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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 Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in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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http://jama.ama-assn.org/cgi/content/full/299/22/2642
. 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% (treatmenttime 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 22 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
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from
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) (P.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
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2645
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from
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 (P.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
grouptime 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
©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, June 11, 2008—Vol 299, No. 22 2649
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from
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 treatmentdrop out or
treatmentinsufficient 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.
REFERENCES
1. Lee HB, Lyketsos CG. Depression in Alzheimer’s dis-
ease: heterogeneity and related issues. Biol Psychiatry.
2003;54(3):353-362.
2. Purandare N, Burns A, Craig S, Faragher B, Scott
K. Depressive symptoms in patients with Alzheimer’s
disease. Int J Geriatr Psychiatry. 2001;16(10):960-
964.
3. Gonza´ lez-Salvador T, Lyketsos CG, Baker A, et al.
Quality of life in dementia patients in long-term care.
Int J Geriatr Psychiatry. 2000;15(2):181-189.
4. Donaldson C, Tarrier N, Burns A. Determinants of
carer stress in Alzheimer’s disease. Int J Geriatr
Psychiatry. 1998;13(4):248-256.
EFFECT OF BRIGHT LIGHT AND MELATONIN ON ELDERLY RESIDENTS
2654 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
5. Dorenlot P, Harboun M, Bige V, Henrard JC, Ankri
J. Major depression as a risk factor for early institu-
tionalization of dementia patients living in the
community. Int J Geriatr Psychiatry. 2005;20(5):
471-478.
6. Devanand DP, Jacobs DM, Tang MX, et al. The
course of psychopathologic features in mild to mod-
erate Alzheimer disease. Arch Gen Psychiatry. 1997;
54(3):257-263.
7. Banerjee S, Murray J, Foley B, Atkins L, Schneider
J, Mann A. Predictors of institutionalisation in people
with dementia. J Neurol Neurosurg Psychiatry. 2003;
74(9):1315-1316.
8. Courtney C, Farrell D, Gray R, et al. Long-term do-
nepezil treatment in 565 patients with Alzheimer’s dis-
ease (AD2000): randomised double-blind trial. Lancet.
2004;363(9427):2105-2115.
9. Sink KM, Holden KF, Yaffe K. Pharmacological treat-
ment of neuropsychiatric symptoms of dementia: a re-
view of the evidence. JAMA. 2005;293(5):596-608.
10. Van Someren EJW. Circadian and sleep distur-
bances in the elderly. Exp Gerontol. 2000;35(9-10):
1229-1237.
11. Salzman C, Wong E, Wright BC. Drug and ECT treat-
ment of depression in the elderly, 1996-2001: a litera-
ture review. Biol Psychiatry. 2002;52(3):265-284.
12. Fekete M, van Ree JM, Niesink RJ, de Wied D. Dis-
rupting circadian rhythms in rats induces retrograde
amnesia. Physiol Behav. 1985;34(6):883-887.
13. Cho K. Chronic ’jet lag’ produces temporal lobe
atrophy and spatial cognitive deficits. Nat Neurosci.
2001;4(6):567-568.
14. Walker MP, Stickgold R. Sleep-dependent learn-
ing and memory consolidation. Neuron. 2004;
44(1):121-133.
15. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic
nucleus of the human brain in relation to sex, age and
senile dementia. Brain Res. 1985;342(1):37-44.
16. Zhou JN, Riemersma RF, Unmehopa UA, et al. Al-
terations in arginine vasopressin neurons in the su-
prachiasmatic nucleus in depression. Arch Gen
Psychiatry. 2001;58(7):655-662.
17. Liu RY, Zhou JN, Hoogendijk WJG, et al. De-
creased vasopressin gene expression in the biological
clock of Alzheimer’s disease patients with and with-
out depression. J Neuropathol Exp Neurol. 2000;
59(4):314-322.
18. Moe KE, Vitiello MV, Larsen LH, Prinz PN. Sleep/
wake patterns in Alzheimer’s disease: relationships with
cognition and function. J Sleep Res. 1995;4(1):
15-20.
19. Moore RY. Entrainment pathways and the func-
tional organization of the circadian system. Prog Brain
Res. 1996;111:103-119.
20. Van Someren EJW, Riemersma RF, Swaab DF.
Functional plasticity of the circadian timing system in
old age: light exposure. Prog Brain Res. 2002;138:
205-231.
21. Riemersma RF, Mattheij CAM, Swaab DF, Van
Someren EJW. Melatonin rhythms, melatonin supple-
mentation and sleep in old age. In: Straub RH, Moc-
chegiani E, eds. The Neuroendocrine Immune Net-
work in Ageing. Vol 4. Amsterdam, the Netherlands:
Elsevier; 2004:195-211.
