Effect of Bright Light and Melatonin on Cognitive and Noncognitive Function in Elderly Residents of Group Care Facilities: A Randomized Controlled Trial

Abstract

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.
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.
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.
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).
Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months.
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 Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in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).
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.
controlled-trials.com/isrctn Identifier: ISRCTN93133646.

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. 2008;299(22):2642-2655 (doi:10.1001/jama.299.22.2642) JAMA
Rixt F. Riemersma-van der Lek; Dick F. Swaab; Jos Twisk; et al.
Care Facilities: A Randomized Controlled Trial
Noncognitive Function in Elderly Residents of Group
Effect of Bright Light and Melatonin on Cognitive and
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ORIGINAL CONTRIBUTION
Effect of B right Light and Melatonin
on Cognitive and Noncognitive Function
in Elderly Residents of Gro up Care Facilities
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
I
N ELDERLY PATIENTS WITH DEMEN-
tia, cognitive decline is frequently
accompanied by disturbances of
mood, behavior, sleep, and activi-
ties of daily living,
1-3
which increase
caregiver burden and the risk of insti-
tutionalization.
4-7
The limited treat-
ment possibilities create an opportu-
nity for other symptom management
approaches.
8-11
Changes in the circadian pacemaker
of the brain, located in the hypothalamic
suprachiasmatic nucleus, may contrib-
ute to cognitive, mood, behavioral, and
sleep disturbances.
12-18
The circadian tim-
ing system is highly sensitive to environ-
mental light and the hormone melato-
nin
19
and may not function optimally in
the absence of their synchronizing ef-
fects. In elderly patients with dementia,
synchronization may be attenuated if
light exposure and melatonin produc-
tion are reduced.
20,21
Indeed, bright light
ameliorates behavioral
22
and sleep
20
dis-
turbances.
To our knowledge, no previous stud-
ies in humans have applied long-term
combined stimulation of the circadian
timing system with daily light and mela-
tonin. We conducted a multicenter,
double-blind, randomized placebo-
controlled trial that evaluated the ef-
fects of up to 3.5 years of daily supple-
mentation of light and/or melatonin.
Using a practical clinical trial ap-
proach,
23
long-term treatment effective-
Author Affiliations are listed at the end of this article.
Corresponding Author: Eus J. W. Van Someren, PhD,
Netherlands Institute for Neuroscience, Meiberg-
dreef 47, 1105 BA Amsterdam, the Netherlands
(e.van.someren@nin.knaw.nl).
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 symp-
toms 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⫻ 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 symp-
toms, 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% con-
fidence 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 du-
ration 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 Ob-
servational 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⫻time effect).
Conclusions Light has a modest benefit in improving some cognitive and noncog-
nitive 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
JAMA. 2008;299(22):2642-2655 www.jama.com
2642 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from

ness on a broad range of health out-
comes including cognitive, mood,
behavioral, functional, and sleep distur-
bances were evaluated in a diverse popu-
lation typical of care facilities for el-
derly residents with dementia. We
hypothesized that long-term treatment
would attenuate cognitive decline and
depression, as the primary and second-
ary outcomes, respectively, and would
moreover ameliorate behavioral, func-
tional, and sleep disturbances.
METHODS
Participants and Group Care Facilities
The participants were 189 residents of
12 different Dutch homes for the
elderly (170 women and 19 men,
which is a rate representative of Dutch
homes for the elderly; mean [SD] age,
85.8 [5.5] years) living in assisted care
facilities, in which residents have their
own apartment where they sleep and
retreat, but spend most of the daytime
in a common living room supervised
by caregivers. The facility is classified
as an open type. Residents may need
to be transferred to a nursing home if
they develop unsolvable behavioral
and/or cognitive problems that lead to
an unsafe situation; when they wander
from the facility; or when physical
disabilities cause too much burden
for the nursing staff. Of the 61 homes
for the elderly that were initially
approached, 12 confirmed that they
had a group facility with daily occupa-
tion and would be willing to partici-
pate. For recruitment, all 253 resi-
dents living in the facilities were asked
for verbal consent and the patients’
responsible relatives were asked to
provide written informed consent.
Consent was obtained from 189. No
other inclusion criteria were applied to
obtain a sample that is representative
of the environment, which is consis-
tent with the design of a practical
clinical trial.
23
Exclusion criteria were
the use of monoamine oxidase inhibi-
tors, long-term use of nonsteroid anti-
inflammatory drugs, severe liver or
kidney dysfunction, and aphakia.
None of the potential participants had
to be excluded. The Medical Ethics
Committees of Hospital De Gelderse
Vallei, Ede, and the VU University
Medical Center, Amsterdam, the
Netherlands, approved the study.
The clinical diagnosis of dementia
was made according to the Diagnostic
and Statistical Manual of Mental Disor-
ders, Fourth Edition (DSM-IV) crite-
ria for dementia and dementia sub-
types.
24
To determine the clinical
diagnosis of probable Alzheimer dis-
ease, criteria from the National Insti-
tute of Neurological and Communica-
tive Disorders and Stroke (NINCDS)
and the Alzheimer’s Disease and Re-
lated Disorders Association (ADRDA)
were used.
25
Of the 189 participants,
120 (63%) met the NINCDS-ADRDA
criteria for probable Alzheimer dis-
ease, 20 (11%) met the DSM-IV crite-
ria for vascular dementia, and 24 (13%)
met criteria for other types of demen-
tia, including dementia due to mul-
tiple etiologies (9 cases), frontal-type
dementia (3 cases), Lewy body demen-
tia (2 cases), Parkinson disease (2
cases), Wernicke-Korsakoff (1 case),
and dementia not otherwise specified
(7 cases). Seventeen participants (8%)
did not meet the criteria for dementia,
but stayed in the group care facility for
various medical or psychosocial rea-
sons. In 8 participants, data on medi-
cal history were insufficient to reach a
reliable clinical diagnosis.
To investigate possible systematic
group differences in the environmental
setting of the participants, all facilities
were rated on the Therapeutic Environ-
ment Screening Scale (TESS).
26,27
The
TESS assesses the quality of nursing
home environments for residents with
dementia and includes items on the gen-
eral conditions of the environment such
as noise, lighting, design, and mainte-
nance, as well as questions about staff
interactions with residents and about the
involvement of residents in planned ac-
tivities. The sum score ranges between
0 and 166, with higher scores indicat-
ing a supposedly more therapeutic en-
vironment. No cutoff scores have been
established. In the present study, TESS
ratings ranged between 90 and 129.
Group means are given in T
ABLE 1.
Study Design
In a 2⫻2 factorial design, facilities were
randomly assigned using the Micro-
soft Excel (Redmond, Washington) ran-
dom number function to 1 of the 2 light
conditions and participants to double-
blind daily intake of melatonin (2.5 mg,
Terafarm, Brielle, the Netherlands,
n=95) or placebo (n=94), given ap-
proximately 1 hour before bedtime
28
by
the nursing staff who ensured adher-
ence. The tablets took about 1 hour to
completely dissolve in water, which can
be considered a medium-fast release
preparation. Timing and dosage were
based on previous studies.
28-30
The 12 homes for the elderly were
randomly assigned to active (6 facili-
ties, n=98) or placebo (6 facilities,
n=91) light exposure. Forty-nine par-
ticipants were assigned to light only, 46
to melatonin only, 49 to their combi-
nation, and 45 to neither light nor mela-
tonin (double placebo). The mean (SD)
ratio of participants assigned to the ac-
tive melatonin group within each fa-
cility was 0.50 (0.06).
Randomization was performed by a re-
search assistant not involved in the study
(J. van Heerikhuize, Netherlands Insti-
tute for Neuroscience, Amsterdam) and
kept concealed. Codes were revealed to
the researchers only after completion of
the study and subsequent data reduc-
tion and processing steps. The flow of the
participants included in the study is
shown in F
IGURE 1.
Light exposure was manipulated by
installing a large number of ceiling-
mounted fixtures with Plexiglas diffus-
ers containing an equal amount of Phil-
ips TLD 840 and 940 fluorescent tubes
(Philips Lighting BV, Eindhoven, the
Netherlands) in the common living
room. Lights were on daily between ap-
proximately 9
AM and 6 PM. The aim was
an exposure of ±1000 lux, measured
before the eyes in the gaze direction. This
intensity is technically feasible and has
in previous studies been confirmed
to synchronize circadian rhythms in
healthy people in temporal isolation
31
and to improve circadian activity rhythm
disturbances in elderly patients with
moderate to severe dementia.
32
For the
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2643
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placebo group, an equal number of fix-
tures were installed, but these con-
tained only half of the tubes, accommo-
dated concealed band-stop filters, and
were installed at a greater distance from
the eyes. The resulting average light ex-
posure measured at eye level in the gaze
direction is shown in F
IGURE 2. Light
intensity was increased to ±1000 lux
between 10
AM and 6 PM at the 6 light
facilities (active condition) (Pⱕ.01 for
all hourly comparisons of the active
condition vs baseline except between
3 and 4
PM) while the intensity was not
altered at any time of the day for the pla-
cebo light facilities (inactive condi-
tion). Caregivers were blinded to ran-
domization and were asked to guess
their facility’s light status. Based on 184
ratings obtained from 89 caregivers over
the treatment period, there was no sig-
nificant difference on a 100-mm illu-
mination pleasantness visual ana-
logue scale (mean [SD] active light
condition, 52 [37]; mean [SD] inac-
tive light condition, 55 [34]; 2-tailed t
test, P= .47); neither was there a differ-
ence in whether they thought their fa-
cility had effective light (active light
condition, 69%; inactive light condi-
tion, 64%; 2-tailed ␹
2
test, P=.62).
