A comprehensive assessment of the association between common drugs and psychiatric disorders using Mendelian randomization and real-world pharmacovigilance databaseResearch in context
Zhuohui Chen,
Xiang Wang,
Ziwei Teng,
Jing Huang,
Jianzhong Mo,
Chunrun Qu,
Yinghua Wu,
Zhixiong Liu,
Fangkun Liu,
Kun Xia
Affiliations
Zhuohui Chen
MOE Key Laboratory of Pediatric Rare Diseases, Hengyang Medical School, University of South China, Hengyang, China; Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China; Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China
Xiang Wang
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China
Ziwei Teng
National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Psychiatry, Hunan Brain Hospital (Hunan Second People's Hospital), Changsha, China
Jing Huang
National Clinical Research Center for Mental Disorders, Department of Psychiatry, China National Technology Institute on Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
Jianzhong Mo
The Third Hospital of Changsha, Changsha, Hunan, China
Chunrun Qu
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China
Yinghua Wu
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China
Zhixiong Liu
Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China; Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China; Corresponding author. Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
Fangkun Liu
MOE Key Laboratory of Pediatric Rare Diseases, Hengyang Medical School, University of South China, Hengyang, China; Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China; Hypothalamic Pituitary Research Centre, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China; Corresponding author. MOE Key Laboratory of Pediatric Rare Diseases, Hengyang Medical School, University of South China, Hengyang, China; Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, China.
Kun Xia
MOE Key Laboratory of Pediatric Rare Diseases, Hengyang Medical School, University of South China, Hengyang, China; Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China; Corresponding author. MOE Key Laboratory of Pediatric Rare Diseases, Hengyang Medical School, University of South China, Hengyang, China; Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Summary: Background: Medications prescribed for chronic diseases can lead to short-term neuropsychiatric symptoms, but their long-term effects on brain structures and psychiatric conditions remain unclear. Methods: We comprehensively analyzed the FDA Adverse Event Reporting System database and conducted drug target Mendelian Randomization (MR) studies on six categories of common drugs, 477 brain imaging-derived phenotypes (IDPs) and eight psychiatric disorders. Genetic instruments were extracted from expression quantitative trait loci (eQTLs) in blood, brain, and other target tissues, protein quantitative trait loci (pQTLs) in blood, and genome-wide association studies (GWAS) of hemoglobin and cholesterol. Summary statistics for brain IDPs, psychiatric disorders, and gut microbiome were obtained from the BIG40, Psychiatric Genomics Consortium, and MiBioGen. A two-step MR and mediation analysis were employed to screen possible mediators of drug-IDP effects from 119 gut microbiota genera and identify their mediation proportions. Findings: Among 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. We identified ten drug-psychiatric disorder associations, 202 drug-IDP associations, 16 drug-microbiota associations, and four drug-microbiota-IDP causal links. For example, PPARG activation mediated HbA1c reduction caused a higher risk of bipolar disorder (BD) II. Genetically proxied GLP-1R agonists were significantly associated with an increase in the volume of the CA3-head of the right hippocampus and the area of the left precuneus cortex, both of which have been shown to correlate with cognition in previous studies. Interpretation: Common drugs may affect brain structure and risk of psychiatric disorder. Oral medications in particular may exert some of these effects by influencing gut microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages drug repurposing. Funding: National Natural Science Foundation of China (grant No. 82330035, 82130043, 82172685, and 82001223), National Natural Science Foundation of Hunan Province (grant No. 2021SK1010), and the Science Foundation for Distinguished Young Scholars of Changsha (grant No. kq2209006).