22. Mishima K, Okawa M, Hishikawa Y, Hozumi S, Hori
H, Takahashi K. Morning bright light therapy for sleep
and behavior disorders in elderly patients with dementia.
Acta Psychiatr Scand. 1994;89(1):1-7.
23. Tunis SR, Stryer DB, Clancy CM. Practical clinical
trials: increasing the value of clinical research for de-
cision making in clinical and health policy. JAMA. 2003;
290(12):1624-1632.
24. American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders. 4th ed. Wash-
ington, DC: American Psychiatric Association; 1994.
25. McKhann G, Drachman D, Folstein M, Katzman R,
Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s dis-
ease: report of the NINCDS-ADRDA Work Group un-
der the auspices of Department of Health and Human
Services Task Force on Alzheimer’s Disease. Neurology.
1984;34(7):939-944.
26. Sloane PD, Mathew LJ. The Therapeutic Environ-
ment Screening Scale. Am J Alz Care Related Disord
Res. 1990;5(1):22-26.
27. Slaughter S, Calkins M, Eliasziw M, Reimer M. Mea-
suring physical and social environments in nursing
homes for people with middle- to late-stage dementia.
J Am Geriatr Soc. 2006;54(9):1436-1441.
28. Zhdanova IV, Lynch HJ, Wurtman RJ. Melatonin—
a sleep-promoting hormone. Sleep. 1997;20(10):
899-907.
29. Singer C, Tractenberg RE, Kaye J, et al. A multi-
center, placebo-controlled trial of melatonin for sleep
disturbance in Alzheimer’s disease. Sleep. 2003;
26(7):893-901.
30. Tozawa T, Mishima K, Satoh K, et al. Melatonin
replacement therapy for rest-activity rhythm disor-
ders in patients with senile dementia of the Alzhei-
mer type. Neurobiol Aging. 1998;19(4S):S182.
31. Middleton B, Stone BM, Arendt J. Human circa-
dian phase in 12:12 h, 200: 8 lux and 1000: 8lux
light-dark cycles, without scheduled sleep or activity.
Neurosci Lett. 2002;329(1):41-44.
32. Van Someren EJW, Kessler A, Mirmiran M, Swaab
DF. Indirect bright light improves circadian rest-
activity rhythm disturbances in demented patients. Biol
Psychiatry. 1997;41(9):955-963.
33. Folstein MF, Folstein SE, McHugh PR. “Mini-
mental state”: a practical method for grading the cog-
nitive state of patients for the clinician. J Psychiatr Res.
1975;12(3):189-198.
34. Alexopoulos GS, Abrams RC, Young RC, Shamoian
CA. Cornell scale for depression in dementia. Biol
Psychiatry. 1988;23(3):271-284.
35. Harwood DG, Ownby RL, Barker WW, Duara R.
The factor structure of the Cornell Scale for Depres-
sion in Dementia among probable Alzheimer’s dis-
ease patients. Am J Geriatr Psychiatry. 1998;6
(3):212-220.
36. Lawton MP. The Philadelphia Geriatric Center
Morale Scale: a revision. J Gerontol. 1975;30(1):
85-89.
37. Ryden MB, Knopman D. Assess not assume–
measuring the morale of cognitively impaired elderly.
J Gerontol Nurs. 1989;15(11):27-32.
38. Lawton MP, Van Haitsma K, Klapper J. Ob-
served affect in nursing home residents with Alzhei-
mer’s disease. J Gerontol B Psychol Sci Soc Sci. 1996;
51(1):P3-P14.
39. Helmes E, Csapo KG, Short JA. Standardization
and validation of the Multidimensional Observation
Scale for Elderly Subjects (MOSES). J Gerontol. 1987;
42(4):395-405.
40. Kaufer DI, Cummings JL, Ketchel P, et al. Vali-
dation of the NPI-Q, a brief clinical form of the Neu-
ropsychiatric Inventory. J Neuropsychiatry Clin
Neurosci. 2000;12(2):233-239.
41. de Jonghe JF, Kat MG, Kalisvaart CJ, Boelaarts L.
Neuropsychiatric Inventory Questionnaire (NPI-Q): a
validity study of the Dutch form [in Dutch]. Tijdschr
Gerontol Geriatr. 2003;34(2):74-77.
42. Cohen-Mansfield J, Marx MS, Rosenthal AS. A
description of agitation in a nursing home. J Gerontol.
1989;44(3):M77-M84.
