in living organisms and their adaptation to solar and lunar related rhythms. These cycles are known as biological rhythms.

A biological rhythm is a self-sustaining oscillation of endogenous origin. period levelAmplitudePhase

The most important rhythm in chronobiology. circadian comes from the Latin circa, meaning "around" and dies, "day", meaning "approximately a day." Circadian Rhythm The circadian rhythm can further be broken down into routine cycles during the day: DiurnalNocturnalCrepuscular

Tidal rhythms commonly observed in marine life, which follow the roughly 12-hour transition from high to low tide and back. Infradian rhythms which are cycles longer than a day, such as the annual migration or reproduction cycles found in certain animals or the human menstrual cycle. Gene oscillations some genes are expressed more during certain hours of the day than during other hours. Ultradian rhythms which are cycles shorter than 24 hours, such as the 90- minute REM cycle, or the 3- hour cycle of growth hormone production. other important cycles

Social zeitgebers Zeitgebers “time giver”

Circadian rhythms and psychiatry: simple practical rules Entrainment needs sustained regular zeitgebers more light! more darkness! Entrainment = rhythms better—sleep better—think better— feel better—behave better Entrainment

Chronobiology is an interdisciplinary field of investigation sleep medicine Endocrinologyspace medicinephotoperiodismGeriatricsSport medicine

Sleep wake cycle is the master output rhythm of the circadian clock

C S controls REM sleep and the ratio of NREM/REM sleep. controls REM sleep and the ratio of NREM/REM sleep. controls NREM sleep SCN MT2MT1 phase-shifting and entrainment effects of melatonin. Inhibits he electrical activity of SCN neurons Melatonin

Retinal Ganglion cells Suprachiasmatic Nucleus Ventral Subparaventricular zone of the hypothalamus Dorsomedial Hypothalamus VLPO(ventrolate ral preoptic area) Sleep LHA Arousal

50–90% of pts with depression complain about impairment of sleep quality. impaired build-up of S during waking (diminished sleep pressure) or an earlier timing of process C clinical sleep disturbance with early morning awakening

prolonged sleep latency Decreased REM sleep latency increased REM sleep density prolonged duration of the first episode of REM sleep decreased slow wave sleep (SWS) decreased sleep maintenance

Melatonin in MDD MDD= “low melatonin syndrome”

Sleep changes as markers for depression depressed patients show a reduction in the absolute number of delta waves during the first NREM depressed patients show a reduction in the absolute number of delta waves during the first NREM depressed patients show a reduction in decrease in delta activity throughout the night sleep abnormalities in the first degree relatives of depressed patients suggests that these sleep changes can be viewed as “markers” of depression patients with decreased REMOL prior to treatment are prone of developing subsequent episodes of depression and experiencing rapid relapses after remission

Chronic Insomnia One of the most frequent and prominent factors that trigger depression. It is often viewed as a predictor of a depressive disorder major It was found as a prodromal symptom prior to the recurrence of a depressive episode. REM sleep abnormalities: Is Considered specific for MDD shortening of REM onset latency (REMOL). increased REM sleep, and sleep continuity disturbances were among the symptoms found in an assessment of untreated depressed patients Depressed patients often complain of difficulties in falling asleep, frequent nocturnal awakenings and early morning wakefulness 90% of depressed patients suffer from impairment of sleep quality

alterations of biological clock at molecular level lead to neurobiological dysfunction which in turn may generate the depressed state. primary circadian disturbance of the sleep– wake cycle lead to insomnia that might facilitate or exacerbate the depressed state. insomnia is a risk factor for the development of depression. There are two theoretical ways:

Morningness (Prefer day activity) Eveningness (Prefer night activity) the older the person, the more the tendency to have a ‘‘morningness’’ depressed patients reported significantly more ‘‘eveningness’’ than age- and sex- matched controls morning type might be protective against depression whereas ‘‘eveningness’’ might cause increased vulnerability ‘‘eveningness–morningness’’ dimension

Non – pharmac ological Sleep Deprivation. Light Therapy. pharmac ological Antidepressants. Mood stabilizers. Melatonin. Agomelatine.

Light Therapy non-seasonal depression seasonal affective disorder (SAD) Dawn simulation therapy Refracto ry unipolar depressi on Bipolar depressi on Antepart um depressio n Ttt of choice

internal coincidence hypothesisS-DeficiencyREM-SleepSlow-Wave-Sleep SuppressionArousal, Cerebral Fatigue

Pharmacological Melatoniergic Drugs Mood stabilizersAntidepressants ValproateLithium Agomel atine Melaton in

Agomelatine (novel antidepressant) MT2 receptor agonist 5 HT2C antagonist MT1 receptor agonist 25 mg/day P450 system