Phototherapy for Psychiatric Disorders

Number: 0370

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses phototherapy for psychiatric disorders.

1. Medical Necessity

   Aetna considers a high-intensity light unit for light box therapy medically necessary durable medical equipment (DME) for members who have seasonal affective disorder (SAD) and meet both of the following criteria.

   1. Member is diagnosed with bipolar disorder or recurrent major depression; and
   2. Member meets DSM-V criteria for a seasonal mood disorder: at least 2 years of seasonal depressive episodes which completely remit when daylight increases in the spring and which substantially outnumber any non-seasonal depressive episodes.

2. Experimental and Investigational

   The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established (not an all-inclusive list):

   1. Light box therapy for depressive symptoms in persons with any of the following:
      
      
      1. Anorexia nervosa
      2. Childhood sleep disorders
      3. Cystic fibrosis
      4. Non-seasonal depression
      5. Parkinson disease
      6. Post-natal depression
      7. Pre-menstrual syndrome
      8. Sleep disorders in the elderly and in visually impaired children
      9. Sleep or behavioral disorders in dementia
      10. Type 2 diabetes
          
          
   2. Extra-ocular light therapy (application of phototherapy to areas of the body other than the retina) for all indications including the treatment of members with SAD.
   3. Non-retinal photo-biomodulation with red and near-infrared light (also known as low-level light therapy) for the treatment of depressive disorder.

3. Notes

   1. Light box therapy requires a high-intensity light unit (e.g., Bio-Light, Brite Lite, Dawn Simulator, etc.). They are not the same as “Tanning Lights” that give off an entirely different band or spectrum of light.
   2. When criteria are met, Aetna covers rental of the high-intensity light unit for the first month to see if home phototherapy is effective in relieving the member's depression.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
96900	Actinotherapy (ultraviolet light)
CPT codes not covered for indications listed in the CPB:
Non-retinal photo-biomodulation with red and near-infrared light (also known as low-level light therapy) - no specific code:
HCPCS codes covered if selection criteria are met:
A4634	Replacement bulb for therapeutic light box, tabletop model
E0203	Therapeutic lightbox, minimum 10,000 lux, table top model
ICD-10 codes covered if selection criteria are met:
F30.10 - F32.9	Bipolar disorder [seasonal affective disorder]
F33.0 - F33.9	Major depression disorder, recurrent [seasonal affective disorder]
ICD-10 codes not covered for indications listed in the CPB:
F02.80 - F02.818	Dementia in other diseases classified elsewhere with or without behavioral disturbance
F03.90 - F03.918	Unspecified dementia
F05	Delirium due to known physiological condition
F03.90 - F03.91 [F05 also required]	Presenile dementia with delusional features
F50.00 - F50.02	Anorexia nervosa
F51.01 - F51.9	Sleep disorders not due to a substance or known physiological condition
F53.0 - F53.1	Mental and behavioral disorders associated with the puerperium, not elsewhere classified
G47.00 - G47.39, G47.50 - G47.9	Sleep disorders
G47.14 [G47.30 also required]	Hypersomnia with sleep apnea, unspecified
H53.001 - H53.9	Visual disturbances [for sleep disorders in visually impaired children]
N94.3	Premenstrual tension syndrome [PMS] [PMDD]
O90.6	Postpartum mood disturbance
O99.310 - O99.315, O99.340 - O99.345	Alcohol use and other mental disorders complicating pregnancy, childbirth and the puerperium
R45.89	Other symptoms and signs involving emotional state
Bright Light Therapy:
CPT codes not covered for indications listed in the CPB:
Bright light therapy - no specific code:
HCPCS codes not covered for indications listed in the CPB:
A4634	Replacement bulb for therapeutic light box, tabletop model
E0203	Therapeutic lightbox, minimum 10,000 lux, tabletop model
ICD-10 codes not covered for indications listed in the CPB:
F32.0 - F33.9	Major depression disorder
G20	Parkinson’s disease
G21.0 - G21.9	Secondary parkinsonism

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Background

Seasonal affective disorder (SAD) is a seasonal form of major depression with features similar to major depressive disorder but occurring on a cyclical basis related to ambient light deprivation during winter months.  Both phototherapy and medications are frequently used (University of Michigan, 2005).  Current evidence-based guidelines on treatment of depression state that use of bright light therapy for the treatment of major depression with a seasonal specifier is well-established (ICSI, 2006; American Psychiatric Association, 2000). 

