Note: This registration is retained as a historical study record. Updated study information and subsequent protocol modifications are available under ClinicalTrials.gov Identifier NCT06934135, which serves as the actively maintained study registration.

The Near-Infrared Transcranial Laser Therapy (NIR-TLT) is a non-invasive intervention that delivers near-infrared light to brain tissue. Photobiomodulation is believed to interact with cytochrome c oxidase, a mitochondrial enzyme involved in cellular energy metabolism, resulting in increased adenosine triphosphate (ATP) production and potential neuroprotective effects.

These mechanisms may promote cellular plasticity and support improvement of depressive symptoms. This study evaluates the safety, tolerability, and potential antidepressant effects of NIR-TLT in adults with Major Depressive Disorder.

Study purpose: To assess and compare the effect(s) of each of the four doses of NIR-TLT on symptomatology of depression: antidepressant effect, in subjects with major depressive disorder (MDD). To assess the safety and tolerability of each dose of NIR-TLT. Compare the effect(s) of each of the four doses of NIR-TLT in brain electrophysiology. To describe the findings visualized in PET, related to the cerebral metabolism of the participants, before and after receiving the intervention under study. Study design: This protocol is a multicentered, randomized, simulated, and double-blind clinical study. This work will randomize 112 subjects into 4 equal groups: bilateral continuous wave (BCW), bilateral pulsed wave (BPW 1-2) y SHAM. All subjects, investigators (except the study statistician), and outcomes assessors will be blind to group assignment. The device operator will be aware of group assignments. All subjects will receive 3 NIR-TLT treatments per week for 6 weeks. A follow-up evaluation will be performed 2 weeks after the end of the study. The treatment will follow these specifications: wavelength 830 nm; average irradiance 54,8 mW / cm2; average fluence of 65,8 J / cm2 (consistently with parameters used in the ELATED-2 study at MGH with the device Omnilux New U), being the total Fluency delivered: 3.6 kJ (bilateral) o 1.8 kJ (unilateral), either on the subject's forehead, at or near electroencephalography sites (EEG) F3 and F4. All NIR-TLT sessions will last 20 minutes, regardless of group assignment. Study population: Patients eligible for study participation will be diagnosed with major depressive disorder (MDD) by DSM criteria. Subjects will be between 18-75 years of age (have not had 76st birthday) on the date of screening. Duration of participation: Subjects will be followed in the study for 8 weeks (a 6-week treatment period, plus 2 weeks of follow-up). The total duration of the study will be 24 months. Assessment criteria: The primary efficacy criteria is the improvement in depressive symptoms from each of the four doses of NIR-TLT. Assessed using HAMD-17, at 3 time points (visit 1, visit 9 and visit 18).

Inclusion Criteria:

1. Subjects age at screening will be between 18 and 75 years old (inclusive).
2. Diagnosis of major depressive disorder (Mini International Neuropsychiatric Interview, MINI)
3. QIDS-CR≥12 at screening
4. CGI-S ≥4 or higher, i.e., "moderately depressed"
5. Women of child-bearing potential must use a double-barrier method for birth control (e.g. condoms plus spermicide) if sexually active.
6. Subject Informed Consent obtained in writing in compliance with local regulations prior to enrollment into this study.
7. The subject is willing to participate in this study for at least 12 weeks.
8. Subjects will need to be on stable dose(s) of antidepressants (if taking any) for at least six weeks prior to enrollment.

Exclusion Criteria:

1. Decrease in Symptoms of Depression Questionnaire (SDQ) self-report from screening to baseline >=30%, calculated as [(SDQ screening-88) - (SDQ initial-88) / (SDQ screening-88)] >=30/100. A score of 88 is "normal" in SDQ.
2. The subject is pregnant or lactating.
3. The subject failed more than 2 adequate treatments with FDA approved antidepressants during current episode per Antidepressant Treatment Response Questionnaire (ATRQ) criteria (less than 50% decrease in depressive symptomatology).
4. Structured psychotherapy focused on treating the subject's depression is permitted if started at least 8 weeks prior to the screening visit.
5. Substance dependence or abuse in the past 3 months.
6. History of a psychotic disorder or psychotic episode (current psychotic episode per MINI assessment).
7. Bipolar affective disorder (per MINI assessment).
8. Unstable medical illness, defined as any medical illness which is not well-controlled with standard-of-care medications (e.g., insulin for diabetes mellitus).
9. Active suicidal or homicidal ideation (both intention and plan are present), as determined by Columbia-Suicide Severity Rating Scale (C-SSRS) screening.
10. The subject has a significant skin condition (i.e., hemangioma, scleroderma, psoriasis, rash, open wound or tattoo) on the subject's scalp that is found to be in proximity to any of the procedure sites.
11. The subject has an implant of any kind in the head (e.g. stent, clipped aneurysm, implantable shunt - Hakim valve).
12. Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment (in US: Visudine (verteporfin) for age related macular degeneration; Aminolevulinic Acid- for actinic keratoses; 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)
13. Recent history of stroke (90 days).
14. The subject failed a device-based intervention FDA-approved for the treatment of depression, during the current episode (e.g. less than 50% decrease in depressive symptomatology with Transcranial Magnetic Stimulation).
15. History of dementia, traumatic brain injury (TBI) or any other organic neurological disorder.

After the completion of the study, the researchers will decide if IPDs can be shared. The data will first be sent to the regulatory institutions involved.