Comparison of clozapine doses and tolerability in patients with and without concurrent valproic acid

Abstract

Introduction: Valproic acid (VPA) and its various formulations can be given in conjunction with clozapine for seizure prophylaxis or for augmentation in schizophrenia. There is conflicting literature on how VPA affects clozapine metabolism and the incidence of clozapine-related side effects. The purpose of this study is to compare the effects of VPA when given concurrently with clozapine to patients on clozapine monotherapy.

Methods: A retrospective medical record review was completed to identify patients admitted to the inpatient psychiatry unit at an academic medical center with an order for clozapine with and without concurrent VPA from August 7, 2010 to August 7, 2020. The primary outcome was the difference in clozapine doses in patients on clozapine as monotherapy versus dual therapy with VPA. Secondary outcomes include the difference in incidence of adverse effects in monotherapy versus dual therapy, as well as clozapine and norclozapine concentrations in both treatment groups.

Results: During the study period, 73 patients were included in the monotherapy group and 35 patients were included in the dual therapy group. The average clozapine dose in the dual therapy group was 250 mg (95% CI = 194.7, 305.4) which was significantly higher than the average monotherapy dose of 175.9 mg (95% CI = 134.0, 208.7; P = .016). However, there was no significant difference in the average clozapine concentration between the dual therapy group (392.5 ng/mL; 95% CI = 252.8, 532.2) and monotherapy group (365.9 ng/mL; 95% CI = 260.5, 471.3; P = .756). There were higher rates of tachycardia (45.7% vs 17.8%; P = .002), sedation (51.4% vs 8.2%; P < .001), and constipation (42.8% vs 9.5%; P < .001) in the dual therapy group compared to the monotherapy group, respectively.

Discussion: Patients on concurrent clozapine and VPA received higher doses of clozapine and experienced a higher incidence of tachycardia, sedation, and constipation.

Keywords: clozapine; divalproex; drug interactions; norclozapine; pharmacokinetics; schizophrenia; valproic acid.