Procedure
Participants were followed up for up to
3.5 years, a mean (SD) of 15 (12)
months. Recruitment and enrollment
commenced in 1999 and data acquisi-
tion continued until April 14, 2004. Fol-
low-up assessments were made 6 weeks
after the start of the treatment, and sub-
sequently every 6 months. Neuropsy-
chiatric symptoms were assessed 6
weeks prior to the start of the treat-
ment in the 129 participants enrolled be-
fore the lights were installed. Another
60 participants were enrolled in the
study later, and the absence of a base-
line assessment in these participants was
accounted for by the mixed-effect re-
gression analyses described below. At
their first assessment, these 60 partici-
pants were similar to those assessed at
baseline on the demographic or clini-
cal variables listed in Table 1, except for
higher mean (SD) scores on the Mini-
Mental State Examination (MMSE) of
18.1 (4.9) vs 14.7 (6.3) (t test, P=.001),
Table 1. Characteristics of Participants
6 Placebo (Inactive) Light Facilities 6 Active Light Facilities
Double Placebo Melatonin Only Light Only Light ⫹ Melatonin
Distribution of Participants Over Groups
Participants, No./total (%) 45/189 (24) 46/189 (24) 49/189 (26) 49/189 (26)
Female sex, No./total (%) 40/170 (24) 38/170 (22) 45/170 (26) 47/170 (28)
Deceased, No./total (%) 18/60 (30) 16/60 (27) 12/60 (20) 14/60 (23)
Outplaced, No./total (%) 9/48 (19) 12/48 (25) 13/48 (27) 14/48 (29)
Diagnosis, No./total (%)
Alzheimer disease 22/120 (18) 28/120 (23) 37/120 (31) 33/120 (28)
Other 23/69 (33) 18/69 (26) 12/69 (17) 16/69 (23)
Characteristics Within Groups
(n = 45) (n = 46) (n = 49) (n = 49)
Allele, present/participants characterized (%)
ApoE2 2/19 (11) 4/31 (13) 2/26 (8) 4/27 (15)
ApoE4 5/19 (26) 7/31 (23) 5/26 (19) 6/27 (22)
Age at first assessment, mean (SD), y 85 (5) 86 (5) 85 (6) 87 (6)
Date of first assessment (SD)
a
May 11 (85 d) May 12 (85 d) June 9 (62 d) June 7 (70 d)
Time followed up, mean (SD), d 381 (343) 433 (324) 550 (389) 443 (393)
TESS score, mean (SD)
b
104 (9) 104 (8) 101 (10) 102 (12)
Medication use at inclusion and at any follow-up, No. (%)
Antipsychotics
Preassessment 11 (24) 12 (26) 18 (37) 13 (27)
During treatment 19 (42) 18 (39) 17 (35) 13 (27)
Anxiolytics
Preassessment 7 (16) 5 (11) 3 (6) 8 (16)
During treatment 10 (22) 7 (15) 4 (8) 9 (18)
Hypnotics
Preassessment 10 (22) 11 (14) 11 (22) 13 (27)
During treatment 15 (33) 11 (24) 13 (27) 12 (24)
Antidepressants
Preassessment 11 (24) 8 (17) 5 (10) 10 (20)
During treatment 13 (29) 8 (17) 9 (18) 10 (20)
Vision, No. (%)
Lens opacity 17 (38) 10 (22) 10 (20) 17 (35)
Glaucoma 2 (4) 2 (4) 2 (4) 3 (6)
Abbreviation: TESS, Therapeutic Environment Screening Scale.
26,27
a
Recruitment and inclusion were staggered so SDs are provided to demonstrate the absence of seasonal differences between the dates of first assessment.
b
Applied to rate the overall quality of the group care facilities.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2644 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
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Figure 1. Flow of Participants Included in the Study
Status at 6-mo follow-up
5 Died
3 Placed in nursing home
0 Participation by facility ended
1 Withdrew
31 Included in analysis
Status at 6-mo follow-up
2 Died
3 Placed in nursing home
1 Participation by facility ended
1 Withdrew
39 Included in analysis
Status at 6-mo follow-up
2 Died
2 Placed in nursing home
0 Participation by facility ended
0 Withdrew
43 Included in analysis
Status at 6-mo follow-up
4 Died
1 Placed in nursing home
2 Participation by facility ended
0 Withdrew
37 Included in analysis
Status at 1-y follow-up
5 Died
1 Placed in nursing home
0 Participation by facility ended
3 Withdrew
22 Included in analysis
Status at 1-y follow-up
7 Died
3 Placed in nursing home
2 Participation by facility ended
0 Withdrew
27 Included in analysis
Status at 1-y follow-up
0 Died
3 Placed in nursing home
7 Participation by facility ended
0 Withdrew
33 Included in analysis
Status at 1-y follow-up
1 Died
5 Placed in nursing home
4 Participation by facility ended
0 Withdrew
27 Included in analysis
Status at 2-y follow-up
1 Died
2 Placed in nursing home
4 Participation by facility ended
1 Withdrew
10 Included in analysis
Status at 2-y follow-up
3 Died
2 Placed in nursing home
4 Participation by facility ended
0 Withdrew
9 Included in analysis
Status at 2-y follow-up
3 Died
2 Placed in nursing home
2 Participation by facility ended
0 Withdrew
16 Included in analysis
Status at 2-y follow-up
4 Died
3 Placed in nursing home
2 Participation by facility ended
0 Withdrew
13 Included in analysis
Status at 1.5-y follow-up
2 Died
0 Placed in nursing home
1 Participation by facility ended
1 Withdrew
18 Included in analysis
Status at 1.5-y follow-up
4 Died
2 Placed in nursing home
3 Participation by facility ended
0 Withdrew
18 Included in analysis
Status at 1.5-y follow-up
4 Died
2 Placed in nursing home
4 Participation by facility ended
0 Withdrew
23 Included in analysis
Status at 1.5-y follow-up
1 Died
1 Placed in nursing home
3 Participation by facility ended
0 Withdrew
22 Included in analysis
45 Randomized not to receive melatonin
(double placebo)
46 Randomized to receive melatonin
(melatonin only)
49 Randomized not to receive melatonin
(light only)
49 Randomized to receive melatonin
(light plus melatonin)
Status at intervention onset
and 6-wk follow-up
3 Died
1 Placed in nursing home
1 Withdrew
40 Included in analysis
Status at intervention onset
and 6-wk follow-up
0 Died
0 Placed in nursing home
0 Withdrew
46 Included in analysis
Status at intervention onset
and 6-wk follow-up
1 Died
1 Placed in nursing home
0 Withdrew
47 Included in analysis
Status at intervention onset
and 6-wk follow-up
2 Died
2 Placed in nursing home
1 Withdrew
44 Included in analysis
Status at 3-y follow-up
0 Placed in nursing home
0 Participation by facility ended
2 Included in analysis
Status at 3-y follow-up
0 Placed in nursing home
2 Participation by facility ended
2 Included in analysis
Status at 3-y follow-up
2 Placed in nursing home
7 Participation by facility ended
4 Included in analysis
Status at 3-y follow-up
2 Placed in nursing home
4 Participation by facility ended
4 Included in analysis
Status at 2.5-y follow-up
2 Died
1 Placed in nursing home
5 Participation by facility ended
2 Included in analysis
Status at 2.5-y follow-up
0 Died
2 Placed in nursing home
3 Participation by facility ended
4 Included in analysis
Status at 2.5-y follow-up
1 Died
1 Placed in nursing home
1 Participation by facility ended
13 Included in analysis
Status at 2.5-y follow-up
2 Died
0 Placed in nursing home
1 Participation by facility ended
10 Included in analysis
61 Facilities assessed for eligibility
12 Facilities randomized
118 Participants assessed 135 Participants assessed
6 Placebo (inactive) light facilities 6 Active light facilities
27 Excluded (no consent obtained
from relatives)
37 Excluded (no consent obtained
from relatives)
Status at 3.5-y follow-up
0 Died
0 Placed in nursing home
0 Participation by facility ended
2 Included in analysis
Status at 3.5-y follow-up
1 Died
0 Placed in nursing home
1 Participation by facility ended
2 Included in analysis
Status at 3.5-y follow-up
0 Died
0 Placed in nursing home
0 Participation by facility ended
4 Included in analysis
Status at 3.5-y follow-up
0 Died
1 Placed in nursing home
0 Participation by facility ended
1 Included in analysis
91 Participants randomized 98 Participants randomized
All available data for participants that were lost to follow-up at any stage were included in the mixed-effect regression analyses.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
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Multi Observational Scale for Elderly
Subjects (MOSES) withdrawn behav-
ior subscale of 19.7 (5.9) vs 16.6 (5.8)
(t test, P=.001), and Cohen-Mansfield
Agitation Index (CMAI) of 47.4 (16.2)
vs 42.0 (13.5) (t test, P =.02). Fol-
low-up was primarily determined by the
duration of participation of the facility,
some of which ended due to logistical
reasons including renovations, mov-
ing, and staff limitations. Participation
of facilities varied between 3.5 years
(4 facilities), 3 years (1 facility), 2.5 years
(2 facilities), 2 years (2 facilities), 1.5
years (2 facilities), and 0.5 years (1 fa-
cility). Secondarily, a major number of
participants were lost to follow-up as-
sessment due to death or outplacement
to a nursing home, which is inherent to
the study population.
