DOI: 10.1111/bdi.

12912

ORIGINAL ARTICLE

A double-blind, randomized, placebo-controlled trial of

adjunctive blue-blocking glasses for the treatment of sleep and
circadian rhythm in patients with bipolar disorder

Yuichi Esaki1,2  | Ipei Takeuchi1 | Soji Tsuboi1 | Kiyoshi Fujita1,3 | Nakao Iwata2 |

Tsuyoshi Kitajima2

1
Department of Psychiatry, Okehazama
Hospital, Toyoake, Aichi, Japan Abstract
2
Department of Psychiatry, Fujita Health Objectives: Recent studies have suggested that evening blue light exposure is associ-
University School of Medicine, Aichi, Japan
ated with sleep and circadian rhythm abnormalities. This study examined the effect
3
The Neuroscience Research Center, Aichi,
Japan
of blue-blocking (BB) glasses on sleep and circadian rhythm in patients with bipolar
disorder (BD).
Correspondence
Yuichi Esaki, Department of Psychiatry,
Methods: We used a randomized, placebo-controlled, double-blinded design.
Fujita Health University School of Medicine, Outpatients with BD and also with insomnia were randomly assigned to wear either
Toyoake, Aichi 4701192, Japan.
Email: esakiz@fujita-hu.ac.jp
orange glasses (BB) or clear ones (placebo) and were instructed to use these from
20:00 hours until bedtime for 2 weeks. The primary outcome metric was the differ-
Funding information
Scientific Research from JSPS KAKENHI,
ence in change from baseline to after intervention in sleep quality, as measured by
Grant/Award Number: 18K15529; the visual analog scale (VAS).
Neuroscience Research Center; Japan
Foundation for Neuroscience and Mental
Results: Forty-three patients were included in this study (BB group, 21; placebo
Health group, 22). The change in sleep quality as per the VAS metric was not significantly
different between the two groups (95% confidence interval [CI], −3.34 to 24.72;
P = .13). However, the Morningness-Eveningness Questionnaire score had shifted to
an advanced rhythm in the BB group and to a delayed rhythm in the placebo group,
and the difference in these changes was statistically significant (95% CI, 1.69-7.45;
P = .003). The change in the actigraphy sleep parameters and mood symptoms was
not significantly different between the two groups.
Conclusion: Although concurrent medications may have influenced, our results sug-
gest that BB glasses may be useful as an adjunctive treatment for circadian rhythm
issues in patients with BD.

KEYWORDS

bipolar disorder, blue light, blue-blocking glasses, circadian rhythm, RCT, sleep

1 |  I NTRO D U C TI O N which often produces substantial sleep and circadian rhythm ab-
normalities.1-4 These problems can occur in all periods, regardless
Bipolar disorder (BD) is a recurrent chronic psychiatric condition of it being a symptomatic period or euthymic period.1,2,4,5 In addi-
characterized by episodes of depression and mania/hypomania, tion, residual sleep disturbances and eveningness chronotypes are

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Bipolar Disorders. 2020;22:739–748.  |

