Chronobiology International

The Journal of Biological and Medical Rhythm Research

ISSN: 0742-0528 (Print) 1525-6073 (Online) Journal homepage: http://www.tandfonline.com/loi/icbi20

Wearing blue light-blocking glasses in the evening

advances circadian rhythms in the patients with
delayed sleep phase disorder: An open-label trial

Yuichi Esaki, Tsuyoshi Kitajima, Yasuhiro Ito, Shigefumi Koike, Yasumi

Nakao, Akiko Tsuchiya, Marina Hirose & Nakao Iwata

To cite this article: Yuichi Esaki, Tsuyoshi Kitajima, Yasuhiro Ito, Shigefumi Koike,
Yasumi Nakao, Akiko Tsuchiya, Marina Hirose & Nakao Iwata (2016): Wearing blue
light-blocking glasses in the evening advances circadian rhythms in the patients with
delayed sleep phase disorder: An open-label trial, Chronobiology International, DOI:
10.1080/07420528.2016.1194289

To link to this article: http://dx.doi.org/10.1080/07420528.2016.1194289

Published online: 20 Jun 2016.

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 CHRONOBIOLOGY INTERNATIONAL
http://dx.doi.org/10.1080/07420528.2016.1194289

Wearing blue light-blocking glasses in the evening advances circadian rhythms

in the patients with delayed sleep phase disorder: An open-label trial
Yuichi Esakia, Tsuyoshi Kitajimaa, Yasuhiro Itob, Shigefumi Koikec, Yasumi Nakaoc, Akiko Tsuchiyaa,
Marina Hirosea, and Nakao Iwataa
a
Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan; bDepartment of Physiology, Fujita Health University
School of Health Sciences, Aichi, Japan; cDepartment of Sleep Medicine, Toyohashi Mates Sleep Disorders Center, Aichi, Japan

ABSTRACT ARTICLE HISTORY

It has been recently discovered that blue wavelengths form the portion of the visible electro- Received 23 March 2016
magnetic spectrum that most potently regulates circadian rhythm. We investigated the effect of Revised 11 May 2016
blue light-blocking glasses in subjects with delayed sleep phase disorder (DSPD). This open-label Accepted 23 May 2016
Downloaded by [University of Kentucky Libraries] at 04:58 21 June 2016

trial was conducted over 4 consecutive weeks. The DSPD patients were instructed to wear blue KEYWORDS
light-blocking amber glasses from 21:00 p.m. to bedtime, every evening for 2 weeks. To ascertain Delayed sleep phase
the outcome of this intervention, we measured dim light melatonin onset (DLMO) and actigraphic disorder; amber lens; blue
sleep data at baseline and after the treatment. Nine consecutive DSPD patients participated in this light; sleep onset; dim light
study. Most subjects could complete the treatment with the exception of one patient who hoped melatonin onset
for changing to drug therapy before the treatment was completed. The patients who used amber
lens showed an advance of 78 min in DLMO value, although the change was not statistically
significant (p = 0.145). Nevertheless, the sleep onset time measured by actigraph was advanced by
132 min after the treatment (p = 0.034). These data suggest that wearing amber lenses may be an
effective and safe intervention for the patients with DSPD. These findings also warrant replication
in a larger patient cohort with controlled observations.

Introduction administration is considered the first-line treat-

ment. Meta-analysis and guidelines have suggested
Delayed sleep phase disorder (DSPD) is a chronic
clinical benefits of using melatonin in the patients
condition characterized by the persistent inability
who require treatment for DSPD (Auger et al.,
to fall asleep and wake up at conventional times
2015; van Geijlswijk et al., 2010). However, in
(Weitzman et al., 1981). In the patients with
Japan, it is hard to use melatonin for treatment
DSPD, sleep onset is often delayed until early
in clinical practice because it is not available as a
morning, and when no attempt is made to con-
formally approved drug. Ramelteon – a melatonin
form to the environment, their usual rise time may
receptor agonist – was approved for the treatment of
even be in the early afternoon. Sleep architecture
insomnia in Japan (Uchiyama et al., 2011) . Studies
and maintenance are not usually disrupted in
show that ramelteon advances the phase of the circa-
DSPD (Regestein & Monk, 1995); however, when
dian rhythm in healthy adults and decreases sleep
the patients attempt to advance their bedtime,
latency in healthy adults with jet lag-associated sleep
severe sleep-onset insomnia is experienced. It is
disturbances (Richardson et al., 2008; Zee et al., 2010).
also difficult or impossible for them to have a
Ramelteon may likewise advance the circadian
socially “normal” or “typical” rise time. If this
rhythm in the DSPD patients; however, to our knowl-
regimen continues on a long-term basis, daytime
edge, there are no reports on this. Another treatment
sleepiness ensues. Onset of DSPD can occur at any
that has been tried in the patients with DSPD is
age, but initial onset most commonly occurs dur-
bright-light therapy, which causes a phase advance
ing adolescence (Wagner, 1996).
of circadian rhythm (Rosenthal et al., 1990).
As for the pharmacological approaches to the
However, the patients with DSPD must receive
treatment of DSPD, exogenous melatonin

