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

doi:10.1038/s41398-020-0792-z

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

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

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 (p_adj = 0.012) and had lower NAA/Glx than both Dep/SI− (p_adj = 0.002) and HC adolescents (p_adj = 0.039). There were significant relationships between SI intensity and Glx (p_FDR = 0.026), SI severity and NAA/Glx (p_FDR = 0.012), and SI intensity and NAA/Glx (p_FDR = 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 language	English (US)
Article number	119
Journal	Translational psychiatry
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41398-020-0792-z
State	Published - Apr 23 2020

Bibliographical note

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.

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© 2020, The Author(s).

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title = "Altered anterior cingulate glutamatergic metabolism in depressed adolescents with current suicidal ideation",

abstract = "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.",

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

note = "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: {\textcopyright} 2020, The Author(s).",

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doi = "10.1038/s41398-020-0792-z",

language = "English (US)",

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AU - Port, John D.

AU - Blacker, Caren J.

AU - Sonmez, A. Irem

AU - Seewoo, Bhedita J.

AU - Leffler, Jarrod M.

AU - Frye, Mark A.

AU - Croarkin, Paul E.

N1 - 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).

PY - 2020/4/23

Y1 - 2020/4/23

N2 - 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.

AB - 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.

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

Abstract

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