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Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial.

ABSTRACT: Importance:A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective:To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and ?-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants:This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention:Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures:Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results:A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36?=?2.81; P?=?.008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36?=?2.25; P?=?.03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33?=?-2.400; P?=?.02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33?=?8.117; P?

SUBMITTER: Milak MS

PROVIDER: S-EPMC7424409 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial.

Milak Matthew S MS Rashid Rain R Dong Zhengchao Z Kegeles Lawrence S LS Grunebaum Michael F MF Ogden R Todd RT Lin Xuejing X Mulhern Stephanie T ST Suckow Raymond F RF Cooper Thomas B TB Keilp John G JG Mao Xiangling X Shungu Dikoma C DC Mann J John JJ

JAMA network open 20200803 8

<h4>Importance</h4>A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain.<h4>Objective</h4>To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects.<h4>Design, setting, and participants</h4>This randomized, parallel-group, tr ...[more]

PMID: 32785636

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Project description:Balance between inhibitory and excitatory neurotransmitter systems and the protective role of the major antioxidant glutathione (GSH) are central to early healthy brain development. Disruption has been implicated in the early life pathophysiology of psychiatric disorders and neurodevelopmental conditions including Autism Spectrum Disorder. Edited magnetic resonance spectroscopy (MRS) methods such as HERMES have great potential for providing important new non-invasive insights into these crucial processes in human infancy. In this work, we describe a systematic approach to minimise the impact of specific technical challenges inherent to acquiring MRS data in a neonatal population, including automatic segmentation, full tissue-correction and optimised GABA+ fitting and consider the minimum requirements for a robust edited-MRS acquisition. With this approach we report for the first time simultaneous GABA+, Glx (glutamate + glutamine) and GSH concentrations in the neonatal brain (n = 18) in two distinct regions (thalamus and anterior cingulate cortex (ACC)) using edited MRS at 3T. The improved sensitivity provided by our method allows specific regional neurochemical differences to be identified including: significantly lower Glx and GSH ratios to total creatine in the thalamus compared to the ACC (p < 0.001 for both), and significantly higher GSH levels in the ACC following tissue-correction (p < 0.01). Furthermore, in contrast to adult GABA+ which can typically be accurately fitted with a single peak, all neonate spectra displayed a characteristic doublet GABA+ peak at 3 ppm, indicating a lower macromolecule (MM) contribution to the 3 ppm signal in neonates. Relatively high group-level variance shows the need to maximise voxel size/acquisition time in edited neonatal MRS acquisitions for robust estimation of metabolites. Application of this method to study how these levels and balance are altered by early-life brain injury or genetic risk can provide important new knowledge about the pathophysiology underlying neurodevelopmental disorders.

Project description:IntroductionConverging evidence suggests that ketamine elicits antidepressant effects via enhanced neuroplasticity precipitated by a surge of glutamate and modulation of GABA. Magnetic resonance spectroscopic imaging (MRSI) illustrates changes to cerebral glutamate and GABA immediately following ketamine administration during dissociation. However, few studies assess subacute changes in the first hours following application, when ketamine's antidepressant effects emerge. Moreover, ketamine metabolites implicated in its antidepressant effects develop during this timeframe. Thus, this study aimed to investigate subacute changes in cerebral Glx (glutamate + glutamine), GABA and their ratio in seven brain regions central to depressive pathophysiology and treatment.MethodsTwenty-five healthy subjects underwent two multivoxel MRS scans using a spiral encoded, MEGA-edited LASER-localized 3D-MRSI sequence, at baseline and 2 h following intravenous administration of racemic ketamine (0.8 mg/kg bodyweight over 50 min). Ketamine, norketamine and dehydronorketamine plasma levels were determined at routine intervals during and after infusion. Automated region-of-interest (ROI)-based quantification of mean metabolite concentration was used to assess changes in GABA+/total creatine (tCr), Glx/tCr, and GABA+/Glx ratios in the thalamus, hippocampus, insula, putamen, rostral anterior cingulate cortex (ACC), caudal ACC, and posterior cingulate cortex. Effects of ketamine on neurotransmitter levels and association with ketamine- and metabolite plasma levels were tested with repeated measures analyses of variance (rmANOVA) and correlation analyses, respectively.ResultsFor GABA+/tCr rmANOVA revealed a measurement by region interaction effect (puncorr < 0.001) and post hoc pairwise comparisons showed a reduction in hippocampal GABA+/tCr after ketamine (pcorr = 0.02). For Glx/tCr and GABA+/Glx neither main effects of measurement nor measurement by region interactions were observed (all puncorr > 0.05). Furthermore, no statistically significant associations between changes in any of the neurotransmitter ratios and plasma levels of ketamine, norketamine, or dehydronorketamine were observed (pcorr > 0.05).ConclusionThis study provides evidence for decreased hippocampal GABA+/tCr ratio 2 h following ketamine administration. As MRS methodology measures total levels of intra- and extracellular GABA, results might indicate drug induced alterations in GABA turnover. Our study in healthy humans suggests that changes in GABA levels, particularly in the hippocampus, should be further assessed for their relevance to ketamine´s antidepressant effects.

Project description:Medulloblastoma (MB) is the most common malignant brain tumor occurring in childhood and rarely found in adult. Based on transcriptome profile MB are currently classified into four major molecular groups reflecting a considerable biological heterogeneity: WNT-activated, SHH-activated, group 3 and group 4. Recently, DNA methylation profiling allowed the identification of additional subgroups within the four major molecular groups associated with different clinic-pathological and molecular features. Isocitrate Dehydrogenase-1 (IDH1) mutations have been described in several tumours, including gliomas, while in MB are exceptionally reported and not routinely investigated. By mean of magnetic resonance spectroscopy (MRS) we unequivocally assessed the presence the oncometabolite D-2-Hydroxyglutarate (2HG), a marker of IDH1 and IDH2 mutation, in a case of adult MB. Immunophenotypical work-up and methylation profiling assigned the diagnosis of MB, subclass SHH-A, and molecular testing revealed the presence of the non-canonical somatic IDH1(p.R132C) mutation and an additional GNAS mutation, also exceptionally described in MB. To our knowledge this is the first reported case of MB harboring both mutations together. Of note, tumour exhibited a heterogeneous phenotype with a tumour component displaying glial differentiation, with robust GFAP expression, and a component with conventional MB features and selective presence of GNAS mutation, suggesting coexistence of two different major tumour clones. These findings draw attention to the need of a deeper genetic characterization of MB in order to get insights into their biology and improve stratification and clinical management of the patients. Moreover, reported data underling the importance of performing MRS for the identification of IDH mutations in non-glial tumours. The use of throughput molecular profiling analysis and advanced medical imaging technology will certainly increase the frequency with which rare tumour entities will be identified. Whether they have any particular therapeutic implications or prognostic relevance requires further investigations.

Dataset Information

Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial.

Publications

Assessment of Relationship of Ketamine Dose With Magnetic Resonance Spectroscopy of Glx and GABA Responses in Adults With Major Depression: A Randomized Clinical Trial.

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