Transcranial Photobiomodulation for the Treatment of Major Depressive Disorder. The ELATED-2 Pilot Trial

Abstract

Objective: Our objective was to test the antidepressant effect of transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light in subjects suffering from major depressive disorder (MDD). Background: 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. Materials and methods: We conducted 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; 20-30 min/session], delivered to dorsolateral prefrontal cortex, bilaterally and simultaneously, twice a week, for 8 weeks, in subjects with MDD. Baseline observation carried forward (BOCF), last observation carried forward (LOCF), and completers analyses were performed. Results: The effect size for the antidepressant 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 adverse events. Conclusions: t-PBM with NIR light demonstrated antidepressant properties with a medium to large effect size in patients with MDD. Replication is warranted, especially in consideration of the small sample size.

Keywords: depression; low-level laser therapy; randomized controlled trial.

Conflict of interest statement

Dr. Cassano's salary was supported by the Harvard Psychiatry Department (Dupont-Warren Fellowship and Livingston Award), by the Brain and Behavior Research Foundation (NARSAD Young Investigator Award) and by the Photothera, Inc. unrestricted grant. Drug donation was from TEVA. Travel reimbursement was from Pharmacia-Upjohn. Dr. Cassano has received consultation fees from Janssen Research and Development. Dr. Cassano has filed a provisional patent related to the use of near-infrared light in psychiatry. PhotoMedex, Inc. supplied four devices for this clinical study. Since completion of the study and of the article, Dr. Cassano is/has (1) received unrestricted funding from Litecure, Inc. to conduct an additional study on transcranial photobiomodulation for the treatment of major depressive disorder; (2) received unrestricted funding from Cerebral Sciences to conduct a study on transcranial photobiomodulation for the treatment of generalized anxiety disorder; (3) co-founded, member of the board of directors and consultant of Niraxx Light Therapeutics, Inc., a company focused on the development of new modalities of treatment based on near-infrared light.

Dr. Mischoulon has received research support from the FisherWallace, Nordic Naturals, Methylation Sciences, Inc. (MSI), and PharmoRx Therapeutics. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy. He has received royalties from Lippincott Williams & Wilkins for published book “Natural Medications for Psychiatric Disorders: Considering the Alternatives.”

Dr. Katnani: Research funding from NINDS 5R01NS086422.

Mr. De Taboada receives salary from LiteCure LLC (Newark, DE) as V.P. of research and Development.

Disclosures Regarding Patents: Mr. De Taboada is a named inventor in multiple patents for the treatment of neurological disorders and injuries, including MDD.

Dr. M. Hamblin: Vielight, Inc., Scientific Advisory Board; Global Photon, Scientific Advisory Board; Lexington, Inc, Scientific Advisory Board; LaserCap Scientific Advisory Board; and USHIO, Inc, Consultant.

Research Support: Dr. J. Alpert: Abbott Laboratories, Alkermes, Lichtwer Pharma GmbH, Lorex Pharmaceuticals; Aspect Medical Systems, Astra-Zeneca, Bristol-Myers Squibb Company, Cephalon, Cyberonics, Eli Lilly & Company, Forest Pharmaceuticals, Inc., GlaxoSmithkline, J&J Pharmaceuticals, National Institutes of Health, NARSAD, Novartis, Organon, Inc., PamLab, LLC, Pfizer, Inc., Pharmavite, Roche, Sanofi/Synthelabo, Solvay Pharmaceuticals, Inc., and Wyeth-Ayerst Laboratories.

Advisory Board/Consultant: Eli Lilly & Company, Luye Pharmaceuticals, PamLab LLC, and Pharmavite LLC.

Speaking/Publishing: MGH Academy, Reed Medical Education, Primedia, Nevada Psychiatric Association, American Society of Clinical Psychopharmacology, American Psychiatric Association, Belvoir Media Group, Eli Lilly & Company, Xian-Janssen, Organon, and Psicofarma.

Research Support: Dr. M. Fava: Abbott Laboratories; Acadia Pharmaceuticals; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; AXSOME Therapeutics; BioResearch; BrainCells, Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck, Inc.; MedAvante; Methylation Sciences, Inc.; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; NeuroRx; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer, Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Takeda Pharmaceuticals; Tal Medical; VistaGen); and Wyeth-Ayerst Laboratories.

Advisory Board/Consultant: Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma, Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells, Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co., Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai, Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; Indivior; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm, Inc.; Lorex Pharmaceuticals; Lundbeck, Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; PamLab, LLC.; Pfizer, Inc.; PharmaStar; Pharmavite LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC.; Sepracor, Inc.; Servier Laboratories; Schering-Plough Corporation; Shenox Pharmaceuticals; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceutical; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; and VistaGen.

Speaking/Publishing: Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer, Inc.; PharmaStar; United BioSource, Corp.; and Wyeth-Ayerst Laboratories.

Stock/Other Financial Options: Equity Holdings: Compellis; PsyBrain, Inc.

Royalty/Patent, Other Income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven.

Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd.

Dr. D. Iosifescu: In the past 5 years, Dr. Iosifescu was a consultant for Avanir, Axsome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, and Sunovion; he has received research support (through the Icahn School of Medicine at Mount Sinai) from Alkermes, Astra Zeneca, Brainsway, Euthymics, Neosync, Roche, and Shire, and he has received speaker honoraria from the Massachusetts General Hospital Psychiatry Academy, Medscape, and Global Medical Education.

All other authors have no conflict of interests to declare.

Figures

FIG. 1.

The pictures show the handheld portions of the Omnilux New U devices, which are pressed against the forehead of the subject, bilaterally and simultaneously on the F3 and F4 sites (reference to EEG placement sites).

FIG. 2.

The picture shows the intensity gradient for the NIR produced by the 28 LEDs of the Omnilux New U device (with a color scale depicting the highest intensity in red). A spot of maximum average intensity across 1 cm aperture is indicated by the black circle. Active device #1124053. NIR, near infrared.

FIG. 3.

CONSORT clinical trial flow diagram.

FIG. 4.

Graph of mean HAM-D17 total score in subjects treated with NIR light (red line) and in subjects treated with sham (blue line); (A) all study subjects included (n = 21); (B) only completers included (n = 13). (A) All subjects (intent to treat—end-point carried forward; mean ± SE). (B) Completers only (imputed values for three missing data points from interim visits; mean ± SE). Error bars on one side of each line. HAM-D17, Hamilton Depression Rating Scale; SE, standard error.