The effects of acute treatment with paroxetine, amitriptyline, and placebo on driving performance and cognitive function in healthy japanese subjects: a double-blind crossover trial

Hum. Psychopharmacol Clin Exp 2008; 23: 399–407.
Published online 26 March 2008 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hup.939 The effects of acute treatment with paroxetine, amitriptyline,and placebo on driving performance and cognitive functionin healthy Japanese subjects: A double-blind crossover trial Kunihiro Iwamoto1, Masahiro Takahashi1, Yukako Nakamura1, Yukiko Kawamura2,Ryoko Ishihara1, Yuji Uchiyama3, Kazutoshi Ebe3, Akiko Noda4, Yukihiro Noda2, Keizo Yoshida1,Tetsuya Iidaka1* and Norio Ozaki1 1Department of Psychiatry, Graduate School of Medicine, Nagoya University, Japan2Division of Clinical Science and Neuropsychopharmacology, Graduate School of Pharmacy, The Meijyo University, Japan3Toyota Central R&D Labs., Inc., Nagakute, Japan4Graduate School of Health Sciences, The Nagoya University, Japan Objective To assess the effects of antidepressants on driving performance from a different methodological viewpoint inlight of the recent traffic accidents.
Methods In this double-blinded, 3-way crossover trial, 17 healthy males received acute doses of 10 mg paroxetine, 25 mgamitriptyline, and placebo. The subjects were administered three driving tasks—road tracking, car following, and harshbraking—performed using a driving simulator and three cognitive tasks—Wisconsin Card Sorting Test, ContinuousPerformance Test, and N-back test at baseline and at 1 h and 4 h post-dosing. The Stanford Sleepiness Scale scores were alsoassessed.
Results At 4 h post-dosing, amitriptyline significantly impaired road-tracking and car-following performance, reduceddriver vigilance, and caused subjective somnolence. Paroxetine impaired neither driving performance nor cognitive function.
Conclusions Acute doses of amitriptyline significantly impaired driving performance in the context of driving on crowdedurban roads at relatively low speeds. This setting is important with respect to skills necessary for daily driving and may bedifficult to measure in actual driving tests. This simulator-based study replicated the results of previous studies and could beconsidered complementary to them. This method may enable easy and safe screening of the driving hazard potential of drugs.
Copyright # 2008 John Wiley & Sons, Ltd.
key words — antidepressants; paroxetine; amitriptyline; driving performance; cognitive function their pharmacological profiles, antidepressants canimpair cognition. Although continuous antidepressant Most of the currently available antidepressants have therapy is required for patients with recurrent similar therapeutic efficacies, regardless of whether depressive disorders to prevent relapse (Geddes they are selective serotonin reuptake inhibitors et al., 2003) and improve their social and occupational (SSRIs) or tricyclic antidepressants (TCAs) (Ander- lives, the unpleasant side effects could force them to son, 2000). The choice of an antidepressant is discontinue treatment (Nemeroff, 2003) and may therefore largely determined by its side effects and impair their daily activities, including driving in a the tolerability profile of an individual. According to Epidemiological data indicate that compared to nonusers, TCA users are twice as likely to be involved * Correspondence to: T. Iidaka, MD, PhD, Department of Psychia- in traffic accidents (Leveille et al., 1994; Ray et al., try, Graduate School of Medicine, Nagoya University, 65 Tsurumai, 1992). Given the cross-sectional nature of these Showa, Nagoya, Aichi 466-8550, Japan.
studies, no study has clarified the causal relationship Copyright # 2008 John Wiley & Sons, Ltd.
