Abstract
Background
The association between antihypertensive medication and schizophrenia has received increasing attention; however, evidence of the impact of antihypertensive medication on subsequent schizophrenia based on large-scale observational studies is limited. We aimed to compare the schizophrenia risk in large claims-based US and Korea cohort of patients with hypertension using angiotensin-converting enzyme (ACE) inhibitors versus those using angiotensin receptor blockers (ARBs) or thiazide diuretics.
Methods
Adults aged 18 years who were newly diagnosed with hypertension and received ACE inhibitors, ARBs, or thiazide diuretics as first-line antihypertensive medications were included. The study population was sub-grouped based on age (> 45 years). The comparison groups were matched using a large-scale propensity score (PS)-matching algorithm. The primary endpoint was incidence of schizophrenia.
Results
5,907,522; 2,923,423; and 1,971,549 patients used ACE inhibitors, ARBs, and thiazide diuretics, respectively. After PS matching, the risk of schizophrenia was not significantly different among the groups (ACE inhibitor vs. ARB: summary hazard ratio [HR] 1.15 [95% confidence interval, CI, 0.99–1.33]; ACE inhibitor vs. thiazide diuretics: summary HR 0.91 [95% CI, 0.78–1.07]). In the older subgroup, there was no significant difference between ACE inhibitors and thiazide diuretics (summary HR, 0.91 [95% CI, 0.71–1.16]). The risk for schizophrenia was significantly higher in the ACE inhibitor group than in the ARB group (summary HR, 1.23 [95% CI, 1.05–1.43]).
Conclusions
The risk of schizophrenia was not significantly different between the ACE inhibitor vs. ARB and ACE inhibitor vs. thiazide diuretic groups. Further investigations are needed to determine the risk of schizophrenia associated with antihypertensive drugs, especially in people aged > 45 years.
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Background
Schizophrenia is a mental disorder affecting approximately 1% of the world’s population and is a severe disorder that leads to functional deterioration [1]. Despite cardinal features of schizophrenia, it remains the least understood psychiatric disorder owing to the lack of pathological hallmarks [2, 49]. For the strictness of diagnosis, we added prescriptions of antipsychotics and occurrences of psychiatry procedures. Lastly, more comprehensive analyses are still needed to generalize our findings. This study only included RAS inhibitors and thiazide diuretics among the main antihypertensive drugs, and additional analyses such as calcium channel blockers could be considered. It also excluded patients on two or more medications, which are prescribed to more than half of all patients with hypertension [50], and further research is needed on patients on such combination therapies.
Conclusions
In conclusion, there was no explicit difference in the risk of schizophrenia between ACE inhibitors, ARBs, and thiazide diuretics across the two large databases in the US and South Korea. These results are not sufficient to justify a change in current prescribing guidelines in hypertensive patients because of the risk of schizophrenia. Considering the unmeasured confounders, further investigations are needed to clarify the association between schizophrenia and antihypertensive drugs.
Data availability
Data are available from the corresponding authors upon reasonable request and with permission of HIRA and IQVIA.
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Acknowledgements
The analysis is based in part on work from the Observational Health Sciences and Informatics collaborative. OHDSI (http://ohdsi.org) is a multi-stakeholder, interdisciplinary collaborative to create open-source solutions that reveal the value of observational health data through large-scale analytics. This work was supported by the Health Insurance Review and Assessment Service (HIRA). The views expressed are those of the authors and not necessarily those of the HIRA.
Funding
This research was supported by a grant of the project for Infectious Disease Medical Safety, funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HG22C0024). Also, this research was supported by a grant (22213MFDS486) from Ministry of Food and Drug Safety in 2022 and a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR16C0001).
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D.Y.L., C.K., and J.K. contributed equally as co-first authors. S.C.Y. and R.W.P. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors substantially contributed to the conception and design of the work and interpretation of the data. D.Y.L drafted the manuscript and all other authors gave critical revision for important intellectual content. All authors gave final approval to the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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The study protocol was approved by the Ajou University Medical Center Institutional Review Board (IRB number: AJIRB-MED-MDB-21-274). Participant informed consent was waived for retrospective studies using de-identified data according to the Ajou University Medical Center Institutional Review Board regulations and decision.
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Lee, D.Y., Kim, C., Kim, J. et al. Comparative estimation of the effects of antihypertensive medications on schizophrenia occurrence: a multinational observational cohort study. BMC Psychiatry 24, 128 (2024). https://doi.org/10.1186/s12888-024-05578-6
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DOI: https://doi.org/10.1186/s12888-024-05578-6