Altered anterior cingulate glutamatergic metabolism in depressed adolescents with current suicidal ideation

Charles P. Lewis, John D. Port, Caren J. Blacker, A. Irem Sonmez, Bhedita J. Seewoo, Jarrod M. Leffler, Mark A. Frye, Paul E. Croarkin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI−, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI− and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI− participants (padj = 0.012) and had lower NAA/Glx than both Dep/SI− (padj = 0.002) and HC adolescents (padj = 0.039). There were significant relationships between SI intensity and Glx (pFDR = 0.026), SI severity and NAA/Glx (pFDR = 0.012), and SI intensity and NAA/Glx (pFDR = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI− from Dep/SI+ participants. Uncoupled NAA−glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

Original languageEnglish (US)
Article number119
JournalTranslational psychiatry
Issue number1
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
C.P.L. receives grant support from the Brain & Behavior Research Foundation as the Alan G. Ross Memorial Investigator. He has been a site investigator for multicenter trials funded by Neuronetics, Inc. and NeoSync, Inc. J.D.P. serves as an imaging consultant for Takeda Pharmaceutical Company, Ltd., Biomedical Systems Corp., and Neuronetics, Inc. C.J.B. receives research support from the Mayo Foundation for Medical Education and Research Departmental Small Grant Program. M.A.F. has received grant support from Assurex Health, Inc., the Mayo Foundation for Medical Education and Research, and Medibio, Ltd.; has served as a paid consultant for Actify Neurotherapies, Allergan plc, IntraCellular Therapies, Inc., Janssen Pharmaceuticals, Inc., Myriad Genetics, Inc., Neuralstem, Inc., Takeda Pharmaceutical Company, Ltd., and Teva Pharmaceutical Industries, Ltd.; and has received honoraria or travel support from American Physician Institute, CME Outfitters, LLC, and Global Academy for Medical Education, LLC. P.E.C. has received research grant support from the National Institute of Mental Health and Pfizer, Inc.; equipment support from Neuronetics, Inc.; and has received supplies and genotyping services from Assurex Health, Inc. for investigator-initiated studies. He is the primary investigator for a multicenter study funded by Neuronetics, Inc. and a site primary investigator for a study funded by NeoSync, Inc., and he has served as a consultant for Procter & Gamble Company and Myriad Neuroscience. A.I.S., B. J.S., and J.M.L. have no financial relationships to disclose.

Funding Information:
This work was supported by grants from the Brain & Behavior Research Foundation (C.P.L., 2018 NARSAD Young Investigator Grant 27488, Alan G. Ross Memorial Investigator) and the National Institute of Mental Health (P.E.C., K23 MH100266 and R01 MH113700). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2020, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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