between antidepressants and traffic accidents. Various treatment on driving performance, particularly in the effects of antidepressants on driving performance context of the recent traffic accidents. We used were recently evaluated in healthy subjects (Kerr et al., simulator scenarios to examine the car-following 1996; Ridout and Hindmarch, 2001; Ridout et al., performance in the context of driving on crowded 2003; Robbe and O’Hanlon, 1995; Wingen et al., urban roads at relatively low speeds. In addition, other 2005) and depressed patients (Brunnauer et al., 2006; established driving performance variables were also Wingen et al., 2006). Most of these recent studies used measured in the simulator scenario. Furthermore, the actual driving tests to measure driving performance. In cognitive functions of subjects were evaluated by the these tests, the driving tasks were designed to reproduce real-life situations; however, these tasksaddressed only certain aspects of driving because of the inherent safety risks and measurement limits ofactual driving tests. Meanwhile, rear-end collisions account for nearly 30% of all traffic accidents in both The study recruited 17 healthy male volunteers aged Authority, 2007) and the United States (National male subjects were included in the study because Highway Traffic Safety Administration, U. S. Depart- the changes in hormone levels occurring during the ment of Transportation, 2007). It is imperative that a menstrual cycle can substantially affect cognition in driver’s ability to maintain a contextually appropriate healthy women (Hampson, 1990; Maki et al., 2002; following distance be reviewed to avoid rear-end Phillips and Sherwin, 1992). All subjects had held a collisions (Brookhuis et al., 1994). Previous car- driving license for at least 10 years and drove a car following tests (Brookhuis et al., 1994; Ramaekers daily for a minimum of 5000 km per year. All et al., 1995; Ramaekers et al., 2002) focused on the participants were drug-free prior to the study. Health perception of speed deceleration of a leading car interviews and the Structured Clinical Interview for traveling at relatively high speeds and on safe DSM-IV (SCID) conducted at the time of the study following distance. The car-following performance indicated that none of the participants had any in the context of driving at relatively low speeds on physical or psychiatric disorders. The study was crowded urban roads has not been fully examined thus approved by the ethics committee of the Nagoya far and may be difficult to evaluate in actual driving University School of Medicine, and written informed consent was obtained from each subject prior to Car driving is a complex task requiring many cognitive processes, including perception, attention,learning, memory, decision making, and actioncontrol. Therefore, the effects of antidepressants should be evaluated in terms of not only the drivingperformance but also each The study used a randomized, double-blind, placebo- Previous studies used conventional tasks such as the controlled, 3-way crossover design. The subjects critical flicker-fusion frequency task, divided attention received acute doses of 10 mg paroxetine, 25 mg task, and choice reaction time task for assessing the amitriptyline, and matched placebo in three different cognitive function. Such studies are prone to yielding treatment sessions. The doses selected were based on varying results, depending on the type of cognitive generally recommended clinical starting dose, and task utilized. Therefore, it is important to employ minimizing possible risks of side effects, such as widely used tasks that are more complicated than nausea and vomiting, which could confound the conventional tasks. The Wisconsin Card Sorting Test results. There was a washout period of at least 7 days (WCST), Continuous Performance Test (CPT), and between the treatment sessions, and the medications N-back test are examples of the desired complicated and placebo were presented as identical capsules.
tasks, and the neural correlates of these tasks involvebroad cortical areas, particularly the frontal cortex, which is related to driving skills. However, the effectsof antidepressants on these three tasks have not yet The subjects received substantial training in driving and cognitive tests 1 or 2 weeks prior to first testing; in Thus, the aim of the present study was to evaluate order to minimize the learning effects, the subjects the influences of acute paroxetine or amitriptyline were trained until they reached the plateau level. On Copyright # 2008 John Wiley & Sons, Ltd.
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antidepressants’ effects on driving skill and cognition each test day, the participants arrived at the laboratory road-tracking test developed previously (O’Hanlon, at 9:00 AM and filled out self-rating questionnaires.
