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A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder

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Abstract

The N-methyl-D-aspartate receptor antagonist ketamine can improve major depressive disorder (MDD) within hours. To evaluate the putative role of glutamatergic and GABAergic systems in ketamine’s antidepressant action, medial prefrontal cortical (mPFC) levels of glutamate+glutamine (Glx) and γ-aminobutyric acid (GABA) were measured before, during, and after ketamine administration using proton magnetic resonance spectroscopy. Ketamine (0.5 mg kg−1 intravenously) was administered to 11 depressed patients with MDD. Glx and GABA mPFC responses were measured as ratios relative to unsuppressed voxel tissue water (W) successfully in 8/11 patients. Ten of 11 patients remitted (50% reduction in 24-item Hamilton Depression Rating Scale and total score 10) within 230 min of commencing ketamine. mPFC Glx/W and GABA/W peaked at 37.8%±7.5% and 38.0%±9.1% above baseline in ~26 min. Mean areas under the curve for Glx/W (P=0.025) and GABA/W (P=0.005) increased and correlated (r=0.796; P=0.018). Clinical improvement correlated with 90-min norketamine concentration (df=6, r=−0.78, P=0.023), but no other measures.

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Acknowledgements

This work was supported by a Brain and Behavior Research Foundation NARSAD Distinguished Investigator Award to Dr Mann and NIMH grants R01 MH-075895 to Dr Shungu and R01 MH-093637 to Dr Milak.

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Dr Milak, Ms Proper, Ms Mulhern, Ms Parter, Dr Ogden, Dr Keilp, Ms Mao, Mr Cooper, Dr Shungu, Dr Rodriguez and Dr Suckow reported no biomedical financial interests or potential conflicts of interest. Dr Kegeles has received research grants from Pfizer and Amgen. Dr Oquendo receives royalties for use of the Columbia Suicide Severity Rating Scale and received financial compensation from Pfizer for the safety evaluation of a clinical facility, unrelated to this study. She has received unrestricted educational grants and/or lecture fees from Astra-Zeneca, Bristol Myers Squibb, Eli Lilly, Janssen, Otsuko, Pfizer, Sanofi-Aventis and Shire. Her family owns stock in Bristol Myers Squibb. Dr Mann received prior unrelated grants from Novartis and GSK and receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Health.

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Milak, M., Proper, C., Mulhern, S. et al. A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder. Mol Psychiatry 21, 320–327 (2016). https://doi.org/10.1038/mp.2015.83

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