Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean±SD age: 43.4±13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0±12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, proton-phosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major depression.

Major depressive disorder (MDD) is a prevalent condition associated with high rates of disability, as well as suicidal ideation and behavior. Current treatments for MDD have significant limitations in efficacy and side effect burden. FDA-approved devices for MDD are burdensome (due to repeated in-office procedures) and are most suitable for severely ill subjects. There is a critical need for device-based treatments in MDD that are efficacious, well-tolerated, and easy to use. In this paper, we review a novel neuromodulation strategy, transcranial photobiomodulation (t-PBM) with near-infrared light (NIR). The scope of our review includes the known biological mechanisms of t-PBM, as well as its efficacy in animal models of depression and in patients with MDD. Theoretically, t-PBM penetrates into the cerebral cortex, stimulating the mitochondrial respiratory chain, and also significantly increases cerebral blood flow. Animal and human studies, using a variety of t-PBM settings and experimental models, suggest that t-PBM may have significant efficacy and good tolerability in MDD. In aggregate, these data support the need for large confirmatory studies for t-PBM as a novel, likely safe, and easy-to-administer antidepressant treatment.