Double-Blind, Placebo-Controlled, Multicenter Trial of a Vasopressin V₂-Receptor Antagonist in Patients with Schizophrenia and Hyponatremia

Objectives: Hyponatremia (serum sodium [Na⁺] concentration <136 mmol/L) is a prevalent and potentially life-threatening medical comorbidity for schizophrenic patients. No definitive pharmacological treatments have been established. Tolvaptan (OPC-41061), an oral non-peptide V₂-receptor antagonist, was recently shown to correct hyponatremia in a diverse population of 448 hyponatremic patients. Efficacy in a sub-set of 19 schizophrenic patients with idiopathic hyponatremia included in that sample is specifically examined. Methods: Nineteen subjects were randomly assigned to receive placebo (n = 12) or tolvaptan (n = 7) once daily for 30 days. Dosage adjustment was based on serum Na⁺ changes, initially 15 mg, titratable to 30 or 60 mg. The average daily area under the curve (AUC) changes in serum Na⁺ from baseline to Day 4 and Day 30 were co-primary end points. Results: Increases in serum Na⁺ concentrations were significantly greater with tolvaptan than placebo at Day 4 (p = .0055) and at Day 30 (p < .0001). Two subjects receiving tolvaptan (28.6%) became dehydrated and experienced hypotension, and five subjects receiving placebo (41.7%) experienced symptoms associated with dilutional hyponatremia. Conclusions: These results suggest that tolvaptan effectively normalizes idiopathic hyponatremia in schizophrenic patients. Clinicians are advised to carefully monitor fluid status especially at the beginning of treatment to prevent dehydration.