326 medication was 100% after single doses and multiple doses of all treatments. Highway driving, cognition, and psychomotor function Overall, mean (SD) SDLP after single doses of esmirtaza- pine 1.5 mg, esmirtazapine 4.5 mg, zopiclone 7.5 mg and placebo were 19.6 (3.6), 20.3 (3.4), 20.6 (3.3), and 18.3 (2.9), respectively. Mean (SD) SDLP after repeated doses of esmirtazapine 1.5 mg, esmirtazapine 4.5 mg and placebo were 19.8 (3.6), 19.8 (3.8), and 19.5 (3.3), respectively. Assay-sensitivity was clearly demonstrated as shown by the inferiority of zopiclone 7.5 mg to placebo: i.e., the lower limit of the 95% CI was above zero. Moreover, the estimated mean difference in SDLP between zopiclone and placebo was larger than the non-inferiority margin of 2.5 cm, with an upper limit of the 95% CI of 3.6 cm. The primary endpoint, mean difference in SDLP after multiple dose treatment of esmirtazapine 4.5 mg with placebo, clearly showed non-inferiority, i.e., the upper limit of the 95% CI of the estimated mean difference in SDLP of multiple-dose esmirtazapine 4.5 mg vs. placebo was lower than the non-inferiority margin of 2.5 cm. In agreement with this finding, the estimated mean difference in SDLP following single- and multiple-dose treatment of esmirta- zapine 1.5 mg as compared to placebo, also showed non- inferiority. However, following single doses of esmirtzapine 4.5 mg, non-inferiority to placebo could not be demon- strated; the upper limit of the 95% CI of SDLP (3.2 cm) exceeded the non-inferiority margin of 2.5 cm. The mean (95% CI) differences from placebo in SDLP values for all treatment conditions are shown in Fig. 2. In total, 7 (22%) subjects were classified as poor metabolizers and 25 (78%) subjects as extensive metabo- lizers. The explorative analysis on poor metabolizers (N = 7) indicated inferiority compared to placebo following single- dose administration of 1.5 and 4.5 mg esmirtazapine, as the upper limits of the 95% CI of SDLP difference vs. placebo exceeded the non-inferiority margin and the lower limits Psychopharmacology (2011) 215:321–332 were above zero. After multiple doses, non-inferiority was demonstrated for the lower dose of esmirtazapine, but not for the higher dose. The analysis of the data subset from extensive metabo- lizers (N = 25) yielded results similar to those obtained from the data of the entire study population. In extensive metabolizers, non-inferiority was shown for the mean difference vs. placebo in SDLP after a single dose of esmirtazapine 1.5 mg and after multiple doses of esmirta- zapine 1.5 and 4.5 mg. Non-inferiority vs. placebo was not shown for SDLP after a single dose of esmirtazapine 4.5 mg. Mean (95% CI) SDLP in poor and extensive metabolizers is shown in Fig. 3. When comparing poor and extensive metabolizers, there were no statistically significant differences between the two metabolizer groups for any of the four treatment compar- isons for interest (i.e., for the comparison of esmirtazapine single dose of 1.5 mg to placebo (p = 0.43), single dose of 4.5 mg to placebo (p = 0.09), multiple dose of 1.5 mg to placebo (p = 0.26), and multiple dose of 4.5 mg to placebo (p = 0.29)). It should be noted that the study was not powered to draw conclusions on non-inferiority within or between subgroups. Laboratory test demonstrated that the effects of zopi- clone on cognition and psychomotor function were not shown to be statistically different from placebo. In general, the cognitive tests results for mirtazapine did not show clear dose–response relationship or major differences between the results following single-dose and multiple-doses ad- ministration. Moreover, esmirtazapine did not show statis- tical differences from placebo for most laboratory measures, except for tracking error in the divided-attention task. The performance on this task was statistically significantly worse than placebo after single and multiple doses of 1.5 mg and single doses of 4.5 mg esmirtazapine, but not after multiple dose of 4.5 mg esmirtazapine. Following esmirtazapine 1.5 mg single doses only, delayed recall in the word learning task and response time in the divided attention task also showed a statistically significant Fig. 2 Mean (95% CI) SDLP difference from placebo after single doses of esmirtazapine (ESM) and zopiclone (ZOP) and after multiple doses of ESM. Single asterisk, non-inferiority not shown, upper bound of the 95% CI is above the non- inferiority margin of 2.5 cm 4.5 3.5 )m 2.5 c ( P 1.5 L D S 0.5 Δ -0.5 -1.5 Single dose * * Multiple doses ESM 1.5 ESM 4.5 ZOP 7.5 ESM 1.5 ESM 4.5 Equivalent effect BAC 0.5 mg/mL Non inferiority margin