Westrin and Lam (2007) stated that clinical studies show equal effectiveness with light and anti-depressants, so patient preference should be considered in the selection of initial treatment.  Dawn stimulation, negative air ions, exercise as well as cognitive behavioral therapy are under investigation and may also be helpful treatments for SAD.

There is a lack of evidence for bright light therapy for indications other than SAD.  Systematic evidence reviews have failed to identify reliable evidence of LT for post-natal depression (Corral et al, 2000; Craig and Howard, 2008), pre-menstrual syndrome (Krasnik, 2005; Kwan and Onwude, 2006), non-seasonal depression (Arja et al, 2004), sleep disorders in children (Montgomery and Dunne, 2006), sleep disorders in the elderly (Montgomery and Dennis, 2002), and sleep or behavioral disorders in dementia (Cohen-Mansfield, 2001; Forbes et al, 2004). 

In a review on bright-light therapy (BLT) for the treatment of mood disorders, Pail and colleagues (2011) stated that BLT is established as the treatment of choice for SAD/winter type.  In the last 2 decades, the use of BLT has expanded beyond SAD: there is preliminary evidence for its effectiveness in chronic depression, antepartum depression, pre-menstrual depression, bipolar depression and disturbances of the sleep-wake cycle.  However, the authors noted that data on the usefulness of BLT in non-seasonal depression are promising; further systematic studies are still needed.

Khan et al (2011) evaluated the current therapeutic options in the management of sleep disorders in visually impaired children to identify knowledge gaps and guide future research.  A search of primary literature was conducted using the bibliographic databases PubMed (1980 to August 2010), EMBASE (1990 to August 2010), Science Citation Index Expanded (1990 to August 2010), and CINHAL (1992 to August 2010) and the Cochrane Central Register of Controlled Trials (CENTRAL).  Additional studies were identified through snowballing search techniques (manually by searching retrieved references and electronically by using citation-tracking software).  Search terms included behavioral treatment, children, circadian rhythm, hypnosedatives, intellectual disability, light therapy, melatonin, phototherapy, random allocation, randomized controlled trial (RCT), sleep disorder, and visual impairment.  Randomized and quasi-randomized clinical trials of therapeutic options (behavioral treatment, LT, melatonin, or hypnosedatives) used in participants aged 3 months to 18 years who had both a visual impairment and a sleep disorder were included.  Independent extraction of articles was performed by 2 authors using pre-defined data fields, including quality of the therapeutic options, based on the Strength of Recommendation Taxonomy evidence-rating system.  Two RCTs were retrieved for melatonin, with improved effect on sleep latency (p = 0.019 and p < 0.05, respectively).  However, separate analysis for visual impairment was not conducted.  No RCTs were retrieved for behavioral intervention, LT, or hypnosedatives.  Three studies using behavioral therapy (2 case reports and 1 case series) anecdotally showed improvement in sleep habit.  No improvement in sleep rhythm was observed with a case series applying LT as an intervention.  The authors concluded that children with visual impairment and sleep disorders are a heterogeneous patient group, making diagnosis and treatment difficult.  Randomized controlled trials on treatment options remain in their infancy, with a lack of evidence for appropriate therapeutic strategies.  Trials across a range of selected diagnoses need to be conducted with adequate sample populations to differentiate the effectiveness of 4 different treatment modalities (namely, behavioral therapy, LT, melatonin, and hypnosedatives) as agents for improving sleep.

Poon and colleagues (2012) stated that many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments.  Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients.  These researchers performed a literature review of the research findings related to treatment-resistant BD reported through February 2012.  Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provided few promising leads other than the use of clozapine.  Far more pressing challenges are the depressive-dysthymic-dysphoric-mixed phases of BD and long-term prophylaxis.  Therapeutic trials for treatment-resistant bipolar depression have assessed anti-convulsants, modern anti-psychotics, glutamate [N-methyl-D-aspartate (NMDA)] antagonists, dopamine agonists, calcium-channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation – all of which are promising but limited in effectiveness.  Several innovative pharmacological treatments (an anti-cholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited.  The authors concluded that most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication.  Moreover, they stated that clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up.

