322 2003; Pinder and van Delft 1983). A range of studies have demonstrated that these drugs produce subjective fatigue and sleepiness and impair psychomotor function, cognition, and actual driving performance after acute dosing and to a lesser degree as well as after repeated dosing (Curran et al. 1986; Mattila et al. 1989; Ramaekers 2003; Ramaekers et al. 1998; 1992; Ridout et al. 2003; Wingen et al. 2005; 2006). Several studies have demonstrated that mirtazapine increases sleep efficiency, total sleep time, and slow wave sleep in patients with major depressive disorder and in healthy subjects (Anttila and Leinonen 2001; Radhakishun et al. 2000; Ruigt et al. 1990; Schmid et al. 2006; Winokur et al. 2000). Most of mirtazapine's abilities to produce daytime sedation comes from H1 blockade which is known to reduce arousal state in humans. Mirtazapine's action at the 5-HT2A receptor may also contribute to its sedative effect; however, antagonism at the 5-HT2A receptor is not thought to be responsible for the residual sedative effects seen following nighttime administration of mirtazapine. In clinical practice, antidepressant drugs with H1 antagonistic properties such as mirtazapine have been frequently used for the treatment of insomnia comorbid with various psychiatric disorders (Mayers and Baldwin 2005; Stahl 2008). Likewise, H1 antagonists such as antihistamines are commonly sold over the counter as hypnotic drugs to treat insomnia because of their sleep-inducing propensities (Stahl 2008). Mirtazapine and mianserin clearly have H1 antagonism as their most potent pharmacological property. Yet both drugs are dosed (i.e., 30 mg or more) far above the minimum dose needed to obtain maximal binding to H1 receptors, in order to achieve sufficient serotonergic and noradrenergic action that is required for an antidepressant response. Mirtazapine has a >100-fold higher potency for the H1 receptor than for the 5HT3 and α2 receptors, and a tenfold higher potency for 5HT2 (De Boer and Ruigt 1995a; Stahl 2008). For esmirtazapine, it is postulated that the action on sleep is mediated via antagonism of both, the H1 and the 5-HT2A receptors. The affinity of esmirtazapine to both receptors is high. Considering the action of these drugs on the H1 and 5HT2 receptor alone, sleep-promoting doses of these drugs can be far lower than the regular doses prescribed to treat depression. Effective sleep-promoting doses of esmirtazapine are expected to range between 1.5 and 4.5 mg. The possibility of developing esmirtazapine as a drug for treatment of insomnia however also raises the issue of residual daytime drowsiness and driving impairment since esmirtazapine elimination half-life is long (i.e., >20 h). The effects of H1 antagonism by mianserin and mirtazapine on actual driving performance has been assessed by means of a standardized road-tracking task in previous studies (Ramaekers 2003; Wingen et al. 2005). Acute, daytime doses of mianserin 10 mg t.i.d. produced Psychopharmacology (2011) 215:321–332 elevations in standard deviation of lateral position (SDLP) during on-the-road driving that were equivalent to the effects of a blood alcohol concentration (BAC) >1.0 mg/ml in the same driving test. After sub-chronic dosing, the impairing effects of mianserin reduced in magnitude but were still comparable to a blood alcohol concentration between 0.5 and 0.8 mg/ml. The impairing effects of mianserin (30–60 mg) on daytime SDLP however where much less (i.e., comparable to a BAC <0.05 mg/ml) when the drug was administered in the evening, even though blood mianserin concentrations during driving after noctur- nal and daytime doses were comparable (Ramaekers et al. 1998). Likewise, mirtazapine 15–30 mg also produced mild residual driving impairment when administered as a nocturnal dose. Single doses of mirtazapine 15 and 30 mg produced elevations in SDLP that were comparable to BACs of 0.5 and 0.8 mg/ml. However, mirtazapine no longer produced any clinically relevant changes in driving performance after 1 or 2 weeks of repeated dosing. The effect of 5HT2A/2C antagonism on actual driving has been previously assessed in a study by van Laar et al. (2001). That study demonstrated that single and repeated doses of ritanserin 5 mg b.i.d. increased nocturnal slow wave sleep, but failed to affect driving performance and sleepiness during daytime. This finding supports the present notion that residual impairment from esmirtazapine, if any at all, is more likely to arise from H1 blockade than from 5HT2 blockade. The present study was designed to assess the effects of low, nocturnal doses of esmirtazapine on the next-day actual driving of healthy volunteers as assessed in a standardized on-the-road driving test and in laboratory performance tasks. Esmirtazapine is metabolized through CYP2D6 and its clearance is twice as low in poor metabolizers as compared to extensive metabolizers (Brockmoller et al. 2007). In the design phase, it was decided to select a representative population for this study, without restrictions on CYP2D metabolizer status. This allowed for an additional “post hoc” explorative analysis on the effects of esmirtazapine on actual driving performance for poor and extensive metabolizers as determined by cytochrome P450 2D6 (CYP2D6) phenotyping. Methods Subjects Thirty-two healthy subjects, 16 men and 16 women, mean (SD) age = 33 (9) years, were recruited by advertisement in local newspapers. Subjects were screened by a telephone interview and a health questionnaire, and all underwent a medical examination (including a standard 12-lead electro-