43. de Jonghe JF, Kat MG. Factor structure and va-
lidity of the Dutch version of the Cohen-Mansfield Agi-
tation Inventory (CMAI-D). J Am Geriatr Soc. 1996;
44(7):888-889.
44. Holmes D, Teresi J, Weiner A, Monaco C, Ronch
J, Vickers R. Impacts associated with special care units
in long-term care facilities. Gerontologist. 1990;
30(2):178-183.
45. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe
MW. The index of ADL: a standardized measure of
biological and psychosocial function. JAMA. 1963;
185:914-919.
46. Ancoli-Israel S, Clopton P, Klauber MR, Fell R,
Mason W. Use of wrist activity for monitoring sleep/
wake in demented nursing-home patients. Sleep. 1997;
20(1):24-27.
47. Kushida CA, Chang A, Gadkary C, Guilleminault
C, Carrillo O, Dement WC. Comparison of acti-
graphic, polysomnographic, and subjective assess-
ment of sleep parameters in sleep-disordered patients.
Sleep Med. 2001;2(5):389-396.
48. Van Someren EJW. Improving actigraphic sleep
estimates: how many nights? J Sleep Res. 2007;
16(3):269-275.
49. Van Someren EJW, Swaab DF, Colenda CC, Cohen
W, McCall WV, Rosenquist PB. Bright light therapy:
improved sensitivity to its effects on rest-activity
rhythms in Alzheimer patients by application of non-
parametric methods. Chronobiol Int. 1999;16(4):
505-518.
50. Gimeno V, Sagales T, Miguel L, Ballarin M. The
statistical distribution of wrist movements during sleep.
Neuropsychobiology. 1998;38(2):108-112.
51. Twisk JWR. Applied Longitudinal Data Analysis
for Epidemiology. Cambridge, England: Cambridge
University Press; 2003:280.
52. Gibbons RD, Hedeker D, Elkin I, et al. Some con-
ceptual and statistical issues in analysis of longitudi-
nal psychiatric data: application to the NIMH treat-
ment of Depression Collaborative Research Program
dataset. Arch Gen Psychiatry. 1993;50(9):739-
750.
53. Petkova E, Teresi J. Some statistical issues in the
analyses of data from longitudinal studies of elderly
chronic care populations. Psychosom Med. 2002;
64(3):531-547.
54. Siddiqui O, Ali MW. A comparison of the random-
effects pattern mixture model with last-observation-
carried-forward (LOCF) analysis in longitudinal clini-
cal trials with dropouts. J Biopharm Stat. 1998;
8(4):545-563.
55. Zhdanova IV, Wurtman RJ, Regan MM, Taylor
JA, Shi JP, Leclair OU. Melatonin treatment for age-
related insomnia. J Clin Endocrinol Metab. 2001;
86(10):4727-4730.
56. Carman JS, Post RM, Buswell R, Goodwin FK.
Negative effects of melatonin on depression. Am J
Psychiatry. 1976;133(10):1181-1186.
57. Edinger JD, Bonnet MH, Bootzin RR, et al. Deri-
vation of research diagnostic criteria for insomnia: re-
port of an American Academy of Sleep Medicine Work
Group. Sleep. 2004;27(8):1567-1596.
58. Serfaty M, Kennell-Webb S, Warner J, Blizard R,
Raven P. Double blind randomised placebo con-
trolled trial of low dose melatonin for sleep disorders
in dementia. Int J Geriatr Psychiatry. 2002;17(12):
1120-1127.
59. Caspi A, Sugden K, Moffitt TE, et al. Influence of
life stress on depression: moderation by a polymor-
phism in the 5-HTT gene. Science. 2003;301(5631):
386-389.
60. Van Someren EJW, Riemersma-Van Der Lek RF.
Live to the rhythm, slave to the rhythm. Sleep Med
Rev. 2007;11(6):465-484.
61. Burback D, Molnar FJ, St John P, Man-Son-Hing
M. Key methodological features of randomized con-
trolled trials of Alzheimer’s disease therapy: Minimal
clinically important difference, sample size and trial
duration. Dement Geriatr Cogn Disord. 1999;10
(6):534-540.
62. Kavirajan H, Schneider LS. Efficacy and adverse
effects of cholinesterase inhibitors and memantine in
vascular dementia: a meta-analysis of randomised con-
trolled trials. Lancet Neurol. 2007;6(9):782-792.
