Wednesday, April 12, 2017

Chronotherapy: Another Compelling Case for Evidence-Based, Data-Driven Medicine

thescientist |  For three consecutive winters, starting in 2011, researchers at the University of Birmingham asked healthy men and women over the age of 65 to come in to clinics across the western Midlands in the U.K. for a seasonal influenza vaccination at specific times of day—either between 9 and 11 a.m., or between 3 and 5 p.m. Blood drawn a month later revealed that participants, who totaled nearly 300 over the three years, had higher levels of anti-flu antibodies if they’d received their vaccinations in the morning.1 The results suggested that daily rhythms of people’s bodies tweaked the vaccine’s effectiveness. Lead author Anna Phillips Whittaker had suspected as much, after observing similar trends in her studies on behavioral factors such as exercise that affect vaccination responses, and in the wake of a growing body of literature suggesting that a little timing can go a long way when it comes to health.

Many hormones and immune signals are produced rhythmically in 24-hour cycles. Cortisol, for example, which is known to suppress inflammation and regulate certain T cell–mediated immune responses, peaks early in the morning and ebbs as the day progresses. Other facets of the immune system undergo similar cycles that could underlie the differences in antibody responses Phillips observed among people receiving the flu vaccine. Much more work is required to nail down the immune mechanisms responsible for such variation and exploit them appropriately, she says. But timing flu vaccine delivery would be straightforward to implement. “It’s such a simple, low-risk intervention that’s free to do, and could have massive implications for vulnerable populations.”

Across diseases, from cancer and cardiac ailments to allergies and arthritis, epidemiological data and clinical trials are revealing that timing medications to the body’s internal clock could improve their effectiveness and reduce side effects. Although this concept, known as chronotherapy, has existed for at least 60 years, it has received little attention from physicians. But as biologists continue to unveil the molecular intricacies of cellular rhythms, they are beginning to realize just how pervasive the circadian clock’s influence is. In a 2014 study of gene expression in mice, for example, researchers found periodic expression in conserved mammalian genes targeted by 56 of the top 100 best-selling drugs in the U.S., including aripiprazole (Abilify, an antipsychotic), esomeprazole (Nexium, for heartburn), and duloxetine (Cymbalta, for depression), even though most are not currently prescribed with suggested dosing times.2

But chronotherapy is gaining clinical traction, says University of Pennsylvania chronobiologist John Hogenesch, senior author on the 2014 study. “Now we have the groundwork to precisely understand a person’s clock and leverage that information for better health,” he says. “Because of the molecular work, we’ve opened new doors here. This [idea] is not coming from left field anymore.”

Even so, researchers and clinicians working on chronotherapy still face skepticism, and implementing a new drug-delivery protocol or gaining regulatory approval from the US Food and Drug Administration (FDA) for time-of-day indications remains challenging. Thus, while the biomedical research community is starting to take notice of the body’s internal rhythms, timed therapies are still the exception to the rule.