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Cited by 12Attention Deficit Hyperactivity DisorderPharmacogenetics and Drug MetabolismNeurotransmitter Receptor Influence on Behavior

Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response

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da Silva, Bruna S., Leffa, Douglas T., Beys-da-Silva, Walter O., Torres, Iraci L. S., Rovaris, Diego L., Victor, Marcelo M., Rohde, Luis A., Mota, Nina R. +10 more·2019·Translational Psychiatry
DOI 10.1038/s41398-019-0649-5PMC PMC6861257
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Abstract

Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < −1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.

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  • Several biological pathways have been suggested to potentially affect MPH mechanisms through patient genotype, mostly concerning monoamine pathways.

    “several biological pathways have been suggested to potentially affect MPH mechanisms through patient genotype, mostly concerning monoamine pathways [43–48].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [43]

    The Discussion (page unavailable) suggests that genetic variants in neurotransmitter-release and GABA-transmission pathways could affect MPH treatment response. The Introduction identifies dopamine and norepinephrine transporters as MPH’s main direct targets, but the paper does not establish that genotype-related pathways are mostly monoamine pathways; its Discussion emphasizes effects beyond dopamine and norepinephrine. (LLM, conf=0.84)

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Authors
da Silva, B. S., Leffa, D. T., Beys-da-Silva, W. O., Torres, I. L. S., Rovaris, D. L., Victor, M. M., Rohde, L. A., Mota, N. R., Oliveira, C. D., Berger, M., Yates, J. R., Sabnis, R., Peña, R. D., Campos, A. R., Grevet, E. H., Santi, L., Bau, C. H. D., & Contini, V.
Affiliations
  • Universidade Federal do Rio Grande do Sul (BR)
  • Hospital de Clínicas de Porto Alegre (BR)
  • Radboud University Nijmegen (NL)
  • Scripps Research Institute (US)
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Univates (BR)
Corresponding author
Bau, Claiton H. D.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-11-18
Volume
9
Issue
1
Pages
308-308
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-019-0649-5
PMC
PMC6861257
OpenAlex
W2985827412
Cited by
12
References
57
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Americanae (AECID Library) (publishedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Lume (Universidade Federal do Rio Grande do Sul) (submittedVersion, cc-by-nc-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (466722/2014-1, 476529/2012-3, 2014-1, /2014-9)
  • Hospital de Clínicas de Porto Alegre (FIPE-HCPA 100358, 08543)
  • Fundação Instituto de Pesquisas Econômicas
  • National Institutes of Health (2014-2020, H2020, CA030199, GM103533)
  • Horizon 2020 Framework Programme (H2020/2014–2020, 667302)
  • National Institute of Mental Health (MH067880, R01MH067880, NIMH 5 R01)
  • National Cancer Institute (P30CA030199)
  • National Institute of General Medical Sciences (P41GM103533)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
methylphenidate, attention deficit hyperactivity disorder, pharmacogenomics, proteomic profiling, treatment response variability, differentially expressed proteins, synaptic transmission, neurotransmitter release, GABA transmission, oxidative stress, cellular respiration, cerebral cortex, Wistar-Kyoto rats
MeSH terms
Adult, Central Nervous System Stimulants, Animals, Attention Deficit Disorder with Hyperactivity, Female, Humans, Male, Methylphenidate, Pharmacogenetics, Random Allocation, Rats, Inbred WKY, Proteomics, Rats

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