Dauphinais et al (2012) stated that treatment of BD often results in patients taking several drugs in an attempt to alleviate residual depressive symptoms, which can lead to an accumulation of side effects.  New treatments for bipolar depression that do not increase the side effect burden are needed.  One non-pharmacological treatment with few side effects, BLT, has been shown to be an effective therapy for seasonal affective disorder, yet has not been extensively studied for other forms of depression.  In this study, a total of 44 adults with BD (depressed phase) were randomized to treatment with BLT, low-density or high-density negative ion generator for 8 weeks.  The primary measure of effectiveness was the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS).  Adverse events were assessed using the Young Mania Rating Scale (YMRS) and Systematic Assessment for Treatment Emergent effects (SAFTEE).  All outcome variables were statistically analyzed using a mixed model repeated measure analysis of variance (ANOVA).  The results showed no statistically significant differences between groups in any outcome measures at study end-point; adverse events, including switches into hypomania, were rare.  The authors concluded that further research is needed to determine the effectiveness of BLT in this population.

In a Cochrane review, Forbes and colleagues (2014) examined the effectiveness of light therapy in improving cognition, activities of daily living (ADLs), sleep, challenging behavior, and psychiatric symptoms associated with dementia.  ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on January 20, 2014 using the terms: "bright light*", "light box*", "light visor*", "dawn-dusk*", phototherapy, "photo therapy", "light therapy" "light treatment", light*.  The CDCIG Specialized Register contains records from all major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.  All relevant RCTs were included in which light therapy, at any intensity and duration, was compared with a control group for the effect of improving cognition, ADLs, sleep, challenging behavior, and psychiatric symptoms associated with dementia (as well as institutionalization rates or cost of care).  Included were people with dementia of any type and degree of severity.  Two review authors independently assessed the retrieved articles for relevance, and 4 review authors independently assessed the selected studies for risk of bias and extracted the data.  Statistically significant differences in outcomes between the treatment and control groups at the end of treatment and follow-up were examined.  Each study was summarized using a measure of effect (e.g., mean difference).  A total of 11 trials (13 articles) met the inclusion criteria.  However, 3 of the studies could not be included in the analyses either because the reported data could not be used in the meta-analysis or these researchers were unable to retrieve the required data from the authors.  This updated review found no effect of light therapy on cognitive function, sleep, challenging behavior (e.g., agitation), or psychiatric symptoms associated with dementia.  Reduction in the development of ADL limitations was reported in 1 study, at 3 of 5 time points, and light therapy was found to have an effect after 6 weeks and 2 years but not after 1 year.  The authors concluded that there is insufficient evidence to justify the use of bright light therapy in dementia.  Moreover, they stated that further research should concentrate on replicating the suggested effect on ADLs, and establishing the biological mechanism for how light therapy improves these important outcomes.

Knapen et al (2014) examined retrospectively whether a single week of LT is as effective as 2 weeks, whether males and females respond differently, and whether there is an effect of expectations as assessed before treatment.  A total of 83 women, and 25 men received either 1-week (n = 42) or 2 weeks (n = 66) of LT were included in 3 studies.  Before LT, patients׳ expectations on therapy response were assessed.  Depression severity was similar in both groups before treatment (F(1,106) = 0.19, non-significant) and decreased significantly during treatment (main effect "time" F(2,105) = 176.7, p < 0.001).  The speed of therapy response differs significantly in treatment duration, in favor of 1 week (F(2,105) = 3.2, p = 0.046).  A significant positive correlation between expectations and therapy response was found in women (ρ = 0.243, p = 0.027) and not in men (ρ = -0.154, non-significant).  When expectation was added as a co-variate in the repeated-measures analysis it showed a positive effect of the level of expectation on the speed of therapy response (F(2,104) = 4.1, p = 0.018).  The authors concluded that there is no difference between 1 and 2 weeks of LT in overall therapy outcome, but the speed of therapy response differed between 1 week LT and 2 weeks LT.  Together with the significant correlation between expectations and therapy response in women, these investigators hypothesized that expectations play a role in the speed of therapy response.

