New Paths Ahead for Circadian Medicine
By Deborah Borfitz
March 23, 2020 | A growing body of evidence suggests there are multiple health benefits to working with, rather than against, the body’s natural circadian rhythms—starting with when we eat, sleep, and take our medicines. Basic science research and observational studies have long dominated the literature, but more interventional trials are now getting underway aimed at correcting disturbances in biological timing triggered by disease, advancing age, and always-on modern lifestyles, as well as optimizing outcomes based on treatment timing.
Well over 100 active and enrolling studies listed on cliniclatrials.gov involve the body’s circadian rhythm, many involving medicines to help people sleep at night or get their circadian clock on local time, says Erik Herzog, a neuroscientist and professor at Washington University as well as president of the Society for Research on Biological Rhythms (SRBR). Relatively rare are chronotherapy studies looking at how the body’s clock is regulating sensitivity to treatment, which are more expensive and complicated to conduct. “But we wonder how many drugs have failed clinically in trials because [researchers] didn’t control for the time when it was delivered.”
Washington University now has about 15 on-campus labs, plus several pharmaceutical companies, learning from one another in a Clocks & Sleep Club, says Herzog. The group represents a lot of basic research about how the circadian system is connected and develops as well as how it relates to human health by looking at circadian input and output and intracellular oscillators. Industry has provided financial support for the training of circadian rhythm scientists and several companies, including Jazz Pharmaceuticals and Vanda Pharmaceuticals, are dedicated to developing chronotherapeutics.
The high prevalence of sleep and circadian disorders has given rise to vast number of treatment clinics dedicated to treating the problem, Herzog says, and growing numbers of neurologists and pulmonologists are being trained in the field. The SRBR has about 700 members, about a third of whom are physicians, and most of the over 1,200 members of the Sleep Research Society (SRS) are medical doctors, clinical psychiatrists, and other practitioners taking care of people with sleep disorders.
Test and Treatment Timing
Circadian medicine remains an emerging field, albeit one with a lot of untapped potential based on what is already known about the rhythmicity of living organisms, says Elizabeth Klerman, M.D., Ph.D., associate professor of neurology and medicine at Harvard Medical School who is also part of the research staff at Massachusetts General Hospital. A study published in Proceedings of the National Academy of Science (PNAS) nearly six years ago listed 23 bestselling drugs whose effectiveness depends on the time of day they’re taken and recent study findings published in Cell Metabolism (doi: 10.1016/j.cmet.2019.11.004) indicate time-restricted feeding can improve cardiometabolic health for patients with metabolic syndrome receiving standard medical care.
Genome-wide studies suggest the majority of drug target genes are controlled by the circadian timing system. Chronopharmacology experts have found that even cancer treatment can be improved by changing the time window of drug administration (doi: 10.1211/0022357991773302), says Charna Dibner, Ph.D., principal investigator in the departments of medicine, cell physiology, and metabolism, the Diabetes Centre at the University of Geneva faculty of medicine, and at University Hospitals of Geneva.
Importantly, circadian rhythms also influence when the symptoms of medical conditions flare and how patients respond to diagnostic tests, Dibner says. “For example, you can measure thyroid-stimulating hormone at different times of the day and get vastly different results, by an amplitude of eight-fold, so we need to take that into account.”
In the past, Klerman says she has studied the relative performance of various markers of the circadian system under different conditions. Figuring out the timing, phase, and amplification of the circadian pacemaker used to involve sitting in a dark room with a test tube for six hours and then waiting on assay results for two weeks. But those methods are now being supplanted by other research groups that extract the information from one or two blood samples.
Patients accustomed to taking a statin drug in the morning might find it difficult to start taking it at night when it is more effective, says Klerman. So, a drug maker might consider producing a delayed-release pill that allows patients to take the drug in the morning and then have the drug be effective at night.
Research labs might find it useful to disassociate the light/dark and feeding/fasting times of nocturnal mice to coincide with the diurnal preferences of their human handlers and lower the possibility of confounding circadian variables on test results, Dibner says. They might also try enhancing the environment of lab animals to reduce unnecessary stress. But these are both hypothetical approaches that may do little to thwart the rhythmic disconnect.
Sleep and circadian medicine are not a major part of medical training at present. But the SRBR has been at the forefront of efforts to close the gap between scientific knowledge and clinical practice, says Klerman. A series of white papers and related public outreach briefs cover the “why, when and how” of our light needs, optimal meal timing, reasons to abolish daylight savings time, the rationale for delaying school start times by 30-60 minutes, and adjusting the time for drug treatments to increase efficacy while reducing side effects.
Ideally, professional societies such as the American Medical Association and American Cardiology Association will issue practice guidelines on the administration of medications or other interventions based on what studies indicate are the best times, she adds. Better outreach to physicians, nurses, social workers, and other educators is also needed to normalize the idea of getting eight hours of sleep for improved health and well-being, including better pain management, weight control, and mood regulation.
In 2018, Klerman’s colleagues at Harvard Medical School and Brigham and Women’s Hospital published a research letter in JAMA Pediatrics demonstrating negative dose response relationships between sleep duration and “every single category of risky behavior in adolescents” as defined by the Centers for Disease Control and Prevention. In a subsequent paper published last year in Sleep (doi: 10.1093/sleep/zsz300), mistimed and irregular sleep and event schedules were associated with lower well-being among college students.
Researchers elsewhere have recently demonstrated (doi: 10.1016/j.jacc.2019.12.054) that variability in sleep duration and timing may also represent a new and independent heart disease risk factor.
Alzheimer’s disease researchers are particularly interested in circadian regulation within the brain, says Herzog. “If you don’t get enough sleep at night your brain has a hard time clearing bad things,” and that could include metabolites such as amyloid-β and Tau that accumulate during wake and are associated with Alzheimer’s disease.
The compelling question scientists are now trying to answer is whether people with a disrupted circadian rhythm are at risk for accumulating those proteins to toxic levels, Herzog says. “There’s a chicken and egg problem here that people are trying to figure out. Do you have bad sleep, so you end up at risk for Alzheimer’s or you’re at risk of Alzheimer’s and that causes bad sleep?”