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

NeuroThera DE50 enrolled

Overview

Major depressive disorder (MDD) is a leading cause of disability worldwide, and many patients do not achieve adequate benefit from current treatments. Transcranial photobiomodulation (tPBM) is a non-invasive neuromodulation technique that delivers near-infrared (808 nm) light through the scalp to frontal brain regions involved in mood regulation. Preclinical and early clinical studies suggest that tPBM may improve symptoms of depression and enhance cortical function. This randomized, sham-controlled, parallel-group trial evaluates the efficacy, safety, and neural effects of tPBM in adults with MDD. Participants are assigned to one of four groups: Continuous Wave, Medium Dose (CW), Continuous Wave, Low Dose (CW\_LOW), Pulsed Wave (PW), or Sham treatment. Interventions are delivered 3 times a week for 6 weeks (total of 18 sessions) to bilateral frontal scalp sites (AF3/F3 and AF4/F4). The primary outcome is change in depressive symptoms measured by the Hamilton Depression Rating Scale (HAMD-17) from baseline to the end of treatment (Week 6, Visit 18). Secondary outcomes include changes in self-reported depression scales (QIDS, SDQ), regional brain glucose metabolism measured by FDG-PET, and resting-state EEG markers. Safety and tolerability are assessed throughout the trial, including adverse events, scalp/site reactions, and suicidality screening. This study will provide proof-of-concept evidence for the clinical efficacy and mechanistic effects of tPBM in major depression and will inform the design of larger, multicenter clinical trials.

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: 1. CW (Continuous Wave, Medium Dose): 808 nm near-infrared laser delivered continuously at an irradiance of 300 mW/cm². 2. CW\_LOW (Continuous Wave, Low Dose): 808 nm near-infrared laser delivered continuously at an irradiance of 50 mW/cm². 3. 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. 4. 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.

Interventions

Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)DEVICE

808-nm near-infrared laser light is delivered through a headset forming approximately uniform, round beams of approximately 12 cm² at each of 2 bilateral frontal scalp sites (EEG positions AF3/F3 and AF4/F4; approximately 24 cm² total), irradiated simultaneously. Arms: (1) CW, Medium Dose, approximately 300 mW/cm² average irradiance (3.6 W per site; 7.2 W both sites); (2) CW\_LOW, approximately 50 mW/cm² (0.6 W per site; 1.2 W both sites); (3) PW, 42 Hz, 33% duty cycle, peak approximately 900 mW/cm² (10.8 W per site; 21.6 W both sites), average approximately 300 mW/cm² (3.6 W per site; 7.2 W both sites); (4) Sham, identical device and procedural cues, no therapeutic emission (0 mW/cm²). Sessions lasted 429 seconds, 3 times weekly for 6 weeks (18 sessions). Sham duration and procedures matched the active arms to maintain blinding.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Effect on depressive symptoms

The primary outcome is change in depressive symptom severity in patients with Major Depressive Disorder (MDD), comparing three active doses of near-infrared transcranial light therapy (NIR-TLT) and Sham. Symptoms are measured using the 17-item Hamilton Depression Rating Scale (HAMD-17).

Time frame: Baseline, mid-treatment (Week 3), post-treatment (Week 6), and at 2-week follow-up (Week 8).

Secondary Outcomes

Secondary Outcome Measures

Self-report symptom scales: Quick Inventory of Depressive Symptomatology (QIDS-C) and Symptoms of Depression Questionnaire (SDQ), measured at the same intervals. Neurophysiological biomarkers: Resting-state EEG. Spectral power (delta, theta, alpha, beta) and functional connectivity will be assessed. Cerebral glucose metabolism via FDG-PET in a substudy of 20 participants. Primary Region of Interest (ROI): Frontal Lobe. Secondary ROI: dorsolateral prefrontal cortex (DLPFC). Exploratory ROIs include other cortical/limbic regions.

Time frame: QIDS-C and SDQ: baseline, mid-treatment (Week 3), and post-intervention (Week 6), EEG: baseline, mid-treatment (Week 3), and post-intervention (Week 6), FDG-PET: baseline and post-intervention (Week 6).