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Glutamatergic Correlates of Bipolar Symptoms in Adolescents.

ABSTRACT: 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.

SUBMITTER: Sonmez AI

PROVIDER: S-EPMC7757593 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents. Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs). Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

Project description:Objectives: Bipolar disorder (BD) is a debilitating illness that often starts at an early age. Prevention of first and subsequent mood episodes, which are usually preceded by a period characterized by subthreshold symptoms is important. We compared demographic and clinical characteristics including severity and duration of subsyndromal symptoms across adolescents with three different bipolar-spectrum disorders. Methods: Syndromal and subsyndromal psychopathology were assessed in adolescent inpatients (age = 12-18 years) with a clinical mood disorder diagnosis. Assessments included the validated Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P). We compared phenomenology across patients with a research consensus conference-confirmed DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnoses of BD-I, BD-not otherwise specified (NOS), or mood disorder (MD) NOS. Results: Seventy-six adolescents (age = 15.6 ± 1.4 years, females = 59.2%) were included (BD-I = 24; BD-NOS = 29; MD-NOS = 23) in this study. Median baseline global assessment of functioning scale score was 21 (interquartile range = 17-40; between-group p = 0.31). Comorbidity was frequent, and similar across groups, including disruptive behavior disorders (55.5%, p = 0.27), anxiety disorders (40.8%, p = 0.98), and personality disorder traits (25.0%, p = 0.21). Mania symptoms (most frequent: irritability = 93.4%, p = 0.82) and depressive symptoms (most frequent: depressed mood = 81.6%, p = 0.14) were common in all three BD-spectrum groups. Manic and depressive symptoms were more severe in both BD-I and BD-NOS versus MD-NOS (p < 0.0001). Median duration of subthreshold manic symptoms was shorter in MD-NOS versus BD-NOS (11.7 vs. 20.4 weeks, p = 0.002) and substantial in both groups. The most used psychotropics upon discharge were antipsychotics (65.8%; BD-I = 79.2%; BD-NOS = 62.1%; MD-NOS = 56.5%, p = 0.227), followed by mood stabilizers (43.4%; BD-I = 66.7%; BD-NOS = 31.0%; MD-NOS = 34.8%, p = 0.02) and antidepressants (19.7%; BD-I = 20.8%; BD-NOS = 10.3%; MD-NOS = 30.4%). Conclusions: Youth with BD-I, BD-NOS, and MD-NOS experience considerable symptomatology and are functionally impaired, with few differences observed in psychiatric comorbidity and clinical severity. Moreover, youth with BD-NOS and MD-NOS undergo a period with subthreshold manic symptoms, enabling identification and, possibly, preventive intervention of those at risk for developing BD or other affective episodes requiring hospitalization.

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Glutamatergic Correlates of Bipolar Symptoms in Adolescents.

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