Near-infrared Transcranial Laser Therapy in Subjects With Major Depressive Disorder

This randomized, sham-controlled, parallel-group clinical trial evaluates the efficacy and safety of transcranial photobiomodulation (tPBM) for adults with major depressive disorder (MDD). Participants are randomly assigned in equal proportions to one of four intervention arms:

• CW (Continuous Wave, Medium Dose): 808 nm near-infrared laser delivered continuously at an irradiance of 300 mW/cm².
• CW_LOW (Continuous Wave, Low Dose): 808 nm near-infrared laser delivered continuously at an irradiance of 50 mW/cm².
• PW (Pulsed Wave): 808 nm near-infrared laser delivered at an average irradiance of 300 mW/cm². Pulse parameters include a frequency of 42 Hz and a duty cycle of 33%, resulting in a peak irradiance of 900 mW/cm².
• SHAM: Identical device without therapeutic light emission. Irradiance = 0 mW/cm².

Treatments are administered three times per week for six consecutive weeks, for a total of 18 treatment sessions. Each treatment session consists of bilateral application to frontal scalp regions corresponding to AF3/F3 and AF4/F4 exposure sites. Each exposure area measures 12 cm², with both sites irradiated simultaneously for 429 seconds per session.

PET Substudy: A subset of 20 participants underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging at baseline (V0) and post-treatment (V18). Following intravenous tracer injection, participants rested quietly for approximately 30 minutes before scanning. Each 30-minute imaging session comprised three consecutive 10-minute acquisition blocks: Block A (no light), Block B (during which 429 seconds of tPBM or sham was delivered according to randomized assignment), and Block C (no light). Blocks A and C were light-free in every arm. The primary PET region of interest was the frontal lobe; the secondary region of interest was the dorsolateral prefrontal cortex (DLPFC); additional cortical and limbic regions were examined in exploratory analyses.

EEG Assessments: Resting-state electroencephalography (EEG) was recorded at V1, V9, and V18 to evaluate spectral power (delta, theta, alpha, beta bands) and connectivity indices.

Safety Assessments: Safety and tolerability are evaluated at every visit, including collection of adverse events (AEs), serious adverse events (SAEs), scalp/site tolerability ratings (e.g., erythema, discomfort), suicidality screening with the Columbia Suicide Severity Rating Scale (C-SSRS), and reasons for discontinuation.

Hypotheses: The primary hypothesis is that CW tPBM will result in a significantly greater reduction in depressive symptom severity (HAMD-17 total score) compared with SHAM at week 6/Visit 18. Secondary hypotheses include improvement in QIDS and SDQ scores, increased FDG-PET metabolism in the frontal lobe, and normalization of EEG markers.

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.