wileyonlinelibrary.com/journal/bdi     739
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740       ESAKI et al.
associated with a risk for mood episode recurrence and depressive
3,6
symptoms. Furthermore, sleep loss has been shown to be asso-
7
ciated with suicide risk. Therefore, the prevention of sleep and
circadian rhythm abnormalities is essential in managing patients
with BD.
Light exposure plays the most important role in the regulation
of circadian rhythms in humans.8 Morning light advances circadian
rhythms, whereas light in the evening or night induces circadian
phase delays.9 Moreover, circadian dysfunction caused by light ex-
posure has been reported to depend not only on the duration and
the intensity of the light but also on its wavelength.10-12 Previous re-
search has demonstrated that blue wavelengths are the most closely
associated with the regulation of circadian rhythm and the direct
13
alerting effect. Therefore, evening blue light exposure in daily life
may affect sleep and circadian rhythm in patients with BD.
In recent years, it has been reported that wearing blue-
blocking (BB) glasses that virtually eliminate blue wavelengths is
­effective for improving sleep, circadian rhythm, and mood. Two ran-
domized controlled trials (RCT) have demonstrated that BB glasses
brought significant improvement in sleep quality compared with pla-
cebo glasses in participants with insomnia.14,15 Our previous open-
label study of delayed sleep-wake phase disorder (DSWPD) showed
that it was possible to advance the sleep onset time for subjects
wearing BB glasses.16 In a 21-patient case series describing euthy-
mic patients with BD who wore BB glasses in the evening, a note-
17
worthy 50% reported improved sleep during the intervention.
Additionally, previous RCTs have shown that BB glasses significantly
improved acute manic symptoms compared with placebo glasses.18
Therefore, it is likely that BB glasses may be effective for sleep and
circadian rhythm in patients with BD. However, to our knowledge,
no previous RCT study has investigated the potential benefits of
BB glasses to improve sleep and circadian rhythm in such patients.
In this placebo-controlled investigation, we examined the effi-
cacy of BB glasses in patients with BD who had insomnia. We hy-
pothesized that BB glasses would improve their sleep quality and
shift their circadian rhythm to morningness.
2 |  M E TH O DS
2.1 | Setting and participants
Patients were recruited from Okehazama Hospital, Fujita Mental
Care Satellite Zengo, Fujita Mental Care Satellite Tokushige between
July 20, 2017 and February 26, 2019. The analysis was conducted
from February 26, 2019 to April 1, 2019. The study was approved
by the Ethics Committee of Okehazama Hospital and was registered
at UMIN-CTR (identifier: UMIN000028125). Written informed con-
sent was obtained from all participants after possible side effects
were fully explained to them. Eligible patients were aged 18-75 years,
and they were diagnosed with BD according to the Diagnostic and
Statistical Manual of Mental Disorders (fifth edition) by an experi-
enced psychiatrist. A score of ≥8 on the Insomnia Severity Index (ISI)
questionnaire at the screening was used to select the patients for
the study.19 Exclusion criteria were night shift workers, people with a
serious suicidal risk as judged by a clinician, and acute manic, mixed,
and depressive episodes (patients with only residual symptoms were
enrolled in this study).
2.2 | Intervention
The trial used a randomized, placebo-controlled, double-blinded
design and was conducted over three consecutive weeks. The first
week was the baseline assessment period, including clinical charac-
teristics, sleep, and circadian rhythm. For the following 2 weeks, the
participants were randomly assigned to either the BB or the placebo
group and then were instructed to wear the allocated glasses from
20:00 hours to bedtime every evening. The BB group wore glasses
with orange lenses (Yamamoto Kogaku, No. 360S UV Orange,
Osaka, Japan) and the placebo group wore glasses with clear lenses
(Yamamoto Kogaku, No. 331, Osaka, Japan). Figure S1 presents light
transmission data for the colored lenses provided by the manufac-
turer. In our previous study, 40% of the participants reported pain
or discomfort from wearing these glasses. 20 Therefore, the temple
parts of the glasses used in this study utilized a size-adjustable ca-
pability to eliminate this potential issue (Yamamoto Kogaku, No. YL-
335, Osaka, Japan). The usual medications and psychotherapy were
maintained during the study period. The use of multimedia devices
(eg, cell phones, computers, and televisions) in the evening was not
limited or prohibited during the study.
2.3 | Randomization and blinding
Our randomization process used computer-generated random
assignments in blocks of four. The allocation of orange (BB) or
clear glasses (placebo) was conducted by medical staff not other-
wise involved in the study, and the allocated glasses were boxed.
Participants were masked as to group assignment and received the
identical limited information about the purpose of the study, that is,
testing the effectiveness of two types of glasses in improving sleep
and rhythm by blocking different light wavelengths. Any participants
with knowledge of BB glasses were excluded from the study. Before
and during the 3 weeks, participants were instructed in the following
topics: (a) not to confirm the contents of the box while in the hospi-
tal; (b) not to research their allocated glasses; and (c) not to discuss
the nature of their glasses with the medical staff.
2.4 | Assessments
The primary outcome metric was sleep quality, as indicated by a vis-
ual analog scale (VAS), which assessed sleep quality for the previous
week at baseline and after the intervention. Sleep quality on the VAS
was defined as the overall quality of the sleep experience, including
ESAKI et al.
falling asleep, sleep maintenance, and waking up, and was rated from
0 (very good) to 100 (very poor).
Secondary outcomes included subjective and objective sleep
and circadian rhythm parameters. The ISI and the Morningness-
Eveningness Questionnaire (MEQ) were assessed at baseline and after
21