Assessment of Outcome Measures
As advocated for practical clinical
trials,
23
a broad range of measure-
ments were obtained, including scales
for cognitive and noncognitive symp-
toms and functional abilities as well as
sleep-quality estimates derived from ac-
tigraphic activity measurement. The
ranges and normative cutoff scores
(when available) for all scales are pro-
vided in T
ABLE 2. All individuals per-
forming assessments were blinded to
treatment allocation.
Three scales were administered by a
trained neuropsychologist. The pri-
mary outcome, cognitive performance,
was assessed with the MMSE.
33
Mood
was determined using the Cornell Scale
for Depression in Dementia (CSDD),
which combines interviews of the pa-
tients and caregivers.
34,35
Self-esteem was
obtained with the Philadelphia Geri-
atric Centre Morale Scale (PGCMS).
36,37
Six scales were completed by the daily
caregivers. The Philadelphia Geriatric
Centre Affect Rating Scale (PGCARS)
rates behavioral expressions of negative
and positive mood.
38
Withdrawn behav-
ior was assessed with a subscale of the
MOSES.
39
The questionnaire format of
the Neuropsychiatric Inventory (NPI-Q)
was used to rate the severity and its re-
sulting distress of 12 psychopathologi-
cal behaviors.
40,41
The CMAI was used to
rate agitated behaviors.
42,43
Limitations
of activities of daily living were rated on
the nurse-informant adaptation
44
(NI-
ADL) of the scale by Katz et al.
45
Fi-
nally, caregivers rated 16 items on pos-
sible adverse effects suggested from
previous studies on light or melatonin
treatment on a 4-point scale (0= absent,
1=probably absent, 2=probably present,
3=present).
Actigraphy, the continuous assess-
ment of activity with a small wrist-worn
recorder, has been recommended as the
technique of choice for studying sleep in
patients with dementia because poor
adherence and diffuse slowing on the
electroencephalogram make sleep assess-
ment with standard polysomnographic
assessment difficult.
46
Estimates of sleep
were obtained from a mean (SD) of 14
(4) days of actigraphic recording using
the Actiwatch and accompanying soft-
ware
47
(Cambridge Neurotechnology,
Cambridge, England). Although actig-
raphy does not discriminate well between
wakefulness without movement and
sleep, reasonable estimates of sleep para-
meters can be obtained from long-term
recordings.
48
Bedtime and wake time,
which are required for sleep estimates,
were provided by the nursing staff. The
calculated variables quantify 2 pro-
cesses of sleep: (1) the quantity of sleep
and wakefulness, expressed as the dura-
tion, onset latency, and efficiency (per-
centage of time asleep while in bed) of
sleep, and nocturnal restlessness (min-
utes per hour containing any activity dur-
ing the most restful 5-hour period of the
average 24-hour pattern)
49
; (2) the
within-sleep structure, expressed as the
average durations of nocturnal awaken-
ings and of uninterrupted periods of
sleep. Longer periods of activity are more
disruptive to sleep while prolonged
periods without activity are associated
with polysomnographically deter-
mined deeper sleep.
50
Figure 2. Median 24-Hour Light Exposure
1600
200
800
600
400
1000
1200
1400
0
12 AM 3 AM 6 AM 9 AM 12 PM 3 PM 6 PM 9 PM 12 AM
Time of Day
Light Intensity, lux
Light condition
Baseline
Placebo
Active
Lights on
Illumination levels were obtained at eye level in the direction of gaze, which was usually slightly downward or
at best representing light falling on the vertical plane. Such illumination levels are considerably lower than as-
sessments representing light falling on the horizontal plane directed toward the light sources, but better rep-
resent light levels that can enter the eye. Daytime assessments include occasional observations made if par-
ticipants were not actually present in the common living room where the lights were installed but in their own
bedroom. The data thus represent the adherence to the light treatment condition. In the active light condition,
the hourly averages between 10
AM and 6 PM were significantly higher compared with pretreatment assess-
ments (Pⱕ.01 for all hourly comparisons of the active condition vs pretreatment assessments; except between
3 and 4
PM, P =.06). At no time of day was the intensity increased in the placebo group relative to the pre-
treatment assessments. Comparisons were made using mixed-effect analysis of 3017 light measurements from
189 participants in 12 facilities assessed repeatedly during the 3.5 years. As long as participants were included
in the study, they each contributed to light measurements several times a day and at several follow-up peri-
ods. Error bars indicate interquartile range.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2646 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from

Table 2. Assessment Scales Up to 2 Years of Follow-up
a
Assessment
Scale
b
Total No.
of Valid
Observa-
tions
No. of
Follow-up
Assess-
ments
No. of
Individuals
c
Treatment
Group
Preassess-
ment, Mean
(SD)
(n = 129)
Follow-up, Mean (SD)
6wk
(n = 177)
6mo
(n = 150)
1y
(n = 109)
1.5 y
(n = 81)
2y
(n = 48)
Cognitive Scale
MMSE (range, 0-30; cutoff, 24) 619 500 174 None
d
14.3 (7.0) 15.4 (7.3) 15.6 (6.4) 14.5 (5.4) 13.7 (7.4) 12.5 (6.6)
Light 14.5 (6.2) 16.6 (5.5) 15.6 (5.2) 16.2 (4.5) 17.4 (3.7) 16.1 (4.5)
Melatonin 15.3 (5.3) 17.1 (6.2) 15.0 (6.3) 16.5 (6.6) 15.1 (6.1) 15.3 (6.0)
L ⫹ M 14.7 (6.8) 15.5 (6.4) 16.5 (6.2) 15.6 (6.1) 15.1 (6.8) 17.8 (4.4)
Mood Scales
CSDD (range, 38-0; cutoff, 8 minor and 12 major) 730 606 187 None
d
7.6 (5.1) 7.8 (5.2) 9.3 (6.1) 11.3 (7.4) 12.0 (7.5) 15.1 (8.6)
Light 7.4 (6.9) 5.8 (4.9) 7.9 (5.6) 11.0 (7.7) 9.9 (5.9) 10.7 (7.3)
Melatonin 7.0 (5.5) 7.5 (6.2) 8.1 (6.5) 9.6 (7.9) 11.3 (7.6) 10.1 (8.0)
L ⫹ M 7.8 (5.4) 6.8 (5.0) 6.6 (5.0) 8.9 (7.6) 9.7 (6.9) 9.7 (5.4)
PGCARS positive (range, 0-15) 699 576 182 None
d
10.9 (3.3) 11.3 (2.4) 10.5 (2.6) 11.9 (2.6) 10.6 (2.9) 11.0 (1.0)
Light 11.0 (3.5) 10.7 (3.5) 10.9 (3.2) 11.6 (3.1) 11.5 (2.2) 11.5 (2.4)
Melatonin 10.7 (3.0) 10.3 (2.5) 10.3 (2.6) 10.3 (2.9) 10.4 (3.2) 10.8 (3.5)
L ⫹ M 10.9 (3.6) 11.0 (3.0) 11.2 (3.0) 12.2 (3.0) 10.8 (2.8) 11.5 (2.7)
PGCARS negative (range, 15-0) 699 576 182 None
d
6.2 (3.2) 7.0 (2.9) 6.7 (2.6) 6.2 (2.0) 6.6 (2.2) 9.1 (2.5)
Light 5.9 (2.3) 5.8 (2.3) 6.1 (2.6) 7.3 (3.2) 6.3 (3.1) 6.4 (2.9)
Melatonin 6.6 (3.2) 6.5 (2.5) 7.0 (2.8) 7.5 (2.8) 7.2 (3.0) 6.8 (3.3)
L ⫹ M 5.4 (2.5) 6.2 (2.7) 5.5 (2.3) 5.8 (2.7) 6.4 (3.1) 4.6 (1.6)
PGCMS (range, 0-17) 604 492 172 None
d
10.6 (4.8) 10.4 (4.9) 11.1 (6.0) 11.3 (6.0) 12.0 (4.4) 11.0 (5.6)
Light 11.9 (4.4) 12.5 (3.7) 13.1 (4.3) 11.3 (3.6) 12.4 (4.1) 11.1 (4.2)
Melatonin 11.9 (4.5) 11.5 (4.4) 12.9 (4.4) 11.6 (4.8) 10.9 (5.2) 9.3 (5.6)
L ⫹ M 11.7 (4.4) 11.7 (4.1) 12.0 (3.4) 12.0 (4.0) 10.9 (5.3) 12.7 (3.7)
Behavioral Scales
MOSES (range, 34-0) 701 577 182 None
d
17.4 (5.2) 16.6 (6.1) 17.9 (6.0) 17.0 (4.1) 19.8 (5.4) 19.9 (5.0)
Light 19.6 (7.1) 17.5 (5.9) 19.0 (6.1) 17.6 (6.2) 15.5 (4.7) 16.4 (6.2)
Melatonin 18.9 (6.4) 18.3 (5.9) 20.4 (6.5) 19.2 (6.6) 20.4 (7.0) 17.0 (5.8)
L ⫹ M 18.1 (6.1) 17.6 (5.7) 18.6 (6.4) 17.6 (5.6) 18.5 (5.1) 18.1 (5.9)
NPI-Q severity (range, 36-0) 706 581 183 None
d
5.2 (5.5) 6.4 (5.3) 5.2 (4.4) 6.1 (3.5) 6.8 (5.0) 8.2 (3.9)
Light 4.3 (4.4) 4.7 (5.0) 5.7 (5.7) 5.8 (5.7) 4.0 (4.6) 4.9 (5.8)
Melatonin 5.7 (5.2) 4.8 (4.5) 4.6 (3.8) 5.4 (4.7) 4.5 (4.5) 5.5 (6.7)
L ⫹ M 3.9 (5.0) 4.6 (5.7) 2.7 (3.0) 4.6 (4.5) 4.4 (5.1) 3.7 (4.1)
NPI-Q distress (range, 60-0) 706 581 183 None
d
4.8 (6.3) 6.0 (5.9) 3.6 (4.6) 3.2 (3.5) 4.2 (4.6) 7.4 (4.5)
Light 4.8 (5.5) 5.1 (6.0) 6.1 (7.4) 6.0 (7.2) 4.2 (5.3) 5.4 (6.8)
Melatonin 5.6 (6.8) 4.6 (5.6) 3.8 (4.2) 3.7 (5.2) 2.6 (4.3) 3.6 (5.5)
L ⫹ M 4.4 (6.0) 4.7 (6.5) 2.2 (3.5) 5.5 (6.2) 4.7 (6.6) 3.1 (4.3)
CMAI (range, 203-0) 708 583 184 None
d
45 (18) 46 (18) 47 (19) 48 (18) 47 (15) 58 (16)
Light 45 (13) 41 (12) 44 (18) 46 (18) 42 (14) 49 (15)