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 2655
at Vrije Universiteit on June 10, 2008 www.jama.comDownloaded from
... All 13 trials included in this metaanalysis were controlled studies, and 10 were randomized controlled trials. Among these, three trials were performed in the United States (Berman Marvin et al., 2017;Chao, 2019;Nizamutdinov et al., 2021), five were performed in Asia (Guo et al., 1998;Huang et al., 2015;Chan et al., 2021;Kim et al., 2021;Liu et al., 2021), four were performed in Europe (Graf et al., 2001;Riemersma-van der Lek et al., 2008;Cremascoli et al., 2022), and one was performed in Egypt (Nagy et al., 2021). ...
... The mean education level of the elderly participants ranged from 3.8 to 18.3 years. Regarding the etiology of dementia, seven studies only included patients with AD (Graf et al., 2001;Huang et al., 2015;Berman Marvin et al., 2017;Chao, 2019;Kim et al., 2021;Nagy et al., 2021;Cremascoli et al., 2022), one study included only patients with VD (Guo et al., 1998), and the remaining five studies included patients with mixed types of dementia (Riemersma-van der Lek et al., 2008;Chan et al., 2021;Liu et al., 2021;Nizamutdinov et al., 2021). Regarding dementia severity, most studies reported mild to moderate dementia. ...
... The evaluated phototherapy interventions could be categorized into three subtypes, namely, normal visible light (Graf et al., 2001;Riemersma-van der Lek et al., 2008;Huang et al., 2015;Kim et al., 2021;Liu et al., 2021;Cremascoli et al., 2022), NIR LED PBM (Berman Marvin et al., 2017;Chao, 2019;Chan et al., 2021;Nizamutdinov et al., 2021), and laser (Guo et al., 1998;Nagy et al., 2021). Normal visible light could be further categorized into traditional bright light and blue-enriched light. ...
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Background Dementia is a major health burden worldwide. As numerous pharmacological trials for dementia have failed, emerging phototherapy studies have evaluated the efficacy of alternative therapies for cognition. Objective The objective of this study was to evaluate the association between phototherapy and changes in cognitive deficits in patients with dementia. Methods PubMed, Embase, Web of Science, PsycINFO, CINAHL, and Cochrane Central Register of Controlled Trials were searched from inception to 27 March 2022. Inclusion criteria were controlled clinical trials of phototherapy interventions reporting pre-post changes in global cognitive function and subdomains in patients with dementia. Data were extracted by two independent reviewers and pooled in random-effects models. Subgroup and meta-regression analyses were conducted to investigate the sources of heterogeneity. Results Our analyses included 13 studies enrolling a total of 608 participants. Phototherapy showed significant associations with improvements of global cognitive function (standardized mean difference [SMD], 0.63; 95% confidence interval [CI], 0.33–0.94; P < 0.001) and subdomains, especially with respect to attention, executive function, and working memory. Near-infrared (NIR) light-emitting diodes (LEDs) photobiomodulation (SMD, 0.91; 95% CI, 0.46–1.36; P < 0.001) and lasers (SMD, 0.99; 95% CI, 0.56–1.43; P < 0.001) showed more significant associations with improved cognitive functions when compared with normal visible light. In addition, the effect sizes of short-term effects (SMD, 0.63; 95% CI, 0.33–0.94; P < 0.001) were larger than effects assessed in long-term follow-up (SMD, 0.49; 95% CI, -0.24–1.21; P = 0.189). Conclusion In this meta-analysis, phototherapy interventions were associated with cognitive improvement in patients with dementia. NIR LEDs and lasers had advantages over normal visible light. Domain-specific effects were indicated for attention, executive function, and working memory. Short-term improvement after phototherapy was supported, while evidence for long-term benefits was lacking. Stronger evidence for individualized parameters, such as optimal dosing, is needed in the future. Systematic Review Registration [ https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=267596 ], identifier [CRD42021267596].
... 24 Clinically, a few studies demonstrated the cognitive-enhancing effects of bright light stimulation in demented patients. [25][26][27] Such findings inspired us to test the effects of transcorneal electrical stimulation (TES)-a noninvasive visual stimulation approach-in animal models of cognitive decline. ...
... Data are presented as mean + SEM. n.s., not significantDISCUSSIONThe application of visual stimulation to alleviate cognitive impairment is a novel idea supported by limited yet promising results from studies using flickering light stimulation and bright light therapy in rodents and humans.[23][24][25][26][27] In our study here, we explored the effects of noninvasive electrical stimulation by TES on cognitive function in two animal models of cognitive decline, namely, aged mice and the 5XFAD model of AD. ...
