In antipsychotics that prolong the corrected QT interval (QTc), is sodium‑channel blockade the primary mechanism of the prolongation?

No—Potassium Channel (hERG/IKr) Blockade, Not Sodium Channel Blockade, Is the Primary Mechanism of Antipsychotic-Induced QTc Prolongation

The main mechanism by which antipsychotics prolong the QTc interval is blockade of the cardiac hERG potassium channel (IKr current), not sodium channel blockade. 1, 2, 3 However, sodium channel activity plays a crucial modulating role that can either worsen or partially offset the QTc prolongation caused by hERG blockade. 2

Primary Mechanism: Potassium Channel (hERG/IKr) Blockade

• Drug-induced QTc prolongation is most often due to dose-dependent inhibition of the cellular IKr current through channels coded by the hERG gene. 1
• Antipsychotic drugs prolong the QT interval primarily by blocking the potassium IKr current, which delays phase 3 repolarization of the cardiac action potential. 3
• The hERG channel is the single best predictor of QTc prolongation across all antipsychotics, explaining the majority of QTc variability. 2
• Loss-of-function mutations in KCNH2 (which encodes the hERG/IKr α-subunit) cause congenital long QT syndrome type 2 (LQT2), demonstrating that impaired IKr function—whether genetic or drug-induced—directly prolongs repolarization. 1

Sodium Channel Blockade: A Modulating Factor, Not the Primary Cause

• Sodium channel (Nav1.5) blockade does not cause QTc prolongation in antipsychotics; instead, it modulates the degree of prolongation caused by hERG blockade. 2
• The hERG/Nav1.5 blockade ratio explains 57% of the overall QTc variability associated with antipsychotics, indicating that sodium channel inhibition acts as a compensatory mechanism. 2
• Inhibition of the late sodium current (late INa) can offset the dysfunctional effects of hERG blockade, reducing the net QTc prolongation and arrhythmia risk. 1, 2
• Drugs that block both hERG and late INa—such as ranolazine—show limited QTc prolongation despite significant IKr inhibition, because sodium channel blockade counteracts the repolarization delay. 1

Clinical Implications: Why This Distinction Matters

• Antipsychotics with high hERG affinity and low Nav1.5 blockade (e.g., thioridazine, ziprasidone) carry the highest risk of QTc prolongation and torsades de pointes. 4, 5, 2
• Thioridazine causes 25–30 ms QTc prolongation and displays little selectivity for dopamine D2 or serotonin 5-HT2A receptors relative to its hERG affinity, explaining its high arrhythmia risk. 6, 5
• Ziprasidone and pimozide similarly show minimal selectivity for therapeutic targets over hERG, resulting in significant QTc prolongation. 4, 5
• In contrast, olanzapine displays 100–1000-fold selectivity for D2 and 5-HT2A receptors compared to its hERG IC50, explaining its lower QTc risk (approximately 4–6 ms prolongation). 5, 3
• Haloperidol causes modest QTc prolongation (≈7 ms) with oral or IM administration, but intravenous haloperidol dramatically increases torsades risk due to higher cardiac drug exposure. 6, 4

Sodium Channel Blockade in Tricyclic Antidepressants: A Different Context

• Tricyclic antidepressants (e.g., amitriptyline) can cause torsades de pointes, but they also produce other arrhythmias due to sodium channel blocker toxicity, such as wide QRS complexes and sinusoidal ventricular tachycardia. 1
• In TCA overdose, sodium channel blockade is the dominant mechanism of cardiotoxicity, but this is distinct from the hERG-mediated QTc prolongation seen with therapeutic antipsychotic use. 1

Common Pitfall: Confusing Sodium Channel Effects with Primary QTc Mechanism

• Do not assume that sodium channel blockade is the primary cause of QTc prolongation in antipsychotics—it is a modulating factor that can reduce (not increase) the arrhythmia risk when present alongside hERG blockade. 2
• The ratio of total plasma drug concentration to hERG IC50 is the most reliable predictor of clinical QTc prolongation, not sodium channel affinity. 5
• Genetic polymorphisms in hERG (not sodium channels) are the primary determinants of individual susceptibility to drug-induced QTc prolongation and torsades de pointes. 1

Risk Stratification Based on Mechanism

• High-risk antipsychotics (thioridazine, ziprasidone, IV haloperidol, pimozide) have high hERG affinity with minimal Nav1.5 blockade, resulting in 13–30 ms QTc increases. 6, 4, 5
• Moderate-risk antipsychotics (quetiapine, risperidone, amisulpride) cause 5–10 ms QTc prolongation and have intermediate hERG/Nav1.5 ratios. 6, 4
• Lower-risk antipsychotics (olanzapine, aripiprazole) have high selectivity for therapeutic targets over hERG and cause minimal QTc changes (≤6 ms). 6, 5, 3