Depression, Depression, Anxiety, Depressive Disorder, Depressive Disorder, Major
Conditions
Keywords
Depression, Major Depressive Disorder, Photobiomodulation, FDG-PET, EEG, Near-Infrared Light Therapy, Brain Metabolism, Neurostimulation, Mental Health, Non-Invasive Therapy
Brief summary
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.
Detailed 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.
Interventions
DEVICEBilateral Near-Infrared Transcranial Photobiomodulation (tPBM)
The system delivers 808 nm near-infrared light via fiber optics through a headset forming \~12 cm² beams at EEG sites AF3/AF4 (dorsolateral prefrontal cortex). Participants are randomized to: (1) Continuous Wave (CW, high dose) \~350 mW/cm² (\~8.4 W total); (2) Continuous Wave Low Dose (CW\_LOW) \~50 mW/cm² (\~1.2 W); (3) Pulsed Wave (PW) peak \~1050 mW/cm², 42 Hz, 33% duty cycle (avg \~350 mW/cm²); or (4) Sham device with identical cues but no light. Sessions last 429 s, 3×/week for 6 weeks (18 total). Sham matches duration/procedures. Outcomes include depressive symptoms (HAMD-17, QIDS, SDQ), FDG-PET, and EEG.
Sponsors
NeuroThera DE
Peruvian Clinical Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants, care providers, investigators, outcome assessors (those evaluating the results), and the sponsor are blinded to the group assignments.
Intervention model description
This randomized, double-blind, sham-controlled, parallel-group trial evaluates the effects of transcranial photobiomodulation (tPBM) on depressive symptoms, brain function, and safety in adults with Major Depressive Disorder (MDD). About 60 participants are randomized to one of four arms: high-dose continuous wave (CW, \ 350 mW/cm²), low-dose CW (\ 50 mW/cm²), pulsed wave (PW, peak \ 1050 mW/cm²; 42 Hz, 33% duty cycle), or sham. Treatments are delivered 3×/week for 6 weeks (18 sessions) bilaterally over frontal EEG sites AF3/AF4 using 808 nm NIR light (\ 12 cm² beams). The primary outcome is change in HAMD-17 (at baseline, mid, and post-treatment). Secondary outcomes include QIDS-SR16, SDQ, safety metrics, EEG biomarkers (at baseline, mid, and post-treatment), and FDG-PET (baseline and post-treatment) in a 20-participant substudy. The study assesses both clinical efficacy and neural mechanisms of action.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect on depressive symptoms | Baseline, mid-treatment (Week 3), post-treatment (Week 6), and at 2-week follow-up (Week 8). | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Outcome Measures | QIDS-SR16 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). | Self-report symptom scales: Quick Inventory of Depressive Symptomatology (QIDS-SR16) 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. Exploratory ROIs include other cortical/limbic regions. |
Countries
Peru
Outcome results
None listed