Atypical Antipsychotic Off Label Use: Should We Worry About Cardiovascular Complications?

Abstract

Despite label warnings for severe metabolic side effects causing insulin resistance and increased mortality, prescribing of atypical antipsychotic drugs (AADs) has increased significantly in recent years, particularly in children and elderly for non‐psychotic behaviors. Adverse cardiovascular (CV) events have been reported, including arrhythmias in elderly; however the underlying pharmacology is unknown. The goal of this study was to evaluate acute CV effects of several AADs. Anesthetized male adult rats were cannulated (femoral vein for drug delivery, right carotid artery for blood pressures), and sc electrodes for EKGs. Drugs selected for diverse receptor pharmacology and metabolic side effect profiles were chosen, and cumulative dose/response measurements were recorded (0.1 – 1.0 mg/kg, ~5 min intervals between doses). All drugs acutely reduced mean arterial pressure (MAP) with no compensatory increase in heart rate. Aripiprazole had the least effect on MAP (<10% reduction), while the other drugs reduced MAP by 50‐60%. Increased pulse pressure accompanied reduced MAP only with Risperidone. MAP effects were transient, recovering ~1‐2 min. No effects on EKG were detected.ConclusionsPotency of drugs on MAP were positively correlated with Ki values for both α1‐adrenergic and D2 receptors: Risperidone<Clozapine<Olanzapine<Aripiprazole, whereas efficacy was similar for all, except reduced for Aripiprazole. Our results support the view that Aripiprazole is least likely to induce orthostatic hypotension, and its more selective D2 effects may contribute to reduced side effects.Funded by grant DK095143 (KLH), Peter Morgane Research Fellowship (JDP)