Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study David W. Hough a , Jaya Natarajan a , An Vandebosch b , Stefan Rossenu b , Michelle Kramer a and Marie ¨ lle Eerdekens b The effect of two atypical antipsychotics on QTc intervals (heart rate-corrected QT interval) was evaluated. Patients (N = 109) with schizophrenia (79%) or schizoaffective disorder (21%) were randomly assigned in 2 : 2 : 1 ratio to paliperidone extended release (ER), quetiapine, or placebo. Doses of 12 and 18 mg/day of paliperidone ER were compared with quetiapine 800 mg/day. Least-squares mean change from baseline in population-specific linear-derived correction method from baseline to days 6–7 at individual t max was 5.1 ms less [90% confidence interval: – 9.2 to – 0.9] with paliperidone ER 12 mg/day than with quetiapine 800 mg/day. On the basis of a prespecified 10-ms noninferiority margin, paliperidone ER was thus declared noninferior to quetiapine (primary analysis). Mean change in population-specific linear-derived correction method from baseline to days 11–12 at individual t max was 2.3 ms less (90% confidence interval: – 6.8 to 2.3) with paliperidone ER 18 mg/day than with quetiapine 800 mg/day. Treatment-emergent adverse events occurred in 36 (82%) patients treated with paliperidone ER, 41 (95%) patients treated with quetiapine, and 14 (64%) patients treated with placebo. No adverse events of a proarrhythmic nature were noted. The effect on the QTc interval in patients with schizophrenia or schizoaffective disorder was comparable between paliperidone ER 12 mg/day (maximum recommended dose), paliperidone ER 18 mg/day (supratherapeutic dose), and quetiapine 800 mg/day. Int Clin Psychopharmacol 00:000–000  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2010, 00:000–000 Keywords: antipsychotics, arrhythmia, electrocardiogram, paliperidone, population-specific linear-derived correction method, quetiapine, QT/corrected QT interval, schizophrenia a Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey, USA and b Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium Correspondence to Marielle Eerdekens, MD, Johnson & Johnson Pharmaceutical Research & Development, Division of Janssen Pharmaceutica N.V., Turnhoutseweg 30, Beerse 2340, Belgium Tel: + 32 14 60 6274; fax: + 32 14 60 5089; e-mail: meerdeke@its.jnj.com Received 30 April 2010 Accepted 31 August 2010 Introduction Abnormal prolongation or shortening in the QT interval, the period of time from the onset of ventricular depolari- zation to the end of ventricular repolarization, increases the risk of developing ventricular arrhythmias. Drug-induced alteration to the QT interval has become important in selecting a pharmacological treatment for patients with schizophrenia. Many antipsychotics increase the QT inter- val to various extents (Taylor, 2003; Harrigan et al., 2004; Stollberger et al., 2005), and case reports and epidemiologic studies have implicated antipsychotics as one of several factors involved in the increased cardiac-related mortality of patients with schizophrenia (Robbins et al., 2003; Taylor, 2003; Straus et al., 2004). In addition, there is natural diurnal variation in QT interval in healthy individuals (Bonnemeier et al., 2003). Thus, the immediate and prolonged release formulations of various antipsychotics may affect the QT interval differently. Paliperidone extended release (ER) tablets [INVEGA; Janssen, LP, Titusville, New Jersey, USA; also marketed as prolonged release (PR) tablets in the European Union] have been approved in the European Union, the US, and many other regions of the world for the treatment of schizophrenia and schizoaffective disorder. As part of the drug development program, studies were conducted to specifically evaluate the cardiovascular profile of paliperidone ER by using a thorough QT assessment. The first study (NCT00791349) in patients used an immediate release (IR) formulation of the com- pound, which produced modest but statistically signifi- cant increases in QTc intervals (heart rate-corrected QT interval) versus placebo. The IR paliperidone (8 mg) produced considerably higher plasma concentrations {mean C max [standard deviation (SD)]: 113 (43.3) ng/ml} on day 8 than did paliperidone ER at either the maximum recommended dose [12 mg/day; mean C max (SD) = 34.6 (16.2) ng/ml after 6 days of dosing] or the supratherapeutic These data were presented at the Society of Biological Psychiatry (SOBP) 62nd Annual Meeting, May 19–24, San Diego, California, 2007; 160th American Psychiatric Association (APA) Annual Meeting, May 19–24, San Diego, California, 2007; 47th Annual Meeting of the National Institute of Mental Health, New Clinical Drug Evaluation Unit (NCDEU), June 14–17, Boca Raton, Florida, 2007; 59th Institute on Psychiatric Services (IPS), October 11–14, New Orleans, Louisiana, 2007; 20th Congress of the European College of Neuropsycho- pharmacology (ECNP), October 13–17,Vienna, 2007. Original article 1 0268-1315  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0b013e3283400d58 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.