Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

J Psychiatry Neurosci 2019;44(6):386-394 | PDF | Appendix

Jennifer G. Levitt, MD; Guldamla Kalender, BA; Joseph O’Neill, PhD; Joel P. Diaz, BS; Ian A. Cook, MD; Nathaniel Ginder, MD, PhD; David Krantz, MD, PhD; Michael J. Minzenberg, MD; Nikita Vince-Cruz, BS; Lydia D. Nguyen, BS; Jeffry R. Alger, PhD; Andrew F. Leuchter, MD

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC).

Methods: In 26 adults with TRD, we used Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents.

Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment.

Limitations: This study had an open-label design in a population receiving naturalistic treatment.

Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.


Submitted Nov. 18, 2018; Revised Feb. 22, 2019; Accepted Mar. 4, 2019; Published online June 13, 2019

Acknowledgements: The authors are grateful to Lawrence S. Kegeles, MD, PhD, of the New York State Psychiatric Institute for details of the prescription of the DLPFC MRS voxel. The authors thank Sinyeob Ahn, PhD, of Siemens Healthcare, San Francisco, for writing the MEGA-PRESS works-in-progress pulse sequence.

Affiliations: From the Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles (Levitt, Diaz, Cook, Ginder, Krantz, Minzenberg, Vince-Cruz, Nguyen, Leuchter); the Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles (Levitt, Kalender, O’Neill, Cook, Krantz, Minzenberg, Leuchter); the Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles (Kalender); the Division of Child and Adolescent Psychiatry, Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles (Levitt, O’Neill); the Department of Bioengineering, Henry Samueli School of Engineering at Applied Science at UCLA, Los Angeles (Cook); the Department of Neurology, UCLA David Geffen School of Medicine at UCLA, Los Angeles (Alger); the Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas (Alger); and the NeuroSpectroScopics, LCC, Sherman Oaks, California (Alger).

Competing interests: I. Cook reports a grant from NeoSync and earns equity interest from Los Angeles TMS Institute Inc., Neuro-Sigma Inc., HeartCloud Inc., and BrainCloud Corporation, outside the submitted work. A. Leuchter reports grants from the National Institutes from Health, Neuronetics, NeuroSigma Inc., the US Department of Defense, and the CHDI Foundation. He is a consultant and stockholder of NeoSync Inc., a consultant with Ionis Pharmaceuticals and EIMindA, and earns equity from Brain Biomarker Analytics LCC. No other competing interests declared.

Contributors: J. Levitt, J. O’Neill and A. Leuchter designed the study. J. Levitt, G. Kalender, J. O’Neill, J. Diaz, I. Cook, N. Ginder, D. Krantz, M. Minzenberg, N. Vince-Cruz, L. Nguyen and A. Leuchter acquired the data, which J. Levitt, G. Kalender J. O’Neill, M. Minzenberg, J. Alger and A. Leuchter analyzed. J. Levitt, J. O’Neill, J. Diaz, N. Ginder, D. Krantz, M. Minzenberg, N. Vince-Cruz, L. Nguyen, J. Alger and A. Leuchter wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/cjs.180230

Correspondence to: J. Levitt, 760 Westwood Plaza, Room 47-417c, Los Angeles, CA 90024; JLevitt@mednet.ucla.edu