Risk of Extrapyramidal Syndromes Associated With Psychotropic Polypharmacy: A Study Based on Large-Scale Japanese Claims Data

  • Yoko HiranoEmail author
Original Research



Psychotropic polypharmacy is common in clinical practice although supporting evidence is limited. Extrapyramidal syndromes (EPS) are adverse events associated with use of psychotropic drugs, especially antipsychotics. There are quite a few reports that suggest association between each psychotropic drug and EPS; however, the risk of EPS associated with their polypharmacy has not been fully evaluated. This study aimed at examining the influence of psychotropic polypharmacy on EPS occurrence by drug category (anxiolytics, hypnotics, antidepressants, and antipsychotics).


Sequence symmetry analyses were conducted using a large-scale Japanese health insurance claims database. This method assessed asymmetry in the distribution of EPS occurrence defined as both a diagnosis of EPS and a prescription for antiparkinsonian drugs before and after initiation of psychotropic drugs. The adjusted sequence ratio (ASR) and its 95% confidence interval (CI) were calculated.


All categories of psychotropic drugs (anxiolytics, hypnotics, antidepressants, and antipsychotics) were significantly associated with EPS, and the tendency was stronger in polypharmacy associated with them. A clearer association between polypharmacy of BZs and EPS was indicated. In the analyses by subclasses of drugs, BZs, tetracyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, typical and atypical antipsychotics were significantly associated with EPS. The ASR of atypical antipsychotics (ASR 11.3, 95% CI 7.95-16.4) was higher than that of typical ones (ASR 2.96, 95% CI 2.06-4.33).


The association between psychotropic polypharmacy and EPS was indicated. Further investigation is needed to confirm these findings because of the pharmacoepidemiologic nature of this study.


claims data drug safety pharmacoepidemiology polypharmacy self-controlled study 


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Supplementary material

43441_2019_26_MOESM1_ESM.pdf (108 kb)
Supplementary material 1 (PDF 108kb)
43441_2019_26_MOESM2_ESM.pdf (187 kb)
Supplementary material 2 (PDF 188kb)

Copyright information

© The Author(s) 2020

Authors and Affiliations

  1. 1.Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical SciencesKitasato UniversityTokyoJapan

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