CONTACT Yuichi Esaki esakiz@fujita-hu.ac.jp Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 4701192, Japan.
Tel: +81-562-93-9250. Fax: +81-562-93-1831.
© 2016 Taylor & Francis
 2 Y. ESAKI ET AL.
bright-light therapy in the morning (i.e., between
6:00 a.m. and 9:00 a.m.). In the clinical context, com-
pliance with this intervention may be a significant
problem, because a significant proportion of the
DSPD patients are not able to wake up before noon
and sometimes awaken even later. Despite increased
awareness of the prevalence and impact of DSPD,
there are limited existing treatment options and the
need for new interventions.
The circadian pacemaker responds differentially
to the resetting effects of light, depending on the
circadian phase of light exposure. Morning light
advances circadian rhythms, whereas light in the
evening induces circadian phase delays (Khalsa
et al., 2003). The impact of light on the circadian
Downloaded by [University of Kentucky Libraries] at 04:58 21 June 2016
timing system is classically measured by suppres-
sion of the “darkness hormone” melatonin, a key
circadian phase marker secreted only during the
night (Lewy et al., 1980). These responses are
mediated by a subset of retinal ganglion cells con-
taining the photopigment melanopsin, which is
most sensitive to blue light wavelengths (around
480 nm) (Brainard et al., 2001; Thapan et al., 2001)
and transmit light signals via the retinohypothala-
mic tract directly to the suprachiasmatic nuclei
(Hattar et al., 2002).
In modern society, evening light exposure has
been shown to worsen circadian rhythms
(Burgess & Molina, 2014). A significant propor-
tion of light produced by light-emitting diode
(LED) screens is of short wavelength (blue and
blue–green). Accordingly, the light emitted by
tablet screens can suppress melatonin (Wood
et al., 2013). A 5-h LED screen exposure in the
evening has been found not only to suppress
melatonin secretion but also to increase subjec-
tive and objective alertness in young adults
(Cajochen et al., 2011). Therefore, controlling light
exposure in the evening, especially short-wavelength
light produced by modern-day LED-enriched envir-
onments, could make a potent intervention to coun-
ter circadian rhythm disturbance.
Since neural pathways from the retina to the
primary circadian pacemaker in the suprachias-
matic nucleus respond only to short-wavelength
light of <550 nm, physiological darkness can be
produced by the use of blue wavelength-blocking
glasses with the advantage of continued evening
functioning. Blue light-blocking glasses have been
shown to preserve normal evening nighttime mela-
tonin production in subjects exposed to light
(Kayumov et al., 2005; Sasseville et al., 2006). One
randomized study of subjects with insomnia
demonstrated improvement in sleep quality and
mood in individuals wearing blue wavelength-
blocking glasses, compared with a placebo group
(Burkhart & Phelps, 2009). Daytime use of such
glasses in permanent night-shift workers resulted in
longer sleep, improved daytime sleep efficiency (SE)
and reduced sleep fragmentation (Sasseville et al.,
2009). A similar open-label study of attention deficit
hyperactivity disorder (ADHD) with insomnia has
also demonstrated improved global Pittsburgh Sleep
Quality Index scores in the subjects wearing blue
wavelength-blocking glasses (Fargason et al., 2013).
However, to the best of our knowledge, there have
been no studies investigating the potential benefits of
blue light-blocking glasses in improving the circa-
dian rhythms of the DSPD patients without ADHD.
We hypothesized that wearing blue light-blocking
glasses in the evening could advance the circadian
rhythms of the DSPD patients.
Materials and methods
Subjects
The study protocol was approved by the ethics com-
mittee of Toyohashi Mates Sleep Disorders Center.
All patients provided written informed consent, con-
firming that they understood the goals, risks and
potential benefits of the study, and their right to with-
draw from the study at any time. The patients with an
established diagnosis of DSPD according to the stan-
dard criteria of the International Classification of
Sleep Disorders, second edition (ICSD-2), were
enrolled (American Academy of Sleep Medicine.,
2006). Diagnoses were made on the basis of both the
ICSD-2 and a clinical interview conducted by a
psychiatrist-sleep specialist. All patients completed a
sleep log at least 1 week before the study, and this log
was used to confirm the clinical diagnosis. Exclusion
criteria included shift working, alcohol or drug abuse,
and severe psychiatric or neurological disorders. We
accessed 15 patients with DSPD and obtained the
agreement for the study in case of 10 patients with
DSPD. However, one of the patients canceled their
medical examination before the baseline assessment.
 CHRONOBIOLOGY INTERNATIONAL 3

