Refining antipsychotic treatment strategies in schizophrenia: discovery of genetic biomarkers for enhanced drug response prediction

Luan Chen; Cong Huai; Chuanfu Song; Shaochang Wu; Yong Xu; Zhenghui Yi; Jinsong Tang; Lingzi Fan; Xuming Wu; Zhenhua Ge; Chuanxin Liu; Deguo Jiang; Saizheng Weng; Guoqiang Wang; Xinfeng Zhang; Xudong Zhao; Lu Shen; Na Zhang; Hao Wu; Yongzhi Wang; Zhenglin Guo; Suli Zhang; Bixuan Jiang; Wei Zhou; Jingsong Ma; Mo Li; Yunpeng Chu; Chenxi Zhou; Qinyu Lv; Qingqing Xu; Wenli Zhu; Yan Zhang; Weibin Lian; Sha Liu; Xinrong Li; Songyin Gao; Aihong Liu; Lei He; Zhenzhen Yang; Bojian Dai; Jiaen Ye; Ruiqian Lin; Yana Lu; Qi Yan; Yalan Hu; Qinghe Xing; Hailiang Huang; Shengying Qin

doi:10.1038/s41380-024-02841-w

Refining antipsychotic treatment strategies in schizophrenia: discovery of genetic biomarkers for enhanced drug response prediction

Mol Psychiatry. 2024 Nov 19. doi: 10.1038/s41380-024-02841-w. Online ahead of print.

Authors

Luan Chen^#¹, Cong Huai^#¹, Chuanfu Song^#², Shaochang Wu^#³, Yong Xu^#^{4

5}, Zhenghui Yi^#⁶, Jinsong Tang^#⁷, Lingzi Fan⁸, Xuming Wu⁹, Zhenhua Ge⁹, Chuanxin Liu¹⁰, Deguo Jiang¹¹, Saizheng Weng¹², Guoqiang Wang¹³, Xinfeng Zhang¹⁴, Xudong Zhao¹⁵, Lu Shen^{1

16}, Na Zhang^{1

17}, Hao Wu¹, Yongzhi Wang¹, Zhenglin Guo¹⁸, Suli Zhang¹, Bixuan Jiang¹, Wei Zhou^{1

19}, Jingsong Ma¹, Mo Li¹, Yunpeng Chu¹, Chenxi Zhou¹, Qinyu Lv⁶, Qingqing Xu⁶, Wenli Zhu², Yan Zhang³, Weibin Lian³, Sha Liu⁴, Xinrong Li⁴, Songyin Gao⁸, Aihong Liu⁸, Lei He⁸, Zhenzhen Yang¹⁰, Bojian Dai¹¹, Jiaen Ye¹¹, Ruiqian Lin¹², Yana Lu¹³, Qi Yan⁹, Yalan Hu⁹, Qinghe Xing²⁰, Hailiang Huang^{21

22

23}, Shengying Qin^{24

25}

Affiliations

¹ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
² The Fourth People's Hospital of Wuhu, Wuhu, China.
³ The Second People's Hospital of Lishui, Lishui, China.
⁴ Shanxi Key Laboratory of Artificial Intelligence Assisted Diagnosis and Treatment for Mental Disorder, First Hospital of Shanxi Medical University, Taiyuan, China.
⁵ Department of Clinical Psychology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen City, Guangdong Province, China.
⁶ Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Psychiatry, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁸ The Affiliated Encephalopathy Hospital of Zhengzhou University, Zhumadian Second People's Hospital, Zhumadian, China.
⁹ Jiangsu Nantong Fourth People's Hospital, Nantong, Jiangsu Province, China.
¹⁰ Department of Psychiatry, Jining Medical University School of Mental Health, Jining, China.
¹¹ Wenzhou Seventh People's Hospital, Wenzhou, China.
¹² Fuzhou Neuro-psychiatric Hospital Affiliated to Fujian Medical University, Fuzhou, China.
¹³ Wuxi Mental Health Center Affiliated to Nanjing Medical University, Wuxi, China.
¹⁴ Jingzhou Mental Health Center, Jingzhou, China.
¹⁵ Shanghai Pudong New Area Mental Health Center, Tongji University School of Medicine, Shanghai, China.
¹⁶ Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
¹⁷ Shanghai Jiao Tong University Sichuan Research Institute (SJTUSRI), Chengdu, Sichuan Province, China.
¹⁸ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁹ Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health & Department of Developmental and Behavioural Paediatric & Child Primary Care, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
²⁰ Children's Hospital of Fudan University and Institutes of Biomedical Sciences of Fudan University, Shanghai, China.
²¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. hhuang@broadinstitute.org.
²² Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA. hhuang@broadinstitute.org.
²³ Department of Medicine, Harvard Medical School, Boston, MA, USA. hhuang@broadinstitute.org.
²⁴ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China. chinsir@sjtu.edu.cn.
²⁵ Shanghai Jiao Tong University Sichuan Research Institute (SJTUSRI), Chengdu, Sichuan Province, China. chinsir@sjtu.edu.cn.

^# Contributed equally.

PMID: 39562719
DOI: 10.1038/s41380-024-02841-w

Abstract

Schizophrenia (SCZ) is a severe mental disorder affecting around 1% of individuals worldwide. The variability in response to antipsychotic drugs (APDs) among SCZ patients presents a significant challenge for clinicians in determining the most effective medication. In this study, we investigated the biological markers and established a predictive model for APD response based on a large-scale genome-wide association study using 3269 Chinese schizophrenia patients. Each participant underwent an 8-week treatment regimen with one of five mono-APDs: olanzapine, risperidone, aripiprazole, quetiapine, or amisulpride. By dividing the response into ordinal groups of "high", "medium", and "low", we mitigated the bias of unclear treatment outcome and identified three novel significantly associated genetic loci in or near CDH12, WDR11, and ELAVL2. Additionally, we developed predictive models of response to each specific APDs, with accuracies ranging from 79.5% to 98.0%. In sum, we established an effective method to predict schizophrenia patients' response to APDs across three categories, integrating novel biomarkers to guide personalized medicine strategies.