Diabetes Care Volume 42, April 2019 529 Annelies Brouwer,1 Daniel H. van Raalte,2 Effects of Light Therapy on Mood Hoang-Ton Nguyen,3 Femke Rutters,4 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Peter M. van de Ven,4 Petra J.M. Elders,5 and Insulin Sensitivity in Patients Annette C. Moll,3 Eus J.W. Van Someren,1,6,7 Frank J. Snoek,8 With Type 2 Diabetes and Aartjan T.F. Beekman,1 and Depression: Results From a Marijke A. Bremmer1 Randomized Placebo-Controlled Trial Diabetes Care 2019;42:529–538 | https://doi.org/10.2337/dc18-1732 1Amsterdam UMC, Vrije Universiteit, and GGZ inGeest, Department of Psychiatry, Amsterdam Public Health research institute, Amsterdam, the OBJECTIVE Netherlands 2Amsterdam UMC, Vrije Universiteit, Depart- Depression is common in patients with type 2 diabetes and adversely affects ment of Internal Medicine, Diabetes Center, quality of life and diabetes outcomes. We assessed whether light therapy, an Amsterdam, the Netherlands 3 antidepressant, improves mood and insulin sensitivity in patients with depression and Amsterdam UMC, Vrije Universiteit, Depart- ment of Ophthalmology, Amsterdam, the Nether- type 2 diabetes. lands 4Amsterdam UMC, Vrije Universiteit, Depart- RESEARCH DESIGN AND METHODS ment of Epidemiology and Biostatistics, Am- This randomized, double-blind, placebo-controlled trial included 83 patients with sterdam Public Health research institute, depression and type 2 diabetes. The intervention comprised 4 weeks of light Amsterdam, the Netherlands 5Amsterdam UMC, Vrije Universiteit, Depart- therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes ment of General Practice and Elderly Care included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) Medicine, Amsterdam Public Health research and insulin sensitivity (M-value derived from the results of a hyperinsulinemic- institute, Amsterdam, the Netherlands 6 euglycemic clamp). Secondary outcomes were related psychological and gluco- Netherlands Institute for Neuroscience, Depart- ment of Sleep and Cognition, Amsterdam, the metabolic measures. Netherlands 7Amsterdam UMC, Vrije Universiteit, Depart- RESULTS ment of Integrative Neurophysiology, Centre Intention-to-treat analysis showed that light therapy was not superior to placebo in for Neurogenomics and Cognitive Research, Neu- reducing depressive symptoms (23.9 IDS points [95% CI 29.0 to 1.2]; P = 0.248) and roscience Campus Amsterdam, Amsterdam, the 2 P Netherlands had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI 0.41 to 0.70]; = 8Amsterdam UMC, Vrije Universiteit and Univer- 0.608). Analyses incorporating only those participants who accurately adhered to sity of Amsterdam, Department of Medical Psy- the light therapy protocol (n = 51) provided similar results, but did suggest positive chology, Amsterdam Public Health research effects of light therapy on depression response rates (‡50% reduction in IDS points) institute, Amsterdam, the Netherlands (26% more response; P = 0.031). Prespecified analysis showed effect moderation Corresponding author: Annelies Brouwer, [email protected] by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication P Received 14 August 2018 and accepted 19 Jan- ( = 0.023). Light therapy did not affect depressive symptoms in participants with uary 2019 higher insulin sensitivity or those who use only oral glucose-lowering medication or Clinical trial reg. no. NTR4942, www.trialregister none at all, but it did produce a relevant effect in participants with lower insulin .nl/trial/4802 sensitivity (212.9 IDS points [95% CI 221.6 to 24.2]; P = 0.017) and a trend This article contains Supplementary Data online toward effectiveness in those using insulin (212.2 IDS points [95% CI 221.3 to at http://care.diabetesjournals.org/lookup/suppl/ 23.1]; P = 0.094). Light therapy was well tolerated. doi:10.2337/dc18-1732/-/DC1. © 2019 by the American Diabetes Association. CONCLUSIONS Readers may use this article as long as the work is Although this trial is essentially inconclusive, secondary analyses indicate that light properly cited, the use is educational and not for profit, and the work is not altered. More infor- therapy might be a promising treatment for depression among a subgroup of highly mation is available at http://www.diabetesjournals insulin-resistant individuals with type 2 diabetes. .org/content/license. 