Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands.
Psychopharmacology (Impact Factor: 3.99). 05/2011; 215(2):321-32. DOI: 10.1007/s00213-010-2149-4
Source: PubMed

ABSTRACT Esmirtazapine is evaluated as a novel drug for treatment of insomnia.
The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control.
Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine.
Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected.
It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving.


Available from: Silke Conen, Apr 18, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Medication and illicit drugs can have detrimental side effects which impair driving performance. A drug's impairing potential should be determined by well-validated, reliable, and sensitive tests and ideally be calibrated by benchmark drugs and doses. To date, no consensus has been reached on the issue of which psychometric tests are best suited for initial screening of a drug's driving impairment potential. The aim of this alcohol calibration study is to determine which performance tests are useful to measure drug-induced impairment. The effects of alcohol are used to compare the psychometric quality between tests and as benchmark to quantify performance changes in each test associated with potentially impairing drug effects. Twenty-four healthy volunteers participated in a double-blind, four-way crossover study. Treatments were placebo and three different doses of alcohol leading to blood alcohol concentrations (BACs) of 0.2, 0.5, and 0.8 g/L. Main effects of alcohol were found in most tests. Compared with placebo, performance in the Divided Attention Test (DAT) was significantly impaired after all alcohol doses and performance in the Psychomotor Vigilance Test (PVT) and the Balance Test was impaired with a BAC of 0.5 and 0.8 g/L. The largest effect sizes were found on postural balance with eyes open and mean reaction time in the divided attention and the psychomotor vigilance test. The preferable tests for initial screening are the DAT and the PVT, as these tests were most sensitive to the impairing effects of alcohol and being considerably valid in assessing potential driving impairment.
    Psychopharmacology 01/2014; 231(12). DOI:10.1007/s00213-013-3408-y · 3.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to assess whether a lower initial dose of mirtazapine can lessen the harmful effect on driving performance or not in a double-blinded, placebo-controlled crossover trial. Thirteen healthy men received 8 days of continuous nocturnal doses of mirtazapine at 7.5 mg or 15 mg, or placebo. At baseline and on days 2 and 9, subjects performed three driving tasks (road-tracking, car-following, and harsh-braking tasks) using a driving simulator and a Continuous Performance Test. Stanford Sleepiness Scale (SSS) scores were also assessed. In the mirtazapine 7.5 mg series, 15 mg of mirtazapine was additionally administered on day 9, followed by all the same assessments on day 10. Mirtazapine 7.5 mg had no significant effects on any tasks except for SSS compared with placebo. Mirtazapine 15 mg impaired road-tracking task and SSS. The increase in mirtazapine dose also had no significant effects on any tasks compared with those before dose increase. Mirtazapine 7.5 mg did not cause driving impairment compared with mirtazapine 15 mg, while both doses of mirtazapine produced subjective somnolence. The increase in mirtazapine had no detrimental effects on psychomotor performance. Initial low-dose mirtazapine may be safer for automobile driving than the normal starting dose. Copyright © 2013 John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 09/2013; 28(5). DOI:10.1002/hup.2327 · 1.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Study Objective: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). Design: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. Setting: Maastricht University, The Netherlands. Participants: Forty healthy volunteers (20 females). Interventions: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. Measurements: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. Result: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. Conclusion: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning = 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. Clinical Trial Information: Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet;
    Sleep 03/2014; 37(3):489-96. DOI:10.5665/sleep.3482 · 5.06 Impact Factor