Study design and conduct Innovations Institute, OH, USA) and we bought
the glasses for this study. Figure 2 shows the light
This open-label trial was conducted over 4 con-
transmission data of amber lenses provided by the
secutive weeks. Figure 1 illustrates the design of
manufacturer. The patients were instructed to remove
the study. The first week was the baseline
the glasses only when in the dark (glasses were not
assessment period. Activity data were recorded
worn overnight). Also, because even limited exposure
by Motionlogger® Micro Watch actigraph
to light (> 80 lux) has been shown to suppress mela-
(Ambulatory Monitoring, Inc., Ardsley, NY,
tonin (Zeitzer et al., 2000), the patients were specifi-
USA) during this week, while the patients
cally instructed to avoid exposing their eyes directly to
were engaged in their usual evening activities.
light without wearing their protective lenses after
On one day during this period, saliva samples
donning their glasses in the evening. In the last
were collected for melatonin measurement (as
week, actigraphic recording and saliva melatonin col-
described later). In the following 2 weeks, the
lection were conducted again while the patients were
patients were instructed to wear amber glasses
wearing amber glasses. The patients were instructed
that blocked wavelengths of light from 530 nm
to maintain their same daily routine during the study,
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and below (blue and violet wavelengths of light)

with the only change being wearing glasses in the
from 21:00 p.m. until bedtime every evening. The
evening. During the study, the use of multimedia
glasses were manufactured by LowBlueLights.com
devices (e.g., cell phones, computers and televisions)
(Photonic Developments LLC and the Lighting
in the evening was not limited or prohibited; the

Figure 1. Study design.

LowBlue Glasses Transmission

100
90
80
70
Transmission (%)

60
50
40
30
20
10
0
400 425 450 475 500 525 550 575 600 625 650 675 700
Wavelength (nm)