Melatonin 48 (17) 45 (15) 47 (19) 48 (16) 49 (19) 44 (19)
L ⫹ M 44 (15) 39 (12) 40 (12) 42 (13) 45 (17) 40 (10)
Functional Limitations Scale
NI-ADL (range, 58-0) 700 575 181 None
d
21 (13) 20 (12) 22 (12) 22 (11) 27 (14) 29 (14)
Light 18 (12) 15 (11) 20 (14) 17 (12) 17 (14) 13 (11)
Melatonin 23 (11) 22 (14) 23 (13) 27 (14) 31 (16) 28 (15)
L ⫹ M 18 (13) 18 (12) 16 (11) 17 (11) 17 (10) 16 (9)
Actigraphic Sleep Estimates
Sleep efficiency (range, 0-100),% 566 466 164 None
d
76 (13) 72 (13) 75 (12) 73 (12) 70 (14) 78 (11)
Light 70 (16) 73 (11) 72 (12) 74 (11) 76 (10) 74 (12)
Melatonin 72 (13) 75 (12) 78 (13) 74 (15) 74 (14) 71 (17)
L ⫹ M 73 (11) 75 (12) 78 (8) 77 (11) 78 (11) 80 (6)
Sleep onset latency, min 566 466 164 None
d
31 (23) 42 (49) 32 (38) 46 (59) 59 (86) 23 (27)
Light 50 (36) 48 (36) 41 (31) 51 (49) 29 (14) 33 (27)
Melatonin 54 (61) 37 (31) 28 (26) 40 (32) 37 (31) 41 (49)
L ⫹ M 44 (34) 42 (37) 26 (17) 40 (30) 28 (27) 20 (18)
Total sleep duration, h 566 466 164 None
d
8.7 (2.1) 8.0 (1.8) 8.1 (1.8) 8.2 (1.7) 8.0 (1.8) 8.0 (2.1)
Light 7.4 (2.1) 7.6 (1.2) 7.5 (1.2) 7.6 (1.1) 7.9 (1.4) 7.4 (1.2)
Melatonin 8.3 (1.5) 8.2 (1.6) 9.1 (2.1) 8.6 (2.0) 8.3 (1.7) 8.0 (2.0)
L ⫹ M 7.7 (1.4) 8.3 (1.8) 8.5 (1.4) 8.3 (1.4) 8.5 (1.5) 8.3 (1.3)
(continued)
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2647
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At each assessment, the prescrip-
tion of antipsychotics, anxiolytics, hyp-
notics, and antidepressants was re-
trieved from the medical record and
scored as present or absent. Finally, a
physician performed a visual examina-
tion focusing on the presence of opac-
ity of the lens and glaucoma.
Statistical Analysis
Mixed-effect regression analysis
51
was
used, which is the analysis of choice for
realistic long-term data sets in psychia-
try and in an elderly long-term care
population,
52,53
which typically have vari-
able numbers of observations due to the
causes described above. The analyses
were performed with the MLwiN soft-
ware (version 2.0, Institute of Educa-
tion, London, England) and accounted
for the 3-level nested structure of the data
set (ie, a variable number of observa-
tions nested within participants and par-
ticipants grouped in 12 facilities). De-
tails are given in the online supplemental
information (see http://www.jama
.com). Melatonin, light, and their inter-
action were dummy coded in 3 vari-
ables indicating the presence of active
treatment at any observation and ana-
lyzed in a 2⫻ 2 factorial design. Both
treatment effects (ie, independent of
time) and time⫻ treatment effects (ie,
treatment effects changing linearly over
time) were evaluated. In addition, the re-
gression models allowed for inclusion of
linear changes over time, and for modi-
fication of level, time course, and treat-
ment effect by missing data patterns. Lo-
gistic mixed-effect regression was applied
to evaluate possible group differences and
group⫻time interactions in the prescrip-
tion of psychotropic medication.
Special attention was given to the fact
that (particularly after 1.5 years) many
cases were lost to follow-up either due
to noninformative reasons (discontinu-
ation of participation by the facility) or
to possibly informative causes (death
or nursing home transfer). In a prede-
termined analysis, missing data due to
(1) death or nursing home placement
and (2) insufficient communicative
abilities at any assessment occasion
were considered to be informative and
dummy coded (indicating presence of
this condition for a participant at any
point in time) to allow for evaluation
of their possible effects in a pattern-
mixture model.
54
Second, to obtain the
most simple acceptable regression equa-
tion insensitive to a reduction in the fol-
low-up time, a post hoc sensitivity
analysis was used to verify whether
treatment effects obtained from analy-
ses on the complete 3.5-year data set
were still present in a reduced data set
including only the first 1.5 years of fol-
low-up data. A further preplanned
analysis examined possible effect modi-
fication by diagnosis by including
dummy coding of the Alzheimer dis-
ease diagnosis in the regression mod-
els. Possible effect modification by opac-
ity of the lens of the eye and glaucoma
were likewise examined in a post hoc
analysis. The most simple acceptable re-
gression equations were selected using
the likelihood ratio ␹
2
test.
Significance levels for effects were set
at less than .05 with 2-sided testing.
Analyses were intention to treat; none
of the participants switched treatment
and the analyses included all random-
ized participants. Additional t tests, ␹
2
tests, and simple logistic regressions
were performed using SPSS version 14.0
(SPSS Inc, Chicago, Illinois).
Statistical Power
At the onset of the study it was esti-
mated that participants would remain
in the protocol for an average of 2.5
Table 2. Assessment Scales Up to 2 Years of Follow-up
a
(cont)
Assessment
Scale
b
Total No.
of Valid
Observa-
tions
No. of
Follow-up
Assess-
ments
No. of
Individuals
c
Treatment
Group
Preassess-
ment, Mean
(SD)
(n = 129)
Follow-up, Mean (SD)
6wk
(n = 177)
6mo
(n = 150)
1y
(n = 109)
1.5 y
(n = 81)
2y
(n = 48)
Actigraphic Sleep Estimates
Nocturnal restlessness (range, 60-0), min/h 566 466 164 None
d
11.3 (6.5) 13.2 (7.9) 11.4 (6.3) 12.0 (6.0) 13.7 (7.0) 13.2 (7.2)
Light 12.9 (9.6) 12.6 (7.4) 12.1 (6.7) 10.5 (6.3) 10.1 (6.1) 10.9 (7.0)
Melatonin 12.1 (6.1) 11.8 (7.1) 10.4 (6.2) 11.1 (8.1) 11.2 (5.5) 12.5 (6.8)
L ⫹ M 11.8 (5.4) 11.6 (6.4) 10.5 (5.6) 9.6 (5.4) 9.0 (5.4) 9.5 (4.1)
Duration of awakenings, min 566 466 164 None
d
4.4 (2.5) 4.8 (2.9) 3.8 (1.9) 4.1 (2.1) 3.7 (1.2) 3.5 (1.0)
Light 5.1 (2.7) 4.1 (1.6) 4.6 (2.0) 4.8 (1.8) 4.5 (1.3) 4.3 (1.8)
Melatonin 4.3 (1.6) 4.5 (2.2) 4.2 (1.8) 4.2 (1.5) 5.5 (4.0) 4.7 (1.7)
L ⫹ M 4.8 (2.2) 4.1 (1.4) 4.1 (1.9) 4.1 (1.5) 4.1 (1.2) 3.5 (1.1)
Duration of uninterrupted sleep epochs, min 566 466 164 None
d
33 (38) 21 (15) 21 (13) 35 (67) 17 (10) 20 (9)
Light 23 (12) 23 (13) 22 (17) 28 (22) 26 (11) 27 (31)
Melatonin 18 (7) 27 (26) 30 (23) 23 (15) 32 (36) 33 (33)
L ⫹ M 25 (15) 24 (17) 29 (25) 39 (62) 26 (13) 22 (8)
Abbreviations: CMAI, Cohen-Mansfield Agitation Index; CSDD, Cornell Scale for Depression in Dementia; L ⫹ M, light plus melatonin; MOSES, Multi Observation Scale for Elderly Sub-
jects; MMSE, Mini-Mental State Examination; NI-ADL, nurse-informant activities of daily living adaptation
44
of the scale by Katz et al
45
; NPI-Q, questionnaire format of the Neuropsy-
chiatric Inventory; PGCARS, Philadelphia Geriatric Center Affect Rating Scale; PGCMS, Philadelphia Geriatric Center Morale Scale.
a
The number of observations during the last 1.5 years were limited and therefore data are only shown up to 2 years of follow-up. Group averages for the cognition ratings appear to
increase over the follow-up assessments. This does not actually reflect within-participant changes, but rather the change in group size at each subsequent follow-up. First, participants
who dropped out had worse cognitive ratings. Second, 60 participants enrolled in the study after lights had already been installed. At their first assessment, these 60 participants had
higher scores on the MMSE.
b
Range is shown as worst to best.
c
For example, the neuropsychologist obtained a total of 619 successful MMSE assessments, of which 500 were follow-up assessments, for 174 participants. In addition to failure of
observation reported in the “Results” section, a few observations were missed for some variables due to issues of ambiguity or readability in the rating reports.
d
Indicates double placebo.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2648 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
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years, allowing for 6 follow-up assess-
ments (1 short-term and 5 half yearly).
