In the realm of adolescent mental health, treatment resistant depression (TRD) presents a daunting challenge. Affecting approximately 20% of youths who suffer from depressive disorders, TRD remains unresponsive to conventional antidepressant therapies, leaving clinicians and families seeking new avenues of care. Recent advances in neuromodulation have spotlighted repetitive transcranial magnetic stimulation (rTMS) as a promising intervention for adults with resistant depression, yet its application in younger populations has remained largely underexplored. A pioneering open-label pilot study delves into this gap, investigating the safety and preliminary efficacy of low-frequency (1 Hz) rTMS targeted at the right dorsolateral prefrontal cortex (DLPFC) in adolescents grappling with TRD.
The study enrolled twenty adolescents, ranging from 13 to 18 years old, diagnosed with treatment resistant unipolar or bipolar depression. These participants had previously endured unsuccessful treatment trials with antidepressants, situating them within a critical risk group that demands alternative strategies. Conducted over 20 to 30 consecutive days, the intervention applied daily sessions of 1 Hz rTMS, a frequency postulated to exert inhibitory effects on right frontal cortical regions implicated in mood regulation. The researchers observed an inclusion rate of nearly one patient per month, and an attrition rate of only 10%, underscoring the feasibility of implementing such neuromodulatory protocols in clinical settings for adolescents.
Measuring symptomatic changes through the Montgomery-Asberg Depression Rating Scale (MADRS) revealed a remarkable statistical decrease in depressive severity, with median scores dropping from 35 at baseline to 23 post-treatment. This significant reduction (p < 0.01) suggests that low-frequency rTMS can attenuate depressive symptoms even in a population traditionally considered resistant to pharmacotherapy. Concurrently, functional assessments via the Children’s Global Assessment Scale (CGAS) indicated improvements in overall functioning, as median scores increased from 45 to 55 (p < 0.05). These dual improvements in mood and daily functioning signal the potential for rTMS to positively impact quality of life in adolescent depression.
Despite these promising findings, it is important to note that only one participant attained the criterion for treatment response, defined as a 50% or greater reduction in MADRS score. This caveat underscores the complexity of adolescent TRD and signals that while rTMS can reduce symptom burden, it may require optimization or adjunctive approaches to achieve full clinical remission for most patients. The nuanced outcome challenges clinicians and researchers to interpret rTMS’s benefits within realistic expectations and motivates further inquiry into dose-response relationships and individualized treatment protocols.
The study’s safety profile also warrants particular attention. Adverse effects reported by participants primarily included scalp pain, headaches, tiredness, and nausea. These side effects were characterized as common yet tolerable and demonstrated a tendency to diminish as treatment progressed. Importantly, no serious adverse events or neurological complications, such as seizures, were recorded, affirming the technique’s safety in a younger demographic. This data strengthens the argument for the incorporation of rTMS into treatment regimens for adolescent TRD, where safety considerations are paramount.
A critical aspect of this pilot investigation is its focus on the right dorsolateral prefrontal cortex as the stimulation target. Neuroimaging studies frequently implicate dysregulated activity in prefrontal networks in depression, with the right DLPFC often associated with negative affect and emotion regulation deficits. The choice of a low-frequency 1 Hz stimulation aims to induce inhibitory neuromodulation, potentially restoring balanced activity within this circuit. Such mechanistic grounding elevates the scientific rigor of the approach and may pave the way for more targeted, individualized brain stimulation therapies as neurobiological insights into depression deepen.
The trial’s open-label design, while appropriate for feasibility studies, inevitably introduces limitations in controlling for placebo effects and observer bias. Future randomized, double-blind controlled trials with larger sample sizes will be instrumental in definitively establishing efficacy and honing stimulation parameters, including frequency, intensity, and session duration. Moreover, combining rTMS with psychotherapeutic or pharmacological interventions could be explored to augment therapeutic outcomes, recognizing that TRD often demands multidimensional treatment strategies.
The significance of this investigation extends beyond clinical outcomes, addressing critical gaps in adolescent psychiatry research. Historically, neuromodulation studies have concentrated on adults, leaving adolescents underserved despite their unique neurodevelopmental trajectories and vulnerability to depressive disorders. Demonstrating feasibility, tolerability, and initial efficacy, this study lays the groundwork for ethically and methodologically sound research tailored to the adolescent brain. It also sets a precedent encouraging clinicians and researchers to adopt innovative technologies in tackling resistant mental illnesses within younger populations.
Moreover, practical considerations highlighted by the study, including recruitment rates and participant retention, inform the logistics of future large-scale trials. The inclusion rate of 0.9 patients per month and low attrition affirm that adolescents and their families are willing to engage with rTMS interventions, dispelling some concerns about acceptability hurdles in this age group. The decreasing trend in adverse effects also suggests that adherence may improve over multiple sessions, a key factor for designing efficient treatment protocols.
The broader neuroscientific community will find this work compelling, as it contributes critical data to ongoing debates regarding optimal neuromodulation targets and frequencies for diverse psychiatric conditions. Insights around low-frequency stimulation’s modulating capacity in the adolescent brain open avenues for novel explorations, potentially extending beyond depression to other refractory mood and anxiety disorders prevalent during adolescence. This promise aligns with a growing emphasis on precision psychiatry, where interventions are informed by an interplay of symptomatology, neural circuitry, and developmental factors.
In conclusion, this feasibility study presents a cautiously optimistic narrative about leveraging low-frequency rTMS for adolescent treatment resistant depression. While conclusive efficacy awaits further rigorous trials, the demonstration of safety, tolerability, and significant symptom and function improvements marks a meaningful stride toward expanding therapeutic options. As depressive disorders continue to impose profound burdens on youth worldwide, the advent of neuromodulatory techniques like rTMS, refined through methodical research, offers hope for more effective, personalized interventions in the near future.
Subject of Research: Treatment resistant depression in adolescents and the application of low-frequency repetitive transcranial magnetic stimulation (rTMS) targeting the right dorsolateral prefrontal cortex.
Article Title: Low-frequency repetitive transcranial magnetic stimulation for adolescent treatment resistant depression – a feasibility study.
Article References:
Jester-Broms, J., Strömbergsson, H., Persson, J. et al. Low-frequency repetitive transcranial magnetic stimulation for adolescent treatment resistant depression – a feasibility study. BMC Psychiatry 25, 679 (2025). https://doi.org/10.1186/s12888-025-07115-5
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