Risk of Neuropsychiatric Adverse Effects of Lipid-Lowering Drugs: A Mendelian Randomization Study

Background: Recent studies have highlighted the possible risk of neuropsychiatric adverse effects during treatment with lipid-lowering medications. However, there are still controversies that require a novel genetic-based approach to verify whether the impact of lipid-lowering drug treatment results in neuropsychiatric troubles including insomnia, depression, and neuroticism. Thus, we applied Mendelian randomization to assess any potential neuropsychiatric adverse effects of conventional lipid-lowering drugs such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ezetimibe. Methods: A 2-sample Mendelian randomization study was conducted based on summary statistics from genome-wide association studies for lipids, insomnia, depression, and neuroticism. Single-nucleotide polymorphisms located in or near drug target genes of HMGCR, PCSK9, and NPC1L1 were used as proxies for statins, PCSK9 inhibitors, and ezetimibe therapy, respectively. To assess the validity of the genetic risk score, their associations with coronary artery disease were used as a positive control. Results: The Mendelian randomization analysis showed a statistically significant (P < .004) increased risk of depression after correcting for multiple testing with both statins (odds ratio = 1.15, 95% CI: 1.04-1.19) and PCSK9 inhibitor treatment (odds ratio = 1.19, 95% CI: 1.1-1.29). The risk of neuroticism was slightly reduced with statin therapy (odds ratio = 0.9, 95% CI: 0.83-0.97). No significant adverse effects were associated with ezetimibe treatment. As expected, the 3 medications significantly reduced the risk of coronary artery disease. Conclusion: Using a genetic-based approach, this study showed an increased risk of depression during statin and PCSK9 inhibitor therapy while their association with insomnia risk was not significant.