Psychopharmacology (2011) 215:321–332 Table 2 Mean (SD) and median esmirtazapine plasma concentrations (nanograms/millilter) in poor and extensive metabolizers Esmirtazapine 1.5 mg 4.5 mg Mean (SD) Median Mean (SD) Median Extensive metabolizers (N=25) Day 2 0.53 (1.02) 0.34 1.05 (0.44) 0.92 Day 8 0.54 (0.42) 0.47 1.52 (0.66) 1.29 Poor metabolizers (N=7) Day 2 0.67 (0.27) 0.66 2.07 (0.84) 1.80 Day 8 0.97 (0.70) 0.81 2.12 (0.96) 2.53 Overall (N=32) Day 2 0.56 (0.91) 0.35 1.28 (0.70) 1.10 329 Day 8 0.63 (0.51) 0.48 1.64 (0.75) 1.38 such as mirtazapine on next-day driving performance however were markedly lower when given in the evening. The impairing effects of antidepressants on driving were mostly present after single doses but disappeared after 1 week of repeated dosing due to tolerance (Ramaekers 2003). Likewise, single doses of antihistamines have been demonstrated to significantly increase SDLP in a dose- related manner (O'Hanlon and Ramaekers 1995). However, the impairing effects of antihistamines on actual driving also resolved after 4–7 days after repeated dosing. In the present study, a single dose of esmirtazapine 4.5 mg also produced significant driving impairment, but the impairing effects rapidly resolved after 1 week of repeated dosing. The implications would be twofold. First, next-day driving need not be a priori contraindicated for esmirtazapine 1.5 mg as overall it did not produce relevant driving impairment after single and repeated doses. Second, next- day driving is not advised for patients taking a higher dose of esmirtazapine (i.e., 4.5 mg), but only during treatment initiation or initially after dose increase. However, while the overall effect of esmirtazapine on driving performance is limited and transient, some subjects may be more susceptible to drug effects on driving impairment. In the case of esmirtazapine, which is a substrate for CYP2D6, patients who are poor metabolizers of CYP2D6 may experience greater impairment. In general, CYP2D6 has high relevance in drug metabolism. CYP2D6 is involved in the metabolism of 20–25% of clinically used drugs and exhibits a clinically relevant gene polymorphism that modifies the pharmacokinetics in patients that are either poor or extensive metabolizers (Ingelman-Sundberg et al. 2007; Tomalik-Scharte et al. 2008). About 5–10% of the Caucasian populations are poor metabolizers of CYP2D6 substrates which may cause elevated substrate concentrations in blood of these individuals. In the present study, seven subjects (22%) were phenotyped as poor metabolizers. Especially for 4.5 mg esmirtazapine, mean and median plasma concentrations of esmirtazapine were about twice as high as the levels observed in extensive metabolizers. Poor metabolizers also appeared to be more Table 3 Summary of adverse events with incidence of at least 5% in any treatment group Esmirtazapine 1.5 mg (N=30) n (%) Esmirtazapine 4.5 mg (N=32) n (%) Zopiclone 7.5 mg (N=30) n (%) Adverse events Fatigue Somnolence Headache Poor quality sleep Dysgeusia Nasopharyngitis Dizziness Disturbance in attention Oral herpes Oropharyngeal pain Dry mouth Vomiting Irritability Placebo (N=31) n (%) 11(35.5) 1(3.2) 2(6.5) 6(19.4) 4(12.9) 1(3.2) 1(3.2) 1(3.2) 0(0.0) 0(0.0) 1(3.2) 2(6.5) 2(6.5) 12(40.0) 9(30.0) 4(13.3) 3(10.0) 2(6.7) 2(6.7) 2(6.7) 2(6.7) 2(6.7) 2(6.7) 1(3.3) 0(0.0) 0(0.0) 9(28.1) 10(31.3) 1(3.1) 1(3.1) 1(3.1) 1(3.1) 2(6.3) 1(3.1) 0(0.0) 0(0.0) 2(6.3) 1(3.1) 0(0.0) 3(10.0) 1(3.3) 2(6.7) 1(3.3) 1(3.3) 0(0.0) 1(3.3) 0(0.0) 0(0.0) 0(0.0) 0(0.0) 1(3.3) 0(0.0)