human psychopharmacology Hum. Psychopharmacol Clin Exp 2013; 28: 281–286. Published online 10 May 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2321 SHORT COMMUNICATION Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and cognitive function in healthy volunteers Kazumi Sasada1, Kunihiro Iwamoto1*, Naoko Kawano1, Kunihiro Kohmura1, Maeri Yamamoto1, Branko Aleksic1, Kazutoshi Ebe2, Yukihiro Noda3,4 and Norio Ozaki1 1Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan 2Toyota Central R&D Labs., Inc., Nagakute, Aichi, Japan 3Division of Clinical Science and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, Aichi, Japan 4The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Meijo University, Nagoya, Aichi, Japan Objective This study aimed to evaluate the effects of repeated treatments with the sedative antidepressants mirtazapine and trazodone on driving performance and cognitive function. Methods Nineteen healthy men received continuous nocturnal doses of 15-mg mirtazapine , 25-mg trazodone, or placebo for 8 days in a double-blinded, three-way crossover trial. Subjects were asked to perform three driving tasks (road tracking, car following, and harsh braking) using a driving simulator and cognitive tasks (the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back Test) at baseline and on Days 2 and 9. Stanford Sleepiness Scale scores were also assessed. Results Mirtazapine significantly increased the standard deviation of lateral position in the road-tracking task as compared with trazodone on Day 2. Mirtazapine significantly increased Stanford Sleepiness Scale scores as compared with trazodone and placebo. For the remaining tasks, no significant effects of treatment were observed. Conclusions Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations. Both initial sedative effects and pharmacological profiles should be taken into consideration when using sedative antidepressants. Copyright © 2013 John Wiley & Sons, Ltd. key words—sedative antidepressant; mirtazapine; trazodone; driving performance; cognitive function INTRODUCTION well as sedative properties. Because of these properties, Many antidepressants are available for psychiatric treat- TCAs have been repeatedly shown to impair cognitive ment, but pharmacological profiles of these drugs differ and psychomotor performance (Serretti et al., 2010), widely. The choice of antidepressant is determined by including car driving (Ramaekers, 2003; Iwamoto safety, tolerability, efficacy, payment, and simplicity, et al., 2008). Thus, non-sedating antidepressants may which are summarized by the mnemonic STEPS represent a better option (Bourin and Briley, 2004; (Preskorn, 1996). Although sedation is one of the un- Versiani et al., 2005). However, the sedative antidepres- pleasant side effects (Bourin and Briley, 2004), sedative sants trazodone and mirtazapine are among the most antidepressants can represent a useful treatment option commonly used drugs for chronic insomnia in the for some patients with agitation or insomnia (Mann, USA because of safety and lower dependence potential. 2005; Linden and Westram, 2010). Therefore, these two drugs need to be examined with Among the sedative antidepressants, tricyclic antide- respect to psychomotor performance in daily life, pressants (TCAs) show anticholinergic properties as including car-driving skills. Previous studies have suggested that mirtazapine could impair road-tracking performance (Wingen et al., 2005). *Correspondence to: K. Iwamoto, MD, PhD, Department of Psychiatry, However, the effects of mirtazapine on driving skills Graduate School of Medicine, Nagoya University, 65, Tsuruma-cho, fi Showa, Nagoya, Aichi 466-8550, Japan. Tel: +81 52 744 2282; Fax: associated with traf c accidents have not been fully +81 52 744 2293. E-mail: [email protected] investigated. Moreover, the effects of trazodone on Received 14 September 2012 Copyright © 2013 John Wiley & Sons, Ltd. Accepted 27 March 2013 282 k. sasada ET AL. driving skills have rarely been studied (Roth et al., 2011). using a computer. The modified version of the The aim of the study was to evaluate the effects of Wisconsin Card Sorting Test (Heaton, 1981) was used repeated treatment with mirtazapine or trazodone on to measure executive function. This performance was driving performance using methods designed to test measured by category achievement, perseverative errors the risk of rear-end collisions, the most common type of Nelson, and difficulty of maintaining set. The of traffic accidents. Continuous Performance Test, Identical Pairs version (Cornblatt et al., 