Clinical Efficacy, Onset Time and Safety of Bright light Therapy in Acute

Bipolar Depression as an Adjunctive Therapy: a Randomized Controlled

Trial

Running Head: Light Therapy in Treating Bipolar Depression

Tian-hang Zhou1, Wei-min Dang1#, Yan-tao Ma1, Chang-qing Hu2, Ning Wang3, Guo-yi Zhang4, Gang
Wang2, Chuan Shi1, Hua Zhang5, Bin Guo3, Shu-zhe Zhou1, Lei Feng2, Shu-xia Geng1, Yu-zhen Tong4,
Guan-wen Tang3, Zhong-kai He4, Long Zhen2, Xin Yu1*

1. Peking University Sixth Hospital, Peking University Institute of Mental Health, the Key Laboratory
of the Ministry of Health (Peking University), National Clinical Research Center for Mental Disorders,
Beijing, China
2. Mood Disorders Center, Beijing Anding Hospital, Capital Medical University & China Clinical
Research Center for Mental Disorders Center of Depression, Beijing Institute for Brain Disorders
Beijing, China.
3. Beijing Huilongguan Hospital, Peking University, Beijing, China.
4. School of physics, Peking University, Beijing, China.
5. Peking University Third Hospital, Beijing, China.
#
This author contributed equally to this study and share first authorship.

*Corresponding author: Xin Yu, yuxin@bjmu.edu.cn, Tel: 86-10-82801999

Professor of Institute of Mental Health, Peking University,
Fax: 86-10-62026310, Peking University Institute of Mental Health, Beijing, China
Mailing address: No. 51, Huayuanbeilu Rd, Haidian District, Beijing 100191 P.R. CHINA

Conflict of Interests: All authors have completed the Unified Competing Interest form at
www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that
(1) none of the authors have received support from the shoe factory for the submitted work; (2) none of
the authors have relationships with the shoe factory that might pertain to the submitted work in the
previous 3 years; (3) the authors' spouses, partners, or children have no financial relationships that may
be relevant to the submitted work; and (4) all of the authors have non-financial interests that may be
relevant to the submitted work.

Manuscript word count: 3250

Background
Bright light therapy (BLT) is an effective treatment for seasonal affective disorder and non- seasonal
depression. The efficacy of BLT in treating patients with bipolar disorder is still unknown.
Aims
The aim of this study is to examine the efficacy, onset time and clinical safety of BLT in treating
patients with acute bipolar depression as an adjunctive therapy (trial registration at ClinicalTrials.gov:
NCT02009371).
Methods
This was a multi-center, single blind, randomized clinical trial. Seventy-four participants were
randomized in one of two treatment conditions: BLT and control (dim red light therapy, dRLT).
Sixty-three participants completed the study (33 BLT, 30 dRLT). Light therapy lasted for two weeks,
one hour every morning. All participants were required to complete several scales assessments at
baseline, and at the end of weeks 1 and 2. The primary outcome measures were the clinical efficacy of
BLT which was assessed by the reduction rate of HAMD-17 scores, and the onset time of BLT which
was assessed by the reduction rate of QIDS-SR16 scores. The secondary outcome measures were rates
of switch into hypomania or mania and adverse events.
Results
1) Clinical efficacy: BLT showed a greater ameliorative effect on bipolar depression than the control,
with response rates of 78.19% vs. 43.33% respectively (p<0.01). 2) Onset day: Median onset day was
4.33 days in BLT group. 3) BLT-emergent hypomania: No participants experienced symptoms of
hypomania. 4) Side effects: No serious adverse events were reported.
Conclusion
BLT can be considered as an effective and safe adjunctive treatment for patients with acute bipolar
depression.
Key words
Bright Light therapy, Bipolar depression, Clinical efficacy, Onset time
Background
Bipolar disorder (BD) is a common severe mental illness which is characterized by recurrent episodes of
depression and mania/hypomania (American et al., 2013). The estimated lifetime prevalence of BD in
general population worldwide was around 1.0% (Clemente et al., 2015), and higher with broader
diagnostic criteria (Zimmermann et al., 2009). A recent meta-analysis has reported the estimated point,
12-month and lifetime prevalence of BD in China were 0.09%, 0.17% and 0.11% (Zhang et al., 2017).
BD is a disabling illness which has been the 12th leading cause of disability worldwide across (Ferrari et
al., 2016), which imposes a great burden to patients and the whole society because of its marked
functional impairment (Sole et al., 2012; Vieta et al., 2013).