Martensson et al (2015) stated that light therapy is an accepted treatment option, at least for SAD.  These investigators evaluated treatment effects of bright white light (BWL) on the depressive symptoms in both SAD and non-seasonal depression.  The systematic review was performed according to the PRISMA guidelines. PubMed, Embase, and PsycINFO were searched (December 1974 through June 2014) for RCTs published in peer-reviewed journals.  Study quality was assessed with a check-list developed by the Swedish Council on Technology Assessment in Health Care.  Only studies with high or medium quality were used in the meta-analyses.  A total of 8 studies of SAD and 2 studies of non-seasonal depression met inclusion and quality criteria.  Effects on SAD were estimated in 2 meta-analyses.  In the first, week-by-week, BWL reached statistical significance only at 2 and 3 weeks of treatment (Standardized Mean Difference, SMD: -0.50 (confidence interval [CI]: 0.94 to -0.05); -0.31 (-0.59 to -0.03) respectively).  The second meta-analysis, of end-point data only, showed a SMD of -0.54 (CI: -0.95 to -0.13), which indicated an advantage for BWL.  No meta-analysis was performed for non-seasonal depression due to heterogeneity between studies.  The authors concluded that most studies of BWL had considerable methodological problems, and the results of published meta-analyses were highly dependent on the study selection.  They stated that even though quality criteria were introduced in the selection procedures of studies, when the results were carefully scrutinized, the evidence was not unequivocal.

Danilenko and Ivanova (2015) noted that studies comparing the effectiveness of dawn simulation to conventional bright light for the treatment of SAD (in parallel groups) have yielded conflicting results.  This cross-over study investigated treatment outcomes and long-term treatment preference.  A total of 40 winter depressives were treated for 1 week with bright light (4.300 lx for 30 to 45 mins shortly after awakening) or dawn simulation (gradually increasing light during the last 30 mins of sleep achieving 100 lx before alarm beep, with the dawn simulator placed closer to the open eyes for a further 15 mins: 250 lx).  The depression level was self-rated using SIGH-SAD-SR.  Depression scores reduced similarly following bright light and dawn simulation: for 43.8 % and 42.2 % (medians), respectively; effectiveness ratio was 23:17.  The preference was also similar (21:19).  Among those who preferred bright light, the most common reason was that they perceived the bright light to be more effective (19/21; it was more effective, p = 0.0096; this subgroup tended to have more severe depression) and ease of use (6/21).  Among those who preferred the dawn simulator, the reasons were a more "natural" action (9/19), device compactness and/or time-saving (10/19) and in 4 cases where bright light caused eye-strain.  The authors concluded that dawn simulation was similarly effective to bright light in the treatment of winter depression.  They stated that patients with more severe depression tended to report greater improvement with bright light; in such cases, this would out-weigh the non-clinical advantages of dawn simulation.

Light Therapy for Patients with Depression and Type 2 Diabetes

Brouwer et al (2015) stated that major depression and type 2 diabetes often co-occur.  Novel treatment strategies for depression in type 2 diabetes patients are needed, as depression in type 2 diabetes patients is associated with poor prognosis and treatment results.  Major depression and concurrent sleep disorders have been related to disturbances of the biological clock.  The biological clock is also involved in regulation of glucose metabolism by modulating peripheral insulin sensitivity.  Light therapy has been shown to be an effective anti-depressant that “re-sets” the biological clock.  These researchers described the protocol of a study that evaluates the hypothesis that light therapy improves mood as well as insulin sensitivity in patients with a major depressive episode and type 2 diabetes.  This study is a randomized, double-blind, parallel-arm trial in 98 participants with type 2 diabetes and a major depressive episode, according to DSM-IV criteria.  These investigators will examine if light therapy improves depressive symptoms and insulin sensitivity, the primary outcome measures.  They also investigate whether these effects are mediated by restoration of the circadian rhythmicity, as measured by sleep and hypothalamic-pituitary-adrenal axis activity.  Participants will be randomly allocated to a bright white-yellowish light condition or dim green light condition.  Participants will undergo light therapy for 30 mins every morning for 4 weeks at home.  At several time-points, namely before the start of light therapy, during light therapy, after completion of 4 weeks of light therapy and after 4 weeks follow-up, several psychometrical, psychophysiological and glucometabolic measures will be performed.  The authors concluded that if light therapy effectively improves mood and insulin sensitivity in type 2 diabetes patients with a major depressive episode, light therapy may be a valuable patient-friendly addition to the currently available treatment strategies.  Additionally, if the data support the role of restoration of circadian rhythmicity, such an observation may guide further development of chrono-biological treatment strategies in this patient population.

