Kaplan + Sadock's Synopsis of Psychiatry, 11e

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1.9 Chronobiology

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. It should be stressed that diurnal preference varies among indi- viduals as a function of age, endogenous circadian periods, and other factors. This variability is paralleled by physiology. Clinically, diurnal preference can be quantified using the Horne–Östberg (HO) Morningness-Eveningness Questionnaire (MEQ). In qualita- tive 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. Sleep depriva- tion studies have shown that the homeostatic component of sleep is remarkably similar among individuals of similar age. (It should be noted that there is a well-established age-dependent decline in sleep need.) Therefore, diurnal preference is dictated almost exclusively by the circadian component of sleep regulation. Circadian Sleep Disorders Advanced sleep phase syndrome (ASPS) is a pathological extreme of the morning lark phenotype. An autosomal-domi- nant familial form of ASPS (FASPS) recently has been geneti- cally characterized. Afflicted family members exhibit a striking 4-hour advance of the daily sleep–wake rhythm. They typi- cally 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. This ade- nine-to-guanine nucleotide polymorphism results in serine- to-glycine amino acid substitution that causes the mutant pro- tein to be inefficiently phosphorylated by casein kinase I e , an established component of the circadian molecular clockwork. Similarly, 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 patients with DSPS, the shorter allele being associated with evening preference. The advent of the light bulb has extended the human day into the natural night. This encroachment on the night, although increasing productivity, has affected human sleep patterns (Fig. 1.9-2). Typical use of artificial lights results in a single, consolidated bout of sleep lasting approximately 8 hours. This pattern of sleep is uncommon among most other mammals, which typically experience more fractured sleep. Human sleep under more natural photoperiods, where the duration of the night is longer, becomes decompressed. Specifically, a bimodal distribution of sleep is observed; bouts of sleep occur in early and late night. Periods of quiet wakefulness are interspersed between the two primary bouts of sleep. This natural sleep pat- tern is more similar to the sleep patterns of other mammals. Seasonality The 24-hour period of the Earth’s rotation around its axis is unchanging. However, the Earth’s axis is tilted 23.45 degrees

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 melato- nin 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.

Sleep and Circadian Rhythms Sleep Regulation

Restful consolidated sleep is most appreciated when sleep dis- turbances 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 accu- mulation and dissipation of sleep debt. The biological substrates encoding sleep debt are not known, although adenosine is emerg- ing as a primary candidate neuromodulator of the sleep homeo- stat. The second oscillatory process is governed by the circadian clock and controls a daily rhythm in sleep propensity or, con- versely, arousal. These interacting oscillations can be dissociated by housing subjects in a timeless environment for several weeks. The circadian cycle in arousal (wakefulness) steadily increases throughout the day, reaching a maximum immediately before the circadian increase in plasma melatonin (Fig. 1.9-1). Arousal subsequently decreases to coincide with the circadian

Figure 1.9-1 Relative phase relationship of sleep in young adults to other circa- dian phase markers. (From Dijk D-J, Lockley SW. Invited review: Integration of human sleep-wake regulation and circadian rhyth- micity. J Appl Physiol. 2002;92:852, with permission.)