A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression.

OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder has advanced slowly. Significant gaps persist in understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1-Hz vs 10-Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of major depressive disorder were randomized to 30 sessions of left prefrontal 1-Hz or 10-Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale-Revised (CDRS-R). The CDRS-R score and ICF biomarker were collected weekly. RESULTS: A total of 41 participants received either 1-Hz (n = 22) or 10-Hz (n = 19) TMS treatments. CDRS-R scores improved compared with baseline in both 1-Hz and 10-Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for participants treated with 1-Hz TMS than for participants who received 10-Hz TMS. There were no significant changes in weekly ICF measurements across 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate receptor activity that facilitates the therapeutic effect of 1-Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, traitlike measure of N-methyl-d-aspartate receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with major depressive disorder. CLINICAL TRIAL REGISTRATION INFORMATION: Biomarkers in Repetitive Transcranial Magnetic Stimulation (rTMS) for Adolescent Depression; https://clinicaltrials.gov; NCT03363919. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list.

Accelerated TMS for Depression: A systematic review and meta-analysis.

Repetitive transcranial magnetic stimulation (TMS) is now widely available for the clinical treatment of depression, but the associated financial and time burdens are problematic for patients. Accelerated TMS (aTMS) protocols address these burdens and attempt to increase the efficiency of standard TMS. This systematic review and meta-analysis aimed to examine accelerated TMS studies for depressive disorders in accordance with PRISMA guidelines. Inclusion criteria consisted of studies with full text publications available in English describing more than one session of TMS (repetitive or theta burst stimulation) per day. Studies describing accelerated TMS protocols for conditions other than depression or alternative neuromodulation methods, preclinical studies, and neurophysiology studies regarding transcranial stimulation were excluded. Eighteen articles describing eleven distinct studies (seven publications described overlapping samples) met eligibility criteria. A Hedges' g effect size and confidence intervals were calculated. The summary analysis of three suitable randomized control trials revealed a cumulative effect size of 0.39 (95% CI 0.005-0.779). A separate analysis including open-label trials and active arms of suitable RCTs revealed a g of 1.27 (95% CI 0.902-1.637). Overall, the meta-analysis suggested that aTMS improves depressive symptom severity. In general, study methodologies were acceptable, but future efforts could enhance sham techniques and blinding.

Preliminary evidence of an association between increased cortical inhibition and reduced suicidal ideation in adolescents treated for major depression.

BACKGROUND: Suicide is a leading cause of death among youth. Prior research using transcranial magnetic stimulation (TMS) has implicated deficits in GABAergic cortical inhibition in adolescent suicidal behavior, yet no studies have assessed whether cortical inhibition varies over time in conjunction with changes in suicidal ideation (SI). This study examined dynamic changes in long-interval intracortical inhibition (LICI), a TMS measure of GABAB-mediated inhibition, and their relationship with changes in SI in a small sample of adolescents undergoing pharmacologic treatment for depression. METHODS: Ten depressed adolescents (aged 13-17) underwent clinical assessment and TMS testing at baseline and again at follow-up. All were treated with antidepressant medication in the interim. SI was measured with the Columbia Suicide Severity Rating Scale (C-SSRS) Intensity of Ideation subscale. LICI was measured at interstimulus intervals of 100 and 150 ms. RESULTS: There was a significant partial correlation, controlling for change in depression severity, between ΔLICI-100 and change in SI as measured by ΔC-SSRS (ρ = .746, df = 7, p = .021), which remained after also controlling for time to follow-up assessment (ρ = .752, df = 6, p = .032). No significant correlation was observed between ΔLICI-150 and change in SI. LIMITATIONS: Sample size; variable follow-up interval; inability to control for age, sex, and potential treatment effects. CONCLUSIONS: These data offer preliminary signal of an association between increases in GABAB-mediated cortical inhibition and reduction in SI over time in adolescents treated for depression. Further studies are warranted to explore the role of cortical inhibition in adolescent suicidal ideation and behavior.

Transcranial Direct Current Stimulation: Mechanisms and Psychiatric Applications.

Transcranial direct current stimulation (tDCS) involves the application of weak electric current to the scalp. tDCS may influence brain functioning through effects on cortical excitability, neural plasticity, and learning. Evidence in adults suggests promising therapeutic applications for depression, and the adverse effect profile is generally mild. Early research indicates complex interactions between tDCS and concurrent cognitive and motor tasks. Further investigation is warranted to understand how tDCS impacts processes relevant to psychiatric conditions.

High-frequency repetitive TMS for suicidal ideation in adolescents with depression.

BACKGROUND: This exploratory study sought to examine the effect of an acute course of high-frequency repetitive TMS on suicidal ideation in adolescents. METHODS: Data were pooled from 3 prior protocols providing a 30-session course of open-label TMS treatment for adolescents with treatment-resistant depression. All participants (n = 19) were outpatients taking antidepressant medication, with TMS provided as adjunctive treatment. Suicidality was assessed at baseline, after 10 treatments, after 20 treatments, and after 30 treatments. Outcome measures of suicidal ideation included the Columbia Suicide Severity Rating Scale (C-SSRS) "Intensity of Ideation" subscale and Item 13 "Suicidality" on the Children's Depression Rating Scale, Revised (CDRS-R). RESULTS: The predicted odds of suicidal ideation (CDRS-R Item 13 and C-SSRS Intensity of Ideation subscale) significantly decreased over 6 weeks of acute TMS treatment without adjustments for illness (depression) severity. However, the magnitude of the decrease in the predicted odds of suicidal ideation across 6 weeks of treatment was attenuated and rendered non-significant in subsequent analyses that adjusted for illness (depression) severity. LIMITATIONS: This was an exploratory study with a small sample size and no sham control. Regulatory and ethical barriers constrained enrollment of adolescents with severe suicidality. CONCLUSIONS: The present findings suggest that open-label TMS mitigated suicidal ideation in adolescents through the treatment and improvement of depressive symptom severity. Although caution is warranted in the interpretation of these results, the findings can inform the design and execution of future interventional trials targeting suicidal ideation in adolescents.