Light Therapy for Patients with Depression and Cystic Fibrosis

In a pilot study, Kopp and colleagues (2016) noted that depression is common in cystic fibrosis (CF) and linked with worse outcomes during hospitalization.  Bright-light therapy during hospitalizations augments anti-depressant regimens and reduces length of stay (LOS) in depressed non-CF patients, but has not been examined in patients with CF.  a total of 30 CF patients used a light box emitting 10,000lx for 30 minutes each day for 7 straight days following hospital admission for pulmonary exacerbation.  Depressive symptom severity (QIDS-C) and quality of life factors (CFQ-R) were recorded pre-/post-light therapy; 80 % of subjects had at least mild depressive symptoms upon admission.  Hospitalized CF patients had a significantly lower mean LOS of 11.0 ± 3.6 days compared to a historical cohort from the year prior (13.3 ± 4.4 days, p = 0.038).  There was a significant decrease in depressive symptoms for all subjects receiving light therapy (p < 0.0001).  There was no relation between depressive symptoms and lung function or vitamin D; 6  out of 12 quality of life indicators improved with light therapy including the domains of vitality, emotion, and health perceptions.  There were no adverse events (AEs) reported.  The authors concluded that light therapy was well-tolerated by hospitalized CF patients and resulted in improved depressive symptoms and quality of life.  They stated that light therapy was associated with a reduced length of stay; however, large, randomized trials of light therapy may be indicated for hospitalized CF patients.  The main drawbacks of this study were the lack of a control group and possible confounding effects of hospitalization treatment on systemic symptoms.

Light Therapy for Patients with Insomnia

Riemann and colleagues (2017) stated that the European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia.  The guideline was based on a systematic review of relevant meta-analyses published till June 2016.  The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder.  The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations.  The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e., blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence).  Polysomnography can be used to evaluate other sleep disorders if suspected (i.e., periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence).  Cognitive behavioral therapy for insomnia is recommended as the 1st-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence).  A pharmacological intervention can be offered if cognitive behavioral therapy for insomnia is not sufficiently effective or not available.  Benzodiazepines, benzodiazepine receptor agonists and some anti-depressants are effective in the short-term treatment of insomnia (less than or equal to 4 weeks; weak recommendation, moderate-quality evidence).  Anti-histamines, anti-psychotics, melatonin and phyto-therapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence).  Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence).  Complementary and alternative treatments (e.g., homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

Photo-Biomodulation for Depressive Disorder / Dementia

In a pilot study, Cassano and colleagues (2018) examined the anti-depressant effect of transcranial photo-biomodulation (t-PBM) with near-infrared (NIR) light in subjects suffering from major depressive disorder (MDD).  t-PBM with NIR light is a new treatment for MDD; NIR light is absorbed by mitochondria; it boosts cerebral metabolism, promotes neuroplasticity, and modulates endogenous opioids, while decreasing inflammation and oxidative stress.  These researchers performed a double-blind, sham-controlled study on the safety and efficacy (change in Hamilton Depression Rating Scale [HAM-D17] total score at end-point) of adjunct t-PBM NIR [823-nm; continuous wave (CW); 28.7 × 2 cm2; 36.2 mW/cm2; up to 65.2 J/cm2; 20 to 30 mins/session], delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice-weekly, for 8 weeks, in subjects with MDD.  Baseline observation carried forward (BOCF), last observation carried forward (LOCF), and completers analyses were performed.  The effect size for the anti-depressant effect of t-PBM, based on change in HAM-D17 total score at end-point, was 0.90, 0.75, and 1.5 (Cohen's d), respectively for BOCF (n = 21), LOCF (n = 19), and completers (n = 13).  Further, t-PBM was fairly well-tolerated, with no serious AEs.  The authors concluded that t-PBM with NIR light demonstrated anti-depressant properties with a medium to large effect size in patients with MDD.  These researchers stated that replication is needed, especially in consideration of the small sample size.

