Psychopharmacology (2011) 215:321–332 cardiogram, blood hematology and chemistry, urinalysis, and drug and pregnancy screening). Selection was based on the following inclusion criteria: possession of a valid driving license for more than 3 years, driving experience of >5,000 km per year on average, normal binocular visual acuity corrected or uncorrected, willingness to use double- barrier method of birth control, body mass index of 18 to 30 kg/m2 and written informed consent. Subjects who met one or more of the following criteria were excluded from the study: history or present evidence of a serious illness such as renal, hepatic, cardiovascular, pulmonary, endocrine, neurologic or psychiatric, hemato- logic, or gastrointestinal diseases; insomnia or other sleep disorders; pregnancy (as determined at screening) or breastfeeding; known hypersensitivity to medicinal drugs; treatment with an investigational drug within 3 months prior to screening; use of medicines (except oral contra- ceptives and paracetamol); excessive smoking (more than five cigarettes a day); night work or rotation shift work, overconsumption of alcohol (more than 2 units per day) or caffeine (more than five cups of regular coffee a day); positive result of urine drug screening at the screening visit for alcohol and/or drug of abuse. The study was approved by the standing Medical Ethics Committee of Maastricht University and was carried out in compliance with the current revision of the Declaration of Helsinki, International Conference on Harmonization guideline for Good Clinical Practice. Design and treatments The study was conducted according to a randomized, double-blind, placebo-controlled, four-way crossover de- sign. Treatments were administered in separate 7-day series, and treatment orders were balanced following a Williams design and assigned by a predetermined randomization schedule, stratified by gender. The following treatment conditions were defined: nocturnal doses of 1.5 mg esmirtazapine on day 1–7; nocturnal doses of 4.5 mg esmirtazapine on day 1–7; nocturnal doses of placebo on day 1–7; and nocturnal doses of placebo on day 1–6 and zopiclone 7.5 mg on day 7. The zopiclone treatment was included to serve as an active control and to demonstrate (assay) sensitivity of the driving test to residual drug effects. Zopiclone 7.5 mg has repeatedly been shown to produce residual driving impairment the in standardized highway driving test (Vermeeren 2004). During days 1–7 of all treatment periods, trial medica- tion was taken by the subjects at their homes. Subjects recorded the time of administration in a diary. On days 2–6, trial medication was taken in the evening, within 30 min before going to bed. On day 1 and 7, trial medication was administered under supervision of a research associate at a 323 fixed time of drug administration (i.e., 2130 hours). Sub- jects went to bed within 1 h after drug intake. The washout period between treatments was at least 7 days. Driving tests and cognitive tests were administered at days 2 and 8 of treatment, with the driving test starting on average 11 h after drug intake (range, between 10 and 11.5 h) and the cognitive and psychomotor tests starting approxi- mately 13 h after drug intake. All subjects scored negative on drug and alcohol screens at all times that were conducted on test days prior to performance testing. A blood sample was taken between the driving test and the cognitive psychomotor performance tests. Subjects were instructed to refrain from alcohol use 24 h prior to and throughout treatment periods. A summary of treatment and performance assessments schedule on day 2 and 8 is given in Fig. 1. Performance tests Driving and psychometric tests were trained during two separate training sessions prior to the first treatment condition in order to minimize learning effects. Highway driving test In the highway driving test (O'Hanlon 1984; O'Hanlon et al. 1982), the subjects operate a specially instrumented vehicle for about 1 h over a 100 km primary highway circuit while maintaining a constant speed (95 km/h) and a steady lateral position between the delineated boundaries of the right (slower) traffic lane. An electro-optical device mounted at the rear back of the car continuously measures lateral distance separating the vehicle and the left lane-line. This signal is digitized at a rate of 4 Hz and stored on an onboard computer disk file for later editing analysis. The off-line editing routine involves removal of all data segments that reveal signal loss, disturbance or occurrence of passing maneuvers. The edited dataset is then used to calculate means and variances for lateral position. SDLP is taken as the primary outcome variable. SDLP is a measure of road tracking error, in practical terms, a composite index of allowed weaving, swerving, and overcorrecting. The high- way driving test has been calibrated in a manner allowing expression of any sedative drug effect in terms of the BAC required to achieve the equivalent level of driving impair- ment (Louwerens et al. 1987). The alcohol calibration curve demonstrates that drinkers' mean SDLP rises exponentially with BAC. Results from the alcohol calibration study can be used for describing drugs' effects on SDLP in terms of respective BAC equivalencies. The change in SDLP at a BAC of 0.5 mg/ml has been used as a criterion level to quantify drug effects. Any drug-induced changes in SDLP that exceed this criterion value are defined as clinically relevant impairing drug effect in the present study.