Trial of Transcranial Photobiomodulation for Depression With PET and EEG Outcomes (NITLT01)

NeuroThera DE

Status: Completed

Conditions: Depression, Anxiety; Depressive Disorder, Major; Depression; Depressive Disorder

Treatments: Device: Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06934135

NITLT01

Details and patient eligibility

About

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: high-dose continuous wave (CW), low-dose continuous wave (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 and AF4).

The primary outcome is change in depressive symptoms measured by the Hamilton Depression Rating Scale (HAMD-17) from baseline to week 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.

Full description

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, high dose): 808 nm near-infrared laser light delivered continuously at an average irradiance of ~350 mW/cm².
2. CW_LOW (Continuous Wave, low dose): 808 nm laser light delivered continuously at an average irradiance of ~50 mW/cm².
3. PW (Pulsed Wave): 808 nm laser light delivered in pulsed mode at a peak irradiance of ~1050 mW/cm², frequency 42 Hz, with 33% duty cycle.
4. SHAM (Placebo control): Identical headset with no therapeutic light emission, producing only background cues to preserve blinding.

Treatments are administered twice weekly for 9 consecutive weeks (18 sessions total). Each session consists of bilateral application to frontal scalp locations AF3 and AF4 (10-20 EEG system), using circular beams of ~12 cm² per site. The device incorporates standardized positioning and timing protocols to ensure reproducibility across participants.

PET Substudy: A subset of 20 participants undergo 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging at baseline (V0) and post-treatment (V18). Following intravenous tracer injection, participants rest quietly for ~30 minutes prior to scanning. During the uptake and imaging period, participants receive a sequence of 10 minutes of simulated treatment, 10 minutes of their randomized intervention (CW, CW_LOW, PW, or SHAM), and 10 minutes of simulated treatment. The primary PET region of interest is the dorsolateral prefrontal cortex (DLPFC); additional cortical and limbic regions are examined in exploratory analyses.

EEG Assessments: Resting-state electroencephalography (EEG) is recorded at V0, 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 18. Secondary hypotheses include improvement in QIDS and SDQ scores, increased FDG-PET metabolism in DLPFC, and normalization of EEG markers.

Enrollment: 50 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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50 participants in 4 patient groups

Arm A - Experimental: Continuous Wave (CW, High Dose)

Experimental group

Description:

Participants receive bilateral tPBM at EEG sites AF3 and AF4 using 808 nm near-infrared light, continuous wave mode. Average irradiance is \~350 mW/cm² (≈4.2 W over two 12 cm² beams). Treatments are delivered twice weekly for 9 weeks (18 sessions total). 429 seconds, 3 times a week for 6 weeks. Delivering to to the brain a total of 3.6 kJ/session, and \~65 kJ/procedure.

Treatment:

Device: Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)

Arm B - Experimental: Continuous Wave Low Dose (CW_LOW)

Experimental group

Description:

Participants receive bilateral tPBM at AF3 and AF4 using 808 nm light in continuous wave mode at reduced average irradiance (\~50 mW/cm²; \~1.2 W total). Each 429-second session, three times per week for 6 weeks (18 sessions), delivers \~0.52 kJ/session and \~9.3 kJ total.

Treatment:

Device: Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)

Arm C - Experimental: Pulsed Wave (PW)

Experimental group

Description:

Participants receive bilateral tPBM at AF3 and AF4 using 808 nm light delivered in pulsed mode (42 Hz, 33% duty cycle). Peak irradiance \~1050 mW/cm²; average \~350 mW/cm² (\~8.4 W total). Each 429-second session, three times per week for 6 weeks (18 sessions), delivers \~3.6 kJ/session and \~65 kJ total.

Treatment:

Device: Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)

Arm D - Sham Comparator: Sham tPBM

Sham Comparator group

Description:

Participants receive sham stimulation at AF3 and AF4 with an identical-appearing device that emits no therapeutic light. Session length (429 seconds), frequency (3×/week for 6 weeks), and procedures are matched to active arms to maintain blinding.

Treatment:

Device: Bilateral Near-Infrared Transcranial Photobiomodulation (tPBM)