Major depressive disorder (MDD) is a severe disorder affecting 21 million Americans (~10 %) per year and is the third leading cause of global disability. There is evidence that the prevalence of MDD is moderately increased in prediabetic patients and in undiagnosed diabetic patients, and markedly increased in the previously diagnosed diabetic patients compared to normal glucose metabolism individuals. The prevalence rates of depression could be up to three-times higher in patients with type-1 diabetes and twice as high in people with type-2 diabetes compared to the general population worldwide. Although effective treatments exist for MDD, 43 % of patients experiencing a longer than six-month MDD episode remain untreated, most of them preferring self-management over professional help and/or prescription medications. A new generation of devices for MDD that are efficacious, safe, well tolerated and easy to use, possibly suitable for self-administration at home, would be very valuable, both accessible and scalable to the needs of MDD subjects. A substantial body of literature proves that transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates robustly into the cerebral cortex and is absorbed by the mitochondrial enzyme cytochrome c oxidase (CCO), stimulating the mitochondrial respiratory chain and leading to increased ATP production. t-PBM also significantly increases cerebral blood flow (CBF) and oxygenation. Antidepressant effects of t-PBM have been reported in animal models and in humans. Based on that, firstly, we will utilize fMRI (functional Magnetic Resonance Imaging) BOLD (blood-oxygenation-level dependent) signal change during t-PBM in 30 MDD subjects to identify the optimal t-PBM irradiance dose (50, 300 or 700 mW/cm2), relative to sham as our objective evidence of target engagement. Secondly, the effect size of CBF-BOLD increase in the prefrontal cortex (PFC) at the optimal t-PBM dose compared to sham will be followed by analyses of clinical symptoms of MDD, antidepressant effects, safety and tolerability. We will identify among MDD subjects included in the study, the occurrence of diabetes mellitus (type-1 and type-2) and chronic pain, trying to stablish a relation between diabetes - chronic pain - MDD, as well as if the possible antidepressant effect promoted by t-PBM is followed by an analgesic effect. The study is classified as randomized, double-blinded, sham-controlled, interventional (clinical trial), crossover assignment, with estimated enrollment of 30 participants diagnosed with MDD. The intervention model consists of four sessions of t-PBM during fMRI; each session will occur, in random order, with t-PBM irradiances of 50, 300 and 700 mW/cm2 as well as sham. All study procedures were already approved by the NYU School of Medicine's Institutional Review Board (IRB) (Approval number i20-00217-CR). Patients' recruitment will occur at the Massachusetts General Hospital (MGH), Charlestown, Massachusetts, USA; New York University (NYU), New York, New York, USA; Nathan Kline Institute (NKI), Orangeburg, New York, USA. The subjects' ages eligible for the study are between 18 and 65 years old, both sexes. After informed consent, MDD subjects undergo psychiatric screening, blood draw for laboratory tests, electrocardiogram, urinalysis, drug screen, pregnancy test for women of fertility age, and physical examination. After a screen visit, eligible participants will attend study visits at the MGH facilities, for a total of four additional visits (weeks 1, 2, 3 and 4). At each visit a study clinician will administer safety and clinical assessments. The laser device is a LiteCure's LightForce® EXPi Deep Tissue Laser TherapyTM System bundle of 34 optic fibers which will deliver the laser light and energy to the subject's forehead in NIR mode. Subjects will be randomized to a specific series of the 4 t-PBM/sham doses. Both subjects and study raters will be blind to the intervention assignment.
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