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A Randomized Controlled Trial

Rixt F. Riemersma-van der Lek, MD; Dick F. Swaab, MD, PhD; Jos Twisk, PhD; Elly M. Hol, PhD; Witte J. G. Hoogendijk, MD, PhD; Eus J. W. Van Someren, PhD

JAMA. 2008;299(22):2642-2655.

Context  Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms.

Objective  To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin.

Design, Setting, and Participants  A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia.

Interventions  Random assignment by facility to long-term daily treatment with whole-day bright (± 1000 lux) or dim (± 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years).

Main Outcome Measures  Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months.

Results  Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (–0.5 points; 95% CI, –0.10 to –1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect).

Conclusions  Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light.

Trial Registration  controlled-trials.com/isrctn Identifier: ISRCTN93133646

Author Affiliations: Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam (Drs Riemersma-van der Lek, Swaab, Hol, and Van Someren); and Departments of Clinical Epidemiology and Biostatistics (Dr Twisk), Psychiatry (Dr Hoogendijk), Neurology (Dr Van Someren), Clinical Neurophysiology (Dr Van Someren), and Medical Psychology (Dr Van Someren), Research Institute Neuroscience CNCR (Dr Hoogendijk), and Alzheimer Center (Dr Van Someren), VU University Medical Center, Amsterdam, the Netherlands. Dr Riemersma-van der Lek is now with the Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands.

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