Assessment of Venous Thromboembolism Risk of Antipsychotic Drugs Using Mendelian Randomization Analysis

See article vol. 31: 396-418

Although several observational studies have reported a possible association between antipsychotic drugs and development of venous thromboembolism (VTE)^{1, 2)}, a definite causal relationship is yet to be established between the two, and the pathogenesis of the association has not been clearly explained. Although cohort studies are the standard protocol to investigate the causal relationship between exposure and outcome, they are often difficult to conduct in practice owing to the large number of resources required. Recently, reports have scrutinized the association between drugs and adverse effects through Mendelian randomization (MR), an epidemiologic method that combines genome-wide association study (GWAS) data with bioinformatics analysis to identify causal relationships between exposure and outcome³⁾. Therefore, the authors combine GWAS data with bioinformatics analysis to evaluate the epidemiological method of MR, an approach that reveals causal relationships between exposure and outcome; furthermore, Li et al. examined the causal relationship between antipsychotic drugs and development of VTE using MR analysis in terms of drug target genes⁴⁾.

As MR analysis uses inherited genetic polymorphisms as measurement variables, and results are not disturbed by confounding factors such as acquired postnatal behavioral factors. Thus, MR analysis is considered a good analysis method for studying the causal relationship between exposure and outcome. However, because it estimates the effects of target genes related to pharmacological effects, rather than the direct effects of drug use on disease, caution should be exercised in interpreting results in cases where the pharmacological effects are not obvious.

This study is an MR analysis based on reports of VTE incidence in the US Food and Drug Administration’s voluntary adverse event reporting system. Reporters in this system include patients as well as healthcare providers, and unfortunately there is a gap in medical knowledge between the two that should not be neglected. Moreover, patients who develop VTE that should be reported may not be reflected as eligible due to patient’s failure to report symptoms. Therefore, it is important to note that studies based on such reporting systems are fraught with the possibility of underestimating the number of patients who actually develop VTE. Furthermore, because Mendelian randomized controlled trials are a form of observational research, caution must be exercised in establishing causality, and it may be difficult to exclude the influence of other factors or confounders. Moreover, the genetic variants identified may not be sufficient to explain causality for a particular trait.

Herein, study results do not provide definitive proof of the effect of antipsychotic drug target genes on VTE; moreover, there are several limiting factors in MR analysis, thus caution must be exercised in interpreting the results. Notably, however, this study found differences in the expression of drug target genes, and provided a new method to analyze potential mechanisms of action and their association with adverse effects, even though the pharmacological mechanism is not known.

Conflicts of Interest

All authors declared no conflicts of interest.

References

• 1)  Hägg S, Spigset O, Söderström TG. Association of venous thromboembolism and clozapine. Lancet, 2000; 355: 1155-1156
• 2)  Liperoti R, Pedone C, Lapane KL, Mor V, Bernabei R, Gambassi G. Venous thromboembolism among elderly patients treated with atypical and conventional antipsychotic agents. Arch Intern Med, 2005; 165: 2677-2682
• 3)  Walker VM, Davey Smith G, Davies NM, Martin RM. Mendelian randomization: a novel approach for the prediction of adverse drug events and drug repurposing opportunities. Int J Epidemiol, 2017; 46: 2078-2089
• 4)  Li T, Ye L, Ma J, Huang L, Guo C, Huang X, Jiang J, Xie X, Guo C, He Q. Association of Antipsychotic Drugs with Venous Thromboembolism: Data Mining of FDA Adverse Event Reporting System and Mendelian Randomization Analysis. J Atheroscler Thromb, 2024; 31: 396-418