Second-generation antipsychotics - Cardiac ion channel modulation and QT interval disturbances: A review

Second-generation antipsychotics (SGAs) are frequently prescribed in psychiatry due to their efficacy and improved tolerability compared to first-generation agents. However, these medications are associated with significant cardiac adverse effects, particularly QT interval prolongation and torsades de pointes (TdP). This review aims to summarize the mechanisms by which SGAs affect cardiac ion channels and how these actions contribute to QT interval disturbances and increased arrhythmia risk. A narrative literature review was conducted using PubMed, Web of Science, and Google Scholar, without year restrictions, focusing on English-language experimental and clinical studies related to clozapine, olanzapine, risperidone, quetiapine, and ziprasidone. The findings indicate that all five SGAs inhibit the rapid delayed rectifier potassium current (IKr) mediated by the human ether-a-go-go-related gene (hERG) potassium channel. Notably, the observed variability in the ratio of half-maximal inhibitory concentration to maximum free plasma concentration (IC₅₀/Cmax,free) reflects its dependence on both the degree of hERG inhibition and the pharmacokinetic properties specific to each SGA. Additionally, several SGAs affect other potassium, sodium, and calcium currents, which may either mitigate or exacerbate the consequences of IKr inhibition. In conclusion, QT interval prolongation associated with SGAs is primarily driven by hERG potassium channel blockade, although the degree of this effect varies significantly among different agents. This variability highlights the necessity for electrocardiogram (ECG) monitoring and individualized cardiac risk assessments, especially for vulnerable patient populations.