Repetitive Transcranial Magnetic Stimulation for Adolescent Major Depressive Disorder: A Focus on Neurodevelopment

Abstract

Adolescent depression is a potentially lethal condition and a leading cause of disability for this age group. There is an urgent need for novel efficacious treatments since half of adolescents with depression fail to respond to current therapies and up to 70% of those who respond will relapse within 5 years. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising treatment for major depressive disorder (MDD) in adults who do not respond to pharmacological or behavioral interventions. In contrast, rTMS has not demonstrated the same degree of efficacy in adolescent MDD. We argue that this is due, in part, to conceptual and methodological shortcomings in the existing literature. In our review, we first provide a neurodevelopmentally focused overview of adolescent depression. We then summarize the rTMS literature in adult and adolescent MDD focusing on both the putative mechanisms of action and neurodevelopmental factors that may influence efficacy in adolescents. We then identify limitations in the existing adolescent MDD rTMS literature and propose specific parameters and approaches that may be used to optimize efficacy in this uniquely vulnerable age group. Specifically, we suggest ways in which future studies reduce clinical and neural heterogeneity, optimize neuronavigation by drawing from functional brain imaging, apply current knowledge of rTMS parameters and neurodevelopment, and employ an experimental therapeutics platform to identify neural targets and biomarkers for response. We conclude that rTMS is worthy of further investigation. Furthermore, we suggest that following these recommendations in future studies will offer a more rigorous test of rTMS as an effective treatment for adolescent depression.

Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters

“…Evidence from other neuromodulatory techniques, such as repetitive transcranial magnetic stimulation (rTMS), indicates that differences in behavioral engagement/arousal cause a potential source of variability of treatment effects because factors such as attention, arousal, and mood state have been shown to affect modulation of excitability by rTMS. 58 It is currently not known whether and how such factors might affect tVNS treatment, and thus, this presents an important avenue for future tVNS research.…”

Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies

“…Collectively, the present studies were also very heterogeneous with respect to dosing protocols for TMS. Of note, only two out of 10 studies included in the present synthesis applied a double-blind, randomized, and shamcontrolled study design, and there have been considerable concerns about open-label trials to inherently inflate effect sizes and to be prone to several further biases, including regression to the mean, investigator biases, and, critically, confounding of active treatment with placebo effects [37,83]. Sham stimulation in rTMS trials can be considered in analogy to pill placebo in pharmacological trials [37], and respective trials suggest larger response rates to pill placebo in adolescent as compared to adult depression [84,85]-with reported rates of placebo response in adolescents ranging between 22 and 59% [86][87][88][89][90][91][92][93].…”

“…Of note, only two out of 10 studies included in the present synthesis applied a double-blind, randomized, and shamcontrolled study design, and there have been considerable concerns about open-label trials to inherently inflate effect sizes and to be prone to several further biases, including regression to the mean, investigator biases, and, critically, confounding of active treatment with placebo effects [37,83]. Sham stimulation in rTMS trials can be considered in analogy to pill placebo in pharmacological trials [37], and respective trials suggest larger response rates to pill placebo in adolescent as compared to adult depression [84,85]-with reported rates of placebo response in adolescents ranging between 22 and 59% [86][87][88][89][90][91][92][93]. Considering rTMS treatment, there is only one large-scale randomized controlled study currently available that would inform on the response rate to sham stimulation in adolescent depression, suggesting a sham response rate of 36.4% [54]which falls well within the range of response rates reported for pill placebo.…”

“…Specifically, drastic changes in structural and functional brain architecture may lead to imbalances in excitation and inhibition, changes in cortical plasticity and connectivity, and less effective information exchange between brain regions that are critical to the processing of emotion [34][35][36]. Of note, it has been suggested previously that neurodevelopmental processes in adolescence might contribute to the currently inconsistent results between studies investigating rTMS in adolescent MDD [37].…”

Selective activation of ABCA1/ApoA1 signaling in the V1 by magnetoelectric stimulation ameliorates depression via regulation of synaptic plasticity

“…Moreover, these limitations increase the rate of suicide, autotomy, and mental disability in MDD patients ( McClintock et al., 2011 ). In 2008, the United States Food and Drug Administration approved the use of repetitive transcranial magnetic stimulation (rTMS) to treat adult treatment-resistant MDD (TRD) ( Oberman et al., 2021 ), in which rTMS targets the left dorsolateral prefrontal cortex (DLPFC) at 10 Hz ( George et al., 2000 ). Recently, our research team reported that individualized rTMS in the left visual cortex shows therapeutic effects without adverse reactions in drug-free MDD patients ( Song et al., 2020 ; Zhang et al., 2021 ).…”