tia, cognitive decline is frequently accompanied by disturbances of mood, behavior, sleep, and activities of daily living, 1-3 which increase caregiver burden and the risk of institutionalization. [4][5][6][7] The limited treatment possibilities create an opportunity for other symptom management approaches. [8][9][10][11] Changes in the circadian pacemaker of the brain, located in the hypothalamic suprachiasmatic nucleus, may contribute to cognitive, mood, behavioral, and sleep disturbances. [12][13][14][15][16][17][18] The circadian timing system is highly sensitive to environmental light and the hormone melatonin 19 and may not function optimally in the absence of their synchronizing effects. In elderly patients with dementia, synchronization may be attenuated if light exposure and melatonin production are reduced. 20,21 Indeed, bright light ameliorates behavioral 22 and sleep 20 disturbances.To our knowledge, no previous studies in humans have applied long-term combined stimulation of the circadian timing system with daily light and melatonin. We conducted a multicenter, double-blind, randomized placebocontrolled trial that evaluated the ef-fects of up to 3.5 years of daily supplementation of light and/or melatonin. Using a practical clinical trial approach, 23 long-term treatment effective-Author Affiliations are listed at the end of this article.

Bipolar disorder (BD) is a major mood disorder that is characterized by manic and depressive symptoms which fluctuate in severity and over time. The affective burden of the illness is compounded by cognitive, psychosocial, and occupational dysfunction, along with increased rates of suicide, medical comorbidity, and premature mortality. [1][2][3][4][5][6][7] Current guidelines for the management of BD include treatments that are limited by suboptimal efficacy rates, medication intolerance, delayed onset of action, iatrogenic mood switches, and variable patient acceptability. There is a pressing public health need for measures to combat these shortcomings. The fields of chronobiology and chronotherapy offer alternative treatment strategies which may address these limitations. The primary aim of this project was to systematically review efficacy and tolerability evidence of the major chronotherapies for BD and propose practice recommendations based on this review. This commences with a brief introduction to chronobiology to provide a rudimentary overview of the basic science which underlies this field of treatment. | Introduction to the circadian systemThe basic science of chronobiology is the study of biological rhythms, biological timekeeping systems, and their effects on human health and disease. 8 The human time-keeping system is a strongly conserved, phylogenetically ancient, hierarchically organized, and open neurobiological network. It evolved to enable organisms to anticipate and coordinate their internal physiology

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