Major depressive disorder (MDD) is often refractory with high mortality in adolescents. Dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) improves MDD in adults by undetermined mechanisms. We hypothesized that DFPLC rTMS would improve symptoms and increase regional glutamate in adolescent MDD.

Methods: We report the first six cases (four females, 15-21 years, mean IQ 102.3±3.39) with treatment-resistant MDD in an open-label rTMS clinical trial. Neuronavigated rTMS was applied to the left DLPFC for 15 consecutive weekdays (120% RMT, 40 pulses over 4 seconds (10 Hz), inter-train interval 26 seconds, 75 trains, 3000 pulses). Treatment response was defined as >50% reduction in Hamilton Depression Rating Scale scores (Ham-D). Secondary outcomes included depression (BDI), anxiety (HAM-A), neuropsychological and safety/tolerability evaluations. Short echo (TE=30msec, TR=2000msec) proton magnetic resonance spectroscopy (1H-MRS, 4.5 cc) quantified DLPFC glutamate (LCModel) before and after treatment.

Results: Procedures were well tolerated with no serious adverse events. Four patients (two females; two males) responded with mean 68% decrease in Ham-D (30.5±5.45 to 9.8±1.26). BDI scores also decreased by 84% (37.3±4.5 to 6.0±3.37). In the two non-responders, Ham-D scores decreased 29% (31.0±7.07 to 22.0±2.83) while BDI scores increased 19% (37.5±4.95 to 44.5±9.19). Responders showed a 78% decrease in Ham-A scores (29.3±8.06 to 6.5±4.20) while in non-responders Ham-A decreased 36%. Responders had lower baseline DFPLC glutamate (9.36±1.33mmol/kg) that increased 11% post-rTMS (10.37±1.48mmol/kg). Non-responders started with higher glutamate levels which decreased by 10%.