Very Low-Level Transcranial Photobiomodulation for Major Depressive Disorder: The ELATED-3 Multicenter, Randomized, Sham-Controlled Trial

Dan V. Iosifescu, MD, MSc; Richard J. Norton, BS; Umit Tural, MD; David Mischoulon, MD, PhD; Katherine Collins, PhD; Erin McDonald, BA; Luis De Taboada, MSEE; Simmie Foster, MD, PhD; Cristina Cusin, MD; Albert Yeung, MD, ScD; Alisabet Clain, MS; David Schoenfeld, PhD; Michael R. Hamblin, PhD; Paolo Cassano, MD, PhD

J Clin Psychiatry 2022;83(5):21m14226

ABSTRACT

Background: Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light might represent a treatment for major depressive disorder (MDD). However, the dosimetry of administered t-PBM varies widely. We tested the efficacy of t-PBM with low irradiance, low energy per session, and low number of sessions in individuals with MDD.

Methods: A 2-site, double-blind, sham-controlled study was conducted of adjunct t-PBM NIR (830 nm; continuous wave; 35.8 cm² treatment area; 54.8 mW/cm² irradiance; 65.8 J/cm² fluence, 20 min/session; ~2 W total power; 2.3 kJ total energy per session), delivered to the prefrontal cortex, bilaterally, twice a week for 6 weeks, in subjects diagnosed with MDD per the DSM-IV criteria. Subjects were recruited between August 2016 and May 2018. A sequential parallel comparison design was used: 18 nonresponders to sham in phase 1 (6 weeks) were re-randomized in phase 2. The primary outcome was reduction in depression severity (Hamilton Depression Rating Scale [HDRS-17] and Quick Inventory of Depressive Symptomatology—Clinician Rating [QIDS-C] scores) from baseline. Statistical analyses used R package SPCDAnalyze2, including all subjects with ≥ 1 post-randomization evaluation.

Results: Of the 54 subjects recruited, we included 49 MDD subjects in the analysis (71% female, mean ± SD age 40.8 ± 16.1 years). There were no significant differences between t-PBM and sham with respect to the change in HDRS-17 (t = −0.319, P = .751) or QIDS-C (t = −0.499, P = .620) scores. The sham effect was reasonably low.

Conclusions: Mostly uncontrolled studies suggest the efficacy of t-PBM for MDD; however, its optimal dose is still to be defined. A minimal dose threshold is likely necessary, similarly to other neuromodulation techniques in MDD (electroconvulsive therapy, transcranial magnetic stimulation). We established a threshold of inefficacy of t-PBM for MDD, based on combined low irradiance, low energy per session, and low number of sessions.

Trial Registration: ClinicalTrials.gov identifier: NCT02959307

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