324 Psychopharmacology (2011) 215:321–332 Esmirtazapine maleate 1.5 mg s t en Esmirtazapine maleate 4.5 mg m t rea PLA T PLA ZOP y a D 1 2 3 4 5 6 7 8 Highway driving, cognitive and psychomotor assessments 8:00h arrival 21:30h 8.30h 9.30h 10.45h 12:00h drug intake alcohol breath test drug screen Highway driving test blood sample Cognitive and psycho- motor assessments end of tests Fig. 1 Summary of treatments and activities schedule on days 2 and 8 in every treatment condition. ZOP zopiclone 7.5 mg, PLA placebo Cognitive and psychomotor tests The word learning task is a verbal memory test for the assessment of immediate recall and delayed recall. Fifteen monosyllabic nouns sounded for 2 s. At the end of the sequence the subject is asked to recall as many words as possible (recall-order unimportant). The number correct is scored as the first trial score. This procedure is repeated three times and the summed trial score is referred to as the immediate recall score (number). After a delay of at least 20 min, the subject is again required to recall as many words as possible (without new presentation of the nouns). The number correct is referred to as the delayed recall score (number). The word learning task was conducted during the highway driving test. The stop-signal task requires subjects to make quick key responses to visually presented go signals and to inhibit any response when a visual stop signal is suddenly presented. The current test is adapted from an earlier version of Fillmore et al. (2002) and has been validated for showing stimulant and sedative drug effects (Ramaekers et al. 2006; Ramaekers and Kuypers 2006). The go signals were four 1.5-cm letters (ABCD) presented one at a time in the center of a computer screen. Subjects were required to respond to each letter as quickly as possible by pressing one of two response buttons. One button is pressed to indicate that “A” or “C” appeared and the other to indicate “B” or “D”. Letters were displayed for 500 ms and the computer screen was blank for 1.5-s interstimulus interval before the next letter was displayed. This provides a period of 2 s during which the subject can respond to a letter. A single test consists of 176 trials in which each of the four-letter stimuli is presented equally often. A stop signal occurs in 48 trials during a test. The stop signal consists of visual cue, i.e., “*”, that appears in one of the four corners of the screen. Subjects are required to withhold any response when a stop-signal is presented. The task lasts about 10 min. Primary dependant variable is reaction time in stop trials (millisecond). Secondary param- eters are response time (millisecond) in go trials and number of errors in go and stop trials (number). The critical tracking task measures the subject's ability to control a displayed error signal in a first-order compensa- tory tracking task. Error is displayed as a horizontal deviation of a cursor from the midpoint on a horizontal, linear scale. Compensatory joystick movements the error by returning the cursor to the midpoint. The frequency at which the subject loses the control is the critical frequency or λc (radians per second). The test includes five trials of which the lowest and the highest score are removed; the average of the remaining scores is taken as the final score. The divided attention task measures the subject's ability to divide attention between two tasks performed simulta- neously. The primary task consist of tracking task as described above but at a constant level of difficulty set at 50% of the subject's maximum capacity. Tracking error is measured as the difference in millimeters between the position of the cursor and the midpoint of the scale. In the secondary task, the subject monitors a central display upon which single digits are presented at 1-s intervals. The occurrence of the digit “2” is a signal for the subject to remove the foot from a pedal as rapidly as possible. Interstimulus interval varies between 1 and 2 s. Mean absolute tracking error (millimeters) and Average Reaction Time (milliseconds) are the main performance measures. CYP2D6 phenotyping CYP2D6 characterization was performed prior to the first intake of trial medication in period 1 of the four-period