330 Table 4 Summary of adverse events during the first 24 h after first drug intake only with an incidence of at least 5% in any treatment group Adverse events Fatigue Somnolence Dysgeusia Disturbance in attention Headache Poor quality sleep Irritability sensitive to the impairing potential of esmirtazapine. Incre- ments in SDLP were more pronounced than placebo after single doses of esmirtazapine 1.5 and 4.5 mg in poor metabolizers. After a week of repeated dosing, the low dose of esmirtazapine no longer produced any relevant impair- ment in poor metabolizers. However, while the absolute effect on SDLP compared to placebo for poor metabolizers was still below the non-inferiority margin of 2.5 cm, the highest dose still produced an increment in SDLP after 1 week of dosing, which may indicate that tolerance to impairing effects of esmirtazapine may not have been complete after 7 days of dosing. These findings support the notion that dose effects of esmirtapine on driving are closely related to the drug's concentration in plasma. For the extensive metabolizers, the results were similar to those obtained in the main analysis. No relevant impairment was observed after single and multiple doses of esmirtazapine 1.5 mg, whereas esmirtazapine 4.5 mg produced a small, but clinically relevant increase in SDLP only after the initial dose. A limitation of this explorative analysis on poor metabolizers is (N = 7) is that the present study was not powered to demonstrate non-inferiority of esmirtazapine to placebo in this small number of subjects (N = 7). Small numbers of subjects lead to wider confidence intervals which increase the chance that upper limits of 95% confidence intervals exceed a pre-specified limit, hamper- ing their interpretation. For example, CIs in poor metabo- lizers (N = 7) are about twice as wide as those in extensive metabolizers (N = 25). Consequently, one must be cautious when comparing the upper CI limit of the mean difference in SDLP with placebo in poor metabolizers to a pre- established alcohol equivalent, as the CI may actually become less wide with increasing subject numbers. None- theless, the results of the current analysis indicated more pronounced driving impairment in poor metabolizers after treatment with esmirtazapine. Although the exact magni- tude of this driving impairment should be determined in a larger subject sample when comparing to alcohol criterion levels, these results are in line with the observation that Psychopharmacology (2011) 215:321–332 Placebo (N=31) n (%) 6 (19.4) 1 (3.2) 3 (9.7) 0 (0.0) 1 (3.2) 5 (16.1) 2 (6.5) Esmirtazapine 1.5 mg (N=30) n (%) 10 (33.3) 4 (13.3) 2 (6.7) 2 (6.7) 2 (6.7) 1 (3.3) 0 (0.0) Esmirtazapine 4.5 mg (N=32) n (%) 9 (28.1) 8 (25.0) 1 (3.1) 1 (3.1) 0 (0.0) 0 (0.0) 0 (0.0) Zopiclone 7.5 mg (N=30) n (%) 2 (6.7) 0 (0.0) 1 (3.3) 0 (0.0) 1 (3.3) 1 (3.3) 0 (0.0) esmirtazapine has a dose-dependent effect on driving performance, with impairment observed after a single dose of 4.5 mg or higher. In subjects with higher exposure, such as CYP2D6 poor metabolizers, the effect on driving performance is therefore likely to be more pronounced and impairment may be experienced even with a lower dose. It should be noted that the CYP2D6 phenotype only accounts for some of the inter-individual variability observed in the driving performance. While an effect on performance by gender and age, for example, was not observed, other factors may still exist that significantly influence the subject's susceptibility to drug effect on car driving performance. Thus, the general implications of these findings with regards to clinical practice may result in a recommendation to start treatment with the lowest available dose until therapeutic effect and tolerability are evaluated. Esmirtazapine is being evaluated for the treatment of insomnia in the dose range of 1.5–4.5 mg. Given the acute effect of esmirtazapine at 4.5 mg on driving performance, a 1.5 mg/day starting dose of esmirtazapine treatment may be recommended until therapeutic effect and tolerance is evaluated and the need to increase the dose is confirmed. It should be noted here that factors that influence variability in drug response in general and, specifically, in CYP2D6 phenotype do not just pertain to esmirtazapine. For example, CYP2D6 is the major route of metabolism for many sedative CNS drugs such as antidepressants, anti- psychotics, opioids, and antihistamines (Ingelman-Sundberg et al. 2007). Previous studies on the effects of drugs on driving have never taken CYP2D6 genotype into account. These explorative results indicate that subjects with genetic CYP deviations (e.g., poor CYP 2D6 metabolizers) may be at higher risk to be exposed to higher levels of drugs or metabolites which have the potential to impair car driving. A distinction in poor and extensive metabolizers may be of particular importance when overall driving impairment levels in the general study population are mild. Based on such an overall finding, the conclusion would be that driving is not contraindicated for a particular substance. However, factors