the intervention. The ISI is a reliable and valid instrument to detect
changes in perceived insomnia severity19 and the MEQ is a psycho-
logical preference for behavior such as daily activity and wakefulness
and is closely related to circadian rhythm.22 A physician employed
the Clinical Global Impression (CGI) instrument to evaluate improve-
ment after the intervention. All participants were instructed to re-
cord bedtime, rising time, and the glasses wearing time using a sleep
diary during the study periods. Objective parameters were assessed
using an actigraph (Actiwatch Spectrum Plus; Philips Respironics Inc).
Participants were instructed to wear an actigraphy device on the wrist
of their non-dominant arm for 24 hours/day, during the 7 days of the
baseline period and during the last 7 days of the second week during
the intervention period. The resulting data were sampled in 1 minute
epochs, and a default threshold (40 counts per minute) was used to
determine sleep and awake periods. Time in bed, regardless of being
asleep or awake, was defined by the sleep diary entries, not by the ac-
tigraphy data. We automatically analyzed the actigraphy data with the
sleep detection algorithm using the software for the device, Actiware
version 6.0.9 (Respironics, Inc). This actigraphy analysis method has
been used in previous studies of BD patients.23,24 We used seven ac-
tigraphy parameters and two sleep disturbance patterns determined
from the actigraphy parameters. Actigraphy parameters were: (a) sleep
start time; (b) sleep end time; (c) total sleep time (TST), which is the
total time spent asleep from sleep start to end during the main sleep
phase, excluding wake after sleep onset; (d) sleep efficiency (SE), which
is the percentage of TST between bedtime and rising time for the main
sleep phase (ie, TST divided by time in bed); (e) wake after sleep onset
(WASO), which is the total time spent awake from sleep start to end; (f)
sleep onset latency (SOL), which is the time from bedtime to the start
of sleep; and (g) midpoint of sleep, which is the mid-time from sleep
start to sleep end. Sleep disturbance patterns were: (a) short sleepers;
which was less than 6 hours TST; (b) circadian rhythm disorder pattern;
which is a delayed sleep phase pattern (sleep start after 2:00 am) and
irregular sleep-wake pattern (at least three periods of sleep but no con-
solidated overnight sleep period). The sleep disturbance patterns were
defined based on a previous study.25
Each participant's current depressive or manic status was as-
sessed using the Montgomery-Åsberg Depression Rating Scale
(MADRS) and the Young Mania Rating Scale (YMRS) at baseline and
at 2 weeks. 26,27 Evening light exposure was assessed at 1 minute
intervals using actigraphy, which could measure ambient light be-
tween 20:00 and bedtime at baseline.
2.5 | Statistical analyses
All randomized participants were included in the intent-to-treat anal-
ysis. Missing data were imputed using the last observation carried
|
      741
forward, and sample size estimates were determined using the power
analysis from a study involving major depressive disorder patients with
insomnia.20 On the basis of sleep quality evaluated by a VAS used in
that study, a power analysis indicated that for a probability level of 0.05
(two-tailed) and 80% power, a total of 52 patients would be enough to
detect a significant difference. However, because of the expiration of
the study deadline, the final sample was 43 patients with BD.
Continuous and categorical variables at baseline were com-
pared between the BB and placebo groups using the unpaired
t tests or Mann-Whitney U test and chi-square test, respectively.
The final doses of antipsychotics, antidepressants, and benzodiaz-
epine hypnotics were evaluated on the basis of chlorpromazine-,
imipramine-, and diazepam equivalent doses, respectively. 28-30 We
evaluated the changes from baseline in sleep, circadian rhythm,
and mood parameters by analysis of covariance, with baseline val-
ues and antidepressants dosages as covariates (because we found
significantly different changes between the BB and placebo groups
in antidepressant dosages at baseline; Table 1). The parameters in-
cluded sleep quality (assessed using the VAS), ISI score, MEQ score,
and actigraphy parameters (SE, SOL, WASO, TST, midpoint of sleep,
sleep start, and sleep end), as well as MADRS and YMRS scores. In
addition, we evaluated the CGI scores and the changes in the sleep
disturbance patterns (“short sleepers” and “circadian rhythm dis-
turbance patterns”) using an ordinal logistic regression model with
antidepressant dosages and MADRS scores (because of marginally
significant differences between the two groups at baseline; Table 1)
as covariates. Considering that the SOL data at baseline were not
normally distributed, it was natural log-transformed for the analy-
ses. YMRS scores and antidepressant dosages at baseline were not
normally distributed, even after log transformation, and were there-
fore treated as categorical variables (YMRS; ≥5 vs <5 points, antide-
pressants dosage; >0 vs 0 mg/day: category based on the median
value). All statistical tests were performed using SPSS version 25.0
for Windows (IBM Inc). The significance level was set at P < .05. Any
adverse events were recorded.
3 | R E S U LT S
Of the 196 outpatients with BD who were screened, a total of 43
were randomly assigned into the two groups (BB group, 21 [48.8%],
placebo group, 22 [51.1%]; Figure 1). In the BB group, one participant
discontinued shortly after the intervention because of discomfort
from wearing the glasses, and another withdrew before the inter-
vention because of patient wish (Figure 1). In the placebo group, a
total of four participants discontinued the intervention because of
pain from the contacting part of the glasses, discomfort from wear-
ing the glasses, or transfer to another clinic (Figure 1). The number
of days and the times of wearing the glasses were not significantly
different between the BB and placebo groups (number of wearing
days: median [interquartile range], 14.0 [10.0-14.0] vs 13.0 [7.25-
14.0] days, P = .31; wearing times: 20:30 [20:10-21:05] vs 21:13
[20:14-21:31], P = .52).
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742       ESAKI et al.

