Psychopharmacology (2011) 215:321–332 Fig. 3 Mean (95% CI) SDLP difference from placebo after single doses of esmirtazapine (ESM) and after multiple doses of ESM in poor (N=7) and extensive metabolizers (N=25). Single asterisk, non-inferiority not shown, upper bound of the 95% CI is above the non- inferiority margin of 2.5 cm 8 7 6 5 ) 4 (cm3 P 2 L D 1 S Δ 0 -1 -2 -3 -4 Poor metabolizers * * * Extensive metabolizers 1 * Single dose Multiple doses Single dose Multiple doses ESM 1.5 ESM 4.5 ESM ESM 1.5 4.5 ESM ESM 1.5 4.5 ESM ESM 1.5 4.5 327 Equivalent effect BAC 1.0 mg/mL 0.8 mg/mL 0.5 mg/mL Non inferiority margin worsening compared with placebo. A summary of perfor- mance on cognitive and psychomotor measures is given in Table 1. Discussion Pharmacokinetics A summary of mean (SD) and median esmirtazapine concentrations is given in Table 2. In general, mean and median esmirtazapine concentrations in poor metabo- lizers were about twice as high as those of extensive metabolizers. Adverse events Treatment of esmirtazapine for 7 days was generally safe and well tolerated. Overall, somnolence and fatigue were the most frequently reported adverse events. Somnolence was mainly experienced by subjects treated with esmirta- zapine 1.5 or 4.5 mg. A summary of adverse events reported with incidence of at least 5% in any treatment during all treatments and during the first 24 h after first treatment dose is given in Table 3 and 4, respectively. After single-dose administration, somnolence and fatigue were also the most frequently reported adverse events. Note that adverse events summarized under placebo were reported on two single-dose days (i.e., combining the first day of placebo in the zopiclone group and first day of placebo in the placebo group). Furthermore, while the single-dose safety evaluation of placebo and esmirtazapine refer to the first day of treatment, the single-dose zopiclone results refer to the seventh day of treatment., where subjects are less likely to report AEs (including drug-related AE) if these AE were already reported earlier during this treatment period while on placebo. As can be seen in Table 4, the overall frequency of adverse events as well as the frequencies of reported somnolence and fatigue while on zopiclone is lower than that reported while on placebo. Overall, non-inferiority vs. placebo was demonstrated for multiple doses of 1.5 mg and multiple doses of 4.5 mg esmirtazapine as compared to placebo. The results for these esmirtazapine doses indicated that the overall effects of esmirtazapine on car driving were mild and of no clinical relevance after 1 week of dosing. However, following a single dose of 4.5 mg esmirtazapine, non-inferiority could not be demonstrated as compared to placebo. While the mean SDLP difference vs. placebo was somewhat lower than the effect observed with 0.05 BAC, the upper limit of the 95% CI exceeded the non-inferiority margin. Thus, a single dose of 4.5 mg esmirtazapine produced a statistically and clinically significant driving impairment. After repeated administration for 1 week, both doses of esmirtazapine did not produce any residual impairment as is evident by the finding that the 95% CI of mean difference in SDLP vs. placebo always contained zero and its upper limit was well below the non-inferiority margin. The finding of driving impairment after single dose of 4.5 mg but not after single doses of 1.5 mg esmirtazapine suggests that the acute effect of esmirtazapine on driving impairment is dose dependent. This effect rapidly resolves after repeated administration. Previous studies (O'Hanlon and Ramaekers 1995; Ramaekers 2003) on the effects of H1 antagonists on actual driving performance have shown more pronounced effects on SDLP than those observed after esmirtazapine in the present study, however, the overall pattern was similar. Antidepressants with strong H1 antagonistic activity such as amitriptyline, imipramine, and doxepin all produced signif- icant driving impairment after single doses administered during the day. Difference in SDLP from placebo after single doses of these sedating antidepressants were compa- rable to those seen in drivers conducting the same test with a blood alcohol concentration (BAC) of 0.8 mg/ml or higher. The impairing effects of sedating antidepressants