A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression - 12/11/24

Doi : 10.1016/j.jaac.2024.08.487

Charles P. Lewis, MD ^a,^b,^c, Paul A. Nakonezny, PhD ^d, Ayse Irem Sonmez, MD ^c,^e, Can Ozger, BS ^c, Juan F. Garzon, MD ^c, Deniz Doruk Camsari, MD ^c, Deniz Yuruk, MD ^c, Magdalena Romanowicz, MD ^c, Julia Shekunov, MD ^c, Michael J. Zaccariello, PhD ^c, Jennifer L. Vande Voort, MD ^c, Paul E. Croarkin, DO, MS ^c,^⁎
^a University of Minnesota, Minneapolis, Minnesota
^b Masonic Institute for the Developing Brain, Minneapolis, Minnesota
^c Mayo Clinic, Rochester, Minnesota
^d University of Texas Southwestern Medical Center, Dallas, Texas
^e Columbia University, New York, New York

^∗Correspondence to Paul E. Croarkin, DO, MS, Department of Psychiatry and Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905Department of Psychiatry and PsychologyMayo Clinic200 First Street SWRochesterMN55905

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Abstract

Objective

Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder has advanced slowly. Significant gaps persist in the 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; 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.

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Key words : adolescent, glutamate, major depressive disorder, N-methyl-d-aspartate receptor, transcranial magnetic stimulation

Plan

Method

Study Design

Participants

Neurophysiology Biomarker

Independent Variable and Covariates

Statistical Analysis

Results

Participant Characteristics

Depressive Symptom Severity

Intracortical Facilitation

Blinding Assessment

Adverse Events

Discussion

CRediT authorship contribution statement

	Research reported in this publication was supported by the National Institute of Mental Health (NIMH) of the National Institutes of Health (NIH) under award numbers R01MH113700 and K23MH127307. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or NIMH. Neuronetics, Inc., provided device and equipment support through a grant-in-kind but had no role in the study design, study execution, data analyses, data interpretation, or drafting of the manuscript.
	The research was performed with permission from the US Food and Drug Administration, NIH, and Mayo Clinic Internal Review Boards.
	Data sharing: Deidentified participant data, data dictionary, study protocol, and statistical analysis plan available to researchers (upon reasonable request) with publication for secondary analyses (upon reasonable request) through NIMH Data Archive (nda.nih.gov/) or data sharing agreement with principal investigator.
	Dr. Nakonezny served as the statistical expert for this research.
	The authors thank the children and families who participated in the study. The authors thank Anosha Zanjani, Associate AIA, BSc, MSc, MArch, of The Center for Health Design, for preparing Figure 1.
	Disclosure: Dr. Lewis has received research grant funding from the NIMH (K23MH127307), the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant No. 27488, Alan G. Ross Memorial Investigator), the American Foundation for Suicide Prevention (Young Investigator Grant YIG-0-108-20), and the Klingenstein Third Generation Foundation. He has served as a site investigator in multicenter studies funded by Neuronetics, Inc., and NeoSync, Inc. He has received a speaker’s honorarium and travel expenses from CentraCare Health System, Inc. Dr. Croarkin has received research support from the NIH, the National Science Foundation, the Agency for Healthcare Research and Quality, the Brain & Behavior Research Foundation, and the Mayo Clinic Foundation. He has received research support from Pfizer, Inc. He has received grant-in-kind equipment support from Neuronetics, Inc., and MagVenture, Inc. He has received grant-in-kind supplies and genotyping from Assurex Health, Inc., for an investigator-initiated study. He has served as the principal investigator for a multicenter study funded by Neuronetics, Inc., and a site principal investigator for a study funded by NeoSync, Inc. He has served as a paid consultant for Engrail Therapeutics, Sunovion, Procter & Gamble Company, Meta Platforms, Inc., and Myriad Neuroscience. He is employed by Mayo Clinic. He has received compensation as the Editor-in-Chief for the Journal of Child and Adolescent Psychopharmacology. Drs. Nakonezny, Sonmez, Garzon, Doruk Camsari, Yuruk, Romanowicz, Shekunov, Zaccariello, and Vande Voort and Mr. Ozger have reported no biomedical financial interests or potential conflicts of interest.