Under baseline conditions, the driving tests started at9:30 AM and lasted for approximately 15 min, while the cognitive tests started at 10:00 AM and tookapproximately 30 min. After the baseline assessment, The test included a straight 2-lane road with no other each subject was administered one of the three drugs.
traffic, except for a single preceding car. When the The assessments of driving skills and cognitive preceding car decelerated, its brake lights came on. As function were repeated at 1 h and 4 h post-dosing.
the preceding car accelerated (to 60 km/h) or Furthermore, the subjects were prohibited from decelerated (to 40 km/h), the subject was required consuming alcohol or caffeinated beverages for 12 h to maintain the distance between the cars as close to before testing and were directed to sleep adequately on 5 m as possible. The car-following distance (m) was the eve of testing. On the test days, the subjects were recorded every 10 ms, and performance was measured also prohibited from ingesting caffeine, supplement as the coefficient of variation (CV) obtained by drinks, chewing gum, or candies to stay awake since dividing the standard deviation of the distance these substances could exert a stimulating effect between the cars by the mean value (Uchiyama on their performance. During the intervals between the et al., 2003). Therefore, a smaller distance CV value test batteries, the subjects were given light tasks to (DCV) indicated better performance. The test duration The test included a straight 2-lane road with no traffic, We divided the daily driving skills associated with but with humanoid models on either side of the left traffic accidents into three tasks. A driving simulator lane. The humanoid models randomly ran onto the (Toyota Central R&D Labs, Inc., Nagakute, Japan) road as the subject’s car approached. The subject was was used to test the driving performance; the same instructed to maintain a constant speed of 50 km/h and simulator was used in a previous functional magnetic to avoid hitting the humanoid models by harsh braking resonance imaging study to determine the neural as quickly as possible. As described previously substrates of driving skills (Uchiyama et al., 2003).
(Hindmarch et al., 1983; Ridout and Hindmarch, This simulator software was run on a personal 2001), the brake reaction time (BRT; in ms) was used computer (PC) (Windows XP) equipped with a as a measure of the cognitive psychomotor perform- steering wheel, accelerator, and brake pedal system ance, including attention efficiency. Each test con- (SIDEWINDER; Microsoft). Images from the PC sisted of 7 BRT trials over a 5-min period, and the were projected onto a 1620 Â 1220 mm2 screen via an mean BRT was calculated from these results.
LCD projector (TH-LB30NT; Panasonic, Osaka,Japan). While watching the driving scenes on thescreen, the subjects controlled the speed and position of their car by manipulating the steering wheel, The cognitive test battery consisted of 3 tasks accelerator, and brake pedal. The driving simulation performed on a PC by manipulating a computer was conducted in a dark, sound-attenuated room.
The gently winding 2-lane road with no other traffic The WCST (Heaton, 1981) was used to measure the continued throughout the test duration of 5 min. The executive function, for example, abstract reasoning subjects were instructed to drive at a constant speed of ability or the ability to shift cognitive strategies in 100 km/h and stabilize the vehicle in the center of the response to changing environmental contingencies. A left lane. The lateral position of the vehicle (in cm) from the right edge of the left lane was recorded every (Kashima et al., 1987) was administered, and the test 10 ms. The standard deviation of the lateral position lasted until such time as 48 cards were sorted. In this (SDLP; in cm), which indicates weaving, was taken as study, performance was measured by the following a performance measure. This test is based on a indices: category achievement (CA), perseverative Copyright # 2008 John Wiley & Sons, Ltd.
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errors of Nelson (PEN), and difficulty of maintaining and 4-h post-dosing values were analyzed. The non-normally distributed variables were analyzed bythe nonparametric Friedman’s x2 r-test. In the case ofa significant treatment effect, a post-hoc analysis was performed by Wilcoxon signed-rank test (nonpara- The CPT was used to measure sustained attention or metric) with Bonferroni’s correction. The BRT and d0 vigilance. We used the CPT-Identical Pairs version data were normally distributed, and the differences (CPT-IP) software, as described previously (Cornblatt between the baseline values and the 1-h and 4-h et al., 1988). A series of 4-digit stimuli were presented post-dosing values were analyzed using repeated for a period of 50 ms, with an interstimulus interval measures analysis of variance (ANOVA). In the case (ISI) of 950 ms. Each complete task consisted of 150 of a significant treatment effect, a post-hoc analysis trials of which 30 were target trials requiring a was done using the Bonferroni test for multiple response. In this study, performance was measured by comparisons. To clarify the correlations between the signal detection index d-prime (d0), a measure of driving performance and cognitive function, single discriminability computed from ‘‘hits’’ and ‘‘false regression analyses were conducted by the Spearman rank-order correlation (nonparametric); however,BRT and d0 were analyzed by the Pearson product-moment correlation. All statistical tests were con- ducted using SPSS version 11 for Windows (SPSS The N-back test was used to measure working memory. We used a working memory task softwarethat requires subjects to update their mental setcontinually while responding to previously seen stimuli (i.e., numbers); the details thereof have been described previously (Callicott et al., 2000; Callicottet al., 2003). The stimulus duration was 0.4 s, and the In the road-tracking test, three subjects administered ISI was 1.4 s; each test comprised 14 trials. The amitriptyline failed to complete the test at 4 h subjects responded to the stimuli by using the numeric post-dosing as they were sliding off the track. These keypad of the PC. In the present study, a 2-back subjects were not factored into the relevant statistical condition was used, and performance was measured as analyses. Because of technical malfunctions, three the percentage of correct responses (accuracy, %).
