ANTIPSYCHOTIC-INDUCED EXTRAPYRAMIDAL SYMPTOMS AND TARDIVE DYSKINESIA: ANALYSIS BASED ON A SPONTANEOUS REPORTING SYSTEM DATABASE IN JAPAN
Authors: Saga *Yosuke , Horio Hiroshi , Chiang Chih-Lin , Wakamatsu Akihide 
Published: February 2025

Abstract

Background
Antipsychotics can potentially induce various involuntary movement, such as extrapyramidal symptoms (EPS) and tardive dyskinesia (TD)1. The specific risk associated with different classes of antipsychotics in causing these side effects in the Japanese population remains unclear.

Aims & Objectives
The aim of this study is to investigate the risk of developing EPS and TD in relation to antipsychotics compared to other medications as well as to assess the variation in risk across different classes of antipsychotics.

Method
We conducted an analysis of the cases of EPS and TD reported in the Japanese Adverse Drug Event Report (JADER) database, published by PMDA, covering the period from April 2011 to March 2021. The reported cases encompassed a range of conditions, including akathisia, dystonia, dyskinesia, tremor, parkinsonism, dysarthria, rigidity, and hypersalivation. To identify potential signals, we calculated the reporting odds ratio (ROR) to compare 1) antipsychotics to other medications, 2) first- generation antipsychotics (FGAs) to second generation antipsychotics (SGAs), and sub-classes within SGA. Furthermore, we calculated the adjusted ROR, accounting for factors such as age, reported year, sex, and concomitant medication use, such as anticholinergic agents, and lithium.

Results
The aggregate number of reported cases of EPS associated with antipsychotics was 3256 cases (including FGA: 398 cases, SGA; 2858 cases). TD cases associated with antipsychotics were 349 (FGA: 76 cases; SGA: 273 cases). Meanwhile, there were 3335 cases of EPS and 433 cases of TD associated with other medications. In comparison with other medications, the adjusted ROR and corresponding 95%CI indicates that antipsychotics were associated with a higher risk for akathisia (1.77 [1.51-2.08]), dyskinesia (2.89 [2.46-3.40]), parkinsonism (2.28 [2.05-2.53]), and hypersalivation (2.53 [2.17-2.96]). When comparing across different classes of antipsychotics, the adjusted ROR for FGAs compared to SGAs showed a higher risk for akathisia (1.61 [1.07-2.43]), dystonia (2.72 [2.17-3.41]), dyskinesia (4.50 [3.56-5.69]), and TD (2.41 [1.73- 3.35]), while SGAs were associated with a higher risk for parkinsonism (1.45 [1.11-1.88]) and hypersalivation (1.91 [1.26-2.89]) compared to FGAs.

Limitation
JADER is relying on reports not only from physicians, but also from other healthcare professionals, caregivers, and family members. The accuracy of EPS and TD diagnosis reported by non-physicians source may be constrained. Moreover, the information regarding the severity of symptoms and treatment outcomes is restricted in this database. Finally, the actual incidence of TD and EPS in patients exposed to antipsychotics and other medications cannot be estimated based on this dataset.

Discussion & Conclusion
The ROR analysis using JADER could identify signals of antipsychotic-induced EPS and TD cases in Japan. Meanwhile, there were variations in the risk of EPS and TD across different types of antipsychotics.
Notably, the EPS and TD risks were observed in both FGAs and SGAs.

References
1. A descriptive analysis of spontaneous reports of antipsychotic-induced tardive dyskinesia and other extrapyramidal symptoms in the Japanese Adverse Drug Event Report database. Y Saga, C-L Chiang, and A Wakamatsu. Neuropsychopharmacology Reports (In press)