Figure 2. The light transmission data of amber lens as detailed by LowBlueLights.com (Photonic Developments LLC and the Lighting
Innovations Institute, OH, USA).
 4 Y. ESAKI ET AL.
subjects were not instructed regarding morning light
exposure.
Outcome measures
Dim light melatonin onset
DLMO is defined as the clock time at which the
endogenous melatonin level starts to rise in the
subjective evening, and it is considered the most
reliable phase marker of the biological clock
rhythm (Klerman et al., 2002). DLMO was
assessed at the first week (baseline) and the last
week (after the treatment). Salivary melatonin
samples were collected on one night at home by
chewing on a cotton swab (Salivetten, Sarstedt,
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Germany) six times at hourly intervals between
19:00 p.m. and 24:00. The patients were instructed
to stay at home during the measurements, to avoid
food intake within 20 min before the measure-
ment, and to collect their samples under dim
light conditions (< 10 lux) to avoid light-induced
suppression of melatonin secretion (Nagtegaal
et al., 1998). We confirmed the subjects had
adhered to giving samples under dim light con-
ditions (< 10 lux) using the Motionlogger® Micro
Watch actigraph, which can measure ambient
light. If the subject had received exposure to
light >10 lux during the measurements, we
defined the subject as “dropped out”. Melatonin
concentrations were assayed in the laboratory of
the Fujita Health University. Enzyme immunoas-
says were performed on all saliva samples in
duplicate using an enzyme linked immunosor-
bent assasy (ELISA) kit [Buhlmann Direct Saliva
Melatonin ELISA (EK-DMS), Buhlmann
Laboratories AG., Germany]. DLMO was calcu-
lated as the linearly interpolated time of the first
sample above 4 pg/mL that was preceded by a
lower value (Duffy et al., 2008). In the patients
whose melatonin levels had reached 4 pg/mL
before 19:00 p.m., or whose melatonin levels
had not yet reached 4 pg/mL by 24:00, we
assumed that DLMO was at 19:00 p.m. or 24:00,
respectively, as conservative estimates allowing
for their inclusion in the data analysis.
Sleep data
Sleep data were estimated using actigraph and sleep
logs on seven consecutive days, at baseline and after
the treatment. Actigraphs, worn on the nondomi-
nant wrist, recorded the amount of movement at 1-
min epochs, 24 h/day. Actigraph data were con-
verted into sleep parameters by the validated auto-
matic actigraphy scoring algorithm (Cole et al., 1992)
using sleep log-derived lights out and rise time, and
by subsequent manual verification based on sleep log
data including sleep onset time (SOT), wake-up time
(WUT), total sleep time (TST) and SE.
Statistical analysis
Our primary outcome measurements with respect
to efficacy were DLMO and sleep data (SOT,
WUT, TST, SE). Data were analyzed for statistical
significance using the two-tailed Student’s t-test
(JMP® 10.0.2; SAS Institute Japan, Tokyo, Japan).
The significance level was set at p < 0.05. Equality
of variance was investigated by Levene test.
Results
We enrolled nine consecutive patients with DSPD
(seven males and two females, mean age 18.11 ±
3.18 years, range 15–22 years). Eight subjects could
complete the treatment, and one of them violated the
protocol by receiving light exposure >10 lux during
the measurements of saliva melatonin. One patient
dropped out because he hoped for changing to drug
therapy from amber lens treatment before the study
was completed. Our results are summarized in
Table 1.
DLMO
The mean DLMO clock time (±SD) before treat-
ment was 22:48 ± 1:21. After the treatment, this was
earlier at 21:30 p.m. ± 1:25. The amber lens-treated
patients showed an advance of 78 min in DLMO
value [95% confidence interval (CI): −34 to 183
min], although this was not statistically different
compared with the value before the treatment [p =
0.145, effect size (r) = 0.56; Table 2]. By employing
60 min as the minimum value for the establishment
of a phase shift, three patients showed an advance
in their DLMO value, with four patients showing
no change (Table 1).
 CHRONOBIOLOGY INTERNATIONAL 5

Table 1. Demographics and results of 9 DSPD patients under amber-lens treatment.

Sleep
DLMO (h: min) SOT (h: min) WUT (h: min) TST (min) SE (%)
Patient
no. Age Sex Baseline Treatment Baseline Treatment Baseline Treatment Baseline Treatment Baseline Treatment
1 19 M 22:20 22:18 0:19 0:04 8:00 8:03 437.14 438.86 95.58 92.76
2 22 M drop out (patient hoped for changing to drug therapy before the study was completed)
3 22 M 23:55 22:27 4:35 2:55 11:14 10:28 382.83 415.33 89.44 93.5
4 17 M 22:20 21:58 0:50 0:31 8:06 8:27 415.57 455.83 96.65 96.97
5 22 F 0:00 19:00 3:34 21:30 10:21 8:41 392.86 616.29 * 93.7
6 15 F 20:14 20:15 23:31 23:14 8:23 8:06 521.29 486.71 95.74 98.27
7 16 M 0:00 21:26 4:34 2:02 13:46 10:07 552.42 467.86 * 98.3
8 15 M drop out (due to protocol violation)
9 15 M 22:47 23:09 4:54 1:31 11:48 10:48 394.25 519.5 94.03 92.24
DLMO, Dim light melatonin onset; SOT, sleep onset time; WUT, wake-up time; TST, total sleep time; SE, sleep efficiency
* We were not able to analyze in actigraph

Table 2. Outcome variables.