Depressive episode is an important clinical stage of BD. Studies have shown that BD patients spend
significantly more time with depressive symptoms than with mood elevation/mixed symptoms (De Dios
et al., 2010). Depressive symptoms are associated with greater social impairments compared with mania/
hypomania (Bonnin et al., 2010). Furthermore, suicide or suicide attempts mostly occur in the
depressive episode of BD (Hauser et al., 2013). However, depressive episode of BD are still not well
controlled by current treatments (Forte et al., 2015; Swartz et al., 2012).

Because of limited research, the clinical evidence is insufficient to support clinical guidelines to make a
clear recommendation for bipolar depression (Frye, 2011; Yatham et al., 2013). Medications currently
used for the treatment of bipolar depression are frequently partially effective, leaving residual depressive
symptoms which are liable to relapse (Geddes et al., 2009; Greil et al., 2012) . Side effects induced by
mood stabilizers and antipsychotics which are a most important reason for poor treatment compliance
also cannot be ignored (Barraco et al., 2012; Selle et al., 2014). Therefore there is a clear need for an
effective adjunctive treatment with less risk of severe side effects. Bright light therapy (BLT) has been
proposed as a promising choice.

Although the efficacy of BLT in treating depression has gradually been recognized, the mechanism of
BLT is still in the stage of hypothesis. Light signals are captured by melanopsin-containing retinal cells
on retina and transduced to electrical signals. The retinohypothalamic tract delivers these signals to
suprachiasmatic nuclei (SCN) which can regulate biologic rhythm (Hattar et al., 2003). The function of
SCN is impacted by the dose and duration of light explosion (Zeitzer et al., 2005). Melatonin directly
regulates SCN through melatonin receptors on SCN (Macchi and Bruce, 2004; Stehle et al., 2003), while
the functional leaf of SCN is controlled by serotonergic neurons located in raphe nuclei (Moore and
Speh, 2004).

Several controlled trials have shown the safety and efficacy of BLT for seasonal affective disorder (SAD)
(Melrose, 2015; Nussbaumer et al., 2015; Rohan et al., 2015). BLT has been approved as a first-line
treatment for SAD by American Psychiatric Association (APA) (Terman, 2007). The application of BLT
in non- seasonal depression (NSD) has been increasing, but the efficacy is controversial (Martiny et al.,
2005; Niederhofer and von Klitzing, 2012; Tuunainen et al., 2004). BLT has been approved as a
supplementary treatment for NSD by APA (Terman, 2007). A recent meta-analysis including 881
participants from 20 RCTs demonstrated a beneficial effect of BLT in the treatment of NSD
[standardized mean difference in depression score: -0.41(95%CI: -0.64~-0.18)], while the overall quality
of evidence is poor due to high risk of bias and inconsistency (Perera et al., 2016).

The efficacy of BLT in bipolar depression has been explored in many studies (Benedetti et al., 2005;
Papatheodorou and Kutcher, 1995; Sit et al., 2007), but seldom in randomized clinical trials (Dauphinais
et al., 2012). In a recent published randomized sham-controlled (negative ion) trial, Chojnacka at al has
examined the efficacy and safety of morning BLT in the treatment of patients with a depressive episode
in bipolar and unipolar disorder(Chojnacka et al., 2016). Though overall improvement in depressive
symptoms, both response and remission rates were significantly higher in BLT group. We hypothesized
that BLT would have a beneficial effect on depressive symptoms in patients with acute bipolar
depression and may have a faster onset time.

Methods
Design
This study was one of the capital health research and development of special programs in Beijing, China
(SF2011-4024-03), and part of Beijing Municipal pooling funds on Science and technology
achievements transformation and industrialization project (Z121100006112057). This was a multi-center,
single-blind, controlled, parallel group study conducted in three tertiary referral centers in Beijing. This
study was approved by the Ethics Committee of the Peking University Institute of Mental Health in
December2012 [No. 2012(47)]. The design for this study is presented in Figure 1.