Under the assumption of a within-
subject correlation of r=0.50 and using
the formulas provided by Twisk,
51
147
participants would be needed to at-
tain, at a 2-sided a level of less than .05,
a power of 0.80 to detect effect sizes of
0.25 for main effects and 0.35 for in-
teractions (ie, between the conven-
tional definition of a small effect size
of 0.20 to a moderate effect size of 0.50).
Because new inhabitants, assigned to
the special care facilities after study ini-
tiation, were faced with the presence of
the dedicated lighting systems, they
were allowed to participate, yielding a
total of 189 participants. A post hoc
power analysis, taking into account the
reduced follow-up and larger sample
size than anticipated (189 partici-
pants followed-up for 3.25 assess-
ments on average), yielded minimal de-
tectable effect sizes of 0.23 for main
effects and 0.33 for interactions.
RESULTS
Randomization was balanced in that
none of the individual or environmen-
tal characteristics, use of medication,
or pretreatment outcome variable lev-
els differed significantly between the 4
groups (Table 1; all P ⬎ .05, average
P=.59; ␹
2
tests performed for frequen-
cies and analyses of variance for lev-
els). The participants included in the
study and followed up in the 4 groups
are shown in Figure 1. An overview of
the number of observations and the sub-
group means and standard deviations
through 2 years are shown in Table 2.
Treatment effects analyzed, taking into
account the factorial design, are given
in T
ABLE 3.
Cognition
Of the maximum number of possible
MMSE observations, 15% (112/744)
failed due to insufficient communica-
tion abilities and 1% (6/744) due to ab-
sence of the participants during the neu-
ropsychologist visit. Regression analysis
showed that light ameliorated cogni-
tive decline overall by 0.9 points (95%
confidence interval [CI], 0.04-1.71,
P=.04) on the MMSE or a relative 5% (all
percentages given relative to intercept
unless stated otherwise). The effect was
best described as a fixed difference at all
time points, and thus left the rate of pro-
gressive worsening unchanged.
Mood Scales
Of the maximum number of possible
CSDD depression observations, 2% (14/
744) were missing due to absence of the
participant or a knowledgeable care-
giver during the neuropsychologist visit.
Light treatment ameliorated depres-
sive symptoms by 1.5 points (95% CI,
0.24-2.70; P =.02) on the CSDD or a
relative 19%. Of the maximum num-
ber of PGCMS scores on the partici-
pants’ self-esteem, 18% (134/744) failed
due to insufficient communication abili-
ties and 1% (6/744) failed due to ab-
sence of the participant during the neu-
ropsychologist visit. No treatment effect
was found for the PGCMS (P =.18 for
light, P=.36 for melatonin, and P=.28
for light plus melatonin). Of the maxi-
mum possible number of caregiver rat-
ings on the PGCARS, MOSES, NPI-Q,
CMAI, and NI-ADL, 4% (30/744) failed
because caregivers stated that they were
unable to provide a rating due to limi-
tations of communication, abilities, or
observability of the participants and 1%
(7/744) due to incomplete data. Mela-
tonin adversely affected observed mood
by lowering positive mood ratings by
0.5 points (95% CI, 0.10-1.00; P=.02)
on the PGCARS positive or 5% and in-
creasing negative mood rating by 0.8
points (95% CI, 0.20-1.44; P=.01) on
the PGCARS negative or 14%. A
light⫻ melatonin interaction effect of
−1.00 point (95% CI, −0.17 to −1.82;
P=.02) on the PGCARS negative or 17%
indicated that the adverse effect of mela-
tonin on negative mood expressions
was compensated for in those partici-
pants who received bright light in ad-
dition to melatonin.
Behavioral Scales
Melatonin treatment aggravated the with-
drawn behavior rating by 1.02 points
(95% CI, 0.18-1.86; P =.02) on the
MOSES or 7%. No treatment effect was
found for the NPI-Q severity (P=.41 for
light, P=.52 for melatonin, and P=.77 for
light plus melatonin) and caregiver dis-
tress (P=.18 for light, P=.32 for mela-
tonin, and P=.80 for light plus melato-
nin). Combined light and melatonin
treatment ameliorated agitated behav-
ior by 3.9 points (95% CI, 0.88-6.92;
P=.01) on the CMAI or a relative 9%.
Activities of Daily Living
Light treatment attenuated the gradual
increase in functional limitations by 1.8
points (95% CI, 0.61-2.92; P=.003) on
the NI-ADL per year (ie, a relative 53%
less steep increase compared with the
increase of 3.3 points per year in par-
ticipants in the inactive light condi-
tion).
Sleep
Of the maximum number of possible
actigraphic recordings, 22% (160/744)
failed due to nonadherence and 2%
(14/744) due to logistics. The percent-
age of missing data did not vary across
time points (␹
2
8
=5.4, P=.71). Light and
melatonin treatment affected sleep in
several ways. As to the quantity of
sleep and wakefulness, the 4 variables
obtained were all affected by the treat-
ments. An important variable is noc-
turnal restlessness, quantified as the
minutes per hour containing any
activity during the most restful 5-hour
period of the average activity profile.
Combined treatment (light and mela-
tonin) ameliorated nocturnal restless-
ness with an effect that increased over
time, ie, by 1.00 minute per hour each
year (95% CI, 0.26-1.78; P = .01) or
9%. Combined treatment also
increased sleep efficiency by 3.5%
(95% CI, 0.8%-6.1%; P=.01). Melato-
nin shortened sleep onset latency by
8.2 minutes (95% CI, 1.08-15.38;
P=.02) or a relative 19% overall. Sleep
duration increased by 27 minutes
(95% CI, 9-46; P =.004) or 6% with
melatonin treatment and in addition
by 10 minutes per year (95% CI, 0.4-
20; P=.04) with light treatment or 2%.
Regarding sleep structure, the treat-
ments significantly reduced sleep frag-
mentation. The combination of light
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
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Table 3. Treatment Effect Estimates
a
Assessment Scale
Treatment
Effect
Overall Analysis
Up to 3.5-y Follow-up
Sensitivity
Analysis for
Up to 1.5-y Follow-up
b
Pattern-Mixture Analysis
c
Effect Modification
by Drop Out
Effect Modification
by Insufficient
Communicative Abilities
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Cognitive Scale
Mini-Mental State
Examination
Light 0.87
(0.04 to 1.71)
.04 1.03
(0.18 to 1.87)
.02 1.45
(−0.14 to 3.03)
.07 −0.27
(−1.77 to 1.23)
.72
Melatonin −0.01
(−0.79 to 0.76)
.97 −0.14
(−0.91 to 0.64)
.73
L ⫻ M −0.23
(−1.38 to 0.93)
.70 −0.49
(−1.64 to 0.66)
.40
Mood Scales
Cornell Scale for Depression
in Dementia
Light −1.47
(−2.70 to −0.24)
.02 −1.76
(−2.98 to −0.53)
.01 1.10
(−0.91 to 3.11)
.28 −0.02
(−2.05 to 2.01)
.98
Melatonin −0.82
(−1.87 to 0.23)
.12 −0.73
(−1.79 to 0.33)
.18
L ⫻ M −0.94
(−2.48 to 0.61)
.24 −1.01
(−2.56 to 0.54)
.20
Philadelphia Geriatric Center
Affect Rating Scale positive
Light −0.17
(−0.81 to 0.48)
.61 −0.21
(−0.86 to 0.45)
.54
Melatonin −0.55
(−1.00 to −0.10)
.02 −0.50
(−0.97 to −0.03)
.04 −0.14
(−1.04 to 0.77)
.76 0.14
(−0.81 to 1.08)
.78
L ⫻ M0.60
(−0.28 to 1.49)
.18 0.57
(−0.35 to 1.48)
.23
Philadelphia Geriatric Center
Affect Rating Scale negative
Light 0.50
(−0.07 to 1.07)
.08 0.38
(−0.19 to 0.94)
.19
Melatonin 0.82
(0.20 to 1.44)
.01 0.82
(0.20 to 1.45)
.01 −0.55
(−1.73 to 0.63)
.36 0.24
(−0.95 to 1.44)
.69
L ⫻ M −1.00
(−1.82 to −0.17)
.02 −0.94
(−1.78 to −0.09)
.03 1.07
(−0.44 to 2.57)
.16 −0.43
(−2.00 to 1.14)
.59
Philadelphia Geriatric Center
Morale Scale
Light 0.35
(−0.28 to 0.98)
.18 0.49
(−0.16 to 1.14)
.18
Melatonin 0.21
(−0.38 to 0.80)
.36 0.25
(−0.36 to 0.86)
.36
L ⫻ M0.07
(−0.71 to 0.85)
.28 0.09
(−0.71 to 0.89)
.28
Behavioral Scales
Multi Observation Scale
for Elderly Subjects
Light −0.51
(−1.55 to 0.53)
.34 −0.68
(−1.76 to 0.40)
.22
Melatonin 1.02
(0.18 to 1.86)
.02 0.81
(−0.07 to 1.69)
.07 0.35
(−1.29 to 1.98)
.68 0.80
(−0.88 to 2.48)
.35
L ⫻ M −0.74
(−2.35 to 0.87)
.37 −0.82
(−2.45 to 0.81)
.32
Neuropsychiatric Inventory
questionnaire format on severity
Light 0.23
(−0.73 to 1.19)
.41 0.06
(−0.92 to 1.04)
.90
Melatonin −0.41
(−1.21 to 0.39)
.52 −0.54
(−1.36 to 0.28)
.20
L ⫻ M −0.36
(−1.42 to 0.70)
.77 −0.42
(−1.50 to 0.66)
.45
Neuropsychiatric Inventory
questionnaire format on distress
Light 0.25
(−0.87 to 1.37)
.18 0.11
(−1.04 to 1.25)
.85
Melatonin −0.68
(−1.64 to 0.28)
.32 −0.72
(−1.71 to 0.26)
.15
L ⫻ M −0.56
(−1.81 to 0.69)
.80 −0.54
(−1.84 to 0.76)
.41
Cohen-Mansfield Agitation Index Light −1.61
(−4.82 to 1.60)
.33 −1.85
(−5.04 to 1.34)
.26
Melatonin 1.28
(−1.99 to 4.55)
.44 1.40
(−1.89 to 4.68)
.41
L ⫻ M −3.90
(−6.92 to −0.88)
.01 −3.83
(−6.90 to −0.75)
.01 −5.35
(−11.19 to 0.49)
.07 −0.51
(−6.64 to 5.61)
.87
(continued)
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2650 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
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and melatonin treatment interacted to
reduce the average duration of indi-
vidual brief nocturnal awakenings by
0.5 minutes per year (95% CI, 0.21-
0.85; P =.01) or a relative 12%. Mela-
tonin treatment increased the average
duration of uninterrupted periods of
sleep by 5.8 minutes (95% CI, 1.0-
10.6; P=.02) or a relative 25%.
