Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.

Autor: Guo LK; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Su Y; Peking University Huilongguan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, 100096, China., Zhang YY; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Yu H; Department of Psychiatry, Jining Medical University, Jining, 272067, Shandong, China., Lu Z; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Li WQ; Henan Key Lab of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 435001, Henan, China., Yang YF; Henan Key Lab of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 435001, Henan, China., Xiao X; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China., Yan H; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Lu TL; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Li J; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Liao YD; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Kang ZW; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Wang LF; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China., Li Y; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, WC2R 2LS, UK., Li M; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China., Liu B; State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, 100875, China., Huang HL; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.; Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA., Lv LX; Henan Key Lab of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 435001, Henan, China., Yao Y; Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai, 200438, China., Tan YL; Peking University Huilongguan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, 100096, China., Breen G; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, WC2R 2LS, UK., Everall I; Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, WC2R 2LS, UK., Wang HX; Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China., Huang Z; State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratory for Neuroscience for Ministry of Education, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China. huangz@hsc.pku.edu.cn., Zhang D; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China. daizhang@bjmu.edu.cn.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China. daizhang@bjmu.edu.cn.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China. daizhang@bjmu.edu.cn.; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China. daizhang@bjmu.edu.cn., Yue WH; Institute of Mental Health, Peking University Sixth Hospital, Beijing, 100191, China. dryue@bjmu.edu.cn.; National Clinical Research Center for Mental Disorders, Peking University Sixth Hospital, Beijing, 100191, China. dryue@bjmu.edu.cn.; NHC Key Laboratory of Mental Health and Research Unit of Diagnosis and Treatment of Mood Cognitive Disorder (2018RU006), Chinese Academy of Medical Sciences, Beijing, 100191, China. dryue@bjmu.edu.cn.; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China. dryue@bjmu.edu.cn.; Chinese Institute for Brain Research, Beijing, 102206, China. dryue@bjmu.edu.cn.
Jazyk: angličtina
Zdroj: Military Medical Research [Mil Med Res] 2023 Jun 02; Vol. 10 (1), pp. 24. Date of Electronic Publication: 2023 Jun 02.
DOI: 10.1186/s40779-023-00459-7
Abstrakt: Background: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment.
Methods: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R 2 for regression, and decision curve analysis.
Results: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R 2  = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R 2  = 0.507].
Conclusions: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).
(© 2023. The Author(s).)
Databáze: MEDLINE
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