Near Infrared Transcranial Laser Therapy Subjects With Major Depressive Disorder

This multi-center, randomized, double-blind, sham-controlled clinical trial investigates the efficacy of near-infrared transcranial photobiomodulation (NIR-TLT) on depressive symptoms in adults with Major Depressive Disorder (MDD).

The primary objective is to evaluate the impact of three different NIR-TLT doses compared to sham treatment on depression severity.

Secondary objectives include exploring changes in brain metabolism (FDG-PET) and electrophysiology (EEG) and examining the relationship between these biological changes and clinical improvement in depressive symptoms.

This study aims to evaluate the efficacy of near-infrared transcranial photobiomodulation (NIR-TLT) as a treatment for Major Depressive Disorder (MDD).

The primary objective is to assess the effect of three different doses of NIR-TLT compared to sham treatment on depressive symptoms, as measured by validated clinical scales. MDD is characterized by impaired mood regulation and has been associated with functional and metabolic abnormalities in the prefrontal cortex and other brain regions.

NIR-TLT, a non-invasive neuromodulation technique, uses near-infrared light to target cortical brain regions, potentially enhancing mitochondrial function, improving cerebral metabolism, and modulating neural activity. This mechanism may directly influence depressive symptoms by restoring functional activity in brain regions implicated in mood regulation.

The secondary objectives include analyzing changes in brain metabolism using FDG-PET imaging and changes in brain electrophysiology using EEG, both obtained before and after the treatment course. These neuroimaging and neurophysiological assessments will help explore the biological mechanisms underlying the potential antidepressant effects of NIR-TLT.

Additionally, the study will investigate whether changes in brain metabolism and electrophysiology correlate with changes in depressive symptoms. This exploratory analysis aims to better understand the relationship between the biological effects of NIR-TLT and clinical outcomes in MDD.

The study is a multi-center, randomized, double-blind, sham-controlled trial. Adults aged 18-75 meeting DSM diagnostic criteria for MDD, confirmed via the MINI interview, will be eligible. Subjects will be randomized into one of four groups: three active NIR-TLT dose groups and one sham control.

NIR-TLT Dosing (Common)

1. Wavelength - 810 nm +/- 10 nm.
2. Treatment Light Parameters: Two round laser beams, each with an area of 12cm², applied at EEG sites F3 and F4 (prefrontal cortex).
3. Treatment Time: Approximately 7 minutes.
4. Treatment Frequency - Three sessions per week.
5. Treatment Intervention Duration - 6 weeks (18 Treatments), followed by a two-week follow-up period.

NIR-TLT Dosing (Group Specific)

1. Group A: Low NIR-TLT Continuous Wave (CW) Dose. 0.6 W at each of F3 and F4 =\> Power Density = 55 mW/cm² - Fluence = 22 J/cm².
2. Group B: Mid Power NIR-TLT Continuous Wave (CW) Dose. 3.5 W at each of F3 and F4 =\> Power Density = 350 mW/cm², Fluence = 150 J/cm².
3. Group C: High Power NIR-TLT Pulsed Wave (PW) Dose. Pulse Repetition Rate = 42 Hz. Pulsed Duty Cycle = 0.33. 12.75 W (Peak Power) at each of F3 and F4 =\> Peak Power Density = 1.06 W/cm². Average Power Density 350 mW/cm², Average Fluence = 150 J/cm².
4. Group D: Sham. 0 W at each of F3 and F4 =\> Power Density = 0 mW/cm² - Fluence 0 J/cm². Total Fluence = 0 J/cm².The sham condition is designed to be indistinguishable from active NIR-TLT treatment. Except for the absence of therapeutic near-infrared light emission, the sham device operates identically-producing the same sounds, device indicators, and treatment duration-so that participants, investigators, outcome assessors, and device operators remain blinded to treatment allocation.

By integrating clinical, metabolic, and electrophysiological measures, this study seeks to determine the therapeutic potential of NIR-TLT for MDD and enhance understanding of its underlying mechanism of action.

Eligibility Criteria:
Inclusion Criteria:

The age of subjects in the study will be between 18 and 75 years (inclusive). Diagnosis of Major Depressive Disorder (MINI). QIDS-C ≥12 at screening. CGI-S ≥4 or higher, i.e., "moderately depressed." Women of childbearing potential must use a double-barrier method of birth control (e.g., condoms plus spermicides) if sexually active.

Written informed consent was obtained from the subject in accordance with local regulations prior to enrollment in this study.

The subject is willing to participate in this study for at least 12 weeks. Subjects must have been on stable doses of antidepressants (if taking any) for at least six weeks before enrollment.

Exclusion Criteria:

A decrease in self-reported SDQ from screening to baseline ≥30%, calculated as \[((SDQ_screening-88) - (SDQ_baseline-88)) / (SDQ_screening-88)\] ≥30/100. A score of 88 is considered "normal" on the SDQ.

The subject is pregnant or breastfeeding. The subject has failed more than 2 adequate treatments with FDA-approved antidepressants during the current episode according to ATRQ criteria (less than a 50% reduction in depressive symptoms).

Structured psychotherapy focused on treating depression (i.e., CBT or IPT) is allowed if initiated at least 8 weeks before the screening visit.

Substance dependence or abuse in the past 3 months. History of a psychotic disorder or psychotic episode (current psychotic episode as per MINI evaluation).

Bipolar affective disorder (as determined by MINI evaluation). Unstable medical illness, is defined as any medical condition that is not well controlled with standard care medications (e.g., insulin for diabetes mellitus, HCTZ for hypertension).

Active suicidal or homicidal ideation (both intent and plan are present), as determined by C-SSRS screening.

The subject has a significant skin condition (e.g., hemangioma, scleroderma, psoriasis, rash, open wound, or tattoo) on the scalp near any of the procedure sites.

The subject has any type of implant in the head (e.g., stent, clipped aneurysm, embolized AVM, implantable shunt - Hakim valve).

Any use of light-activated medications (photodynamic therapy) within 14 days prior to study enrollment (in the U.S.: Visudyne (verteporfin) - for age-related macular degeneration; Aminolevulinic Acid - for actinic keratosis; Photofrin (porfimer sodium) - for esophageal cancer, non-small cell lung cancer; Levulan Kerastick (aminolevulinic acid HCl) - for actinic keratosis; 5-aminolevulinic acid (ALA) - for non-melanoma skin cancer).

Recent history of stroke (within 90 days). The subject had a failed intervention with an FDA-approved device for depression treatment during the current episode (e.g., less than a 50% reduction in depressive symptoms with TMS, ECT, or VNS).

History of dementia, traumatic brain injury (TBI), or any other organic neurological disorder.