Participants
Seventy-four participants who met all inclusion/exclusion criteria were recruited from December 2013
to March 2015. Participants were volunteers, aged 18 to 65, and signed written informed consent. All
met clinical criteria for Bipolar disorder, depressed phase. All met clinical criteria for Bipolar disorder,
depressed phase. The diagnosis of patient was verified by a review of medical record. Participants were
required to be on a stable psychotropic medication for at least 2 weeks prior to enrollment, and to have a
total score of 17 or more on the Hamilton Depression Scale with 17 items (HAMD-17) at baseline visits
(Sharp, 2015; Tang and Zhang, 1984).

Participants were excluded from the study if they had a diagnosis of any other Axis I disorder according
to DSM-IV criteria or a score of12 or more on the Young Mania Rating Scale (YMRS) at either
screening or baseline (Young et al., 1978; Zhang, 1998). The other main exclusion criteria were having
been treated with Transcranial Magnetic Stimulation (TMS) or Modified Electroconvulsive Therapy
(MECT) in the 3 months prior to screening, a significant suicide risk, a history of substance abuse or
dependency in the 6 months prior to screening, and being regarded by investigators as being an
unsuitable candidate for the protocol. Participants were also excluded if they had an ocular disorder or
they were taking a photosensitizing agent, which made it potentially unsafe to undergo BLT. Women
who were pregnant, lactating or planning to become pregnant were also excluded.

Since this is the first controlled trial of BLT and dRLT for treatment of bipolar depression in China and
there are few data about the effect size of the two interventions, the sample size could not be estimated
on the basis of statistical considerations. The preliminary results obtained from our first 20 participants,
with 10 in BLT group and 10 in dRLT group. Preliminary results showed that the effective rate of BLT
and dRLT was 80% and 40% respectively. We assumed the loss rate was 20%, so a total sample size of
32 in each group was considered adequate for this exploratory study.

Interventions
The participants were randomized to the intervention (BLT) and placebo (dim Red Light Therapy, dRLT)
arm on receipt of the completed consent form using an automated permuted block randomization with a
block size of 10 and an allocation ratio of 1:1. Trained raters from each center who had passed
consistent training for many research projects before and who remained blind to allocated treatments
evaluated each participant using the HAMD-17, YMRS, Clinical Global Impression (CGI) (Forkmann et
al., 2011; Wu, 1984) and Side Effects Rating Scale (SERS) of Asberg (Asberg et al., 1970; Qian et al.,
2015), at baseline visit (V0), the end of week 1 (V1) and the end of week 2 (V2). A modified
self-administered questionnaire, the 16-item Quick Inventory of Depressive Symptomatology,
Self-report (QIDS-SR16) (Liu et al., 2017; Rush et al., 2003)，which was used to measure the onset day
of BLT was required in the first week daily. Both senior investigators who conducted the statistical
analyses and wrote up the results were masked to the code throughout the study and at the time of data
analyses.

During the study, research staff who were not blind to treatment assignment were responsible for
treatment management. All participants were required to be on a mood stabilizer or a combination of
mood stabilizers judged by their clinicians to be sufficient. Participants were prohibited from taking any
antidepressant medications during the study. No change in the dosage of any psychotropic medication
was allowed. Benzodiazepines were allowed at up to 2 mg of lorazepam-equivalents per day.

In order to balance expectations, participants were told that both BLT and dRLT have been found to be
effective in treating some forms of depression, although this had not been well studied in bipolar
depression. The study design was presented as a comparison of different light therapies.

Treatment devices and procedures

Light therapy was administered by light boxes made by School of Physics, Peking University. The BLT
device measures 60×80×10cm, with a 100% UV filter and several 180-watt Light-Emitting Diodes
(LED) bulbs of 10000-Kelvin color temperature. The dRLT device is in the same shape. Light boxes
were placed on a tabletop. The heights of light boxes were adjusted to make sure the center of the box
was at eye level. 5000 lux at 100 cm setting in the BLT device and less than 100 lux in the dRLT device
were used. According to Terman’s results(Terman et al., 2001), the antidepressant effect of light is
potentiated by early-morning administration in circadian time. Participants whose face fully exposed
without staring into the light were treated every morning for 1 hour between 6:30 am to 9:00am during
the 2-week treatment phase of this trial.

