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Chronobiological therapies for mood disorders include manipulations of the sleep–wake cycle such as sleep deprivation and sleep phase advance and the controlled exposure to light and darkness. Their antidepressant efficacy can overcome drug resistance and targets the core depressive symptoms including suicide, thus making them treatment options to be tried either alone or as adjunctive treatments combined with common psychopharmacological interventions. The specific pattern of mood change observed with chronobiological therapies is characterized by rapid and sustained effects, when used among themselves or combined with drugs. Effects sizes are the same reported for the most effective psychiatric treatments, but side effects are usually marginal or absent. New treatment protocols are developed to adapt them in different clinical settings. This review deals with the general principles of clinical chronobiology and the latest findings in this rapidly developing field.

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional \"rush hours\" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spiiceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

Molecular insights into diurnal variations in human physiology and behavior are extending our understanding of a wide range of disease processes. Chronobiology is also providing testable hypotheses regarding the timing of treatments.

Circadian precision medicine may supplement genetic precision to improve drug action Physicians diagnose and administer treatment as needed; time of day is rarely considered. Yet, accumulating evidence shows that our molecular clocks orchestrate 24-hour circadian rhythms in vital cardio-metabolic, endocrine, immunologic, and behavioral functions. Time, therefore, adds a potentially important dimension to medicine. Circadian medicine aims to incorporate knowledge of 24-hour biological rhythms to enhance diagnosis and treatment. How is research and technology shaping this endeavor?

Background Current evidence suggests that good quality sleep is associated with preserved cognitive function and reduced dementia risk in older adults. Sleep complaints are especially common among older adults with mild cognitive impairment (MCI), and this may contribute to their increased risk for progression to dementia. Thus, improving their sleep may be important for maintaining their cognitive health. Chronotherapy is a set of intervention strategies that can improve sleep quality through strengthening the entrainment of the biological clock to the solar light-dark cycle, and includes strategies such as (1) bright light therapy (BLT); (2) physical activity (PA); and (3) good sleep hygiene. Of these strategies, BLT is the most potent and is based on providing individualized timing to entrain circadian rhythms. Thus, a personalized chronotherapy intervention of individually timed BLT and individually tailored PA promotion, in conjunction with general sleep hygiene education may promote older adult sleep quality. We therefore aim to carry out a proof-of-concept randomized controlled trial (RCT) to examine the efficacy of such a personalized chronotherapy intervention to improve sleep quality among older adults with MCI. Methods/design This was a 24-week RCT of a personalized chronotherapy intervention aimed to primarily improve sleep quality as measured by the MotionWatch8©. Participants in the personalized chronotherapy group (INT) will receive four once-weekly, general sleep hygiene education classes, followed by 20 weeks of (1) individually timed BLT and (2) bi-weekly, individually tailored PA counseling phone calls in conjunction with receiving a consumer-available PA tracker—the Fitbit® Flex™. Ninety-six adults (aged 65–85 years) classified as having MCI (i.e., Mini-Mental State Exam (MMSE) ≥ 24; Montreal Cognitive Assessment (MoCA) ≤ 26; without dementia or significant functional impairment) will be randomized to either INT or a waitlist control group (CON). Discussion The results of this trial will help determine if a personalized chronotherapy intervention that includes individually timed BLT and individually tailored PA promotion, along with general sleep hygiene education can promote sleep quality among older adults at increased risk for dementia. Our results will help inform best practices for promoting sleep quality among older adults with MCI. Trial registration ClinicalTrials.gov , NCT02926157 . Registered on 6 October 2016.

Purpose of ReviewGiven the emerging knowledge that circadian rhythmicity exists in every cell and all organ systems, there is increasing interest in the possible benefits of chronotherapy for many diseases. There is a well-documented 24-h pattern of blood pressure with a morning surge that may contribute to the observed morning increase in adverse cardiovascular events. Historically, antihypertensive therapy involves morning doses, usually aimed at reducing daytime blood pressure surges, but an absence of nocturnal dipping blood pressure is also associated with increased cardiovascular risk.Recent FindingsTo more effectively reduce nocturnal blood pressure and still counteract the morning surge in blood pressure, a number of studies have examined moving one or more antihypertensives from morning to bedtime dosing. More recently, such studies of chronotherapy have studied comorbid populations including obstructive sleep apnea, chronic kidney disease, or diabetes.SummaryHere, we summarize major findings from recent research in this area (2013–2017). In general, nighttime administration of antihypertensives improved overall 24-h blood pressure profiles regardless of disease comorbidity. However, inconsistencies between studies suggest a need for more prospective randomized controlled trials with sufficient statistical power. In addition, experimental studies to ascertain mechanisms by which chronotherapy is beneficial could aid drug design and guidelines for timed administration.

A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, molecular-timetable method with human blood enables highly optimized and personalized medicine.

The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics.

Circadian clock is an impressive timing system responsible for the control of several metabolic, physiological and behavioural processes. Nowadays, the connection between the circadian clock and cancer occurrence and development is consensual. Therefore, the inclusion of circadian timing into cancer therapy may potentially offer a more effective and less toxic approach. This way, chronotherapy has been shown to improve cancer treatment efficacy. Despite this relevant finding, its clinical application is poorly exploited. The conception of novel anticancer drug delivery systems and the combination of chronobiology with nanotechnology may provide a powerful tool to optimize cancer therapy, instigating the incorporation of the circadian timing into clinical practice towards a more personalized drug delivery. This review focuses on the recent advances in the field of cancer chronobiology, on the link between cancer and the disruption of circadian rhythms and on the promising targeted drug nanodelivery approaches aiming the clinical application of cancer chronotherapy.

Purpose Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers. Methods A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique. Results Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer. Conclusions Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.