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Dementia is a major burden on global health for which there are no effective treatments. The use of non-invasive visual stimulation to ameliorate cognitive deficits is a novel concept that may be applicable for treating dementia. In this study, we investigated the effects of transcorneal electrical stimulation (TES) on memory enhancement using two mouse models, in aged mice and in the 5XFAD model of Alzheimer’s disease. After 3 weeks of TES treatment, mice were subjected to Y-maze and Morris water maze (MWM) tests to assess hippocampal-dependent learning and memory. Immunostaining of the hippocampus of 5XFAD mice was also performed to examine effects of TES on amyloid plaque pathology. The results showed that TES improved the performance of both aged and 5XFAD mice in memory tests. TES also reduced hippocampal plaque deposition in male, but not female, 5XFAD mice. Moreover, TES significantly reversed the downregulated level of postsynaptic protein 95 in the hippocampus of male 5XFAD mice, suggesting the effects of TES involve a postsynaptic mechanism. Overall, these findings support further investigation of TES as a potential treatment for cognitive dysfunction and mechanistic studies of TES effects in other dementia models.
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En gélule, en comprimé, sous forme de gomme, de spray ou encore de tisane, parfois associée à des plantes, la mélatonine s’est fait une place sur les linéaires des officines. Nombreux sont les clients qui s’y intéressent dans le but de résoudre leurs problèmes de sommeil.
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Objectives Falls in care home residents have major health and economic implications. Given the impact of lighting on visual acuity, alertness, and sleep and their potential influence on falls, we aimed to assess the impact of upgraded lighting on the rate of falls in long-term care home residents. Design An observational study of 2 pairs of care homes (4 sites total). One site from each pair was selected for solid-state lighting upgrade, and the other site served as a control. Setting and Participants Two pairs of care homes with 758 residents (126,479 resident-days; mean age (±SD) 81.0 ± 11.7 years; 57% female; 31% with dementia). Methods One “experimental” site from each pair had solid-state lighting installed throughout the facility that changed in intensity and spectrum to increase short-wavelength (blue light) exposure during the day (6 am–6 pm) and decrease it overnight (6 pm–6 am). The control sites retained standard lighting with no change in intensity or spectrum throughout the day. The number of falls aggregated from medical records were assessed over an approximately 24-month interval. The primary comparison between the sites was the rate of falls per 1000 resident-days. Results Before the lighting upgrade, the rate of falls was similar between experimental and control sites (6.94 vs 6.62 falls per 1000 resident-days, respectively; rate ratio [RR] 1.05; 95% CI 0.70–1.58; P = .82). Following the upgrade, falls were reduced by 43% at experimental sites compared with control sites (4.82 vs 8.44 falls per 1000 resident-days, respectively; RR 0.57; 95% CI 0.39–0.84; P = .004). Conclusions and Implications Upgrading ambient lighting to incorporate higher intensity blue-enriched white light during the daytime and lower intensity overnight represents an effective, passive, low-cost, low-burden addition to current preventive strategies to reduce fall risk in long-term care settings.
Article
Recent studies reported that bright light exposure can impact mood and cognitive functions in various age groups. However, these studies have not adequately addressed the effects of ambient lighting in living spaces on healthy older adults. In the present study, the effects of a whole-day lighting scheme were examined in residential units inhabited by older adults. The lighting condition (LT) was designed to create a direct/indirect ambient illumination that delivered bright, blue-enriched light (illuminance level: 500 lx, Correlated Color Temperature (CCT): 6500K) in the morning, followed by gradually lower illuminance levels and CCT throughout the rest of the day, reaching 100 lx and 2700K in the evening. To further examine the effects of spectrum, we also included another lighting condition (LP) with the same range of illuminance levels and constant CCT of 2700K from morning to evening. Twenty-one healthy older adults (mean age = 76.81 years; 16 females) completed a counterbalanced crossover experiment, with two baseline measurements (before and after interventions) and eighteen days of interventions. Data were collected using standardized questionnaires and tests. Significant improvements were observed in mood and cognitive functions measured after exposure to both lighting conditions (LP and LT); there were significantly greater improvements for the LT as compared to the LP condition. This study found promising evidence that a whole-day lighting scheme that follows the natural light/dark cycle could be an effective design solution to create a healthy and healing living environment in living spaces and promote mood, cognitive functions, and hence the quality of life in senior residents.
