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Candidates for Drug Repurposing to Address the Cognitive Symptoms in Schizophrenia
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). NORMENT, Centre for Mental Disorders Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.ORCID iD: 0000-0003-3727-4470
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.ORCID iD: 0000-0003-4908-341X
Department of Radiology and Center for Multimodal Imaging and Genetics, University of California San Diego, USA.
2023 (English)In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 20, article id 110637Article in journal (Refereed) Published
Abstract [en]

In the protein-protein interactome, we have previously identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance. Here, we further studied this overlap to identify potential candidate drugs for repurposing to treat the cognitive symptoms in schizophrenia. We first defined a cognition-related schizophrenia interactome from network propagation analyses, and identified drugs known to target more than one protein within this network. Thereafter, we used gene expression data to further select drugs that could counteract schizophrenia-associated gene expression perturbations. Additionally, we stratified these analyses by sex to identify sex-specific pharmacological treatment options for the cognitive symptoms in schizophrenia. After excluding drugs contraindicated in schizophrenia, we identified 12 drug repurposing candidates, most of which have anti-inflammatory and neuroprotective effects. Sex-stratified analyses showed that out of these 12 drugs, four were identified in females only, three were identified in males only, and five were identified in both sexes. Based on our bioinformatics analyses of disease genetics, we suggest 12 candidate drugs that warrant further examination for repurposing to treat the cognitive symptoms in schizophrenia, and suggest that these symptoms could be addressed by sex-specific pharmacological treatment options.

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 20, article id 110637
Keywords [en]
Cognition, Genetics, Network medicine, Protein-protein interactome, Schizophrenia, Sex differences
National Category
Medical Genetics and Genomics
Identifiers
URN: urn:nbn:se:umu:diva-193658DOI: 10.1016/j.pnpbp.2022.110637ISI: 000885857500001PubMedID: 36099967Scopus ID: 2-s2.0-85139721645OAI: oai:DiVA.org:umu-193658DiVA, id: diva2:1651020
Funder
NIH (National Institutes of Health), R56AG061163NIH (National Institutes of Health), R01MH118281Swedish Research Council, 2017-03011
Note

Originally included in thesis in manuscript form. 

Available from: 2022-04-10 Created: 2022-04-10 Last updated: 2025-02-10Bibliographically approved
In thesis
1. The genetics of schizophrenia: sex, drugs, and cognition
Open this publication in new window or tab >>The genetics of schizophrenia: sex, drugs, and cognition
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Genetiken bakom de kognitiva symtomen i schizofreni
Abstract [en]

Cognitive impairment constitutes an important predictor of general functional outcomes in schizophrenia. Polygenic risk for schizophrenia has been linked to cognitive ability as well as brain activation during cognitive processing. Although sex differences have long been observed in schizophrenia patients, it is not known if genetic effects on cognitive phenotypes differ between males and females. Despite attempts to develop drugs that address the cognitive symptoms in schizophrenia or to investigate existing drugs with potential procognitive effects, there are currently no available medications that efficiently treat these symptoms in schizophrenia. The aim of this PhD project was to explore the genetic underpinnings of cognitive symptoms in schizophrenia, and to identify existing drugs that potentially could be used for repurposing to address these symptoms. We identified male-specific effects of polygenic risk for schizophrenia on lifespan cognitive functioning as well as brain activation during cognitive processing. Within gene networks, we identified a significant overlap between schizophrenia risk genes and genes associated with cognitive performance, and identified novel schizophrenia risk genes that are related to cognitive functioning. Utilizing gene networks incorporating gene expression data, we identified eight existing drugs that could potentially be used for repurposing to address the cognitive symptoms in schizophrenia, most of which have anti-inflammatory and neuroprotective effects. Using sex-specific gene expression data, we identified different repurposing candidates for male and female schizophrenia patients. In conclusion, the findings of this PhD project indicate that the effects of schizophrenia genetics on cognitive functioning are dependent on biological processes that differ between the sexes, and suggest that the cognitive symptoms in schizophrenia should be addressed by sex-specific pharmacological treatments.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2022. p. 65
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2185
Keywords
schizophrenia, genetics, cognition, sex differences, polygenic risk, fMRI, network medicine, drug repurposing, precision medicine
National Category
Medical Genetics and Genomics Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-193660 (URN)978-91-7855-755-4 (ISBN)978-91-7855-756-1 (ISBN)
Public defence
2022-05-06, KBE303, stora hörsalen, KBC-huset, Umeå, 13:00 (English)
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Uppgift om nummer i serie saknas i publikationen.

Available from: 2022-04-14 Created: 2022-04-10 Last updated: 2025-02-10Bibliographically approved

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Koch, EliseKauppi, Karolina

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