Physiological and psychological effects of clorazepate in man

Abstract

1 In the first study, eight healthy volunteers were given single oral doses of 5, 7.5 and 15 mg clorazepate dipotassium (Tranxene), a precursor of n-desmethyldiazepam, and placebo. Drug effects up to 5 h after administration were assessed on a battery of physiological, psychomotor and subjective tests.

2 Psychotropic effects were not marked but decreases in EEG auditory responses and increases in EEG fast-wave activity were detected. Some psychomotor impairment was apparent after the 15 mg dose. Subjective effects comprised some lowering of alertness and changes in sociability. Plasma concentrations of n-desmethyldiazepam 3 h after ingestion were related to dose and correlations were found with the other variables.

3 In the second study, nine subjects received clorazepate 7.5 and 15 mg, and placebo, in a single daily dose for 14 days, with at least 5 weeks between courses. Psychotropic effects were evaluated on the first and last days of drug administration, for up to 5 h following the daily dose. After 15 days, EEG auditory responses were diminished and fast-wave activity increased. Anxiety was diminished but psychomotor effects were minimal.

4 Psychotropic effects following the dose of clorazepate dipotassium on day 15 were compared with those on day 1. Objective measures, the EEG auditory response, fast-wave activity and critical flicker fusion, were significantly less affected on day 15 than on day 1 whereas subjective ratings and the digit-symbol substitution test were more affected.

5 Plasma concentrations of n-desmethyldiazepam increased in a dose-related way over the 2 weeks. Increases following the drug on day 15 were at least as large as those on day 1 suggesting that pharmacokinetic factors could not account for the physiological tolerance noted above.

6 It was concluded that clorazepate dipotassium in doses of 7.5 mg/day provided useful anxiolytic actions without undue sedation.