Caldieraro and Cassano (2019) stated that PBM)with red and NIR – also known as low-level light therapy, is a low-risk, inexpensive treatment based on non-retinal exposure – under study for several neuropsychiatric conditions.  These researchers discussed the proposed mechanism of action and carried out a systematic review of pre-clinical and clinical studies on PBM for MDD.  They performed a search on Medline and Embase databases in July 2017; no time or language restrictions were used.  Studies with a primary focus on MDD and presenting original data were included (n = 17).  References on the mechanisms of action of PBM also included review articles and studies not focused on MDD.  Red and NIR light penetrate the skull and modulate brain cortex; an indirect effect of red and NIR light, when delivered non-transcranially, is also postulated.  The main proposed mechanism for PBM is the enhancement of mitochondrial metabolism after absorption of NIR energy by the cytochrome C oxidase; however, actions on other pathways relevant to MDD were also reported.  Studies on animal models indicated a benefit from PBM that was comparable to anti-depressant medications.  Clinical studies also indicated a significant anti-depressant effect and good tolerability.  The authors concluded that these preliminary evidence supported the potential of non-retinal PBM as a novel treatment for MDD.  These researchers stated that future studies should clarify the ideal stimulation parameters as well as the overall safety and effectiveness of this treatment. 

The main drawbacks of this study were that clinical studies employed in this review were heterogeneous for population and treatment parameters, and most lacked an appropriate control.

Salehpour and colleagues (2021) stated that PBM entails the use of red and/or near-infrared (NIR) light from lasers or LEDs to improve a wide range of medical disorders; and t-PBM, sometimes accompanied by intra-nasal PBM, has been tested to improve many brain disorders, including dementia.  These investigators conducted a systematic review according to PRISMA guidelines of pre-clinical and clinical studies reporting the use of PBM, which were considered relevant to dementia.  They searched the literature between 1967 and 2020 using a range of keywords relevant to PBM and dementia.  The light source and wavelength(s), output power, irradiance, irradiation time, fluence or total energy (dose), operation mode (continuous or pulsed) irradiation, approach and site, number of treatment sessions, as well as study outcome(s) were extracted.  Out of 10,473 initial articles, 36 studies met the inclusion criteria; 9 articles reported in-vitro studies, 17 articles reported studies in animal models of dementia, and 10 studies were carried out in patients with dementia.  All of the included studies reported positive results.  The clinical studies were limited by the small number of patients, lack of placebo controls in some instances, and only a few used objective neuroimaging methods.  The authors concluded that the preliminary evidence of clinical benefit, the lack of any adverse effects, and the remarkable ease of use, suggested larger clinical trials should be performed as soon as possible.

Bright Light Therapy for the Treatment of Bipolar Disorder

In a systematic review and meta-analysis, Takeshima and colleagues (2020) examined if BLT is a safe and effective treatment for manic/depressive symptoms and a preventive measure for recurrent mood episodes in patients with bipolar disorder.  These researchers carried out a literature search of major electronic databases in June 2019, including all published articles up to that date; 2 investigators independently selected relevant publications, extracted data, and examined methodological quality according to the Cochrane criteria.  A total of 6 RCTs evaluated the efficacy of BLT for bipolar depression.  A meta-analysis found no significant differences between BLT and placebo for the following outcomes: rates of remission from depressive episodes (risk ratio [RR]: 1.81, 95 % CI: 0.43 to 7.64, p = 0.42); depressive symptom scores (SMD: -0.25, 95 % CI: -0.74 to 0.23, p = 0.30); and rates of manic switching (RR: 1.00, 95 % CI: 0.28 to 3.59, p = 0.26).  The sensitivity analysis for studies with low overall indirectness did show a significant anti-depressant effect for BLT (RR: 3.09, 95 % CI: 1.62 to 5.90, p = 0.006).  No RCT examined the effect of BLT in preventing the recurrence of mood episodes in the euthymic state or in improving manic symptoms in the manic state.  No severe AEs were reported.  The authors concluded that while a meta-analysis was unable to demonstrate the efficacy of BLT for bipolar depression, a sensitivity analysis did show a significant effect.  These researchers stated that further well-designed studies are needed to clarify the effectiveness of BLT, not only for the depressive state but also for other states, in the treatment of bipolar disorder.

