Psychopharmacology (2011) 215:321–332 DOI 10.1007/s00213-010-2149-4 ORIGINAL INVESTIGATION Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype Johannes G. Ramaekers & Silke Conen & Pieter Jan de Kam & Sabine Braat & Pierre Peeters & Eef L. Theunissen & Neely Ivgy-may Received: 25 October 2010 / Accepted: 8 December 2010 / Published online: 19 January 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Introduction Esmirtazapine is evaluated as a novel drug for treatment of insomnia. Purpose 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. Methods Treatments were administered in the evening. Driv- ing 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. Results 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 This trial has been registered at ClinicalTrials.gov as NCT00798395 http:// www.clinicaltrials.gov/ct2/show/NCT00798395?term=21105&rank=1 J. G. Ramaekers (*) : S. Conen : E. L. Theunissen Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands e-mail: j.ramaekers@maastrichtuniversity.nl P. J. de Kam : S. Braat : P. Peeters MSD, Oss, The Netherlands N. Ivgy-may Merck & Co., Summit, NJ, USA select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. Conclusion 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. Explorato- ry 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. Keywords Hypnotics . H1 antagonism . Driving . Cognition . CYP2D6 phenotype Introduction Esmirtazapine maleate (Org 50081) is the maleate salt of the S(+)-enantiomer of the racemic drug mirtazapine. Racemic mirtazapine is marketed for the treatment of major depressive disorder. Mirtazapine is a close analog of its predecessor mianserin that also has been marketed for major depressive disorder. Esmirtazapine and mirtazapine bind to presynaptic α2 receptors as well as to postsynaptic 5HT2 and H1 receptors where they act as antagonists of the endogeneous ligands (de Boer and Ruigt 1995b; Pinder and van Delft 1983); however, compared with mirtazapine and R-mirtazapine, esmirtazapine has higher affinity to 5-HT2 receptors and low affinity to the 5-HT3 receptors and to the muscarinic receptors (de Boer et al. 1988; Kooyman et al. 1994). Esmirtazapine is under development for the treat- ment of primary insomnia and hot flushes. Antidepressants such as mirtazapine and mianserin are well known for their sedative properties (Biswas et al.