Outcome measures
The primary outcome measure of this trial was clinical efficacy and the onset day of BLT. Clinical
efficacy of BLT was measured by HAMD-17 at V2. Responders were defined as those participants with
a decrease in HAMD-17 score (V2) of 50% or more from baseline. The onset day was defined as the day
when a decrease in QIDS-SR16 score of 50% or more from baseline occurred. The secondary outcome
measures were rates of switches into hypomania or mania which were measured by YMRS and adverse
events which were measured by SERS.
Statistical methods
Data analyses were conducted using SPSS version 17.0. Basic descriptive statistics including the mean,
standard deviation, variance and range were calculated for primary, secondary and demographic
variables. Differences in measurement data were compared with t-test for those data with normal
distributions, and non- parametric tests for ratings that did not exhibit normal distributions. Differences
in categorical data were compared with chi square test. Logistic regression analysis was applied to
assess the relationship between possible predictors and BLT efficacy. Odds ratio and 95% confidence
intervals were applied to measure the degree of association.

Results
[Figure 1 approximately here]

[Figure 2 approximately here]

The participants’ flow diagram for the study is presented in Figure 2. 220 participants were assessed for
eligibility and 74 participants were recruited to the trial. 63participants completed the study (33 BLT,
30dRLT) and returned full questionnaire data for analyses. Table 1 listed demographics and clinical
characteristics of participants in BLT and dRLT groups. Patients received the first-line pharmacho-
therapy for bipolar depression, namely quetiapine (200mg~600mg), valproate (500mg~1500mg) and
lithium carbonate (500mg~1500mg) or joint. The type and dosage of drugs used in two groups were
balanced. Main mood stabilizers include quetiapine (36.36% in BLT group vs. 36.67% in dRLT group),
quetiapine combined with sodium valproate(30.30% in BLT group vs. 33.33% in dRLT group), and
quetiapine combined with lithium(15.15% in BLT group vs. 13.33% in dRLT group). There were no
statistically significant difference between two groups (p=0.98).
[Table 1 approximately here]

Primary outcome
The participants treated with BLT demonstrated a significantly improvement in response to treatment
compared with patients treated with dRLT at the end of this trial. The total score of HAMD-17 were
both significantly decreased after 2 weeks of this trial (p<0.01). At the end of this trial, the total score of
HAMD-17 in the BLT group was significantly lower than dRLT group (p=0.03). The mean end point
HAMD-17 score showed 57.82% reduction from baseline for BLT and 45.44% for dRLT. 78.79% of
participants (n=26) of BLT group were responders, while the response rate was 43.33% in the dRLT
group (n=13). The response rates were significantly different between two groups (p<0.01).
[Table 2 approximately here]

Mauchly’s test indicated that the assumption of sphericity had been violated, 2 (2) = 8.04, p = 0.02,
therefore degrees of freedom were corrected using Greenhouse-Geisser estimates of sphericity (=0.89).
The results show that there was significant effect of HAMD score on the time, F (1.78, 40.38) = 7.92,
p=0.01. These results suggested that the total score of HAMD-17 in the BLT group was significantly
lower than dRLT group over time during the study period.
[Table 3 approximately here]

Since outpatient/inpatient ratio in BLT and dRLT groups was significantly different at baseline, the
effect of outpatient versus inpatient status on treatment efficacy was further explored. 64.29% of
participants (n=18) in outpatients were responders, while the response rate was 60.00% in inpatients
(n=21). There were no statistically significant difference (p=0.93). Previous studies have indicated that
gender is a predictor of clinical efficacy of light therapy (Roecklein et al., 2012). The effect of gender on
BLT efficacy was then further discussed. We found that 76.47% of female participants (n=26) were
responders, while the response rate was 44.83% in male participants (n=13). The difference was
statistically significant (p=0.02).

Results from single factor analysis showed that group (BLT vs. dRLT) and gender were two influence
factors of the clinical efficacy of light therapy. Multivariate Logistic regression analysis was done to
explore risk factors of effectiveness. Results showed that gender and group were 2 independent factors
(OR BLT/dRLT=4.69, 95%CI: 1.47, 14.94,p=0.01; ORF/M=3.94, 95%CI: 1.22, 12.16,p=0.02).

The onset day was defined as the day when a decrease in QIDS-SR16 score of 50% or more from
baseline occurred. Total score of QIDS-SR 16 was 12.41 (3, 24) at baseline visit and 8.77 (3, 15) at the
end of the first week. 9 patients from BLT group responded to BLT within 2 weeks. The longest time
was 6 days (2 cases) and the shortest time was 2 days (1 case) recorded in this study. The median onset
time was 4.33 days. There were no responders in the dRLT group during first week (measured by QIDS)
in this trial.