TA B L E 1   Demographic and clinical characteristics at baseline between the BB and the placebo groups

BB group Placebo group

Variables (n = 21) (n = 22) P

Demographic characteristics
Age, years, mean (SD) 44.1 (11.8) 41.1 (10.4) .38
Gender, female, n (%) 21 (42.9) 22 (63.6) .17
Married, n (%) 11 (52.4) 12 (54.5) .88
Employed, n (%) 7 (33.3) 9 (40.9) .6
Clinical characteristics
Type of BD, BD-I, n (%) 10 (47.6) 6 (27.3) .16
Onset age of BD, years, mean (SD) 33.5 (10.3) 30.0 (9.2) .25
Duration of illness, years, mean (SD) 10.6 (5.5) 11.5 (7.2) .65
Family history of psychiatric disorders, n (%) 3 (14.3) 5 (22.7) .47
MADRS score, points, mean (SD) 12.1 (9.3) 17.6 (10.3) .07
YMRS score, points, median (IQR) 2.0 (0-5.5) 3.0 (1.7-6.0) .25
Average evening light, lux, median (IQR) 22.8 (14.6-41.4) 34.8 (18.7-61.4) .34
Medications
Lithium, n (%) 8 (38.1) 7 (31.8) .66
Lamotrigine, n (%) 9 (42.9) 10 (45.5) .86
Valproate, n (%) 4 (19.0) 7 (31.8) .33
Antipsychotic, n (%) 11 (52.4) 11 (50.0) .87
a
Antipsychotics, mg/day, median (IQR)   10.0 (0-200.0) 0 (0-136.2) .75
Antidepressant, n (%) 13 (61.9) 8 (36.4) .09
b
Antidepressants, mg/day, median (IQR)   150.0 (0-225.0) 0 (0-38.0) .009
SSRI, n (%) 4 (19.0) 2 (9.0) .34
Benzodiazepine hypnotics, n (%) 15 (71.4) 11 (50.0) .15
Benzodiazepine hypnotics, mg/day, median (IQR)c  5.0 (0-10.0) 0 (0-6.25) .74
Ramelteon, n (%) 3 (14.3) 3 (13.6) .95
Suvorexant, n (%) 3 (14.3) 5 (22.7) .47

Note: Data are expressed as mean (standard deviation), median (interquartile range), or number (proportion).
Abbreviations: BB, blue-blocking; MADRS, Montgomery-Åsberg Depression Rating Scale; YMRS, Young Mania Rating Scale; SSRI, Selective
Serotonin Reuptake Inhibitors.
a
Chlorpromazine equivalent dose.
b
Imipramine equivalent dose.
c
Diazepam equivalent dose.