Article
Use of plasma adrenocorticotropic hormone (ACTH) concentrations for the diagnosis of PPID in equids requires awareness of other factors that might influence ACTH concentrations, including breed and time of year. This study was designed to investigate effects of breed on plasma ACTH concentrations and potential interactions between breed and time of year. Ten breeds were selected from a laboratory database containing data on plasma ACTH concentrations. Breeds represented were Arabians, Cobs, Connemara ponies, donkeys, Irish Sports horses, New Forest ponies, Shetland ponies, Thoroughbreds, Warmbloods and Welsh breeds. Multivariable analysis was used to determine the effects of month and breed on plasma ACTH concentrations. A circannual pattern of ACTH concentration was documented, with a nadir in April and a peak in September. Arabian horses and donkeys had significantly higher ACTH concentrations than some other breeds, primarily from May to November, whereas in Shetland ponies and Welsh breeds, relatively higher ACTH concentrations only occurred from July to November. The annual increase in plasma ACTH appeared to commence in late April/early May in response to increasing daylight and decreased again promptly after the late September equinox as daylength fell below 12 h per day. Inter-breed differences in plasma ACTH were substantial and indicated that breed and time of year should be considered when interpreting plasma ACTH concentrations in equids suspected for PPID.
Article
Objectives: In what way the physical environment of nursing homes (NHs) influences the health and well-being of nursing residents is not well codified. The authors aimed to review scientifically based knowledge on this topic. Design: A systematic scoping review of research into the effect that physical environment in nursing homes has on residents' health. Setting and participants: Search for relevant English-language articles in PubMed and the Cochrane database before April 15, 2022. Article selection and data extraction were performed by 2 researchers. Studies were included if conducted on nursing home residents and if they examined associations between components of the physical environment and health outcomes. Measures: The review was performed in accordance with the PRISMA statement. Results: Of 1347 articles retrieved, 59 met the inclusion criteria-40 observational, 1 survey, and 18 interventional studies, of which 5 were randomized controlled trials. Certain environmental features repeatedly show significant positive effect on resident's health, such as noise reduction, tuning of lighting, natural light, easy access to garden, dining environment, and resident-centered interior renovation. Nursing home size was not found to have a direct relationship to resident health and well-being, although it is related to more than only the physical environment (eg, social environment). Conclusions and implications: This review provides guidance in selective areas of the physical environment for the design of nursing homes, with potential benefits for the health and well-being of residents.
Thesis
Full-text available
According to Person-Centred Care, as far as possible, people with dementia should be cared for in a way that takes into account their personality, life experiences and preferences. Personalisation is hence the core of Person- Centred Care, yet the approaches, recommendations and tools are lacking for this purpose. This thesis explores how this personalisation could be facilitated by design. Three Human-Centred Design approaches are investigated, and recommendations and tools are generated throughout this process. The findings of this thesis encourage designers and healthcare professionals to design for personalised dementia care. In this way, each person with dementia could receive care personalised by one or more elements, such as their life experiences, hobbies, remaining capabilities, preferred interaction styles, and current status. Therefore, this thesis contributes to Person-Centred Care for people with dementia, a core part of their quality of life.
Article
The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows for wakefulness throughout the day and a long consolidated sleep episode at night. Changes to either the sleep regulatory process or how they interact can result in an inability to fall asleep at the desired time, difficulty remaining asleep, waking too early, and/or difficulty remaining awake throughout the day. This mismatch between the desired timing of sleep and the ability to fall asleep and remain asleep is a hallmark of a class of sleep disorders called the circadian rhythm sleep-wake disorders. In this updated article, we discuss typical changes in the circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep disorders; and how neurologic diseases in older patient impact circadian rhythms and sleep.
Article
Full-text available
Circadian rhythm disturbances are frequently present in Alzheimer disease (AD). In the present study, we investigated the expression of vasopressin (AVP) mRNA in the human suprachiasmatic nucleus (SCN). The in situ hybridization procedure on formalin-fixed paraffin-embedded material was improved to such a degree that we could, for the first time, visualize AVP mRNA expressing neurons in the human SCN and carry out quantitative measurements. The total amount of AVP mRNA expressed as masked silver grains in the SCN was 3 times lower in AD patients (n = 14; 2,135 +/- 597 microm2) than in age- and time-of-death-matched controls (n = 11; 6,667 +/- 1466 microm2) (p = 0.003). No significant difference was found in the amount of AVP mRNA between AD patients with depression (n = 7) and without depression (n = 7) (2,985 +/-1103 microm2 and 1,285 +/- 298 microm2, respectively; p = 0.38). In addition, the human SCN AVP mRNA expressing neurons showed a marked day-night difference in controls under 80 years of age. The amount of AVP mRNA was more than 3 times higher during the daytime (9,028 +/- 1709 microm2, n = 7) than at night (2,536 +/- 740 microm2, n = 4; p = 0.02), whereas no clear diurnal rhythm of AVP mRNA in the SCN was observed in AD patients. There was no relationship between the amount of AVP mRNA in the SCN and age at onset of dementia, duration of AD and the neuropathological changes in the cerebral cortex. These findings suggest that the neurobiological basis of the circadian rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. It also explains the beneficial effects of light therapy on nightly restlessness in AD patients.
