Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial
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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 (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 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 (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 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 (t5 = 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: ClinicalTrials.gov Identifier: NCT01558063.
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Altered expression of NMDA, AMPA, and kainite glutamate receptors is linked to suicidal behavior and may play a role in the rapid-onset antidepressant and antisuicidal effects of ketamine.
“Altered expression of glutamate receptor N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainite glutamate receptors is linked to suicidal behavior (129) and may play a role in the rapid-onset antidepressant and antisuicidal effects of ketamine (130-135).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [135]
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- Authors
- Milak, M. S., Rashid, R., Dong, Z., Kegeles, L. S., Grunebaum, M. F., Ogden, R. T., Lin, X., Mulhern, S. T., Suckow, R. F., Cooper, T. B., Keilp, J. G., Mao, X., Shungu, D. C., & Mann, J. J.
- Affiliations
- New York State Psychiatric Institute (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Mann, J. John
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2020-08-12
- Volume
- 3
- Issue
- 8
- Pages
- e2013211
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC7424409
- OpenAlex
- W3048755251
- Cited by
- 63
- References
- 70
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 10 · 2023: 7 · 2022: 13 · 2021: 13 · 2020: 1
- FWCI
- 5.09
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (5R01MH093637, R01MH075895)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- ketamine, major depressive disorder, antidepressant response, ketamine dose, glutamate, glutamine, GABA, 1H NMR, ventromedial prefrontal cortex, ketamine metabolites, ketamine side effects, depression biomarkers
- MeSH terms
- Adult, Antidepressive Agents, Major Depressive Disorder, Depressive Disorder, Major, Female, gamma-Aminobutyric Acid, Humans, Ketamine, Magnetic Resonance Imaging, Male, Middle Aged, Prefrontal Cortex, Glutamic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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