Tables 1 and 2 present the information at baseline for the BB and
placebo groups. The MADRS score was marginally significantly lower
in the BB group compared with that in the placebo group (mean, 12.1
vs 17.6 points; P = .07; Table 1), and the dosage of the antidepressant
was significantly higher (median, 150.0 vs 0 mg/day; P = .009; Table 1).
SE as using actigraphy was significantly lower in the BB compared with
that in the placebo group (76.2% vs 82.6%; P = .02; Table 2). Other
values did not significantly differ between the two groups.
The mean (SD) change from baseline in sleep quality on the VAS
showed an improvement of 19.0 (24.5) points in the BB group and
10.1 (25.8) points in the placebo group (Figure 2A), but the differ-
ence in these changes in sleep quality was not statistically signifi-
cant (P = .13; Table 3). The MEQ score had shifted to an advanced
rhythm in the BB group (mean 1.48 points; Figure 2B) and to a de-
layed rhythm in the placebo group (mean 2.82 points; Figure 2B).
The difference in changes between the two groups was statisti-
cally significant (P = .003; Table 3). The change in the other sleep
and circadian rhythm parameters, including ISI and actigraphy data
(SE, SOL, WASO, TST, midpoint of sleep, sleep start time, and sleep
end time) was not significantly different between the two groups
(Table 3). Regarding the patterns of sleep disturbance, the number
of short sleepers decreased in the BB group by two patients and
increased in the placebo group by two patients, but this change was
not statistically significant (P = .16). Delayed sleep phase patterns
increased by one patient in the BB group and by one patient in the
placebo group (P = .80).
ESAKI et al.
Assessed for eligibility (n = 196)
Randomized (n = 43)
Allocated to blue-blocking glasses (n = 21)
Discontinued intervention (n = 2)
• Discomfort from wearing the glasses (n = 1)
• Patient wish (n = 1)
Intention-to-treat analyzed (n = 21)
F I G U R E 1   Subject selection profile for a randomized controlled trial of blue-blocking glasses vs placebo glasses for patients with bipolar
disorder
Table 4 presents the CGI data measuring improvement. In the
BB group, 57.1% showed improvement, whereas for 42.9%, there
was no change. In the placebo group, 40.9% were improved, 40.9%
had no change, and 18.2% were worse. In the univariable ordinal
logistic regression model, the improvement in the CGI score of BB
group compared with the placebo group was marginally significant
(P = .051). In the multivariable ordinal logistic regression model,
which included antidepressants dosages and MADRS scores, these
associations remained marginally significantly improved (P = .092).
No serious adverse event was recorded during the trial. Adverse
events in general involved discomfort from wearing the glasses (BB
group, 2; placebo group, 3) and pain from the contacting part of the
glasses (BB group, 1; placebo group, 4), as well as lowered mood (BB
group, 1). All participants reported that the discomfort or pain im-
proved after removing the glasses. One participant in the BB group
reported lowered mood after intervention week 1. The baseline
MADRS score of the participant was 12 points, and the 2-week end-
point was 26 points. The treatment team, the patient, and the pa-
tient's family judged the event to be more likely related to the stress
caused by returning to work than to the intervention. The partici-
pant completed the intervention without a further lowered mood.
4 | D I S CU S S I O N
To the best of our knowledge, this is the first placebo-controlled
study to examine the effectiveness of BB glasses for sleep and cir-
cadian rhythm in BD patients with insomnia compared with a pla-
cebo condition. Sleep quality, as evaluated using the VAS, did not
significantly differ between the two groups. However, BB glasses did
significantly advance the chronotype in patients with BD compared
|
      743
Excluded (n = 153)
• Not meeting inclusion criteria (n = 73)
• Declined to participate (n = 80)
Allocated to placebo glasses (n = 22)
Discontinued intervention (n = 4)
• Pain from the wearing part of the glasses (n = 2)
• Discomfort from wearing the glasses (n = 1)
• Transfer to another clinic (n = 1)
Intention-to-treat analyzed (n = 22)
with the placebo glasses and marginally significantly improved the
CGI scores.
In an earlier effort, a 20-patient case series using amber BB
glasses improved sleep as evaluated by CGI in more than 50% of
the patients with BD.17 Previous studies in general populations have
demonstrated that wearing BB glasses for subjects with insomnia
significantly improved sleep quality compared with the use of pla-
cebo glasses.14,15 Our results indicated that wearing BB glasses im-
proved the CGI scores in 57.1% of the BD patients with insomnia and
that this improvement was marginally significantly higher in the BB
group than that in the placebo group. However, we failed to show
that BB glasses resulted in a statistically significant improvement in
subjective and objectively assessed sleep quality compared with pla-
cebo glasses. This failure to detect an improvement in these particu-
lar metrics may have resulted from the small sample size in our study.
Although we calculated the required sample size (52 participants)
based on our previous research on sleep quality, 20 the number of
subjects in this study (43 participants) was smaller than the calcu-
lated optimal size. In addition, the dosage of the antidepressant was
significantly higher in the BB group compared with that in the pla-
cebo group. Antidepressants have been suggested to be associated
with both insomnia and hypersomnia.31 Therefore, the antidepres-
sants may have masked the effects of the BB glasses by modulat-
ing sleep. However, sleep quality based on the VAS improved in the
BB group more than that in the placebo group (mean; 19.0 vs 10.1
points; Table 3), suggesting that further investigations regarding the
effect on sleep quality that might be due to BB glasses would be
highly productive.
A previous study reported that BB glasses significantly attenu-
ated evening light-induced melatonin suppression in male teenag-
ers compared with clear glasses. 32 Additionally, our previous study
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744       ESAKI et al.

