Neurometabolic abnormalities in the associative striatum in antipsychotic-naïve first episode psychosis patients

Sivaraman, Soumya; Kraguljac, Nina; White, David M.; Morgan, Charity; Gonzales, Sara S.; Lahti, Adrienne C.

doi:10.1016/j.pscychresns.2018.06.003

Cited by 12 publications

(3 citation statements)

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“…First, N-methyl-D-aspartate (NMDA) receptor hypofunction is thought to be a core feature of the pathophysiology [10][11][12][13][14] , possibly resulting in downstream dopaminergic dysfunction [15][16][17] . Second, several groups, including ours, have reported alterations in glutamatergic measures including glutamate, glutamine, and glutamine + glutamate (Glx) in schizophrenia [18][19][20][21][22][23][24] . Third, a growing body of evidence suggests that antipsychotic treatment may decrease glutamatergic metabolite levels 22,[25][26][27][28][29][30] , but also see a recent study by our group that did not find changes in glutamatergic metabolites in the anterior cingulate cortex and hippocampus after 6 weeks of antipsychotic treatment in patients with schizophrenia 31 .…”

Section: Introductionmentioning

confidence: 99%

Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients

et al. 2020

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Antipsychotic medications are the cornerstone of treatment in schizophrenia spectrum disorders. In first-episode psychosis, the recommended time for an antipsychotic medication trial is up to 16 weeks, but the biological correlates of shorter and longer antipsychotic treatment trials in these cohorts remain largely unknown. We enrolled 29 medication-naive first-episode patients (FEP) and 22 matched healthy controls (HC) in this magnetic resonance spectroscopy (MRS) study, examining the levels of combined glutamate and glutamine (commonly referred to as Glx) in the bilateral medial prefrontal cortex (MPFC) with a PRESS sequence (TR/TE = 2000/80 ms) before initiation of antipsychotic treatment, after 6 and 16 weeks of treatment with risperidone. Data were quantified in 18 HC and 20 FEP at baseline, for 19 HC and 15 FEP at week 6, and for 14 HC and 16 FEP at week 16. At baseline, none of the metabolites differed between groups. Metabolite levels did not change after 6 or 16 weeks of treatment in patients. Our data suggest that metabolite levels do not change after 6 or 16 weeks of treatment with risperidone in FEP. It is possible that our choice of sequence parameters and the limited sample size contributed to negative findings reported here. On the other hand, longer follow-up may be needed to detect treatment-related metabolic changes with MRS. In summary, our study adds to the efforts in better understanding glutamatergic neurometabolism in schizophrenia, especially as it relates to antipsychotic exposure.

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Section: Introductionmentioning

confidence: 99%

Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients

et al. 2020

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“…In magnetic resonance spectroscopy studies, we found elevated choline and a disruption of the relationship between NAA and glutamate in the left striatum, indicating possible mitochondrial, membrane, and glial dysfunction (72). However, we reported no neurometabolite abnormalities in the medial prefrontal cortex or the hippocampus when contrasting antipsychotic medication-naïve first episode patients and controls in the overall group (31, 69).…”

Section: Can Neuroimaging Data Aid In Predicting Subsequent Clinical mentioning

confidence: 78%

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

Kraguljac

Lahti

2021

Front. Psychiatry

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Schizophrenia is a complex neuropsychiatric disorder with a diverse clinical phenotype that has a substantial personal and public health burden. To advance the mechanistic understanding of the illness, neuroimaging can be utilized to capture different aspects of brain pathology in vivo, including brain structural integrity deficits, functional dysconnectivity, and altered neurotransmitter systems. In this review, we consider a number of key scientific questions relevant in the context of neuroimaging studies aimed at unraveling the pathophysiology of schizophrenia and take the opportunity to reflect on our progress toward advancing the mechanistic understanding of the illness. Our data is congruent with the idea that the brain is fundamentally affected in the illness, where widespread structural gray and white matter involvement, functionally abnormal cortical and subcortical information processing, and neurometabolic dysregulation are present in patients. Importantly, certain brain circuits appear preferentially affected and subtle abnormalities are already evident in first episode psychosis patients. We also demonstrated that brain circuitry alterations are clinically relevant by showing that these pathological signatures can be leveraged for predicting subsequent response to antipsychotic treatment. Interestingly, dopamine D2 receptor blockers alleviate neural abnormalities to some extent. Taken together, it is highly unlikely that the pathogenesis of schizophrenia is uniform, it is more plausible that there may be multiple different etiologies that converge to the behavioral phenotype of schizophrenia. Our data underscore that mechanistically oriented neuroimaging studies must take non-specific factors such as antipsychotic drug exposure or illness chronicity into consideration when interpreting disease signatures, as a clear characterization of primary pathophysiological processes is an imperative prerequisite for rational drug development and for alleviating disease burden in our patients.

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“…In schizophrenia, hippocampal Glx/NAA was increased compared to healthy adults 83 . Significant positive correlations between Glx and NAA concentrations were present in healthy controls but not in schizophrenic patients in the hippocampus 83,85 right DLPFC 86 , and left striatum 87 , suggesting that the usually linked metabolism of NAA and glutamate becomes uncoupled in these regions in the disease state. Similarly, right hippocampal Glu/NAA was elevated in posttraumatic stress disorder (PTSD) patients compared to trauma-exposed controls, which correlated with reexperiencing symptoms and trauma load in patients 88 .…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2020

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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 (1 H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluidcorrected 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.

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Neurometabolic abnormalities in the associative striatum in antipsychotic-naïve first episode psychosis patients

Cited by 12 publications

References 59 publications

Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients

Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

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

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