Major depressive disorder (MDD) is highly prevalent among adolescents, and a substantial subset of patients has inadequate response or limited tolerability to first-line interventions such as selective serotonin reuptake inhibitors and cognitive behavioral therapy. There is therefore a clinical need for additional treatment options. Repetitive transcranial magnetic stimulation (rTMS) has established efficacy in adult depression, but evidence for rTMS in adolescents remains limited. Resting-state functional connectivity MRI (rs-fcMRI) can be used to identify individualized stimulation targets within the dorsolateral prefrontal cortex (DLPFC) by locating the DLPFC site exhibiting the strongest negative functional connectivity with the subgenual anterior cingulate cortex (sgACC). This imaging-guided, circuit-informed approach may enable more precise neuromodulation in adolescent MDD.
The study is a randomized, double-blind, three-arm, sham-controlled pilot trial. Forty-five adolescents with MDD will be randomized in a 1:1:1 ratio to one of three groups: (1) conventional left DLPFC-targeted rTMS, (2) rs-fcMRI-guided rTMS targeting the individualized DLPFC site showing the strongest negative connectivity with the sgACC, or (3) sham stimulation. The treatment course is scheduled over 4 weeks. Primary objectives focus on feasibility, acceptability, safety, and preliminary clinical efficacy signals of the imaging-guided rTMS approach compared with conventional and sham stimulation.
Eligible participants are adolescents diagnosed with MDD. The protocol specifies enrollment of 45 participants, allocated equally across the three arms. Primary feasibility metrics include successful recruitment and retention to the study, defined in part by completion of the planned treatment sessions and follow-up assessments. The protocol anticipates assessing 6-month retention as a key feasibility outcome.
The trial compares three intervention strategies:
Comparing individualized, circuit-informed targeting against conventional left DLPFC stimulation and sham will help determine whether imaging-guided neuromodulation is practicable and clinically informative in adolescents with MDD.
Treatment will be delivered over a 4-week period. A key adherence metric is completion of 20 treatment sessions. The trial specifies completion of the full course (20 sessions) as a primary outcome component for assessing intervention adherence. Follow-up includes assessment at 6 months to measure longer-term retention and outcomes.
Primary outcomes focus on feasibility, adherence, retention, preliminary clinical efficacy, and safety. Specific primary measures reported in the protocol are:
Secondary outcomes listed in the protocol include measures of depressive and anxiety symptoms, suicidality, sleep quality, global clinical status and improvement, rumination, and pediatric health-related quality of life.
Safety assessment is an explicit primary aim of the pilot. Adverse events and serious adverse events will be systematically recorded and analyzed as part of the trial’s primary safety outcomes. The protocol intends to evaluate acceptability and tolerability of both conventional and rs-fcMRI-guided rTMS in an adolescent clinical population.
The trial protocol is registered on ClinicalTrials.gov (NCT07185438). The published report declares that the authors have no competing interests. Additional ethical and data-handling details are reported in the source protocol publication; specific procedural or consent details not enumerated in the abstract were not reported in the source provided here.
As a pilot study, this randomized, double-blind, three-arm, sham-controlled trial aims to provide preliminary evidence on the feasibility, acceptability, safety, and early clinical efficacy signals associated with rs-fcMRI-guided rTMS in adolescents with MDD. By directly comparing individualized circuit-informed targeting with conventional left DLPFC stimulation and sham, the study seeks to clarify whether imaging-guided neuromodulation is practicable and clinically informative in this population. Findings are intended to inform refinement of study procedures, selection of outcomes, and design considerations for a future fully powered randomized controlled trial.