TA B L E 2   Comparisons of sleep and rhythm parameters at in the evening during the study. Although the purpose of this ex-
baseline between the BB and the placebo groups planation was to have the participants maintain their daily rou-
BB group Placebo group tine, this explanation might have increased their times of using
multimedia devices in the evening during the study, especially
Variables (n = 21) (n = 22) P
while wearing the glasses. As a result, the placebo group may have
Subjective parameters, mean (SD) shifted to the delayed rhythm. In contrast, even though all partic-
Sleep quality on 57.4 (18.2) 58.6 (18.7) .82 ipants received the same information, the BB group shifted to the
VAS, points
advanced rhythm. Although this advance was small, these results
ISI, points 14.8 (3.4) 15.7 (3.9) .44 may indicate that the BB glasses prevented the circadian dysfunc-
Bed in time, clock 23:34 (1:15) 23:56 (2:10) .5 tion by light exposure and advanced the chronotype. However, the
time
change in the light exposure situation remains unknown because
Bed out time, clock 7:54 (1:45) 8:03 (2:09) .8 we did not collect evening light exposure during the intervention
time
period. In general, dim light melatonin onset is considered the
MEQ, points 45.6 (12.4) 45.1 (10.9) .88
most reliable phase marker for circadian rhythms. 33 Therefore, fu-
Actigraphy parameters ture studies that are measuring dim light melatonin onset would
SE, %, mean (SD) 76.1 (10.3) 82.6 (8.1) .02 reveal a more productive effect in this regard on BD subjects using
SOL, min, median 28.4 19.3 (13.4-31.2) .36 BB glasses.
(IQR) (12.5-44.2)
In this study, the use of BB glasses did not result in a significant
WASO, min, mean 59.3 (29.3) 46.2 (31.1) .16 change in mood for patients with BD. A recent RCT involving 32 pa-
(SD)
tients with bipolar mania demonstrated that the use of BB glasses
TST, min, mean (SD) 380.3 (97.0) 397.7 (73.1) .5
significantly improved the YMRS scores relative to placebo glasses
Midpoint of sleep, 3:48 (1:20) 4:06 (1:59) .55 (Cohen's d = 1.86). In that study, the mean (SD) YMRS scores at the
clock time, mean
start of the intervention were 23.4 (8.0) points, whereas the median
(SD)
(IQR) YMRS score in our study was very low 3.0 (0-6.0). Therefore,
Sleep start time, 24:06 (1:22) 24:24 (2:06) .58
clock time, mean the fact that manic symptoms in our study did not result in a signif-
(SD) icant change might be due to the low manic symptoms score of our
Sleep end time, clock 7:30 (1:47) 7:49 (2:07) .60 subjects at baseline.
time, mean (SD) Our results did show that BB glasses have high tolerance and
Sleep disturbance patterns safety in patients with BD. We had only two (9%) dropouts in the BB
Short sleeper, n (%) 11 (42.9) 7 (40.9) .16 group, one of whom left at the patient's wish before the intervention
Circadian rhythm 3 (14.3) 4 (18.3) .72 began. Therefore, one patient (5%) only dropped out because of the
disturbance intervention itself. The number of adverse events of any kind caused
pattern, n (%) by wearing BB glasses was four (19%), but there were no serious ad-
Delayed sleep phase 3 (14.3) 3 (13.6) .95 verse events. A previous study found that BB glasses were generally
pattern, n (%)
well tolerated by patients with mania and that their use was also
Irregular sleep-wake 1 (4.8) 1 (4.8) .97 feasible for several patients with psychotic symptoms.18 Thus, we
pattern, n (%)
conclude that BB glasses are a safe and well-tolerated treatment in
Note: Data are expressed as mean (standard deviation), median patients with BD.
(interquartile range), or number (percentage).
They might also be useful as an adjunctive treatment for circa-
Abbreviations: BB, blue-blocking; VAS, visual analog scale; ISI, Insomnia
dian rhythm issues for patients with BD, who are prone to exhibit
Severity Index; MEQ, Morningness-Eveningness Questionnaire; SE,
sleep efficiency; SOL, sleep onset latency; TST, total sleep time. the evening chronotype regardless of their mood state,5 which is
frequently influenced by DSWPD.34 The evening chronotype is as-
in patients with DSWPD demonstrated that BB glasses advanced sociated with depressive symptoms and suicidal ideation,35,36 and
16
sleep onset time measured using actigraphy by about 2 hours. DSWPD is a predictor of symptom relapse in BD.37 Additionally,
Our results showed that the BB group shifted to the advanced it has been suggested that chronobiological treatment, including
rhythm as expected, but the placebo group unexpectedly shifted bright light therapy and melatonin, is effective for both the improve-
to the delayed rhythm (Figure 2B). Although the change in MEQ ment of mood symptoms and recurrence prevention of BD through
scores showed significant differences between two groups, the the adjustment of sleep and circadian rhythm dysfunction.38 The
difference was due to the two groups shifting in opposite direc- proportion of BD types collected in this study (BD-I vs BD-II = 37.2%
tions. The possible reason why the placebo group shifted to the vs 62.8%) was similar to the results of a Japanese epidemiological
delayed rhythm may have been due to the explanation about our trial (BD-I vs BD-II vs BD not otherwise specified = 36.8% vs 57.0%
study to the participants. We explained to the participants that vs 6.2%).39 Furthermore, many of the patients in this study had mild
they need not limit to or prohibit the use of multimedia devices to moderate depressive symptoms (mean MADRS score 14.9 points)
ESAKI et al. |
      745

