Association of Genotypes and Haplotypes of Low-Functioning and Non-Functional Single Nucleotide Variants of the ABCB1 Gene with the Risk of Antipsychotic-Induced Cognitive Disorders in Patients with Schizophrenia Spectrum Disorders

Abstract

Cognitive disorders (CDs) are among the most disabling components of the clinical picture of schizophrenia spectrum disorders (SSDs) and lead to a pronounced decline in the quality of life, as well as in social and occupational functioning of patients. CDs in patients with SSDs may be primary or secondary, with the latter developing during antipsychotic (AP) therapy. Individual predisposition to AP-induced CDs may arise from genetically rooted features of AP pharmacokinetics — in particular, the functional state of the efflux transporter P-glycoprotein (P-gp), encoded by the ABCB1 gene. This narrative review demonstrates that three single nucleotide variants of the ABCB1 gene (3435C>T, 1236C>T, and 2677G>T/A) have a proven effect on P-gp expression and substrate specificity. Carriage of the non‑functional TTT haplotype — the most common alongside the “wild‑type” CGC haplotype — is associated with increased AP concentrations in the blood and brain tissue, leading to enhanced neurotoxic adverse drug reactions (ADRs). Analysis of clinical studies confirms an association between non‑functional ABCB1 genotypes and haplotypes and an increased risk of ADRs to AP therapy. However, direct evidence linking ABCB1 haplotypes to neurocognitive outcomes in SSD has not yet been found. The association of certain ABCB1 haplotypes with AP-induced CDs is theoretically justified but requires clinical confirmation in prospective studies. Preventive pharmacogenetic testing for the ABCB1 gene appears to be a promising tool for personalizing АР therapy in patients with SSDs. It enables the identification of patients at risk for CDs prior to treatment initiation and allows adjustment of drug selection and dosing regimen.