Secondary outcome
Participants from both groups did not experience symptoms of hypomania during this trial. One
participant from each group developed irritability, with an increase in YMRS score to 10 in BLT group
and 8 in dRLT group. One participant from each group had an increase in YMRS score to 5. There were
no statistically significant differences in the rate of hypomania as measured by YMRS between the BLT
and dRLT groups (p=0.60).

No serious adverse events were reported. New adverse events occurred in BLT group including 1
dizziness, 1 fatigue and 2 sleep disturbance compared with the dRLT group. Most adverse events were
mild-to-moderate and responded to treatment adjustments when indicated. There were no statistically
significant differences in adverse events as measured by SERS between BLT and dRLT groups
(p=0.98).

Discussion
BLT has been widely used in the treatment of SAD and NSD, and its clinical efficacy has been
confirmed by a number of clinical studies (Baxendale et al., 2013; Brouwer et al., 2015; Martensson et
al., 2015). The use of BLT for treating bipolar depression was still in the exploratory stage. Although
many studies have attempted to investigate the efficacy of BLT in the treatment of bipolar depression,
there has been no consistent conclusion yet (Benedetti et al., 2005; Papatheodorou and Kutcher, 1995;
Sit et al., 2007). The results of a recent controlled trial have shown no statistically significant differences
in any outcome measures at study end point for patients with bipolar depression treated with morning
BLT compared with the control group (Dauphinais et al., 2012).

Our study has shown that there was a significant difference (p=0.01)in the ameliorating effects of
depressive symptoms (in terms of HAMD-17 reduction rate) among patients with bipolar depression
treated with morning BLT combine with first- line drug therapy compared with the control group treated
with dRLT combine with first-line drug therapy after 2 week treatment phase. This is by far the first
randomized controlled trial to show the clinical efficacy of BLT in the treatment of bipolar depression
compared with the control group (particular kind of dRLT placebo) as an adjust treatment.

Patients’ expectation towards the treatment has become a general problem for clinical research among
depression patients. Rutherford and colleagues have found that patients’ expectation had a significant
improve impact on the antidepressant effect (Rutherford et al., 2013). Research on BLT have found
similar consequences, that is high expectations can improve the efficacy of BLT in treating patients with
depression (Eastman, 1990; Knapen et al., 2014). In order to balance patients’ expectations, patients
from the control group were treated with dRLT which is in the same device and environment, but with
no antidepressant effects in this trial.

BLT has been considered as a rapid onset treatment. 50~65% SAD patients can achieve remission
within 1 week treatment (Terman and Terman, 2005). Researches on BLT treating patients with bipolar
depression have shown that most patients can achieve remission with 2 week BLT (Papatheodorou and
Kutcher, 1995; Sit et al., 2007). This is the first study using QIDS-SR16 to measure the onset time of
BLT. We found the median onset time of BLT combined with first-line drug therapy for patients with
acute bipolar depression was about 4 days, which was consistent with previous studies.

Treatment-emergent hypomania or mania is well known to be associated with antidepressant medication

for bipolar depression (Biernacka et al., 2012; Daray et al., 2010; Mundo et al., 2006). The switch rate
has become lower since newer antidepressant agents and mood stabilizers used together, yet it remains
problematic (Post et al., 2006; Viktorin et al., 2014). In this study, only 2 cases developed irritability at
the end of the trial. Compared with the control group, the light therapy used in this study were
considered not to increase the risk of switch rate.

Emergent hypomania under light therapy has occurred in previous related studies (Leibenluft et al., 1995;
Papatheodorou and Kutcher, 1995; Sit et al., 2007). The rate of light therapy-emergent hypomania in our
study was lower than previous studies, which may be attributable to sufficient mood stabilizers. We
recommend that further use of BLT for patients with bipolar depression should combine with mood
stabilizers in order to control the switch rate.
BLT was given by a fluorescent light box with a diffusing shield in many studies before. Nausea,
vomiting, dizziness, headache and vision damage were noted as possible side effects due to
full-spectrum fluorescent (Botanov and Ilardi, 2013; Leichtfried et al., 2010). A number of fluorescent
lamps were needed to achieve a sufficient light intensity, which can produce a higher temperature and
also a certain security risk. Light-Emitting Diodes (LED), which is low heat radiation, energy
consumption and more environmental friendly, was used in this study. The LED wavelength range can
be adjusted in accordance with the requirements and the peak wavelength is more stable (Tridente and
De Luca, 2012). No serious adverse events were reported. According to this study, LED was
recommended as a proper device for further BLT researches.