Article
Background Cholinesterase inhibitors produce small improvements in cognitive and global assessments in Alzheimer's disease. We aimed to determine whether donepezil produces worthwhile improvements in disability, dependency, behavioural and psychological symptoms, carers' psychological wellbeing, or delay in institutionalisation. If so, which patients benefit, from what dose, and for how long? Methods 565 community-resident patients with mild to moderate Alzheimer's disease entered a 12-week run-in period in which they were randomly allocated donepezil (5 mg/day) or placebo. 486 who completed this period were rerandomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability, defined by loss of either two of four basic, or six of 11 instrumental, activities on the Bristol activities of daily living scale (BADLS). Outcome assessments were sought for all patients and analysed by logrank and multilevel models. Findings Cognition averaged 0·8 MMSE (mini-mental state examination) points better (95% Cl 0·5–1·2; p<0·0001) and functionality 1·0 BADLS points better (0·5–1·6; p<0·0001) with donepezil over the first 2 years. No significant benefits were seen with donepezil compared with placebo in institutionalisation (42% vs 44% at 3 years; p=0·4) or progression of disability (58% vs 59% at 3 years; p=0·4). The relative risk of entering institutional care in the donepezil group compared with placebo was 0·97 (95% Cl 0·72–1·30; p=0·8); the relative risk of progression of disability or entering institutional care was 0·96 (95% Cl 0·74–1·24; p=0·7). Similarly, no significant differences were seen between donepezil and placebo in behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5 mg and 10 mg donepezil. Interpretation Donepezil is not cost effective, with benefits below minimally relevant thresholds. More effective treatments than Cholinesterase inhibitors are needed for Alzheimer's disease.
Article
As part of a study of care for patients with Alzheimer's disease and related disorders in 31 dementia units, (special care units) and 32 traditional units in five states, an observational screening checklist was designed and field tested. That checklist the Therapeutic Environment Screening Scale (TESS) uses 12 items to evaluate the appropriateness of a nursing home unit for residents with dementing disorders. The therapeutic principles evaluated by the instrument are: eliminating potentially noxious stimuli, enhancing mood and self image, promoting safety, accommodating a range of private and social activities, and providing access to the outdoors. Application of the instrument showed that the 63 settings studied did differ in the 12 environmental characteristics studied, and that as a whole, dementia units scored significantly better than traditional nursing home units.
Article
Background: The results of clinical trials are routinely presented in terms of statistical significance, which may or may not indicate clinical significance. Analysis of the minimal clinically important difference (MCID) of cognitive scales has received little attention to date. Objectives: By reviewing the key methodological features (sample size, duration, statistical and clinical significance) of clinical trials examining the efficacy of tacrine in the treatment of Alzheimer’s disease (AD), we assessed their ability to detect clinically important changes in cognition. Design: The value for the MCID of the Mini-Mental State Examination (MMSE) was determined by surveying specialists in neurology and geriatric medicine. This value was then used to interpret the clinical significance of the results of published randomized controlled trials (RCTs) assessing the efficacy of tacrine in the treatment of AD and to retrospectively determine their optimal sample size and trial duration. Results: The mean survey MCID for the MMSE was 3.72 (95% confidence interval 3.50–3.95) points. Only 2 of 12 tacrine RCTs using the MMSE found a statistically significant difference in MMSE scores for patients taking tacrine compared with those taking placebo. These improvements were not clinically significant when compared with the survey MMSE MCID. For parallel trials of tacrine in AD, the smallest sample size and minimum trial duration required to demonstrate a clinically significant difference were calculated to be 53 subjects and 1 year, respectively. Five of the 7 parallel trials met the required sample size; however, none of them met the criteria for trial duration. Conclusions: When using the MMSE as an outcome measure, no tacrine trial reported results that were clinically significant as perceived by clinicians working with dementia patients. Application of a range of plausible MCIDs to the parallel design RCTs also demonstrated that 2 of 7 of these trials did not have sufficient sample size, and none had sufficient duration of treatment to reliably detect clinically meaningful changes in cognition. Future clinical trials in this area will need to incorporate the evolving knowledge of MCIDs in order to increase their chance of detecting clinically relevant results.