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Baseline Treatment DLMO (h: min) Effect size (r)

Mean ± SD Mean ± SD Change 95% CI p-value
DLMO (h: min) 22:48 ± 1:21 21:30 ± 1:25 −1:18 −3:00 to 0:34 0.145 0.56
Sleep
SOT (h: min) 2:36 ± 2:18 0:23 ± 1:38 −2:12 −4:12 to −0:13 0.034 * 0.74
WUT (h: min) 10:14 ± 2:11 9:14 ± 1:10 −0:59 −2:14 to 0:15 0.099 0.62
TST (min) 442.33 ± 62.56 485.76 ± 61.59 43.28 −51 to 138 0.304 0.41
SE (%) 94.28 ± 2.56 95.10 ± 2.44 0.33 −3.1 to 4.0 0.738 0.17
DLMO, Dim Light Melatonin Onset; SOT, sleep onset time; WUT, wake-up time; TST, total sleep time; SE, sleep efficiency, *Statistically significant
difference (p < 0.05, two-sided)

Sleep advance in DLMO value and a 132 min advance in

The mean sleep onset clock time (±SD) before the
treatment was 2:36 ± 2:18. After the treatment, this
was earlier at 0:23 ± 1:38. The amber lens-treated
patients showed an advance of 132 min in SOT (95%
CI: 13–252 min), which was significantly earlier than
the value before the treatment (p = 0.034, r = 0.74;
Table 2). After the treatment, four out of seven
(57.1%) subjects, for whom actigraphic data were
available, showed an advance of >60 min in SOT
(Table 1). The mean actigraphic estimate of WUT
advanced by 59 min with the treatment, although
this was not statistically different compared with the
value before the treatment (p = 0.099, r = 0.62;
Table 2). The changes before and after the treatment
regarding other actigraphic sleep measures were not
statistically different.
Discussion
This is the first open-label trial, to our knowledge,
that investigates the effect of blocking blue light on
the circadian rhythm of the DSPD patients.
Intervention using amber lens showed a 78 min
SOT. The advance in SOT measured by actigraph
was statistically different, although that of DLMO
did not reach statistical significance. For the
patients whose melatonin levels had reached 4
pg/mL before 19:00 p.m. or had not yet reached
4 pg/mL by 24:00, we assumed that DLMO was at
19:00 p.m. or 24:00, respectively. This assumption
might however make the extent of the change in
DLMO less than the true value; thus, extending the
measurement period may reveal a statistically sig-
nificant advance also in DLMO value. A larger
sample size may also reveal a significant difference
here, particularly given that the effect size calcu-
lated in our data was large (r = 0.56).
There were notable changes in individual cases.
After the treatment, four out of seven (57.1%)
subjects, for whom actigraphic data were available,
showed an advance of >60 min in SOT.
Additionally, three of seven (42.8%) subjects
showed an advance of >60 min in DLMO value.
A study by Heijden et al. showed that after exo-
genous melatonin administration, 20 of 41 chil-
dren (48.8%) for whom actigraphic data were
 6 Y. ESAKI ET AL.
available had an advance of >30 min in SOT (Van
der Heijden et al., 2007). Our result may therefore
be comparable with this melatonin study, showing
that half of the subjects have an acceptable clear
effect. Social, psychological and environmental
factors may also play significant roles in the devel-
opment of delayed sleep phase, and the diagnostic
criterion of DSPD by ICSD-2 admits the two fac-
tors of chronobiologic and behavioral (American
Academy of Sleep Medicine., 2006). The DSPD
patients dominantly affected by social and envir-
onmental factors may not benefit from biological
treatment alone; simultaneous interventions for
these factors remain an outstanding issue.
There have been previous reports regarding the
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effects of glasses on sleep disorders. A study of the
efficacy of blue wavelength light-filtering glasses
for insomnia subjects showed significant improve-
ment in sleep quality and mood (as measured by a
sleep diary) compared with the use of yellow-
tinted “control” glasses, with no change in sleep
timing measures such as time to bed or wake-time
following use (Burkhart & Phelps, 2009). A shift-
work study investigating blue-blocking lenses also
showed improvement primarily in sleep quality
rather than circadian measures (Sasseville et al.,
2009). The results of this study build on these
previous findings investigating the use of light-
filtering glasses in sleep disorders.
No adverse effects following the usage of amber
lenses have been reported in previous studies and
our study (Burkhart & Phelps, 2009; Kayumov
et al., 2005). We therefore consider that the use of
amber lenses to block blue light is a safe treatment.
Indeed, it is hard to imagine a risk of amber glasses,
except for potential danger when they are worn
while driving or potential increase in sleepiness.
Intervention using amber lens may be useful for
the DSPD patients not only as monotherapy but
also in combination with exogenous melatonin
treatment or bright-light therapy. Bright-light
therapy compliance is a problem for the DSPD
patients since it may be difficult for the DSPD
patients to wake up in the morning. If the use of
amber lenses could advance the circadian rhythm
of the DSPD patients, this might make it easier for
the DSPD patients to undergo bright-light therapy.
Although exogenous melatonin treatment causes
very few side effects, it can cause nausea and
next-day grogginess (Buscemi et al., 2005).
Amber lenses might therefore also be useful for
the patients with DSPD who are unable to take
exogenous melatonin or who are resistant to exo-
genous melatonin treatment.
The mechanism for the beneficial effect of
amber lenses on the DSPD remains unclear. A
previous study has shown that larger melatonin
suppression and a greater phase delay can be
induced by shorter wavelengths light (blue, blue/
green and green) but not by larger wavelengths
light (red and orange) (Wright & Lack, 2001).
These melatonin modulations have also been
reported to be induced by blue wavelength light
emitted from cell phones, computers, and televi-
sions (Cajochen et al., 2011; Chang et al., 2015;
Gooley et al., 2010). In the patients with DSPD,
sleep onset is often delayed until early morning.
They often use the above-mentioned multimedia
devices in the evening when they cannot fall
asleep; this results in a further insomnia and cir-
cadian disturbance. It has been reported that mel-
atonin suppression is significantly lower after
exposure to half blue light displays compared
with normal blue light displays (Komada et al.,
2015). Blocking light of low wavelengths in
bright-light conditions can prevent the resulting
suppression of melatonin (Kayumov et al., 2005),
and perhaps the progression of the circadian delay.
Wearing amber lenses may have the same effect as
darkness. As a result, the sleep–wake rhythm of
the DSPD patients wearing amber lenses advances
because they can live a normal life while avoiding
blue light in the evening. Further, melatonin sup-
pression by light exposure is higher in children
than in adults because children have large pupils
and pure crystal lenses (Higuchi et al., 2014).
Amber-lens treatment may be more effective in
the adolescent DSPD patients.
This study has some limitations. First, this study
was not a randomized controlled investigation.
Performing a randomized controlled trial using a
placebo condition (e.g., yellow-tinted glasses that
block only ultraviolet light) (Burkhart & Phelps,
2009) would be necessary to confirm our findings.
Second, the patients were enrolled from one insti-
tute, and the number of study subjects was small.
Third, this study covered only a short period of
experimentation, only 2 weeks. A longer term