Table 3. Treatment Effect Estimates
a
(cont)
Assessment Scale
Treatment
Effect
Overall Analysis
Up to 3.5-y Follow-up
Sensitivity
Analysis for
Up to 1.5-y Follow-up
b
Pattern-Mixture Analysis
c
Effect Modification
by Drop Out
Effect Modification
by Insufficient
Communicative Abilities
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Functional Scale
Nurse-informant activities
of daily living scale
44,45
Light −1.77/y
(−2.92 to −0.61)
.003 −2.02/y
(−3.78 to −0.26)
.02 −0.26
(−2.72 to 2.21)
.84 0.04
(−1.39 to 1.48)
.95
Melatonin −0.92
(−2.33 to 0.49)
.20 −1.52
(−3.00 to −0.04)
.04
L ⫻ M −1.25
(−3.13 to 0.63)
.19 −1.73
(−3.70 to 0.23)
.08
Actigraphic Sleep Estimates
Sleep efficiency, % Light 0.83
(−1.89 to 3.55)
.55 1.00
(−1.77 to 3.78)
.48
Melatonin 1.50
(−1.40 to 4.40)
.31 1.72
(−1.18 to 4.62)
.25
L ⫻ M3.46
(0.84 to 6.09)
.01 2.92
(0.25 to 5.58)
.03 1.66
(−3.49 to 6.81)
.53 −0.55
(−7.47 to 6.38)
.88
Sleep onset latency, min Light −3.61
(−11.23 to 4.01)
.35 −2.46
(−10.38 to 5.45)
.54
Melatonin −8.23
(−15.38 to −1.08)
.02 −7.16
(−14.56 to 0.23)
.06 1.33
(−13.05 to 15.72)
.86 1.54
(−15.60 to 18.67)
.86
L ⫻ M −1.71
(−14.3 to 10.8)
.79 0.29
(−12.7 to 13.3)
.97
Total sleep duration, min Light 10.14/y
(0.38 to 19.90)
.04 15.66/y
(2.14 to 29.18)
.02 0.05
(−0.24 to 0.34)
.75 0.15
(−0.14 to 0.44)
.31
Melatonin 27.48
(8.55 to 46.41)
.004 20.28
(4.05 to 36.51)
.01 0.14
(−0.39 to 0.66)
.61 −0.13
(−0.76 to 0.51)
.70
L ⫻ M8.46
(−27.6 to 44.6)
.65 8.64
(−22.8 to 40.0)
.59
Nocturnal restlessness, min/h Light −0.25
(−1.47 to 0.97)
.69 −0.17
(−1.44 to 1.10)
.79
Melatonin −0.48
(−1.62 to 0.66)
.41 −0.40
(−1.60 to 0.79)
.51
L ⫻ M −1.00
(−1.78 to −0.26)
.01 −1.39
(−2.62 to −0.17)
.03 −0.54
(−2.17 to 1.09)
.52 0.26
(−2.26 to 2.77)
.84
Duration of awakenings, min Light −0.50
(−1.04 to 0.04)
.07 −0.57
(−1.15 to 0.02)
.06
Melatonin −0.05
(−0.52 to 0.41)
.83 −0.02
(−0.52 to 0.49)
.95
L ⫻ M −0.53/y
(−0.85 to −0.21)
.01 −0.63/y
(−1.21 to −0.05)
.03 −0.20
(−0.89 to 0.50)
.58 −1.00
(−2.16 to 0.16)
.09
Duration uninterrupted sleep
epochs, min
Light 0.05
(−4.93 to 5.03)
.98 0.29
(−5.07 to 5.66)
.91
Melatonin 5.83
(1.05 to 10.61)
.02 6.03
(0.96 to 11.09)
.02 2.02
(−7.56 to 11.60)
.68 −7.71
(−18.98 to 3.56)
.18
L ⫻ M −0.15
(−8.30 to 8.00)
.97 0.50
(−8.16 to 9.15)
.91
Abbreviations: CI, confidence interval; L ⫻ M, light ⫻ melatonin interaction.
a
Obtained from analyses using all available data assessed during up to 3.5 years of follow-up. The estimates indicate factorial effects; for example, light treatment increased MMSE scores
by 0.87 points (95% CI, 0.04-1.71), irrespective of whether participants were assigned to the active or placebo melatonin condition. Effect estimates were obtained from intent-to-treat
mixed-effect regression analyses including a pattern-mixture model approach
56
to account for missing data. Treatment effects were best modeled as modulated by time for the effect
of light on the NI-ADL, and for the effect of the combination of light and melatonin on nocturnal restlessness and the mean duration of intermittent awakenings (expressed in units of
effect per year).
b
Because, after 1.5 years of follow-up, only a limited number of observations could be obtained, a sensitivity analysis was performed to estimate effects as obtained from analysis on a
data set that was limited to the first 1.5 years of follow-up.
c
Missing data due to (1) death or nursing home placement and (2) insufficient communicative abilities at any assessment occasion were considered to be informative and dummy coded
(indicating presence of this condition for a participant at any point in time) to allow for evaluation of their possible effects in a pattern mixture model.
56
None of the treatment ⫻ dropout
pattern effect estimates reached significance, indicating that treatment effects that reached significance in the overall analyses were not a result of confounding by selective missing data
and were of equal size for participants with and without missing data.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2651
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Prescription of Medication
The 4 groups did not differ in the pro-
portion of participants receiving psy-
chotropic medication at the onset of
their participation (Table 1, all P⬎ .32
by ␹
2
test). Logistic mixed-effect re-
gression analysis showed that the pre-
scription use of antipsychotics, anxio-
lytics, hypnotics, and antidepressants
did not change after treatment onset
compared with prescription use prior
to treatment onset (all P ⬎ .80). There
were no effects on prescription use with
either light or melatonin treatment or
their interaction (all P⬎ .35).
Missing Data and Effect
Modification by Diagnosis
and Visual Impairment
Because, particularly after 1.5 years,many
cases were lost to follow-up, it was im-
portant to determine whether treatment
effects obtained fromanalyseson the com-
plete 3.5-year data set were present when
only the first 1.5 years of follow-up were
included in the analysis. Compared with
the treatment effect estimates based on
all available data, only marginal changes
occurred when theestimates were derived
from only the first 1.5 years of follow-up
(Table 3). In fact, positive treatment effect
size estimates were similar or increased
when based on the first 1.5 years com-
pared with the full data set. Adverse treat-
ment effect sizes were generally less or
unchanged. This sensitivity analysis sug-
gests that the results cannot be attributed
to confounding by drop out.
The second approach to assess the im-
pact of dropouts was to code missing data
due to (1) death or nursing home place-
ment or (2) insufficient communication
abilities in 2 dummyvariables to allow for
inclusionin the regressionanalysis accord-
ing to a pattern-mixture model approach.