F I G U R E 2   The change from baseline

(A)
to the 2-week endpoint in the sleep
70

Sleep quality on VAS score (point)

quality on the visual analog scale
(VAS) score (A) and the Morningness- 65
Eveningness Questionnaire (MEQ) score
1BB
(B). Values are reported as mean with 60
95% confidence interval. The orange line
55
shows blue-blocking (BB) group, and the
2Placebo
gray line presents the placebo group. 50
Sleep quality on the VAS is rated from 0
(very good) to 100 (very poor) 45
40
35
30
25
1.00
baseline 2-week2.00
endpoint

(B)
55
53
51 1 BB
MEQ score (point)

49
2 Placebo
47
45
43
41
39
37
35
baseline 2-week endpoint

and patients with BD spend more time with depressive symptoms
than with mania/hypomania in a clinical course.40 Therefore, the
samples collected in our study may be representative samples of
general clinical practice and it is suggested that adjunctive treatment
using BB glasses can be generalized as a new treatment option for
patients with BD.
The mechanism of the effect of BB glasses on BD remains un-
clear, but a possible explanation is suggested by the light exposure
environment in modern society. The use of electronic devices, such
as cell phones, tablets, and computers, has dramatically increased
in recent years. Light-emitting diode (LED) screens used in these
devices present a significant proportion of blue wavelengths.41
A 5-hour LED screen exposure in the evening has been found not
only to suppress melatonin secretion but also to increase subjective
13
and objective alertness in young adults. Another study demon-
strated that the use of LED devices for reading before bedtime
can cause prolonged sleep latency and delay the circadian clock.42
Additionally, experimental studies have shown that patients with
BD are supersensitive to the suppression of nocturnal melatonin by
light.43 Thus, wearing BB glasses in the evening may prevent light-in-
duced circadian dysfunction and sleep disorder in patients with BD.
This study had several limitations. First, although we assessed
eligibility for 196 patients with BD, we could not collect the full
number of participants we wanted on the basis of a previous study
on sleep quality. 20 Our sample size might have not had sufficient
statistical power to detect significant differences in sleep quality
between the patient groups. Therefore, it is hard to state whether
the effect on sleep quality with BB glasses is truly a negative re-
sult, and it is important that the study be repeated using a more
appropriate sample size. Additionally, sample size estimates were
calculated based on sleep quality evaluated by VAS. Sleep qual-
ity is generally evaluated using the ISI or Pittsburgh Sleep Quality
Index.44 However, before the start of our study, no previous study
has investigated the use of these scales to evaluate the poten-
tial benefits of BB glasses. Second, most of our subjects (74.4%)
had already been treated with hypnotic drugs. This fact might
 |
746       ESAKI et al.

TA B L E 3   Change from baseline to the 2-week endpoint and analysis of covariance between BB and placebo groups

Change from baseline to the 2-week endpoint

  BB group (n = 21) Placebo group (n = 22) P 95% CI Std Beta

Subjective parameters, mean (SD)

Sleep quality on VAS, 19.0 (24.5) 10.1 (25.8) .13 −3.34 to 24.72 0.21
points
ISI, points 1.9 (4.8) 2.1 (4.3) .93 −2.76 to 2.54 0.12
MEQ, points 1.4 (3.3) −2.8 (5.4) .003 1.69 to 7.45 0.46
Actigraphy parameters, mean (SD)
SE, % 1.5 (6.3) −0.2 (4.9) .38 −2.18 to 5.64 0.16
SOL, min 1.5 (6.3) 1.5 (4.9) .85 −10.72 to 8.86 0.03
WASO, min 5.6 (16.9) 2.8 (13.1) .73 −11.51 to 8.15 0.05
TST, min 1.1 (55.9) −12.6 (52.7) .42 −45.46 to 19.40 0.12
Midpoint of sleep, min 2.0 (51.3) −3.5 (62.2) .65 −42.24 to 26.58 0.07
Sleep start time, min 0.8 (35.1) −2.4 (61.6) .81 −34.0 to 26.8 0.03
Sleep end time, min 7.1 (58.5) 10.5 (73.3) .70 −33.0 to 48.6 0.06
MADRS score, points 1.1 (1.9) 1.7 (8.3) .39 −6.80 to 2.71 0.13
YMRS score, points 0.9 (2.9) −0.32 (5.0) .27 −1.13 to 3.88 0.17

Note: Covariate: each baseline value and use of antidepressant. Values presented as mean (standard deviation).
Abbreviations: BB, blue-blocking; VAS, visual analog scale; ISI, Insomnia Severity Index; MEQ, Morningness-Eveningness Questionnaire; SE, sleep
efficiency; SOL, sleep onset latency; TST, total sleep time; MADRS, Montgomery-Åsberg Depression Rating Scale; YMRS, Young Mania Rating Scale.

