This week, Dr. Sydney Spiesel discusses circadian rhythms in relation to a treatment for arthritis and a link to bipolar disorder, a big hike in the price for the inhalers used to treat asthma, and whether the drug Imodium is safe for children.
Circadian rhythms and treating arthritis
Affliction: In common with many diseases caused or characterized by chronic inflammation, rheumatoid arthritis has symptoms that vary strikingly in the course of a day. Joint pain, morning stiffness, and functional disability are particularly bad in the early morning hours and least oppressive in the early evening. The difference can be measured objectively, with an average 27 percent increase in grip strength at 6 p.m. compared with 6 a.m., and a 28 percent reduction in pain at 6 p.m. compared with 8 a.m.
Question: Why should this be so? An exceptional paper by two European physicians has examined the effect on rheumatoid arthritis of circadian rhythms, which tell us when to sleep and when to wake up (and tells children at 4 in the afternoon that the witching hour has arrived).
New findings: Circadian rhythms affect, among other things, the production and release of two different hormones, cortisol and melatonin, which modulate the immune response and many aspects of inflammation. Melatonin, which peaks at night and plays a role in putting us to sleep, seems to increase the inflammatory products of activated immune cells. Cortisol, on the other hand, regulates these cells downward. At night, there's less cortisol, and the decrease results in a release of the things that cause inflammation (leakage of fluid into joint tissue, for instance, makes for morning stiffness). With less cortisol also comes less endorphin, the body's natural pain-blocker, so the pain of inflamed joints (and other pain) is felt more acutely in the night.
Implications: These observations about circadian effects suggest that there is a better time of day (or night) for giving anti-inflammatory treatments. Many of these drugs have harmful side effects, and time-targeted administration might improve both their efficacy and safety. One study showed that giving an oral steroid treatment to rheumatoid arthritis patients at 2 a.m. led to much better outcomes than treatment at 7:30 a.m. Since the effects of circadian rhythms are pervasive, many illnesses may similarly respond favorably to time-targeting.
Circadian rhythms and manic mice
Gene: Speaking of circadian rhythm, another recent paper (subscription required) by Kole Roybal, Coleen McClung, and a number of colleagues explores what happens when the "clock" gene goes mutant. This gene controls circadian rhythms and operates in most of our cells. The gene, or its near relatives, is active in cells of creatures as diverse as fruit flies, fungi, plants, and worms. In humans and other mammals, it does its most important work at a location in the brain called the suprachiasmatic nucleus. That's where messages about ambient light levels, generated from the retina, interact with messages from the clock gene to keep us to our daily 24-hour schedule, changing body functions across day and night and regulating the release of hormones. (See above.)
Question: What happens when the function of the clock gene is badly disrupted? Certain variations in this gene have been associated with bipolar disorder in humans, especially its expression in manic behavior. And bipolar patients almost always have abnormal patterns of sleep, activity, appetite, and physiological functions.
New research: The Roybal team showed that abnormalities in the clock gene of mice lead to similar behavioral changes. Compared to littermates with normal clocks, mice with the gene mutation are hyperactive and sleep less. Bipolar people in a manic state have a propensity toward drug abuse; mice with a defective clock gene are more sensitive to the reward effects of cocaine. Finally, lithium alleviates both the symptoms of mania in humans and the effects of a bad clock gene in mice. One difference: The clock-mutant mice don't appear to cycle between mania and depression like bipolar people do.