1988), was used to measure sustained attention. A series of four-digit stimuli were used, and MATERIAL AND METHODS performance was measured by the signal detection index Nineteen healthy male volunteers (26–49 years old, d-prime, a measure of discriminability computed from mean Æ standard deviation, 38.8 Æ 6.8 years) were “hits” and “false alarms.” The N-back test (Callicott included through health interviews and the Structured et al., 2000, 2003) was used to assess working memory. Clinical Interview for the Diagnostic and Statistical A two-back condition was used, and performance was Manual of Mental Disorders, fourth edition. All measured as the percentage of correct responses. All participants had a driving license for ≥5years and subjects were trained in both driving and cognitive tests regularly drove a car (minimum, 5000 km/year). The 1–2weeksbeforefirst testing until the plateau level. The study was approved by the ethics committee of the Stanford Sleepiness Scale (SSS) (Hoddes et al., 1973) is Nagoya University Graduate School of Medicine and used to examine the level of alertness. Nagoya University Hospital, and written informed A two-way repeated-measures analysis of vari- consent was obtained from each individual before ance with time and drug as factors was used to participation. analyze percentage changes in outcome variables This study used a double-blind, placebo-controlled, over 8 days. If a significant interaction between three-way crossover design. Each subject received factors was observed, these variables at each evalu- 8 days of continuous bedtime dosing with either 15-mg ation point were examined with one-way repeated- mirtazapine, 25-mg trazodone, or matched placebo in measures analysis of variance, followed by the identical capsules across three different treatment series. Bonferroni post hoc test. All tests were two tailed, The doses selected were clinical recommended starting and the alpha value was set at 0.05. doses (Sadock et al., 2005). Dosing started at bedtime on Day 1, preceding the first test day (Day 2). A washout period of ≥7 days was provided between treatment series. Baseline assessments were conducted only once RESULTS before the treatment session. After baseline assess- In the road-tracking test, one subject administered ments without treatment, subsequent assessments mirtazapine failed to complete the test on Day 2. were performed on Days 2 and 9 at 09:30 AM for Because of technical malfunctions, car-following each treatment series. We used a driving simulator test, road-tracking test, and Continuous Performance (DS) (Toyota Central R&D Labs, Nagakute, Japan) Test data were incomplete for one subject, and to examine three driving skills that appeared to be harsh-braking test data were incomplete for two associated with traffic accidents, including frequent subjects. Only complete data sets were included in rear-end collisions. The details of DS configuration the analyses. and tasks have been described previously (Iwamoto A summary of the results is shown in Table 1. There is et al., 2008). The road-tracking test measures the stan- a significant Drug  Time interaction in the road- dard deviation of lateral position (SDLP) on a gently tracking test (F = 3.520, df = 2, 46, p = 0.023). The SDLP winding road at a constant speed of 100 km/h. The of the mirtazapine condition was significantly greater car-following test measures the coefficient of variation than that observed in the trazodone condition on Day 2 of the distance between a preceding car and subject’s ( p = 0.001). The results of SDLP are presented in own (Uchiyama et al., 2003). Subjects were required Figure 1. There is no significant Drug  Time interac- to maintain a constant distance between cars. The tion in other driving tests and cognitive tests. harsh-braking test measures mean brake reaction time There is a significant Drug  Time interaction in in seven braking trials to avoid crashing into the sleepiness (F = 10.630, df = 1, 34, p < 0.001). SSS humanoid models that randomly ran into the road. scores under mirtazapine conditions were significantly Each test was recorded every 20 ms and lasted for greater than those observed under trazodone and pla- 5 min. The three cognitive tests, described in detail cebo conditions on Day 2 ( p < 0.001 each). Results previously (Iwamoto et al., 2008), were examined of the SSS are presented in Figure 2. Copyright © 2013 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp 2013; 28: 281–286. DOI: 10.1002/hup sedative antidepressants and driving performance 283 Table 1. Summary of the results