The effects of intranasal esketamine (84 mg) and oral mirtazapine (30 mg) on on-road driving performance: a double-blind, placebo-controlled study

Adriana C Bervoets,Aurora J A E Van De Loo,Noor H Bouwmeester,Ewa Wajs,Rob Zuiker,Randall Morrison,Joris C Verster,Maggie Fedgchin,Jaskaran Singh,Peter Van Der Ark,Loes Mooren,Joop Van Gerven,Johan Garssen,Guido Van Amerongen

doi:10.1007/s00213-017-4706-6

Abstract

RationaleThe purpose of this study is to evaluate the single dose effect of intranasal esketamine (84 mg) compared to placebo on on-road driving performance. Mirtazapine (oral, 30 mg) was used as a positive control, as this antidepressant drug is known to negatively affect driving performance.MethodsTwenty-six healthy volunteers aged 21 to 60 years were enrolled in this study. In the evening, 8 h after treatment administration, participants conducted the standardized 100-km on-road driving test. Primary outcome measure was the standard deviation of lateral position (SDLP), i.e., the weaving of the car. Mean lateral position, mean speed, and standard deviation of speed were secondary outcome measures. For SDLP, non-inferiority analyses were conducted, using +2.4 cm (relative to placebo) as a predefined non-inferiority margin for clinical relevant impairment.ResultsTwenty-four participants completed the study. No significant SDLP difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001). The upper limit of the two-sided 95% confidence interval (CI) of the mean difference between esketamine and placebo was +0.86 cm, i.e., <+2.4 cm, thus demonstrating that esketamine was non-inferior to placebo. Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo). No significant differences in mean speed, standard deviation of speed, and mean lateral position were observed between the active treatments and placebo.ConclusionsNo significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo. In contrast, oral mirtazapine (30 mg) significantly impaired on road driving performance.

Highlights

Despite efforts to improve automobile safety and decrease unsafe driving practices, road trauma remains a serious public health problem (World Health Organization 2009)
No significant standard deviation of lateral position (SDLP) difference was found between esketamine and placebo (p = 0.7638), whereas the SDLP after mirtazapine was significantly higher when compared to placebo (p = 0.0001)
Non-inferiority could not be concluded for mirtazapine (+3.15 cm SDLP relative to placebo)

Summary

Introduction

Despite efforts to improve automobile safety and decrease unsafe driving practices, road trauma remains a serious public health problem (World Health Organization 2009). Psychoactive drugs that affect the central nervous system have the potential to impair driving performance (Walsh et al 2008). Various factors leading to road accidents after taking psychoactive drugs involve poor vehicle control, impairment of basic driving skills, and impaired decision-making, which increase the risk of accidents during driving (Corazza et al 2012; Mozayani 2002; Schifano et al 2015). Rapid antidepressant effects can be achieved using intranasal ketamine with low treatment-associated adverse events (Lapidus et al 2014). Anesthetic as well as sub-anesthetic concentrations of ketamine have shown to produce neuropsychological effects and rapid mood-enhancing actions in electroconvulsive therapy for treatment-resistant depression, while anesthetic concentrations result in greater magnitudes of antidepression and cognitive protection (Zhong et al 2016). The effect of ketamine on depression will be reached at doses lower than the typical anesthetic doses, and at that low dose level, side-effects are generally mild and transient (Bobo et al 2016)

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