530 Light Therapy for Mood and Insulin Sensitivity Diabetes Care Volume 42, April 2019 One of five patients with type 2 diabetes So far, no experimental evidence is created blocks of six participants, with suffers from clinical depression (1). The available on the effects of light therapy randomly varying sequences within prevalence of depression among patients on either mood or glycemic control in blocks. Participants who agreed to par- with type 2 diabetes is double that people with type 2 diabetes. To our ticipate in the hyperinsulinemic-euglycemic among the general population, and this knowledge, we are the first to conduct clamp (HEC) procedure were randomized comorbidity is recognized as a global a randomized, placebo-controlled trial to separately. Upon approval by the ethics public health challenge (2,3). Previous test effects of light therapy on mood and committee, participants were informed research suggests a bidirectional cause- insulin sensitivity in people with depres- that the study investigated differences and-effect relationship between type 2 sion and type 2 diabetes. between white-yellow and green light diabetes and depression (4,5). In addition, therapy, but they were unaware that one shared underlying pathophysiological mech- RESEARCH DESIGN AND METHODS of the conditions was a placebo. Partic- anisms, such as a disturbance of the sleep- Design ipants were told that we could not ensure wake cycle, have been described (4,5). We performed a randomized, double- the effects of either intervention under Unfortunately, depression in people blind, placebo-controlled, parallel-arm study. The research assistants who de- with type 2 diabetes is associated with a trial to compare the effects of light livered the lamps to the participants’ poor prognosis and poor treatment re- therapy with those of a placebo. A de- homes were aware of the treatment al- sults. The depression seems to be more scription of the methods was published location but were not involved in any persistent and recurrent (6), and some at the start of the trial (18), and the trial other study activities; they received ex- antidepressant drugs may even worsen has been registered in the Netherlands plicit instructions regarding their inter- glycemic control (7). Furthermore, pa- Trial Register (NTR4942). Participants actions with the participants in order to tients with depression and type 2 di- were assessed at baseline (week 0), prevent disclosure of treatment alloca- abetes exhibit a higher risk for diabetes after 4 weeks of receiving light therapy or tion. All other study personnel, including complications and mortality (8). Clearly, placebo (week 4), and after 4 weeks of the research assistants and physicians in- more efficacious depression treatments are follow-up (week 8). Some measures were volved in obtaining measurements, were needed for patients with type 2 diabetes. obtained at weekly intervals during the fully blinded to the conditions. Light therapy, in which patients are intervention (weeks 1, 2, and 3). Study exposed to bright light early in the morn- procedures were performed at two loca- Intervention ing for several days, is a patient-friendly tions. Participant enrollment started in Participants were randomly assigned to and low-cost treatment, with early onset 2014 and ended in 2017. Participants gave receive active (broad-spectrum, white- of action and low risk for adverse effects informed consent before participating. The yellow light, 10,000 lux) or placebo (9). It is a first-line treatment for seasonal study was executed in accordance with the (monochromatic green light [545 nm], depression and has recently been proven Declaration of Helsinki and with approval 470 lux) light therapy at home, scheduled to be successful in treating nonseasonal from the medical ethics committee of Am- for 30 min every morning over 4 weeks. depression as well, even in several difficult- sterdam University Medical Centers (Am- CE-certified Diamond-5 SAD Lightbox to-treat patient groups (10–12). Light sterdam UMC), location Vrije Universiteit. light therapy lamps (SAD Lightbox Com- therapy is traditionally assumed to act pany, Berkshire, U.K.), adapted with light by entraining the sleep-wake cycle via Participants filters, were used. Estimates of irradiance ocular stimulation of the brain’s supra- Participants were recruited through ad- are provided in Supplementary Table 1. chiasmatic nucleus (the biological clock) vertisements, referrals from clinicians, Timing of light therapy was set in accor- (9), thereby improving sleep and circa- and databases of patients who con- dance with results from the Morningness- dian rhythmicity (13). Yet, recent findings sented to be informed about research Eveningness Questionnaire (MEQ) (19), also point to effects of light on mood via studies open for participation. Eligibility but each participant agreed to the time other cerebral pathways (14). The brain was determined by a telephone screening in order to ensure the therapy could biological clock plays a main role in and a screening visit. Included patients be incorporated in the participant’s regulating glucose metabolism, and 1) were