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

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收录情况: ◇ SCIE ◇ 统计源期刊 ◇ CSCD-C ◇ 卓越:梯队期刊

机构: [1]Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191,China [2]National Clinical Research Center for Mental Disorders, Peking Uni‑versity Sixth Hospital, Beijing 100191, China [3]NHC Key Laboratory of MentalHealth and Research Unit of Diagnosis and Treatment of Mood CognitiveDisorder (2018RU006), Chinese Academy of Medical Sciences, Beijing 100191,China [4]Peking University Huilongguan Clinical Medical School, BeijingHuilongguan Hospital, Beijing 100096, China [5]Department of Psychiatry,Jining Medical University, Jining 272067, Shandong, China [6]Henan Key Labof Biological Psychiatry, The Second Afliated Hospital of Xinxiang Medi‑cal University, Xinxiang 435001, Henan, China [7]Key Laboratory of AnimalModels and Human Disease Mechanisms of the Chinese Academy of Sci‑ences and Yunnan Province, Kunming Institute of Zoology, Chinese Academyof Sciences, Kunming 650223, China [8]Institute of Psychiatry, Psychologyand Neuroscience, King’s College London, London WC2R 2LS, UK [9]State KeyLaboratory of Cognitive Neuroscience and Learning, Beijing Normal University,Beijing 100875, China [10]Analytic and Translational Genetics Unit, Massachu‑setts General Hospital, Boston, MA 02114, USA [11]Stanley Center for PsychiatricResearch, The Broad Institute of MIT and Harvard, Cambridge, MA 02141,USA [12]Department of Medicine, Harvard Medical School, Boston, MA 02115,USA [13]Department of Biostatistics and Computational Biology, School of Life Sciences, Fudan University, Shanghai 200438, China [14]Department of Neurol‑ogy, Xuanwu Hospital, Capital Medical University, Beijing 100053, China [15]State Key Laboratory of Natural and Biomimetic Drugs, Key Laboratoryfor Neuroscience for Ministry of Education, School of Pharmaceutical Sciences,Peking University Health Science Center, Beijing 100191, China [16]PKU‑IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871,China [17]Chinese Institute for Brain Research, Beijing 102206, China
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关键词: Schizophrenia Antipsychotic drug Treatment response Prediction model Genetics Epigenetics

摘要:
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.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, R2 for regression, and decision curve analysis.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), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507].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).

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出版当年[2022]版:
大类 | 1 区 医学
小类 | 1 区 医学:内科
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大类 | 2 区 医学
小类 | 2 区 医学:内科
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Q1 MEDICINE, GENERAL & INTERNAL
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Q1 MEDICINE, GENERAL & INTERNAL

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第一作者机构: [1]Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191,China [2]National Clinical Research Center for Mental Disorders, Peking Uni‑versity Sixth Hospital, Beijing 100191, China [3]NHC Key Laboratory of MentalHealth and Research Unit of Diagnosis and Treatment of Mood CognitiveDisorder (2018RU006), Chinese Academy of Medical Sciences, Beijing 100191,China
通讯作者:
通讯机构: [1]Institute of Mental Health, Peking University Sixth Hospital, Beijing 100191,China [2]National Clinical Research Center for Mental Disorders, Peking Uni‑versity Sixth Hospital, Beijing 100191, China [3]NHC Key Laboratory of MentalHealth and Research Unit of Diagnosis and Treatment of Mood CognitiveDisorder (2018RU006), Chinese Academy of Medical Sciences, Beijing 100191,China [16]PKU‑IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871,China [17]Chinese Institute for Brain Research, Beijing 102206, China
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