Emerging findings of glutamate–glutamine imbalance in the medial prefrontal cortex in attention deficit/hyperactivity disorder: Systematic review and meta-analysis of spectroscopy studies
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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Fronto-striatal dysfunction in ADHD may be a product of imbalanced glutamate/GABA-DA interactions.
“this suggests that fronto-striatal dysfunction in ADHD may be a product of imbalanced glutamate/GABA-DA interactions”
From ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives (2025) · cites this paper as [70]
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Succi nervorum: a brief history of neurochemistry
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Vidor, M. V., Panzenhagen, A. C., Martins, A. R., Cupertino, R. B., Bandeira, C. E., Rohde, L. A., Rovaris, D. L., Bau, C. H. D., & Grevet, E. H. (2021) · Trends in Psychiatry and Psychotherapy · doi:10.47626/2237-6089-2019-0111 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
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From neurons to brain networks, pharmacodynamics of stimulant medication for ADHD
Parlatini, V., Bellato, A., Murphy, D., & Cortese, S. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105841 · Cited by 26 · see citing works
ADHD in Adulthood: Clinical Presentation, Comorbidities, and Treatment Perspectives
Bogdańska-Chomczyk, E., Majewski, M. K., & Kozłowska, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211020 · Cited by 15 · see citing works
“Given that glutamate signaling is tightly coupled with and modulates DA release, this suggests that fronto-striatal dysfunction in ADHD may be a product of imbalanced glutamate/GABA-DA interactions [70].”
Lavigne-Cerván, R., Collado-Valero, J. A., Martínez-González, A. E., & Navarro-Soria, I. N.-S. (2026) · Revista de Psicología Clínica Con Niños y Adolescentes · doi:10.21134/rpcna.2026.13.1.2 · Cited by 1 · see citing works
- Authors
- Vidor, M. V., Panzenhagen, A. C., Martins, A. R., Cupertino, R. B., Bandeira, C. E., Picon, F. A., da Silva, B. S., Vitola, E. S., Rohde, L. A., Rovaris, D. L., Bau, C. H. D., & Grevet, E. H.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- University of Vermont (US)
- Hospital de Clínicas de Porto Alegre (BR)
- Universidade de São Paulo (BR)
- ORCID
- Venue
- European Archives of Psychiatry and Clinical Neuroscience
- Published
- 2022-03-24
- Volume
- 272
- Issue
- 8
- Pages
- 1395-1411
- ISSN
- 0003-9373 (ISSN-L)
- 0940-1334
- 1433-8491
- OpenAlex
- W4220745962
- Cited by
- 29
- References
- 103
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 6 · 2023: 3 · 2022: 3
- FWCI
- 0.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Archives of Psychiatry and Clinical Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- attention deficit hyperactivity disorder, medial prefrontal cortex, brain metabolites, magnetic resonance spectroscopy, glutamate, glutamine, cortical thinning, brain development, children and adolescents, adults
- MeSH terms
- Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Child, Glutamine, Humans, Magnetic Resonance Spectroscopy, Prefrontal Cortex, Glutamic Acid
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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