12 Jun 2008

In addition to cognitive decline, patients with advanced Alzheimer disease frequently have psychiatric problems such as mood swings, depression, and periods of aggression. These symptoms make life even more difficult for both patient and caregiver, and they can hasten the decision to institutionalize the patient. Some patients also have disturbed sleep patterns and exhibit “sundowning”—changes in behavior that peak in the early evening—suggesting all is not well with the brain’s circadian rhythm in AD. Approved treatments for AD do little to help with psychiatric symptoms (see ARF related news story), and both the safety and efficacy of off-label antipsychotics, which can ameliorate aggression, anxiety, agitation, and other neuropsychiatric disturbances, have been called into question, particularly when given to frail AD patients in nursing homes (see ARF related news story and ARF news story). Just last month, clinical leaders published a consensus statement advising, among other things, that such drugs be given only after non-pharmacological treatments have failed (Salzman et al., 2008). This reinforces the need for such alternative treatments, and yesterday’s Journal of the American Medical Association brings news of modest efficacy of a relatively simple one—light. Researchers led by Eus Van Someren at the VU University Medical Center, Amsterdam, the Netherlands, report that bright light improves patients’ depression, activities of daily living, and even cognition. A combination of bright light and melatonin—the “dark” hormone—works even better for some symptoms. The results suggest that propping up patients’ natural circadian rhythm could go some way toward relieving some of the behavioral consequences of AD.

Circadian disturbances are well documented in AD patients, and studies suggest that light therapy improves behavior and sleep patterns (see, e.g., Mishima et al., 1994 and Dowling et al., 2007), but this is the first multicenter, randomized clinical trial to address the treatment. First author Rixt Riemersma-van der Lek and colleagues used a 2 x 2 design to randomize 189 patients at 12 care group facilities into placebo, melatonin, light, and light plus melatonin groups. Patients receiving the light treatment lived in care facilities that had constant whole-day bright light (1,000 lux—about three to five times the intensity of a typical living room), while those receiving melatonin were given 2.5 mg each evening. The treatments lasted for as long as 3.5 years.

Riemersma-van der Lek and colleagues found that the light treatment alone attenuated cognitive decline on the Mini-Mental State Exam (MMSE) by 0.9 points (or 5 percent), reduced depression as assessed by the Cornell Scale for Depression in Dementia (CSDD) by 19 percent, and slowed the gradual deterioration in activities of daily living (nurse-informant activities of daily living scale) by about half. Melatonin helped patients fall asleep faster and increased their amount of sleep by nearly half an hour. The combination of light and melatonin reduced aggressive behavior by 9 percent, increased sleep efficiency, and improved nocturnal restlessness. The only downside appears to be that melatonin by itself increased withdrawn behavior and had bad outcomes on mood, lowering scores on positive mood scales and increasing negative ones. Van Someren told ARF that this might be because the dose selected was too high. When the researchers examined plasma melatonin, they found that daytime levels were elevated, which may contribute to the behavioral problems (melatonin is naturally released only during the dark period). “It may be that in older adults, metabolism becomes so slow that some melatonin leaks into fat tissue and then leaks out again during the day when it should not be available,” Van Someren said. He suggested that a lower dose of the hormone might be just as good while having fewer side effects, but cautioned that it will need to be tested.

Van Someren stressed that this is not a cure for AD. “I don’t want to give people false hope by making the suggestion that we have something to cure AD. We definitely do not,” he said. Then how does strengthening the circadian rhythm help? Van Someren made a comparison between a shift-working AD patient with jet-lag who has had a terrible night’s sleep and the same patient on vacation with no jet-lag who had a great night’s sleep. The first patient will be more irritable and perform more poorly in a cognitive test. “Light helps the biological clock to enforce better rhythms on the brain so you sleep better during the night, you are more alert during the day, and you feel better and function better even though the [pathological] decline is going on,” he said.—Tom Fagan