Individuals who dropped out of the study
due to nursing home placement or death
scored markedly worse on the MMSE
(−3.5; 95% CI, −5.1 to −1.8), PGARS posi-
tive (−0.9; 95% CI, −1.5 to −0.4), PGARS
negative (0.9; 95% CI, 0.3 to1.5), MOSES
(4.4; 95% CI,2.9 to 5.8),and NI-ADL (5.5;
95% CI, 2.3 to8.8). Relative to the decline
participants showed overall (all of the fol-
lowing expressed in scale points per year)
on the MMSE(−1.1; 95% CI,−1.4 to −0.7),
CSDD (2.1; 95% CI, 1.5 to 2.6), MOSES
(1.1; 95%CI, 0.8 to 1.5), CMAI (1.3; 95%
CI, 0.2 to 2.5), and NI-ADL (3.3; 95% CI,
2.3 to 4.3), participants who dropped out
worsened at a faster rate on the MMSE
(−1.5; 95% CI, −2.1 to −0.9), CSDD (1.5;
95% CI, 0.6 to 2.4), NPI-Q severity (2.1;
95% CI, 1.3 to 2.9), NPI-Q distress (2.5;
95% CI, 1.5 to 3.5), CMAI (4.2; 95% CI,
2.2 to 6.2), and NI-ADL (2.9; 95% CI,
1.6 to 4.2). Therefore, a pattern-mixture
analysis was performed that considered
dropouts as informative for the out-
come measures. These analyses showed
that none of the treatment⫻drop out or
treatment⫻insufficient communicative
abilities interaction terms reached sig-
nificance when added to the regression
models of the outcomes that showed sig-
nificant treatment effects in the overall
analysis (Table 3). Moreover, treatment
groups did not differ with regard to the
frequency of participants with dropout
pattern 1 (P⬎.99) or 2 (P=.51) (␹
2
test).
Finally, none of the treatment effects was
modulated by the presence or absence
of the diagnosis of probable Alzheimer
disease or by visual impairment (data
available on request). Attenuations of the
favorable treatment effects on nocturnal
restlessness (P=.07) and on the mean
duration of intermittent awakenings
(P=.08) for participants with opacity of
1 or both lenses of the eye were the clos-
est to significance.
Adverse Effects
An overview of the average ratings prior
to and during treatment is given in
T
ABLE 4. Items with the highest overall
ratings were drowsiness and irritability.
Of note, in contrast to previous studies
on light and melatonin that suggested an
increased occurrence of complaints, an
increased occurrence by either light or
melatonin treatment or their interaction
was not found.Onthe contrary, compared
with the pretreatment assessment and the
placebo-treated participants, light treat-
ment significantly reduced the ratings on
irritability, dizziness, headache, consti-
pation, and inability to sleep. Melatonin
reduced the ratings on constipation. No
severe adverse eventswere reported bythe
patients’ physicians. In the only case re-
portedby others, thedaughterof a 90-year-
old participant diagnosed with probable
Lewy body dementia suspected hermoth-
er’s increase in restlessness and falls to be
related to the treatment andrequested dis-
continuation. This patient had been as-
signed to the double placebo group.
COMMENT
This, to our knowledge, is the first
double-blind, placebo-controlled ran-
domized trial evaluating a combination
of the circadian stimuli light and mela-
tonin on a daily basis for an average of
15 months. The application of indirect
ceiling-mounted, whole-day bright light
resulted in optimal adherence and al-
lowed for a verifiable placebo group.
Light reduced the cognitive deficits by
5% without decelerating the progressive
cognitive worsening (as is also the case
for acetylcholinesterase inhibitors
8
). Light
also reduced depressive symptoms by a
relative 19% and attenuated the gradual
increase in functional limitations by 53%.
A similar increase in efficacy over time
by 2% was found for its effect on sleep
duration.
Melatonin had no effect on the CSDD
depression ratings but adversely affected
caregiver ratings of withdrawn behavior
and mood expressions. We suspect that
the long-term daily application of 2.5 mg
of melatonin may have induced supra-
physiological daytime levels, which are
associated with sleepiness and dyspho-
ria.
55,56
Bright light amelioratedtheadverse
effect on mood. For practical application
in elderly residents, a dose lower than 2.5
mg should be consideredas well as simul-
taneous application of bright light.
However, melatonin also induced
positive effects. In combination with
bright light, it attenuated agitated be-
havior by 9%. Most notably, melatonin
reduced sleep onset latency by a rela-
tive 19%, increased total sleep duration
by 6%, and increased the mean dura-
tion of uninterrupted sleep periods,
which has been related to the depth of
sleep,
50
by 25%. Furthermore, in com-
bination with bright light, melatonin im-
proved sleep efficiency (3.5%), noctur-
nal restlessness (9% per year), and the
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2652 JAMA, June 11, 2008—Vol 299, No. 22 (Reprinted) ©2008 American Medical Association. All rights reserved.
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from

average duration of brief nocturnal awak-
enings (12% per year). The strength of
the latter 2 effects increased over time
with treatment. If effects were sus-
tained over time, prolonged combined
treatment could help maintain sleep ef-
ficiency above 85%, which has been re-
garded as a cutoff for clinically relevant
disturbed sleep.
57
Our novel finding that
some melatonin effects develop slowly
and/or only in combination with light
treatment may explain the lack of ef-
fects in some of the previous short-
term studies.
29,58
Four limitations should be dis-
cussed. First, the study was performed
in a somewhat heterogeneous group of
elderly people, most of whom had
dementia, representative of residents in
group care facilities. Our trial should
therefore be considered a practical clini-
cal trial, which includes a more diverse
study population than is usually the case
in clinical trials with restricted eligibil-
ity criteria. Practical clinical trials have
been recommended to provide health
care decision makers with a more reli-
able estimate of applicability.
23
Second,
intrinsic to the aim of a practical clinical
trial, one should be cautious regarding
the multiplicity of analyses and out-
comes. However, light consistently
improved several important clinical para-
meters. As noted by Caspi et al,
59
the con-
sistency of results in several parameters
suggests a robust finding because the
number of significant effects far exceeds
the proportion that could be explained
by chance. A third issue concerns the lim-
ited number of men participating in the
present study. Although representative
of care facility occupancy in the Neth-
erlands, which is dominated by women,
these results may not be generalizable to
men. A fourth limitation was the sub-
stantial number of participants eventu-
ally lost to follow-up. Drop out was pri-
marily due to logistic limitations (ie,
discontinuation of facilities) and sec-
ondarily related to the very nature of the
population under study, which is at high
risk of death and transfer to a nursing
home. We verified that the treatment
effects were not modulated by dropout
pattern and were robust in a sensitivity
analysis limiting the data set to the first
1.5 years of follow-up.
Table 4. Evaluation of Potential Adverse Effects
a
Complaint
Rating, Mean (SD)
b
Light
c
Melatonin Light ⫹ Melatonin
Preas-
sessment None Light Melatonin
Light ⫹
Melatonin
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Effect Estimate
(95% CI)
P
Value
Dizziness 0.94
(1.15)
0.89
(1.16)
0.44
(0.94)
0.73
(0.98)
0.56
(1.00)
−0.37
(−0.55 to −0.19)
⬍.001 −0.24
(−0.49 to 0.01)
.06 0.31
(−0.06 to 0.69)
.12
Drowsiness 0.98
(1.25)
0.97
(1.22)
0.93
(1.25)
1.12
(1.24)
0.94
(1.26)
−0.01
(−0.31 to 0.29)
.93 0.12
(−0.18 to 0.42)
.42 −0.06
(−0.50 to 0.37)
.77
Eye complaints 0.86
(1.22)
0.65
(0.98)
0.52
(0.93)
0.74
(1.08)
0.65
(1.12)
−0.01
(−0.23 to 0.21)
.91 −0.12
(−0.30 to 0.06)
.19 0.36
(−0.01 to 0.74)
.06
Feebleness 0.69
(1.11)
0.52
(0.97)
0.30
(0.80)
0.73
(1.06)
0.43
(0.95)
−0.17
(−0.38 to 0.04)
.11 −0.02
(−0.26 to 0.22)
.88 0.19
(−0.16 to 0.54)
.29
Headache 0.75
(1.07)
0.60
(0.88)
0.52
(0.97)
0.86
(1.03)
0.55
(1.01)
−0.22
(−0.41 to −0.02)
.03 0.01
(−0.23 to 0.24)
.96 0.03
(−0.32 to 0.37)
.88
Hunger 0.38
(0.84)
0.49
(0.92)
0.22
(0.70)
0.32
(0.77)
0.22
(0.74)
0
(−0.20 to 0.19)
.98 −0.15
(−0.34 to 0.05)
.14 −0.08
(−0.36 to 0.20)
.57
Hyperactivity 0.26
(0.80)
0.50
(0.98)
0.25
(0.70)
0.34
(0.80)
0.16
(0.55)
−0.07
(−0.24 to 0.11)
.46 0.10
(−0.09 to 0.28)
.31 −0.21
(−0.48 to 0.06)
.13
Inability to sleep 0.63
(0.96)
0.94
(1.09)
0.20
(0.60)
0.75
(0.95)
0.32
(0.80)
−0.52
(−0.67 to −0.37)
⬍.001 −0.02
(−0.24 to 0.21)
.87 0.24
(−0.08 to 0.57)
.14
Irritability 1.07
(1.27)
1.29
(1.22)
0.93
(1.20)
1.00
(1.16)
0.57
(1.07)
−0.34
(−0.57 to −0.11)
.004 −0.12
(−0.41 to 0.16)
.40 −0.16
(−0.58 to 0.26)
.45
Nausea 0.36
(0.86)
0.40
(0.77)
0.27
(0.75)
0.40
(0.80)
0.27
(0.79)
−0.05
(−0.23 to 0.14)
.62 0
(−0.19 to 0.19)
⬎.99 −0.11
(−0.39 to 0.17)
.45
Constipation 0.84
(1.11)
0.88
(1.09)
0.46
(0.92)
0.67
(0.99)
0.23
(0.67)
−0.33
(−0.54 to −0.11)
.003 −0.17
(−0.33 to 0)
.05 0.10
(−0.23 to 0.43)
.55
Pins and needles 0.24
(0.62)
0.46
(0.77)
0.09
(0.38)
0.23
(0.51)
0.19
(0.66)
−0.10
(−0.25 to 0.04)
.16 −0.14
(−0.28 to 0.01)
.06 0.16
(−0.04 to 0.37)
.12
Stomach ache 0.23
(0.62)
0.26
(0.58)
0.21
(0.66)
0.31
(0.65)
0.11
(0.47)
0.02
(−0.12 to 0.16)
.75 −0.02
(−0.16 to 0.13)
.83 −0.04
(−0.25 to 0.18)
.73
Sweating 0.37
(0.89)
0.48
(0.93)
0.26
(0.79)
0.41
(0.88)
0.18
(0.65)
0.17
(−0.02 to 0.37)
.09 0.01
(−0.20 to 0.21)
.96 −0.07
(−0.36 to 0.23)
.66
Trembling hands 0.37
(0.91)
0.45
(0.92)
0.22
(0.69)
0.56
(1.05)
0.39
(0.92)
−0.05
(−0.25 to 0.14)
.61 0.01
(−0.20 to 0.22)
.92 0.07
(−0.25 to 0.39)
.68
Other complaints 0.48
(1.09)
0.30
(0.85)
0.29
(0.88)
0.41
(0.97)
0.28
(0.86)
−0.05
(−0.27 to 0.18)
.69 −0.02
(−0.23 to 0.19)
.85 0.02
(−0.28 to 0.31)
.91
Abbreviation: CI, confidence interval.
