Subchronic effects of the GABA-agonist lorazepam and the 5-HT2A/2C antagonist ritanserin on driving performance, slow wave sleep and daytime sleepiness in healthy volunteers

Rationale: Lorazepam, a benzodiazepine anxiolytic, may increase daytime sle epiness and impair psychomotor performance, which is hazardous for patients engaging in daily activities such as car driving. Given current prescripti on practice, information on the repeated dose effects is required. The 5-HT 2A/2C antagonist ritanserin was originally developed as a safer alternative to the benzodiazepines, yet having limited clinical efficacy. 5HT(2A/2C) r eceptors have been implicated in regulating slow-wave sleep but little is k nown about their role in human performance. Objective: The present study in vestigated the subchronic effects of the benzodiazepine anxiolytic lorazepa m and the 5-HT2A/2C antagonist ritanserin on actual driving performance, ob jective and subjective sleepiness, and nocturnal slow wave sleep. Methods: Eighteen healthy volunteers were treated twice daily for 7 days with ritans erin 5 mg, lorazepam 1.5 mg or placebo. Treatments were administered accord ing to a double-blind, cross-over design. Tests were performed on day 7 of each treatment week. Sleep EEG was recorded during the preceding night, Res ults: Lorazepam had a pronounced impairing effect on lateral position contr ol and induced daytime sleepiness, while having no effect on other paramete rs. In contrast, ritanserin did not impair driving performance or affect ob jectively measured daytime sleepiness, while subjects reported to feel more alert during daytime. Moreover, consistent with its effects on 5-HT2 recep tors, ritanserin increased the amount of nocturnal slow wave sleep. There w ere no relationships between changes in slow wave sleep and performance par ameters. Conclusions: Lorazepam administered for 7 consecutive days may be hazardous for patients who engage in driving activities. Antagonism of 5-HT 2A/2C receptors, as accomplished by ritanserin, increases slow wave sleep a nd is devoid of effects on objective sleepiness and driving behaviour. Whet her this extends to other cognitive and psychomotor domains remains to be e stablished.