Autonomic signs and dosing during the initial stages of clozapine therapy

Recent reports implicate clozapine in heart rate variability, QTc prolongation, torsade de pointes and sudden death at therapeutic doses, even in physically healthy patients. This study aims to examine whether autonomic (vital) signs are correlated with clozapine dose titration and blood levels of clozapine and nor-clozapine during clozapine therapy.

Thirty-seven consecutive patients with diagnosis of schizophrenia treated with clozapine were included in this prospective longitudinal study. The study was restricted to only the first 8 weeks of treatment. After obtaining informed consent, serum concentrations of clozapine and nor-clozapine were determined weekly at trough, as doses were administered q12h and adjusted according to clinical guidelines for clozapine use. Autonomic signs including BP (supine and erect), pulse (supine and erect) and temperature were monitored daily each morning before and one hour after the morning's dose of clozapine was administered.

We calculated analyses of covariance (ANCOVAs) to evaluate the changes in vital signs parameters, from baseline to week 8, with clozapine variables as covariates (i.e, the dose of clozapine, as well as the levels of serum clozapine and nor-clozapine). The blood pressure and pulse did not change significantly (p<0.01) from baseline to weeks 8. The temperature was inversely related to clozapine dose (p<0.003). Higher nor-clozapine to clozapine ratios were associated with higher BP measures (p=0.002). The magnitude of these relationships is weak (r<0.30).

There is a tendency to autonomic dysregulation during clozapine use. This has cardiac function implications, justifying cautious dose adjustment with frequent monitoring of vital signs.