a
Caregivers provided a total of 694 adverse effects scale ratings, of which 571 were follow-up assessments, for 182 participants.
b
The 16-item ratings were given on a 4-point scale (0 = absent, 1 = probably absent, 2 = probably present, 3 = present).
c
Light treatment lowered the ratings on irritability, dizziness, headache, constipation, and inability to sleep; treatment with melatonin lowered the ratings on constipation.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2653
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from

We hypothesize that enhancement of
the function of circadian timing system
has been involved in thetreatment effects.
Several previous studies
12-18
suggest an in-
volvement of the circadian timing system
in optimal brain function, while other
studies
20-22
indicate functional deficits in
the circadian timing system at advanced
age and in dementia. The long-term
supplementation of light as the primary
stimuli acting on the suprachiasmatic
nucleus may have improved its abilities
to synchronize rhythms in for example,
hormones, metabolism, and peripheral
oscillators, which concertedly contrib-
ute to an individual’s general function-
ing. This synchronization may be a slow
process, which could account for the
gradual increase in some of the effects.
For example, even in healthyhumans and
animals, some studies have shown that
it may take months until effects of light
or exercise on day-night rhythms become
evident (reviewed previously
60
). From a
practical point of view, one might imag-
ine the effects of enhanced rhythm syn-
chronization on general well-being as
comparable with recoveryfrom detrimen-
tal effects of jet lag and disturbed sleep.
A final issue to be discussed is whether
the statistically significant findings can
be interpreted as clinically relevant. Al-
though effects between 3.5 and 3.9
points on the MMSE have been consid-
ered clinically significant,
61
no treat-
ments have come close to this large an
effect. A meta-analysis concluded that
acetylcholinesterase inhibitors im-
prove cognitive performance by about
0.60 to 1.10 points on the MMSE.
62
Al-
though no direct comparison with our
findings can be made because our par-
ticipants were not all diagnosed with Alz-
heimer disease and showed more se-
vere cognitive deterioration at onset, the
effect by light of 0.87 points (95% CI,
0.04-1.71) on the MMSE is of a compa-
rable magnitude. Unlike acetylcholin-
esterase inhibitors, it did not manifest
adverse effects. Of further importance for
the evaluation of clinical relevance is that
light also contributed to improve-
ments in mood, behavior, functional
limitations, and sleep. Given the CSDD
cutoff scores of 8 for minor and 12 for
major depression, and the present CSDD
scores varying between about 8 and 12
on average in the placebo group, the light
treatment-related amelioration by 1.5
points (95% CI, 0.24-2.70) on the CSDD
or 19% could change the score from ma-
jor depression to minor depression, or
minor depression to no depression. Al-
though we are not aware of cutoff scores
for the behavioral and functional scales,
a reduction of 58% in the gradual in-
crease in functional limitations could be
clinically relevant. On the other hand,
with sleep efficiency varying between
about 70% and 76% on average in the
placebo group, the improvement of 3.5%
by combined treatment is not suffi-
cient to reach the often-used cutoff of
85% to overcome clinically relevant dis-
turbed sleep. On the whole, light treat-
ment could have clinically beneficial ef-
fects. We did not assess the cost of light
treatment; lights were provided at re-
duced cost and installation was not
changed.
In conclusion, the simple measure of
increasing the illumination level in
group care facilities ameliorated symp-
toms of disturbed cognition, mood, be-
havior, functional abilities, and sleep.
Melatonin improved sleep, but its long-
term use by elderly individuals can only
be recommended in combination with
light to suppress adverse effects on
mood. The long-term application of
whole-day bright light did not have ad-
verse effects, on the contrary, and could
be considered for use in care facilities
for elderly individuals with dementia.
Author Affiliations: Netherlands Institute for Neuro-
science, Royal Netherlands Academy of Arts and Sci-
ences, Amsterdam (Drs Riemersma-van der Lek,
Swaab, Hol, and Van Someren); and Departments of
Clinical Epidemiology and Biostatistics (Dr Twisk), Psy-
chiatry (Dr Hoogendijk), Neurology (Dr Van Some-
ren), Clinical Neurophysiology (Dr Van Someren), and
Medical Psychology (Dr Van Someren), Research In-
stitute Neuroscience CNCR (Dr Hoogendijk), and Alz-
heimer Center (Dr Van Someren), VU University Medi-
cal Center, Amsterdam, the Netherlands. Dr
Riemersma-van der Lek is now with the Department
of Psychiatry, University Medical Center Groningen,
Groningen, the Netherlands.
Author Contributions: Dr Van Someren had full ac-
cess to all of the data in the study and takes respon-
sibility for the integrity of the data and the accuracy
of the data analysis.
Study concept and design: Riemersma-van der Lek,
Swaab, Hoogendijk, Van Someren.
Acquisition of data: Riemersma-van der Lek, Hol, Van
Someren.
Analysis and interpretation of data: Riemersma-van
der Lek, Swaab, Twisk, Hol, Van Someren.
Drafting of the manuscript: Riemersma-van der Lek,
Hol, Van Someren.
Critical revision of the manuscript for important in-
tellectual content: Riemersma-van der Lek, Swaab,
Twisk, Hol, Hoogendijk, Van Someren.
Statistical analysis: Twisk, Van Someren.
Obtained funding: Riemersma-van der Lek, Swaab,
Van Someren.
Administrative, technical, or material support: Swaab,
Hol, Hoogendijk, Van Someren.
Study supervision: Swaab, Hoogendijk, Van Someren.
Financial Disclosures: None reported.
Funding/Support: Financial and material support were
provided by the Netherlands Organization for Health
Research, the Hague, by grants 0028-300-30 and 907-
00-012; the Netherlands Organisation for Scientific Re-
search, the Hague, by grants 016.025.041 and
051.04.010; the Stichting De Drie Lichten, Leiden;
Stichting RVVZ; Zeist by grant 01-220; Japan Foun-
dation for Aging and Health; Hersenstichting Neder-
land by grant 11F04-2.47; Internationale Stichting Alz-
heimer Onderzoek by grant 05511. Philips Lighting
BV, Braun, and Cambridge Neurotechnology sup-
plied material for this study at reduced cost.
Role of the Sponsor: None of the sponsors or fun-
ders had any involvement in the design or conduct of
the study; collection, management, analysis, and in-
terpretation of the data; and preparation, review or
approval of the manuscript.
Additional Information: An equation and additional
details about the mixed-effect regression analysis is
available at http://www.jama.com.
Additional Contributions: We thank the inhabitants
and staff of the participating homes for the elderly.
Renske van Hutten, MSc, Annemarie Kalis, MSc, and
Rene den Haan, MSc, provided neuropsychological as-
sessments, Jacqueline Sluijs, BSc, provided the assess-
ment of the apolipoprotein E genotype, Joop van Heer-
ikhuize, BSc, participated in the randomization and
distribution of tablets, Jenneke Kruisbrink, PhD, pro-
vided library assistance, and Tini Eikelboom, MSc, and
Wilma Verweij, MSc, corrected the English spelling and
grammar; all are from the Netherlands Institute for
Neuroscience, Amsterdam. The following persons pro-
vided advice on the protocol: Marcel Smits, MD, PhD
(Centre for Sleep-Wake disorders and Chronobiol-
ogy, Hospital Gelderse Vallei, Ede, the Netherlands)
and Elsbeth Nagtegaal, PhD (Meander Medical Cen-
ter, Department of Pharmacy, Amersfoort, the Neth-
erlands). The following persons provided advice on
multilevel analysis: Hans Berkhof, PhD (Department
of Clinical Epidemiology and Biostatistics, VU Univer-
sity Medical Center, Amsterdam, the Netherlands) and
Min Yang, PhD (Centre for Statistics at Queen Mary
University of London, London, England). Debra Skene,
PhD (Neuroendocrinology Research Group, School of
Biomedical and Molecular Sciences, University of Sur-
rey, Guildford, England) provided critical reading of
the manuscript and useful comments. None of the ac-
knowledged persons received any compensation.
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