study is expected in the future. Fourth, if the
patients wearing the glasses could awaken earlier,
they may have had increased exposure to morning
light, which may have affected phase advance. It is
difficult to discriminate between the effect of the
glasses and that of the morning light. In either
case, we considered that this was the direct or
indirect effect of wearing glasses.
In conclusion, the use of amber lenses to block blue
light was an effective treatment for the patients with
DSPD. No adverse effect of amber lenses were noted
during the 2 weeks of the treatment. The amber-lens
treatment significantly improved SOT compared with
that before the treatment, but its effect on DLMO or
WUT was not significant. Further studies adopting
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controlled observations will be required to determine
the intrinsic mechanisms involved in the chronobio-
logical effects of amber lenses in DSPD. Scales of
Morningness–Eveningness preference and insomnia
will be useful in such studies to help understand the
mechanisms and/or predictive factors of treatment
efficacy. The factors, such as lens-wearing time, con-
sequences of long-term use, and the possibility of
relapse after discontinuation of amber-lens treatment,
remain to be explored.
Acknowledgments
The authors are grateful to the patients who participated in this
study and thank MARUZEN Editing Light service (http://kw.
maruzen.co.jp/kousei-honyaku/) for English language review.
Declaration of interest statement
The authors report no conflicts of interest in this research. Dr
Kitajima has received speaker’s honoraria from Eizai,
Mitsubishi Tanabe, Otsuka, Takeda, Eli Lilly, MSD,
Yoshitomi, Fukuda, Dainippon Sumitomo, and Shionogi
and has received research grant from Eizai, MSD and
Takeda. Dr. Iwata has received speaker’s honoraria from
Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline,
Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, and
Pfizer and has research grants from Dainippon Sumitomo,
GlaxoSmithKline, Tanabe-Mitsubishi and Otsuka.
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