Heterogeneity in the association between CYP2D6 genotype and antipsychotic-induced extrapyramidal symptoms: A systematic review

Abstract

Introduction

Cytochrome‑P450 2D6 (CYP2D6) activity modulates the biotransformation of many antipsychotics and neuroactive endobiotics. Functional polymorphisms yielding poor (PM), intermediate (IM), normal (NM) or ultrarapid (UM) metabolic phenotypes could therefore influence vulnerability to extrapyramidal symptoms (EPS). Aim of the present review was to critically summarize the evidence linking CYP2D6 genotype with antipsychotic‑induced EPS.

Methods

A systematic search of PubMed, MEDLINE and EBSCO (1 January 1997 – 28 April 2025) identified studies that: (i) examined CYP2D6 genotype or phenotype in relation to antipsychotic exposure, (ii) quantitatively assessed EPS, and (iii) enrolled ≥ 10 participants.

Results

Eighteen studies (7 prospective cohorts, 10 cross‑sectional studies, 1 randomized controlled trial; total n= 2037 participants) met inclusion criteria. Typical antipsychotics—particularly haloperidol and zuclopenthixol—dominated the exposure profile (64 % of participants). Eleven studies reported a genotype‑EPS association, consistently showing greater EPS prevalence or severity in PM and IM carriers. Reported odds ratios for EPS across included studies ranged ∼2–5 for PM/IM vs EM/UM. Risperidone and haloperidol were the antipsychotics most frequently associated with EPS. Null findings were primarily reported by studies devoid of PM genotypes and enrolling adolescent cohorts receiving second‑generation antipsychotics.

Conclusion

Some studies summarized in the present review supported the role of CYP2D6 genotype in the occurrence of EPS in patients treated with antipsychotics, particularly with high-potency D₂ antagonists. Prospective, genotype‑stratified trials that incorporate concomitant inhibitors/inducers, polygenic scores and pharmacodynamic modifiers are still required before cost‑effective implementation algorithms can be finalized.