TA B L E 4   Clinical Global Impressions for Improvement
Clinical Global
Impressions Scale Score
1: Very much improved
2: Much improved
3: Minimally improved
4: No change
5: Minimally worse
6: Much worse
7: Very much worse
of the depressive scores and the baseline values of the antidepres-
sant dosages were different in the two groups. The differences in
Placebo group
BB group (n = 21) (n = 22) these baseline values may have influenced the results. Fifth, we
did not exclude other sleep disorders, including obstructive sleep
5 (23.8) 2 (9.1)
apnea and restless legs syndrome, in eligibility assessments. These
4 (19.0) 1 (4.5)
sleep disorders may have influenced the results because they are
3 (14.3) 6 (27.3)
often associated with insomnia.46,47 Sixth, although an actigraphy
9 (42.9) 9 (40.9) device is useful to evaluate the objectivity of the sleep experiences
0 2 (9.1) of the patients, automatic analysis with actigraphy might not have
0 2 (9.1) been able to accurately detect improvements in sleep parameters.
0 0 Additionally, wearing actigraphy devices continuously may have

Note: Values presented as number (percentage). BB, blue-blocking.
There was a marginally significant improvement in the CGI in the BB
group compared with the placebo group (P = .092).
have weakened the effect of BB glasses. Third, we employed
only a short intervention period (2 weeks). Previous studies sug-
gest that the response to BB glasses is rapid; it occurs within
days.17,18 Therefore, although the intervention period for acute
symptoms may not be longer than 2 weeks, a study to clarify the
long-term efficacy and safety of BB glasses may also be neces-
sary. Additionally, the intervention started for all at 20:00. The
intervention timing of chronobiological therapy, such as melatonin
administration, was different depending on the individual patient's
endogenous circadian timing.45 The chronotypes of patients who
participated in our study varied. Therefore, tailored treatment ac-
cording to each chronotype may show a more accurate effect of
the BB lens. Fourth, although we used a randomized controlled
trial design to distribute the two groups equally, the baseline value
affected the sleep of the patients. Finally, complete blinding was
challenging to achieve. The participants could potentially have
searched for information about the glasses despite instructions to
not to do so during the study period. However, our study included
maximized blinding by excluding the participants with knowledge
of BB glasses from the study. The knowledge of blue light and BB
glasses has become a general understanding. Subsequent stud-
ies of the BB glasses will require further contrivance to maintain
blinding.
In conclusion, we failed to show that BB glasses resulted in a
significant improvement in sleep quality for patients with BD and
insomnia. The possible reason could be due to a “ceiling effect,”
wherein 74% of all patients were already taking hypnotic medica-
tions. However, the use of BB glasses did advance the chronotype
in patients with BD, improve the clinical impression, and created
changes for actigraphic sleep efficiency. Since our results may have
been influenced by the medications associated with sleep regula-
tion, such as antidepressants and benzodiazepine hypnotics, further
ESAKI et al.
studies are necessary to determine the fundamental mechanisms in-
volved in the chronobiological effects of BB glasses in patients with
BD.
AC K N OW L E D G M E N T
We are grateful to the patients who participated in this study. We
also thank Miyuki Yamamoto for their valuable support during this
research and MARUZEN-YUSHODO Co., Ltd. (https://kw.maruz​
en.co.jp/kouse​i-honya​ku/) for the English language editing.
C O N FL I C T O F I N T E R E S T
The authors report no conflicts of interest related to this re-
search. Dr. Fujita has received speaker's honoraria from Dainippon
Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka,
Meiji, Shionogi, Novartis, and Kracie. Dr. Iwata has received speak-
er's honoraria from Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline,
Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Novartis, Astellas, and
Pfizer and has had research grants from GlaxoSmithKline, Meiji,
Otsuka, Mitsubishi Tanabe, Dainippon Sumitomo, Daiichisankyo,
and Eisai. Dr. Kitajima has received speaker's honoraria from
Dainippon Sumitomo, Eli Lilly, Eisai, Mitsubishi Tanabe, Otsuka,
Takeda, MSD, Meiji, Yoshitomi, Fukuda, Shionogi, and Novo
Nordisk and has received a research grant from Eisai, MSD, and
Takeda.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from
the corresponding author upon reasonable request.
ORCID
Yuichi Esaki  https://orcid.org/0000-0001-5165-6171
Tsuyoshi Kitajima  https://orcid.org/0000-0002-8785-9330
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Esaki Y, Takeuchi P, Tsuboi S, Fujita K,
Iwata N, Kitajima T. A double-blind, randomized, placebo-
controlled trial of adjunctive blue-blocking glasses for the
treatment of sleep and circadian rhythm in patients with
bipolar disorder. Bipolar Disord. 2020;22:739–748. https://doi.
org/10.1111/bdi.12912