Kaplan + Sadock's Synopsis of Psychiatry, 11e

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1.9 Chronobiology

pressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) reduce elevated nocturnal body temperature while simultaneously enhancing circadian amplitude. Similarly, many depressed patients exhibit a dampened amplitude in daily activity rhythms. Like body temperature, the amplitude in daily activity cycles of depressed individuals may be augmented by TCA or SSRI therapy. The use of lithium to treat bipolar disorder has been long established. However, lithium also affects the circadian system, resulting in a lengthening of circadian period. The molecular mechanism by which this occurs remains unknown. Glycogen synthase kinase 3 b (GSK3 b ) has been implicated in participat- ing within the molecular clock mechanism. Of interest, GSK3 b is inhibited by lithium. In cell culture, GSK3 b has been shown to stabilize the negative clockwork regulator REV-ERB a via phos- phorylation. REV-ERB a typically represses the transcription of the BMAL1 gene. In the presence of lithium, however, GSK3 b is inhibited, thereby preventing the phosphorylation and stabi- lization of REV-ERB a , which as a consequence is targeted for proteasomal degradation. The degradation of REV-ERB a results in the de-repression of BMAL1 transcription. Whether lithium’s influence on circadian behavior is attributable to its inhibitory effect on GSK3 b - mediated stabilization of REV-ERB a remains to be determined. Short-acting benzodiazepines (e.g., triazolam [Halcion] and brotizolam [Lendormin]) also exert chronobiological effects. In hamsters, triazolam or brotizolam administered during the mid- dle of the subjective day induces circadian phase advances in activity. Brotizolam has been shown to reduce the light-induced expression of clock genes Per1 and Per2 in the SCN. Although benzodiazepines are allosteric modulators of g -aminobutyric acid A receptors (GABA A ), several lines of evidence indicate that the circadian effects of short-acting benzodiazepines require an intact serotonergic system. When the 5-HT 1A/7 receptor ago- nist 8-hydroxy-2-(di- n -propylamino)-tetralin (8-OH-DPAT) is injected into hamsters at subjective midday, phase advances in locomotor behavior and SCN neuronal activity are observed in addition to a reduction in Per1 and Per2 gene expression in the SCN. Recreational drugs of abuse also affect the circadian system. 3,4-Methylenedioxymethamphetamine (MDMA), or “ecstasy,” can act as a serotonin neurotoxin. Hamsters treated with MDMA showed reduced triazolam-induced phase shifts in circadian locomotor activity and a diminished ability to reentrain rhythms posttreatment. MDMA-treated animals exhibited a reduction of serotonergic axonal terminals in the SCN, again emphasizing the importance of an intact seroto- nergic system in the regulation of the circadian axis. Recre- ational use of methamphetamine has increased dramatically. Chronic administration of methamphetamine disorganizes rodent activity rhythms. However, administration of metham- phetamine to rodents rendered arrhythmic through ablation of the SCN results in a reemergence of rhythmicity. The mecha- nism involved in the rescue of rhythmicity or site of action remains unknown. The efficacy and toxicity of many pharmacotherapeutics vary as a function of circadian phase. Daily variations in fixed- dose lethal toxicity have been appreciated in rodents for years. Many anticancer drugs, ranging in mechanism from antimetab- olites to deoxyribonucleic acid (DNA) intercalators to mitotic inhibitors, have been shown to have 2- to 10-fold changes in

The decompressed bimodal structure of human sleep during long nights indicates that the length of natural sleep is related to the length of the night. Potentially, a two-oscillator system could function to maintain proper sleep patterns during changing pho- toperiods. Such a proposed system would consist of an evening oscillator that tracks the transition from day to night (dusk) and a morning oscillator that tracks the transition from night to day (dawn). The relative phase differences between these oscillators may encode the changing day lengths associated with the pass- ing of the seasons. Biological evidence for a two-oscillator sys- tem exists in rodents and humans. The melatonin profile of many vertebrates, including some humans, is bimodal, with evening and morning peaks. In rodents, metabolic and electrophysiological studies of the SCN typically have been done in brain slices cut in the coronal plane. Results of electrophysiological studies conducted in brain slices cut in the horizontal plane have provided new insights. The action potential frequency in SCN neurons from horizontally cut preparations is bimodal, with peaks in the early and late sub- jective day. Furthermore, the interpeak interval varies as a func- tion of the photoperiod in which the animal was housed. These studies lend credence to long-standing suspicions that the SCN of seasonally breeding mammals and, perhaps, nonseasonal mammals harbor a morning and evening oscillator that interact to convey day-length information. Effect of Aging In general, as humans age, the circadian period shortens, the 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. Again, a mouse model has provided interesting insight into the interaction of the aging process and the circadian clock. The effect of chronic jet-lag on aged mice has dramatic conse- quences on mortality. About half of aged mice forced to phase advance 6 hours once per week survive this treatment compared with an 83 percent survival rate in unshifted age-matched mice. Aged mice subjected to weekly 6-hour phase delays show an intermediate survival of 68 percent. These profound effects of phase shifting are not observed in younger mice. The pathogen- esis of chronic jet-lag remains to be determined. Of interest, these mice did not have an increased rate of tumorigenesis. It is likely that in humans, as in mice, the internal desynchrony of oscillators that result from a rotating light schedule may have dire consequences that may be exacerbated by aging. Circadian rhythmicity can be affected by drugs, and conversely, the circadian clock can modulate the efficacy of drugs through- out the course of the day. A better understanding of these inter- actions will lead to more effective pharmacotherapies. Some of the best-studied interactions between medications and the circadian clock have included the circadian effects of antide- pressants. Elevated nocturnal body temperature is a common feature among depressed patients. This effect may be due to a reduced amplitude of the master circadian oscillator in the hypothalamus that drives body temperature. Tricyclic antide- Circadian Rhythms and Pharmacotherapy