Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

Elevated prefrontal cortex GABA in patients with major depressive disorder after TMS treatment measured with proton magnetic resonance spectroscopy

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J Psychiatry Neurosci 2016;41(3):E37-E45

Marc J. Dubin, MD, PhD; Xiangling Mao, MS; Samprit Banerjee, PhD; Zachary Goodman, BS; Kyle A.B. Lapidus, MD; Guoxin Kang, PhD; Conor Liston, MD, PhD; Dikoma C. Shungu, PhD


Background: GABAergic and glutamatergic neurotransmitter systems are central to the pathophysiology of depression and are potential targets of repetitive transcranial magnetic stimulation (rTMS). We assessed the effect of 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) of patients with major depressive disorder on the levels of medial prefrontal cortex (MPFC) γ-aminobutyric acid (GABA) and the combined resonance of glutamate and glutamine (Glx) as assessed in vivo with proton magnetic resonance spectroscopy (1H MRS).

Methods: Currently depressed individuals between the ages of 23 and 68 years participated in a 5-week naturalistic, open-label treatment study of rTMS, with 1H MRS measurements of MPFC GABA and Glx levels at baseline and following 5 weeks of the rTMS intervention. We applied rTMS pulses over the left DLPFC at 10 Hz and 80%–120% of motor threshold for 25 daily sessions, with each session consisting of 3000 pulses. We assessed therapeutic response using the 24-item Hamilton Rating Scale for Depression (HAMD24). The GABA and Glx levels are expressed as ratios of peak areas relative to the area of the synchronously acquired and similarly fitted unsuppressed voxel water signal (W).

Results: Twenty-three currently depressed individuals (7 men) participated in the study. GABA/W in the MPFC increased 13.8% (p = 0.013) in all depressed individuals. There were no significant effects of rTMS on Glx/W. GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but not after TMS.

Limitations: The primary study limitations are the open-label design and the inclusion of participants currently taking stable regimens of antidepressant medications.

Conclusion: These results implicate GABAergic and glutamatergic systems in the mechanism of action of rTMS for major depression, warranting further investigation in larger samples.

Submitted June 13, 2015; Revised Oct. 1, 2015; Accepted Oct. 16, 2015; Early-released Feb. 23, 2016

Acknowledgements: The authors thank Rebecca Gordon and Jude Allen for technical assistance in administering transcranial magnetic stimulation and Rebecca Gordon for administering the Hamilton Rating Scales for Depression.

Affiliations: From the Department of Psychiatry, Weill Cornell Medical College, New York, USA (Dubin, Liston); the Brain and Mind Research Institute, Weill Cornell Medical College, New York, USA ( Dubin, Liston); the Department of Radiology, Weill Cornell Medical College, New York, USA (Mao, Kang, Shungu); the Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, USA (Banerjee); the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, USA (Lapidus); and the Johns Hopkins University, Baltimore, USA (Goodman).

Funding: Research reported in this publication was supported by the Office of the Director, National Institutes of Health under Award Number S10OD021782. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported by grants from the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia and Depression Young Investigator Award) to M. Dubin and by funds from the Department of Psychiatry at Weill Cornell Medical College. C. Liston was supported by grants from the National Institutes of Health (K99 MH097822) and the DeWitt Wallace Reader’s Digest Foundation at Weill Cornell. These sources of funding had no further role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Competing interests: M. Dubin reports receiving a materials transfer from Neuronetics, Inc to complete this study, but received no compensation from Neuronetics. K. Lapidus serves on the advisory board for Halo Neuro, Inc., has received devices from Medtronic and Brainsway, and consults for LCN Consulting, Inc. No other competing interests declared.

Contributors: M. Dubin and D. Shungu designed the study. M. Dubin, X. Mao, Z. Goodman and D. Shungu acquired the data, which M. Dubin, X. Mao, S. Banerjee, K. Lapidus, G. Kang, C. Liston and D. Shungu analyzed. M. Dubin, S. Banerjee, K. Lapidus, C. Liston and D. Shungu wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150223

Correspondence to: M. Dubin, Weill Cornell Medical College, 525 East 68th Street, Box 140, New York, NY 10065;