Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype.
BACKGROUND
Esmirtazapine is evaluated as a novel drug for treatment of insomnia.


OBJECTIVE
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. 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.


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 select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected.


CONCLUSIONS
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.
Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands. j.ramaekers@maastrichtuniversity.nl
Johannes G
JG
Ramaekers
Silke
S
Conen
Pieter Jan
PJ
de Kam
Sabine
S
Braat
Pierre
P
Peeters
Eef L
EL
Theunissen
Neely
N
Ivgy-May
D000328:Adult; D001334:Automobile Driving; D053961:Azabicyclo Compounds / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology*; D003915:Dextromethorphan / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005260:Female; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000078785:Mirtazapine; D009483:Neuropsychological Tests; D016017:Odds Ratio; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011594:Psychometrics; D011597:Psychomotor Performance / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013997:Time Factors
D053961:Azabicyclo Compounds; D018691:Excitatory Amino Acid Antagonists; D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D010879:Piperazines; C515050:zopiclone; D008803:Mianserin; D003915:Dextromethorphan; D000078785:Mirtazapine; D019389:Cytochrome P-450 CYP2D6
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