other subjects with incomplete data records were notfactored into the statistical analyses of the N-back test.
There were no missing data for the other driving and Subjective measurements —Stanford Sleepiness The Stanford Sleepiness Scale (SSS) is a 7-point,self-reporting measure with proven sensitivity in several studies (Hoddes et al., 1973) and examinesthe level of alertness of an individual. The subjects Summaries of results of the driving and cognitive tests were instructed to evaluate themselves on this scale are provided in Table 1 (a and b). Friedman’s x2 r-test before the initiation of the test battery at baseline and revealed a statistically significant effect of treatment at 1 h and 4 h post-dosing. In addition, the adverse on the differences between the baseline and 4-h events spontaneously reported by the subjects or post-dosing SDLP (x2 ¼ 12.0, df ¼ 2, p ¼ 0.0025) and elicited by a nonleading question were recorded.
DCV (x2 ¼ 8.82, df ¼ 2, p ¼ 0.0121) values. Thepost-hoc test demonstrated that the SDLP wassignificantly greater under the amitriptyline condition than under the other two conditions ( p < 0.05 vs.
None of the outcome variables of the driving tests, placebo, p < 0.01 vs. paroxetine), and the DCV was cognitive tests, and subjective scales, except for BRT significantly greater under the amitriptyline condition (harsh-braking test) and d0 (CPT), showed normal than under the paroxetine condition ( p < 0.01).
distribution. In order to compare the conditions Repeated measures ANOVA showed no statistically following the administration of the 3 drugs, the significant differences in BRT among the three differences between the baseline values and the 1-h conditions. The results of the SDLP and DCV are Copyright # 2008 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2008; 23: 399–407.
antidepressants’ effects on driving skill and cognition Summary of the results of driving tests, cognitive tests, and subjective measurements in healthy male subjects enrolled in a crossover trial of paroxetine, amitriptyline and placebo (N ¼ 17) SDLP, Standard deviation of lateral position; DCV, Distance coefficient of variation; BRT, Brake reaction time; WCST, Wisconsin CardSorting Test; CA, Category achievement; PEN, Perseverative errors of Nelson; DMS, Difficulty of maintaining set; CPT, ContinuousPerformance Test; SSS, Stanford Sleepiness Scale.0 ÃÃp < 0.01 overall treatment effect between the three groups (difference between 4 h and baseline); ÃÃÃp < 0.05 overall treatment effectbetween the three groups (difference between 4 h and baseline); ÃÃÃÃp < 0.001 overall treatment effect between the three groups (differencebetween 4 h and baseline).
presented in Figures 1 and 2. No subject suffered from the amitriptyline condition when compared with the simulator sickness during the experiment.
placebo condition ( p < 0.05). The CPT results arepresented in Figure 3. In the WCST, Friedman’s x2r-test revealed a statistically significant effect of treatment on the difference between baseline and 4-h In the CPT, repeated measures ANOVA revealed a post-dosing CA values (x2 ¼ 6.54, df ¼ 2, p ¼ 0.038); statistically significant effect of treatment on the however, the post-hoc test did not show significant difference between the baseline and 4-h post-dosing d0 differences among the three groups. For the remaining values (F ¼ 4.79, df ¼ 2, p ¼ 0.015). The post-hoc test cognitive measurements, no statistically significant demonstrated that d0 was significantly decreased under Copyright # 2008 John Wiley & Sons, Ltd.
