Ventricular repolarization heterogeneity in schizophrenia: A systematic review and meta-analysis of traditional and novel ECG markers.

BACKGROUND

Patients with schizophrenia experience a markedly increased risk of sudden cardiac death that cannot be fully explained by conventional cardiovascular risk factors or QTc prolongation alone. Novel electrocardiographic markers reflecting ventricular repolarization heterogeneity may provide more sensitive indicators of arrhythmic vulnerability.

METHODS

We conducted a systematic review and meta-analysis of observational studies published between 2015 and 2025 comparing traditional and novel ECG repolarization markers in adults with schizophrenia and healthy controls. PubMed, Scopus, Embase, and Web of Science were searched. Outcomes included heart rate, QT/QTc indices, frontal QRS-T angle, Tp-e interval, Tp-e/QT ratio, and dispersion measures. Pooled mean differences (MDs) with 95% confidence intervals were estimated using random-effects models, with subgroup analyses according to treatment status (drug-naïve vs medicated).

RESULTS

Eleven studies comprising 5648 patients with schizophrenia and 23,636 healthy controls were included. Compared with controls, patients with schizophrenia exhibited a higher heart rate (MD = 6.24 bpm, 95% CI 2.01-10.46), increased QT dispersion (MD = 13.00 ms, 95% CI 3.58-22.42), and markedly elevated QTc dispersion (MD = 21.23 ms, 95% CI 18.23-24.23), while QTc prolongation was modest and QT interval showed no significant difference. Novel repolarization markers demonstrated pronounced abnormalities, including an increased frontal QRS-T angle (MD = 26.11°, 95% CI 19.10-33.11), prolonged Tp-e interval (MD = 3.92 ms, 95% CI 2.35-5.49), and greater Tp-e dispersion (MD = 8.21 ms, 95% CI 6.56-9.85), whereas the Tp-e/QT ratio did not differ significantly. These electrophysiological alterations were consistently observed in both drug-naïve and medicated patients.

CONCLUSIONS

Schizophrenia is associated with pronounced ventricular repolarization heterogeneity that extends beyond conventional QTc prolongation and is evident even in drug-naïve patients. To our knowledge, this is the first systematic review and meta-analysis to comprehensively quantify both traditional and novel ventricular repolarization markers in schizophrenia.