There are some major limitations of this study. Firstly, 2 weeks is too short of duration to assess
depression outcomes in BD, which is a major limitation. Secondly, we did not measure the seasonality
scores and use Morningness-Eveningness Questionnaire to measure biological rhythm which may affect
the efficacy of light therapy. Thirdly, since it is difficult to enroll a large number of participants in our
settings, we did not control the drug distribution and outpatient/inpatient strictly, which may have some
effects on the final efficacy of light therapy. Last but not least, the clinical assessments of all participants
were not comprehensive. Clinical related information, including bipolar subtypes, were not recorded
accordingly.

Conclusion
Bright Light therapy combined with first-line drug medication showed certain efficacy, faster onset time
and did not increase the rate of switch into hypomania and side effects compared with simple drug
treatments for patients with acute bipolar depression. Bright Light therapy can be considered as an
effective and safe adjunctive treatment choice for acute bipolar depression according to our study.

Future directions
Further trials would be needed to establish a therapeutic effect in this population. Patients with bipolar
depression are in a high heterogeneity. Further work for patients in homogeneity, such as similar general
characteristics, seasonal pattern and sleep- wake cycle, might help to elucidate the mechanism that may
underlie this clinical response.
Acknowledgements
Funding for this study was provided by Beijing Municipal Commission of Health and Family Planning.
The funding sources played no further role in the study design; in the collection, analysis and
interpretation of data; in the writing of the report, or in the decision to submit the report for publication.
We thank Dr. Huali Wang and Dr. Yanbo Yuan from Peking University Institute of Mental Health, for
their helpful comments for study design. We thank Dr. Yuqing Song, Dr. Yue Zhu, Dr. Huijun Zhang,
Dr. Zhiying Li and Dr. Huimin Gao from Peking University Institute of Mental Health, for their help in
recruiting patients. We thank Haijuan Zhang, LPN, Jianghua Li, LPN, and other nurses from Peking
University Institute of Mental Health, for their helpful support. We also thank Xiaozhen Lv, Ph D, from
Peking University Institute of Mental Health, for data analyses and helpful comments.

Author Disclosure

Dr. Tianhang Zhou has no relevant financial and nonfinancial relationships to disclose.

Mrs. Weimin Dang has no relevant financial and nonfinancial relationships to disclose.

Dr. Yantao Ma has no relevant financial and nonfinancial relationships to disclose.

Dr. Changqing Hu has no relevant financial and nonfinancial relationships to disclose.

Dr. Ning Wang has no relevant financial and nonfinancial relationships to disclose.

Pro. Guoyi Zhang has no relevant financial and nonfinancial relationships to disclose.

Dr. Gang Wang has no relevant financial and nonfinancial relationships to disclose.

Dr. Chuan Shi has no relevant financial and nonfinancial relationships to disclose.

Mr. Hua Zhang has no relevant financial and nonfinancial relationships to disclose.

Dr. Bin Guo has no relevant financial and nonfinancial relationships to disclose.

Dr. Shuzhe Zhou has no relevant financial and nonfinancial relationships to disclose.

Dr. Lei Feng has no relevant financial and nonfinancial relationships to disclose.

Mrs. Shuxia Geng has no relevant financial and nonfinancial relationships to disclose.

Pro. Yuzhen Tong has no relevant financial and nonfinancial relationships to disclose.

Dr. Guanwen Tang has no relevant financial and nonfinancial relationships to disclose.

Dr. Long Zhen has no relevant financial and nonfinancial relationships to disclose.
Dr. Xin Yu has no relevant financial and nonfinancial relationships to disclose.

