Accepted for/Published in: JMIR Public Health and Surveillance
Date Submitted: Aug 5, 2025
Open Peer Review Period: Nov 11, 2025 - Nov 20, 2025
Date Accepted: Dec 30, 2025
(closed for review but you can still tweet)
Warning: This is an author submission that is not peer-reviewed or edited. Preprints - unless they show as "accepted" - should not be relied on to guide clinical practice or health-related behavior and should not be reported in news media as established information.
Comparison of in vitro metrics with real-world risk of drug-induced parkinsonism: An evaluation of antipsychotic drugs
ABSTRACT
Background:
Drug-induced parkinsonism (DIP) predominantly occurs due to antipsychotic drugs (APDs) blocking dopamine D2 receptors (D2R). Despite assessing drug mechanisms and side effects, in vitro assays fail to fully reflect real-world clinical outcomes. This study developed novel in vitro metrics to more accurately predict real-world DIP.
Objective:
This study aimed to develop novel in vitro metrics to more accurately predict real-world DIP.
Methods:
We focused on eight APDs (haloperidol, amisulpride, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and aripiprazole) and measured key in vitro parameters, including the D2R and serotonin 2A receptor inhibition constants (Ki), D2R reversal rate (Kr), and blood-brain barrier penetration rate (BBBpr). The six composite DIP risk metrics were calculated by combining these factors. The real-world DIP risk was assessed using data from the Seoul National University Hospital Common Data Model (2002–2021). After 1:1 propensity score matching, each APD cohort was compared with selective serotonin reuptake inhibitor controls, and Cox proportional hazards regression was performed to estimate the hazard ratios (HRs) for DIP.
Results:
Among the 324,449 patients, 109,436 selective serotonin reuptake inhibitor users and 28,945 APD users formed eight matched cohorts. Haloperidol showed the highest DIP risk (HR 4.56; 95% confidence interval [CI], 2.29–9.07), whereas aripiprazole exhibited the lowest risk (HR 2.11; 95% CI, 1.56–2.86). The composite metric (pKr × BBBpr) displayed the strongest correlation with real-world DIP risk (R2 = 0.95); however, aripiprazole was an outlier, likely owing to its partial agonistic properties.
Conclusions:
Combining receptor-binding kinetics with BBB penetration provides a robust in vitro predictor of clinical DIP risk and underscores assessing receptor kinetics alongside central nervous system accessibility for drug safety evaluations.
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Copyright
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