Genetic Variations in the Dopaminergic Signaling Pathways and Their Implications for Antipsychotics Pharmacogenetics

The role of neurotransmitter systems in the pathology and management of psychiatric disorders is well documented. Targeting these systems has remained the mainstay of standard pharmacological interventions, with typical and atypical antipsychotics demonstrating effectiveness in reducing both positive and negative symptoms of schizophrenia. However, their clinical efficacy and side effect profiles vary among individuals due to genetic differences. This review aims to examine key genetic variants in the dopaminergic neurotransmitter system that influence antipsychotic response, with particular emphasis on clinically relevant single-nucleotide polymorphisms (SNPs), to support improved treatment outcome prediction and precision psychiatry. Polymorphisms in genes encoding dopamine receptors, transporters, and metabolising enzymes have been associated with variability in antipsychotic efficacy and susceptibility to adverse effects. Across multiple studies, the catechol-O-methyltransferase (COMT) Val158Met (rs4680) polymorphism and the dopamine D2 receptor/ANKK1 Taq1A (rs1800497) variant are among the most consistently reported genetic contributors to variability in dopamine signalling, receptor availability, and drug metabolism. These variants have been linked to differential therapeutic outcomes, including improved response in some treatment-resistant patients, as well as an increased risk of extrapyramidal symptoms, hyperprolactinaemia, and metabolic disturbances. These findings indicate that genetic variation in the dopaminergic system is a key contributor to differences in antipsychotic response. Integrating pharmacogenomic information in clinical practice may enhance personalised treatment strategies, reduce trial-and-error prescribing, and improve long-term outcomes in schizophrenia.