QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study

We compared heart rate-corrected QT interval (QTc) and its within-and between-subject variability, in ECGs recorded several days apart for 207 patients with schizophrenia (age range 19-60 yr) with age-and gender-matched healthy controls. Patients had higher heart rates (mean +/- S. D.) than controls [75 +/- 15 beats per minute (bpm) vs. 63 +/- 10 bpm; p < 0.0001]. QTc by Bazett's formula (QTcB) overestimated QTc interval at high heart rates; consequently QTcB was longer in patients (412 +/- 24 ms) than in controls (404 +/- 24 ms; p = 0.0003). QTc by Fridericia's method (QTcF), which was not influenced by heart rate, was comparable (398 +/- 22 ms in patients vs. 401 +/- 19 ms in controls; p = 0.17). Between-subject variability in QTcF was similar in patients (17 ms) and controls (16.2 ms) but within-subject variability was larger (13.1 ms vs. 10 ms, respectively). Thus, a larger sample size is required when thorough QTc studies with a cross-over design are performed in patients with schizophrenia than in healthy subjects; sample size is not increased for studies with a parallel design. Last, QTcF is preferred over QTcB in schizophrenia patients with higher heart rates.