Plasma concentrations of diazepam and of its metabolite <i>N</i>‐desmethyldiazepam in relation to anxiolytic effect

Abstract

Fifteen nonpsychotic patients suffering from acute anxiety in a crisis situation, admitted for a short inpatient treatment, were treated orally with diazepam (Valium), 20 mg daily, for a period of at least 5 consecutive days. Measurements were made on 3 levels: (1) psychometric measurements, using rating scales, for the degree of improvement of a wide variety of anxiety symptoms, (2) pharmacochemical measurements of plasma levels of diazepam and its main active derivative N‐desmethyldiazepam, (3) clearance rates relative to body weight were calculated, (4) correlation between improvement ratings on the one hand and plasma concentrations and clearance ratings of both substances on the other hand. A control group consisted of 15 similar patients receiving placebo. The design was double‐blind and randomized. Our results suggest that the degree of the diazepam effect is directly proportional to plasma concentrations and reCiprocal clearance values of diazepam and N‐desmethyldiazepam. The minimal effective plasma concentration in the steady state is 400 ng per milliliter. The desmethyl metabolite has a slightly different action than diazepam, even a disturbing action on certain symptoms, with plasma levels of 300 ng per milliliter or more. Monitoring of diazepam treatment on the basis of plasma concentrations seems to be advisable.