The HTR2A polymorphisms rs6311 (A-1438G) and rs6313 (T102C) have been thoroughly studied for their impact on atypical antipsychotics (AAPs) responsiveness in schizophrenia. However, the results remain inconsistent owing to the complex genetic and pharmacodynamic interactions. The Joanna Briggs Institute and Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews criteria were followed in this scoping review to map the available data on the association between HTR2A polymorphisms and outcomes. We identified 28 studies published before May 2025. Several studies reported that the rs6311 A allele was more frequently associated with improved treatment response, whereas the G allele was linked to poorer or absent response. In contrast, rs6313 exhibited heterogeneous patterns, with some studies reporting poorer response associated with the C allele and others reporting improved response associated with the T allele. This variability across studies likely reflects differences related to specific AAPs, as well as variations in study design and outcome definitions, rather than population or ethnicity-specific biological effects. Overall, HTR2A variants may contribute to interindividual variability in response to AAPs in schizophrenia. However, the current evidence remains insufficient for clinical application and requires further validation in well-designed and adequately powered studies.
Nurul Hidayah, M. Ikawati, M. M. Amin et al.· Pharmacogenetics & Genomics· 0 citations
BACKGROUND
Risperidone-clozapine response varies substantially in schizophrenia. HTR2A polymorphisms may influence antipsychotic response, but rs6311-rs6313 haplotypes remain unexplored in the Indonesian Batak population. This study evaluated associations of HTR2A rs6311-rs6313 with early risperidone-clozapine response.
METHODS
This prospective observational case-control study included 160 Batak inpatients with schizophrenia, comprising 80 responders and 80 nonresponders to risperidone-clozapine therapy. Genetic analyses included Hardy-Weinberg equilibrium (HWE), minor allele frequency (MAF), linkage disequilibrium, genotype and allele association, haplotype, permutation testing, genetic models, and multivariable logistic regression.
RESULTS
Genotype distributions conformed to HWE (P > 0.05), with both variants showing a MAF of 0.28 and strong linkage disequilibrium (r2 = 0.969, D' = 0.98). The rs6311 GG/rs6313 CC genotype was significantly associated with nonresponse to risperidone-clozapine therapy [odds ratio (OR) = 3.69, 95% confidence interval (CI): 1.10-12.36; P = 0.034], while the rs6311 G/rs6313 C allele was also associated with nonresponse (OR = 1.71, 95% CI: 1.04-2.80; P = 0.034). The recessive model remained significant after multivariable adjustment (adjusted OR = 3.36, 95% CI: 1.02-11.07; P = 0.046). TA and CG haplotypes remained significant after 10 000 permutations (P = 0.0415 and P = 0.0416), whereas single-marker associations lost significance (P = 0.0607).
CONCLUSION
HTR2A variation was associated with early risperidone-clozapine response, with consistent signals under the recessive model and at the haplotype level. Haplotype associations remained significant after permutation correction, suggesting that haplotype analysis may provide a more robust approach for detecting pharmacogenetic contributions to treatment response.
Nurul Hidayah, M. Ikawati, M. M. Amin et al.· Pharmacogenetics & Genomics· 0 citations
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