Bright Light Therapy for the Treatment of Depression in Parkinson Disease

In a double-blind, controlled trial, Rutten and colleagues (2019) examined the efficacy of BLT in reducing depressive symptoms in patients with Parkinson disease (PD) and MDD compared to a control light.  These researchers randomized patients with PD and MDD to treatment with BLT (± 10,000 lux) or a control light (± 200 lux).  Subjects were treated for 3 months, followed by a 6-month naturalistic follow-up.  The primary outcome of the study was the HDRS score; secondary outcomes were objective and subjective sleep measures and salivary melatonin and cortisol concentrations.  Assessments were repeated halfway, at the end of treatment, and 1, 3, and 6 months following treatment.  Data were analyzed with a linear mixed-model analysis.  These investigators enrolled 83 subjects; HDRS scores decreased in both groups without a significant between-group difference at the end of treatment.  Subjective sleep quality improved in both groups, with a larger improvement in the BLT group (B [SE] = 0.32 [0.16], p = 0.04).  Total salivary cortisol secretion decreased in the BLT group, while it increased in the control group (B [SE] = -8.11 [3.93], p = 0.04).  The authors concluded that BLT was not more effective in reducing depressive symptoms than a control light.  Mood and subjective sleep improved in both groups.  These researchers noted that BLT was more effective in improving subjective sleep quality than control light, possibly through a BLT-induced decrease in cortisol levels.  This study provided Class I evidence that BLT was not superior to a control light device in reducing depressive symptoms in patients with PD with MDD.

Blue-Wavelength Light Therapy for Post-Traumatic Brain Injury Sleepiness, Sleep Disturbance, Depression, and Fatigue

In a systematic review and meta-analysis, Srisurapanont and colleagues (2021) examined the effectiveness of blue-wavelength light therapy (BWLT) for post-traumatic brain injury (TBI) sleepiness, sleep disturbance, depression, and fatigue.  Data sources included PubMed, Scopus, Web of Science, Cochrane Library, Academic Search Complete, and CINAHL; included trials were RCTs of BWLT in adults with a history of TBI.  Outcome measures included sleepiness, sleep disturbance, depression, or fatigue.  Two reviewers independently screened the searched items, selected the trials, extracted the data, and rating the quality of trials.  They aggregated the data using a random-effect, frequentist network meta-analysis (NMA).  These investigators searched the databases on July 4, 2020.  This review included 4 RCTs of 117 patients with a history of TBI who were randomized to receive BWLT, amber light therapy (ALT), or no light therapy (NLT).  Moderate-quality evidence revealed the following: BWLT was significantly superior to NLT in reducing depression (SMD = 0.81, 95 % CI: 0.20 to 1.43); BWLT reduced fatigue at a significantly greater extent than NLT (SMD = 1.09, 95 % CI: 0.41 to 1.76) and ALT (SMD = 1.00, 95 % CI: 0.14 to 1.86).  Low-quality evidence suggested that BWLT reduced depression at a greater extent than ALT (SMD = 0.57, 95 % CI: 0.04 to 1.10).  Low-quality evidence found that the drop-out rates of those receiving BWLT and ALT were not significantly different (RR = 3.72, 95 % CI: 0.65 to 21.34).  The authors concluded that moderate-quality evidence suggested that BWLT may be useful for post-TBI depression and fatigue.  Moreover, these researchers stated that future studies in large sample sizes with longer study duration are needed.

The authors stated that this systematic review had several drawbacks.  First, this review included only 4 RCTs with 117 subjects.  For some outcomes (e.g., fatigue, drop-out rates), the analyses included only 50 or 67 subjects of 2 RCTs; thus, a type II error could not be excluded in interpreting the inconclusive results regarding the benefits of BWLT on sleepiness and sleep disturbance.  Second, the study duration of the included trials was relatively short (4 to 6 weeks) in comparison to the chronic nature of post-TBI sleepiness, sleep disturbance, depression, and fatigue.  Future studies should have a longer study duration and include the evaluation of symptoms several months after the end of treatment.  Third, the subjects included in this systematic review had a diverse history of TBI.  While the severity varied from mild-to-severe, the mean duration following TBI ranged from 6.75 months to 9.03 years.  This limitation might also contribute to the high inconsistency of some outcomes.  Finally, the changed scores of many outcomes in the trials included in this systematic review were not available.  The requests for these data were unsuccessful.  Although these researchers tried to apply some methods to calculate the missing SDs, these might be less accurate than the actual ones.