Contributors of each author

Dr. Tianhang Zhou: Drafting of manuscript, acquisition of data, analysis and interpretation of data

Mrs. Weimin Dang: Drafting of manuscript, critical revision

Dr. Yantao Ma: Analysis and interpretation of data, critical revision

Dr. Changqing Hu: Acquisition of data, analysis and interpretation of data

Dr. Ning Wang: Study conception and design, acquisition of data

Pro. Guoyi Zhang: Study conception and design

Dr. Gang Wang: Study conception and design, critical revision

Dr. Chuan Shi: Critical revision, acquisition of data

Mr. Hua Zhang: Critical revision

Dr. Bin Guo: Study conception and design

Dr. Shuzhe Zhou: Acquisition of data

Dr. Lei Feng: Acquisition of data, analysis and interpretation of data

Mrs. Shuxia Geng: Acquisition of data

Pro. Yuzhen Tong: Study conception and design

Dr. Guanwen Tang: Acquisition of data

Dr. Long Zhen: Acquisition of data

Dr. Xin Yu: Study conception and design, analysis and interpretation of data, critical revision

Funding source

This study was one of the capital health research and development of special programs in Beijing, China
(SF2011-4024-03), and part of Beijing Municipal pooling funds on Science and technology achievements
transformation and industrialization project (Z121100006112057).

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 Assessed for eligibility
(N=220)
Excluded (N=146)
Not meeting inclusion
criteria (N = 110)
Declined to participate (N
36)
Randomization（N=74）

BLT（n=37） dRLT（n=37）

Discontinued intervention Discontinued intervention

（n=4） （n=7）
Refused intervention Refused intervention
（n=2） （n=1）
Perceived lack of Perceived lack of
efficacy（n=1） efficacy（n=4）
I ld l t

Analyse
d（n=30）
Analyse
d（n=33）

Fig. 2 Participants’ flow diagram.

Table 1 Baseline demographic and clinical characteristics of the group

BLT(n=33) dRLT(n=30) t/2 p

Age, years: mean±sd 35.09±14.19 39.73±13.53 -1.33 0.19
Gender: M/F 13/20 16/14 0.73 0.39
Marital status: 15/16/2 10/18/2 0.98 0.61
Single/Married/Divorced
Education: 8/10/15 15/8/7 5.13 0.08
Primary school and
lower/Middle school/College
and higher
Outpatient/Inpatient 22/11 6/24 12.03 0.01*
Course of disease, month: 48 (6,240) 54 (6, 288) 0.42 0.68
M (min, max)
HAMD-17 score: mean±sd 20.39±2.59 19.30±2.18 1.81 0.08
YMRS score: M (min, max) 0 (0,6) 0 (0,6) 1.18 0.24
CGI, severity of illness: M 5 (4,6) 5 (4,6) 1.00 0.92
(min, max)

Table 2 Comparison of HAMD-17 score between 2 groups

BLT(n=33) dRLT(n=30) p
Baseline 20.39±2.18 19.30±2.59 0.08
End of 1st week 13.45±4.24 13.93±3.18 0.62
End of 2nd week 8.61±3.41 10.53±3.22 0.03*
Score reducing 11.79±3.23 8.77±3.44 <0.01*
p<0.05
Table 3 Repeated Measures ANOVA of changes in HAMD-17 score between 2 groups over time
Tests of Within-Subjects Effects
Source Type IV Sum df Mean F Sig
of Squares Square
Time Greenhouse-Geisser 3362.68 1.78 1892.24 371.34 <0.001
Huynh-Feldt 3362.68 1.86 1811.15 371.34 <0.001
Lower-bound 3362.68 1.00 3362.68 371.34 <0.001
Time*Group Greenhouse-Geisser 71.76 1.78 40.38 7.92 0.001
Huynh-Feldt 71.76 1.86 38.65 7.92 0.001
Lower-bound 71.76 1.00 71.76 7.92 0.007
Error (Time) Greenhouse-Geisser 552.39 108.40 5.096
Huynh-Feldt 552.39 113.26 4.877
Lower-bound 552.39 61.00 9.056

Highlights

1. This is by far the first randomized controlled trial to show the clinical efficacy of bright light therapy in the
treatment of bipolar depression compared with the control group (particular dim Red Light Therapy) as an
adjust treatment.
2. Bright Light therapy combined with first-line drug medication showed certain efficacy, faster onset time and
did not increase the rate of switch into hypomania and side effects compared with simple drug treatments
for patients with acute bipolar depression.
3. Bright Light therapy can be considered as an effective and safe adjunctive treatment choice for acute bipolar
depression according to our study.