The Role of Genetic Variants and Iron Homeostasis in Antipsychotic-Induced Akathisia: A Systematic Review and Meta-Analysis Publisher



Ahmadi A ; Salimian M H ; Mansouri F ; Firouzi Y M
Source: Progress in Neuro-Psychopharmacology and Biological Psychiatry Published:2026

Abstract

Background: Antipsychotic-induced akathisia (AIA) is a common and highly distressing adverse drug reaction that significantly impacts treatment adherence and quality of life. The considerable interindividual variability in susceptibility suggests a role for underlying biological and genetic factors. This study aimed to systematically review and meta-analyze the evidence for genetic and biomarker predictors of AIA. Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, Embase, and other relevant databases to identify all case-control or cohort studies investigating the association between genetic polymorphisms or biological markers and AIA. Included studies were assessed for methodological quality using the Newcastle-Ottawa Scale (NOS). For genetic predictors, a pooled Odds Ratio (OR) was calculated using a random-effects model. For biomarker predictors, the Standardized Mean Difference (SMD) was calculated. This review was prospectively registered with PROSPERO (CRD420251082148). Results: The search yielded 2576 records, from which six studies (total N = 806) met the full inclusion criteria. The overall methodological quality of the included studies was high. From five eligible genetic studies, four provided sufficient data for a pooled analysis. This analysis of variants in dopaminergic, serotonergic, and metabolic pathways revealed a statistically significant increased risk of akathisia associated with genetic variants (Pooled OR = 1.73; 95% CI: 1.20 to 2.49) with no statistical heterogeneity (I2 = 0%). Preliminary analysis of one biomarker study suggests an association between lower serum ferritin levels and the presence of akathisia (SMD = −0.59; 95% CI: −1.13 to −0.05). Conclusion: This meta-analysis provides evidence for a multifactorial etiology of antipsychotic-induced akathisia. Preliminary evidence suggests lower serum ferritin levels may act as a biomarker of risk, though this requires independent replication and further validation. Furthermore, there is a consistent trend suggesting that genetic variants across several key neurotransmitter pathways increase the risk of AIA, highlighting the need for larger, prospective studies to confirm these associations and inform future personalized medicine strategies. © 2026 Elsevier Inc.