Blue-Light Therapy for Non-Seasonal Depression

In a meta-analysis, Do et al (2022) examined the safety and effectiveness of blue-light therapy in seasonal and non-seasonal major depressive disorder (MDD), by comparison to active and inactive control conditions.  These investigators searched Web of Science, Embase, Medline, PsycInfo, and Clinicaltrials.gov through January 17, 2022 for RCTs using search terms for blue/blue-enhanced, light therapy, and depression/seasonal affective disorder.  Two independent reviewers extracted data.  The primary outcome was the difference in endpoint scores on the Structured Interview Guide for the Hamilton Depression Rating Scale - Seasonal Affective Disorder (SIGH-SAD) or the Structured Interview Guide for the Hamilton Depression Rating Scale with Atypical Depression Supplement (SIGH-ADS) between blue light and comparison conditions.  Secondary outcomes were response (50 % or greater improvement from baseline to endpoint on a depression scale) and remission rates (endpoint score in the remission range).  Of 582 articles retrieved, these researchers included 9 RCTs (n = 347 subjects) assessing blue-light therapy; 7 studies had subjects with seasonal MDD and 2 studies included subjects with non-seasonal MDD; 4 studies compared blue light to an inactive light condition (efficacy studies), and 5 studies compared it to an active condition (comparison studies).  For the primary outcome, a meta-analysis with random-effects models found no evidence for the effectiveness of blue-light conditions compared to inactive conditions (mean difference [MD] = 2.43; 95 % CI: -1.28 to 6.14, p = 0.20); however, blue-light also showed no differences compared to active conditions (MD = -0.11; 95 % CI: -2.38 to 2.16, p = 0.93).  There were no significant differences in response and remission rates between blue-light conditions and inactive or active light conditions.  Blue-light therapy was overall well-tolerated.  The authors concluded that the effectiveness of blue-light therapy in the treatment of seasonal and non-seasonal MDD remains unproven.  These researchers stated that future trials should be of longer duration, include larger sample sizes, and attempt to better standardize the parameters of light therapy.

The authors stated that these findings should be interpreted with caution given the drawbacks of this meta-analyses.  First, the included studies had variable heterogeneity and quality (e.g., the light parameters for both active and inactive conditions, duration of daily light exposure, and duration of study treatment varied considerably across all the studies).  Both seasonal and non-seasonal depression were included, although the sensitivity analyses with only SAD studies were no different than the primary analyses; 1 study also included 3 patients with bipolar disorder.  Only 1 of the 9 studies had an overall low risk of bias.  Second, the included studies had small sample sizes that were likely under-powered; thus, limiting the ability to detect a treatment effect.  Third, since all the studies were of short treatment duration (with the longest duration only 6 weeks, in 1 study), the longer-term effects of blue-light therapy remain unstudied.

Bright Light Therapy as Adjunctive Treatment in Bipolar Depression

Cuomo et al (2023) noted that approximately 1 % to 4 % of patients suffering from depression is affected by bipolar disorder.  Few patients respond to the 1st-line anti-depressants, and a 4-week latency pharmacotherapy period has been observed.  In a pilot study, these researchers examined the safety and effectiveness of BLT in accelerating and enhancing therapeutic response in patients with bipolar depression.  Patients with bipolar depression, already treated with anti-depressants, were included.  The treatment group was composed of patients treated with anti-depressants combined with BLT (30 mins/4 days a week at 10,000 lx for 8 weeks).  The control group included patients treated with anti-depressants with exposure to red light (30 mins/4 days a week at a red light for 8 weeks).  Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale (HAM-D)-17, Clinical Global Impressions-Severity (CGI-S), Fatigue Severity Scale (FSS), and quality of life scale (QOLS) were collected at the baseline and after 4 and 8 weeks of treatments.  A total of 41 patients (18 men and 23 women; mean age of 49.1 ± 15 years) were included in the study.  After 4 weeks, MADRS and HAMD-17 scores in treatment groups were significantly lower than those reported in the control group (p < 0.001).  After 8 weeks, all scales except FSS reported significantly lower values in patients treated with BLT (p < 0.0001).  The authors concluded that BLT has shown reliable safety and effectiveness in the treatment of patients with bipolar depression and should be considered a clinically relevant approach in accelerating patients' therapeutic response and reducing the impact of long-lasting therapy.  These investigators noted that the main drawbacks of this pilot study were its small sample size (n = 41) and significant heterogeneity in the anti-depressant treatments.

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