Clinical Study Near-Infrared Transcranial Radiation for Major Depressive Disorder: Proof of Concept Study Paolo Cassano, 1 Cristina Cusin, 1 David Mischoulon, 1 Michael R. Hamblin, 2 Luis De Taboada, 3 Angela Pisoni, 1 Trina Chang, 1 Albert Yeung, 1 Dawn F. Ionescu, 1 Samuel R. Petrie, 1 Andrew A. Nierenberg, 1 Maurizio Fava, 1 and Dan V. Iosifescu 1,4 1 Depression Clinical & Research Program, Massachusetts General Hospital, Boston, MA 02114, USA 2 Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA 3 LiteCure LLC, Newark, DE 19702, USA 4 Department of Psychiatry, Te Mount Sinai Hospital, New York, NY 10029, USA Correspondence should be addressed to Paolo Cassano; pcassano@mgh.harvard.edu Received 4 May 2015; Accepted 21 July 2015 Academic Editor: Antonio Vita Copyright © 2015 Paolo Cassano et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Transcranial near-infrared radiation (NIR) is an innovative treatment for major depressive disorder (MDD), but clinical evidence for its efcacy is limited. Our objective was to investigate the tolerability and efcacy of NIR in patients with MDD. We conducted a proof of concept, prospective, double-blind, randomized study of 6 sessions of NIR versus sham treatment for patients with MDD, using a crossover design. Four patients with MDD with mean age 47 ± 14 (SD) years (1 woman and 3 men) were exposed to irradiance of 700 mW/cm 2 and a fuence of 84 J/cm 2 for a total NIR energy of 2.40 kJ delivered per session for 6 sessions. Baseline mean HAM-D 17 scores decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) afer treatment ( = 7.905;  =3;  = 0.004). Patients tolerated the treatment well without any serious adverse events. Tese fndings confrm and extend the preliminary data on NIR as a novel intervention for patients with MDD, but further clinical trials are needed to better understand the efcacy of this new treatment. Tis trial is registered with ClinicalTrials.gov NCT01538199. 1. Introduction Near-Infrared Radiation: Mechanism of Action. In experi- mental and animal models, laser near-infrared radiation (NIR) noninvasively delivers energy to cytochrome c oxidase and by stimulating this key mitochondrial respiratory chain enzyme (COMPLEX IV, electron transfer chain) leads to increased adenosine triphosphate (ATP) production [1–3]. While several NIR wavelengths have been shown to beneft neuronal cell cultures, the most efective ones (830 nm, 670 nm) paralleled the NIR and red action spectra of oxidized cytochrome c oxidase [4]. Data suggest that coherent red light (670 nm diode laser) protects the viability of cell culture afer oxidative stress, as indicated by increased mitochondrial membrane potentials [5]. NIR also stimulates neurite out- growth mediated by nerve growth factor, and this efect could also have positive implications for axonal protection [5]. Neuroprotective efects of incoherent red light, 670 nm light emitting diode (LED) and 630 nm narrow angle LED, have been documented in in vivo models of mitochondrial optic neuropathy [6, 7]. In vivo bioenergetic changes with coherent NIR (810 nm diode laser) were observed at McLean Hospital (Belmont, MA) in beagle dogs, where a shif towards greater bioenergetic efciency (PCr/-NTP ratio) occurred in the anterior cingulate cortex afer transcranial NIR exposure (3 times/week for 2 weeks) (Mintzopoulos et al., unpublished). In animal models of traumatic brain injury (TBI), coherent NIR (810 nm diode laser) appears to be an efective treatment [8–10] and improves neurogenesis [11]. In addition, incoher- ent NIR exposure (1072 nm LED) has been shown to improve memory performance in middle-aged mice [12]. Near-Infrared Radiation for Depression and Cognition. In a double-blind randomized study in healthy volunteers, expo- sure to coherent NIR (1064 nm laser) signifcantly improved overall afect, sustained attention, and visual memory [13]. Hindawi Publishing Corporation Psychiatry Journal Volume 2015, Article ID 352979, 8 pages http://dx.doi.org/10.1155/2015/352979