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

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

doi:10.1038/s41398-020-0792-z

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.

Highlights

Suicide and suicide attempts have increased among adolescents and young adults during the past two decades[1,2,3]
Comparing the two depressed groups, Dep/suicidal ideation (SI)− and Dep/SI+ adolescents did not differ in the proportions of participants who had family histories of psychiatric illness, mood disorders, or attempted or completed suicide (Fisher’s exact tests, p > 0.99, p = 0.458, p = 0.414, respectively)
Dep/SI− and Dep/SI+ groups did not differ in number of depressive episodes (t = −0.640, p = 0.529), current episode duration (t = −1.643, p = 0.127), Table 1 Demographic and clinical characteristics by group

Summary

Introduction

Suicide and suicide attempts have increased among adolescents and young adults during the past two decades[1,2,3]. Suicide is the second leading cause of death in young people[1,4]. Suicidal behavior accounts for a substantial and increasing proportion of pediatric hospital visits[5]. The broad spectrum of suicidal thoughts and behaviors is remarkably common in youth; large epidemiological surveys of adolescents[6,7] estimate high prevalence of suicidal ideation (SI; 12.1–17.7%), planning (4.0–14.6%), and attempts (4.1–8.6%). Adolescence represents a critical time in the development of suicidal behavior. Childhood and adolescent suicidality predict suicidal behavior and attempts later in life[9].

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