Glutamatergic Correlates of Bipolar Symptoms in Adolescents

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Objectives: Prior studies demonstrate elevated cortical glutamate (Glu) in patients with bipolar disorder (BD). Studies assessing neurochemistry in early stages of bipolar illness before the emergence of manic symptoms are lacking. This study aimed to examine neurochemical correlates measured by proton magnetic resonance spectroscopy (1H-MRS) and a dimensional measure of bipolarity in a sample of depressed adolescents. Methods: Adolescent participants (aged 13-21 years) underwent a semistructured diagnostic interview and clinical assessment, which included the General Behavior Inventory Parent Version (P-GBI), a 73-item, parent-rated assessment of symptoms and behaviors. 1H-MRS scans of a left dorsolateral prefrontal cortex (L-DLPFC) voxel (8 cm3) were collected using a two-dimensional J-averaged sequence to assess N-acetylaspartate (NAA), Glu, Glx (glutamate + glutamine), and NAA/Glx concentrations. We used generalized linear models to assess the relationships between P-GBI scores and metabolite levels in L-DLPFC. Results: Thirty-six participants (17 healthy controls, 19 depressed) underwent 1H-MRS scans and clinical evaluation with the P-GBI. There was a significant negative relationship between P-GBI score and L-DLPFC NAA/Glx in the whole sample. However, the magnitude of the effect was small and statistical significance was lost after correcting for multiple comparisons. Conclusions: These preliminary results suggest that NAA/Glx may have utility as a marker of bipolar traits in healthy and depressed adolescents. If replicated, 1H-MRS measures of glutamatergic metabolism anomalies might have a role in identifying depressed adolescents at risk for mixed symptom presentations or BD. Identifying bipolarity in the early stages of the disease would have a significant impact on treatment planning and prognosis. Further longitudinal studies should examine neurochemical correlates of mood state during the developmental emergence of BD.

Original languageEnglish (US)
Pages (from-to)599-605
Number of pages7
JournalJournal of child and adolescent psychopharmacology
Issue number10
StatePublished - Dec 2020

Bibliographical note

Funding Information:
Funding: This work was supported by grants from the Brain and Behavior Research Foundation (C.P.L., 2018 National Alliance for Research on Schizophrenia and Depression Young Investigator Grant 27488, Alan G. Ross Memorial Investigator) and the National Institute of Mental Health (P.E.C., K23 MH100266 and R01 MH113700).

Funding Information:
C.P.L. receives grant support from the Brain and Behavior Research Foundation as the Alan G. Ross Memorial Investigator. He has been a site investigator for multicenter trials funded by Neu-ronetics, Inc. and NeoSync, Inc. J.D.P. serves as an imaging consultant for Takeda Pharmaceutical Company, Ltd. and Bioclinica. The other consulting activities have ended. M.A.F. has received grant support from Assurex Health, Inc., the Mayo Foundation for Medical Education and Research, and Medibio, Ltd. He 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. He 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. He has received 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. He has served as a paid consultant for Procter & Gamble Company and Myriad Neuroscience. A.I.S., A.C.-A., C.J.B., B.J.S., A.J.M., and J.M.L. have no financial relationships to disclose.

Publisher Copyright:
© Mary Ann Liebert, Inc. 2020.


  • H-MRS
  • NAA
  • adolescent
  • bipolar disorder
  • glutamate


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