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Emerging findings of glutamate–glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies

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Abstract

One of the main challenges in investigating the neurobiology of ADHD is our limited capacity to study its neurochemistry in vivo. Magnetic resonance spectroscopy (MRS) estimates metabolite concentrations within the brain, but approaches and findings have been heterogeneous. To assess differences in brain metabolites between patients with ADHD and healthy controls, we searched 12 databases screening for MRS studies. Studies were divided into ‘children and adolescents’ and ‘adults’ and meta-analyses were performed for each brain region with more than five studies. The quality of studies was assessed by the Newcastle–Ottawa Scale. Thirty-three studies met our eligibility criteria, including 874 patients with ADHD. Primary analyses revealed that the right medial frontal area of children with ADHD presented higher concentrations of a composite of glutamate and glutamine (p = 0.02, SMD = 0.53). Glutamate might be implicated in pruning and neurodegenerative processes as an excitotoxin, while glutamine excess might signal a glutamate depletion that could hinder neurotrophic activity. Both neuro metabolites could be implicated in the differential cortical thinning observed in patients with ADHD across all ages. Notably, more homogeneous designs and reporting guidelines are the key factors to determine how suitable MRS is for research and, perhaps, for clinical psychiatry. Results of this meta-analysis provided an overall map of the brain regions evaluated so far, addressed the role of glutamatergic metabolites in the pathophysiology of ADHD, and pointed to new perspectives for consistent use of the tool in the field.

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Correspondence to Eugênio Horácio Grevet.

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Mr. Vidor is the recipient of a PhD scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES—PBE-DPM, Bolsa Especial para Doutorado em Pesquisa Médica). Mr. Martins is affiliated to private companies related to clinical imaging services. Luis Augusto Rohde has received honoraria, has been on the speakers’ bureau/advisory board, and/or has acted as a consultant for Medice, Novartis/Sandoz, and Shire/Takeda in the last two years; and receives authorship royalties from OxfordPress and ArtMed. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him has received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Janssen-Cilag, Novartis/Sandoz, and Shire/Takeda. Eugênio Horácio Grevet has served as a speakers’ bureau/advisory board for Shire Pharmaceuticals in the past 3 years; and has received travel awards from Shire for taking part in psychiatric meetings. Ms. Panzenhagen, Dr. Cupertino, Ms. Bandeira, Dr. Picon, Dr. Silva, Dr. Vitola, Dr. Rovaris, and Dr. Bau reported no biomedical financial interests or potential conflicts of interest.

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Vidor, M.V., Panzenhagen, A.C., Martins, A.R. et al. Emerging findings of glutamate–glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: systematic review and meta-analysis of spectroscopy studies. Eur Arch Psychiatry Clin Neurosci 272, 1395–1411 (2022). https://doi.org/10.1007/s00406-022-01397-6

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