Article
SUMMARY  Alzheimer's disease (AD), the most common dementing disorder of aging, is a progressive neurodegenerative disease of unknown etiology. Two of the common clinical features of AD are progressive cognitive and functional impairment, and disturbed sleep/wake patterns. We examined sleep/wake patterns and cognitive and functional status measures in a large sample of AD subjects ranging from mild to moderate-severe in impairment. All subjects survived at least 2 years after initial diagnosis. Regression analyses revealed that sleep/wake variables were highly correlated with and explained significant variance in cognitive and functional measures. More wakefulness during the night and longer REM latencies were associated with impaired cognition and function while more REM and slow-wave sleep were associated with preserved cognition and function. These results indicate that with advancing severity of the disease, sleep/wake patterns are disrupted in parallel with the disturbances in cognition and function that are the hallmarks of AD. Further, they suggest that the neural substrates underlying each process degenerate at somewhat comparable rates.
Article
Objective To evaluate variables associated with quality of life (QOL) in dementia residents in a long-term care facility using a recently standardized and validated dementia-specific QOL scale (ADRQL).MethodA cross-sectional, case-control design was employed using validated scales to assess dementia-related symptomatology. Thirty-two facility staff members were interviewed to assess the QOL of 120 patients meeting DSM-IV for dementia criteria residing in long-term care.ResultsADRQL scores were higher in assisted living residents than in skilled nursing facility residents. In univariate analyses, worse orientation, greater physical dependency, depression, and treatment with anxiolytics were associated with lower ADRQL scores. In multivariate analyses, lower scores were associated with worse orientation, greater physical dependency, depression, and anxiolytic treatment.Conclusions Residents exhibited better QOL than expected. Future longitudinal studies should address if reorientation, activity therapy, treatment of depression, and avoidance of benzodiazepines might improve QOL in this population. Interventions that might improve orientation and physical abilities, such as cholinomimetic therapies, psychosocial interventions, or behavioral strategies, should also be studied in future research on QOL. Copyright © 2000 John Wiley & Sons, Ltd.
Article
Objectives: To explore the impact of subgroups and individual symptoms of non-cognitive disturbance on the carers of Alzheimer's disease patients. Design: Cross-sectional study using clinically valid scales to assess patient symptomatology and self-report questionnaires to measure carer variables. Setting: Old age psychiatry outreach services in South and Central Manchester. Subjects: 100 patients with Alzheimer's disease living at home and their carers. Main outcome measures: Subjective burden and distress in carers. Results: Separate statistical analyses were performed for subgroups and individual symptoms of non-cognitive disturbance. For subgroups, multivariate analyses identified depression and behavioural disturbances in patients as significant predictors of subjective burden in carers. Carer distress was predicted by depression, psychosis and cognitive impairments in patients and carer gender. For individual symptoms of non-cognitive disturbance, three features of depression in patients (mood-related signs, physical signs and behaviour changes), walking disruptions and the patient-carer relationship predicted of subjective burden in carers. Variance in the level of carer distress was accounted for by sleep disruptions, hallucinations and mood-related depressive features in patients and carer gender. Conclusion: The findings confirm that the non-cognitive features of Alzheimer's disease are stressful for carers and indicate specific relationships between mood-related and behavioural signs of depression, walking and sleep disruptions and hallucinations in patients and adverse carer outcomes. Patient depression and the mood-related signs of depression in particular were the most consistent and powerful predictors of psychological morbidity in carers. Intervention strategies need to identify and target troublesome behaviours in patients and aim to either change these behaviours or alter the way carers respond to them. Thus, interventions need to be symptoms-rather than service-led and are likely to require multidisciplinary and multi-agency approaches.
Article
The circadian timing system (CTS) allows organisms on earth to synchronize internal rhythms to the environmental 24-hour light-dark cycle and anticipate the body on the forthcoming period of either activity or rest. The central pacemaker of the CTS is the hypothalamic suprachiasmatic nucleus (SCN) regulating most, if not all, circadian rhythms in the body. The plasticity of this system at old age is the subject of this review, with special regard to its major internal stimulus, the pineal hormone melatonin.The circadian rhythm in melatonin production is regulated by the SCN and results in low daytime circulating levels of melatonin and an increase of circulating melatonin after darkness onset. This rhythm, like other circadian rhythms, is attenuated in elderly subjects. The relation between the age-related change in melatonin levels and sleep is discussed in this paper.Based on the hypothesis that there is a relationship between the increased prevalence of sleep-disturbances and decreased melatonin levels in elderly, several studies have been performed to investigate the effect of exogenous melatonin supplementation on sleep in elderly and demented subjects. An overview of these findings is presented and the various results are discussed.
Article
In order to test the efficacy of the pineal neurohumor melatonin on depression, the hormone was administered in varying doses to six moderately to severely depressed patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin exacerbated symptoms of dysphoria in these patients, as well as causing a loss of sleep and weight and a drop in oral temperature. Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and calcium in three of four patients studied. The authors discuss the implications of this finding.