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Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression

  • Milak, Matthew S.1, 2
  • Rashid, Rain1, 2
  • Dong, Zhengchao1, 2
  • Kegeles, Lawrence S.1, 2, 3
  • Grunebaum, Michael F.1, 2
  • Ogden, R. Todd2, 4
  • Lin, Xuejing2, 4
  • Mulhern, Stephanie T.1, 2
  • Suckow, Raymond F.1, 2, 5
  • Cooper, Thomas B.1, 2, 5
  • Keilp, John G.1, 2
  • Mao, Xiangling6
  • Shungu, Dikoma C.6
  • Mann, J. John1, 2, 3
  • 1 Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York
  • 2 Molecular Imaging and Neuropathology Division, The New York State Psychiatric Institute, New York
  • 3 Department of Radiology, College of Physicians and Surgeons, Columbia University, New York, New York
  • 4 Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York
  • 5 Analytical Psychopharmacology Laboratory, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York
  • 6 Department of Radiology, Weill Cornell Medicine, New York, New York
Published Article
JAMA Network Open
American Medical Association
Publication Date
Aug 12, 2020
DOI: 10.1001/jamanetworkopen.2020.13211
PMID: 32785636
PMCID: PMC7424409
PubMed Central
  • Psychiatry
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Importance A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication–free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose ( t 36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level ( t 36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response ( t 33 = −2.400; P = .02; slope estimate, −9.85 [95% CI, −18.2 to −1.50]). Although GABA levels correlated with Glx ( t 33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only ( t 5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. Conclusions and Relevance In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration Identifier: NCT01558063

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