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when compared with the paroxetine ( p < 0.01) andplacebo ( p < 0.01) conditions. A summary of adverseevents is provided in Table 2.
Correlations among driving performance,cognitive function, and subjective assessments Single regression analyses revealed significant corre-lations between driving performance and cognitivefunction. The significant correlations are outlined inTable 3.
Box-and-whisker plot of the SDLP at baseline and at 1 h post dose and 4 h post-dosing in the crossover treatment with The results of the present study demonstrated that 4 h paroxetine, amitriptyline, and placebo (N ¼ 14). Boxes indicate after taking a single 25-mg dose of amitriptyline, there the interquartile ranges, with medians designated by the horizontal was significant impairment of DCV and of the line. The differences between the baseline and the 4-h post-dosing established driving performance variable SDLP in the values under the three conditions were compared. There was asignificant effect of treatment (Ãp ¼ 0.0025). The post-hoc test context of driving on crowded urban roads at relatively demonstrated that the SDLP was significantly greater under the low speeds. Vigilance in the CPT and subjective amitriptyline condition than under the placebo condition ( p < 0.05) somnolence in the SSS were also significantly impaired and the paroxetine condition ( p < 0.01) at 4 h after amitriptyline dosing. In contrast, acute dosesof paroxetine or placebo did not significantly impair driving performance or cognitive function.
A summary of results of the SSS is shown in Table 1-c.
Although most of the present results are consistent Friedman’s x2 r-test showed that there was a significant with those of prior studies (Ramaekers, 2003; Ridout effect of treatment on the difference between the baseline and Hindmarch, 2001; Ridout et al., 2003; Wingen and 4-h post-dosing SSS scores (x2 ¼ 31.3, df ¼ 2, et al., 2005), the present study was conducted p < 0.001). Post-hoc tests clarified that alertness was from a different methodological viewpoint. The significantly decreased under the amitriptyline condition car-following performance is important with respect Box-and-whisker plot of the DCV at baseline and at 1 h and 4 h post-dosing in the crossover treatment with paroxetine, Box-and-whisker plot of the CPT (d0) at baseline and at amitriptyline, and placebo (N ¼ 17). Boxes indicate the interquartile 1 h post dose and 4 h post dose of crossover treatment with parox- ranges, with medians designated by the horizontal line. The four etine, amitriptyline, and placebo (N ¼ 17). Boxes indicate the inter- outlier values (1.5- to 3-fold of the interquartile range) and four quartile ranges, with medians designated by the horizontal line. The extreme values (>3-fold of the interquartile range) have been seven outlier values (1.5- to 3-fold of the interquartile range) and two omitted from the figure, but these values were included in the extreme values (>3-fold of the interquartile range) have been statistical analysis. The differences between the baseline and 4-h omitted from the figure, but these values were included in the post-dosing values under the three conditions were compared. There statistic analysis. The differences between the baseline and 4-h was a significant effect of treatment (Ãp ¼ 0.012). The post-hoc test post-dosing values under the three conditions were compared. There demonstrated that the DCV was significantly greater under the was a significant effect of treatment (Ãp ¼ 0.015). The post-hoc test amitriptyline condition than under the paroxetine condition demonstrated that the d0 was significantly decreased under the amitriptyline condition than under the placebo condition ( p < 0.05) Copyright # 2008 John Wiley & Sons, Ltd.
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antidepressants’ effects on driving skill and cognition Adverse events in healthy male subjects enrolled in a crossover trial of paroxetine, amitriptyline and placebo, N (%) (N ¼ 17) to skills necessary for daily driving on crowded urban Driving skills comprise many basic cognitive and roads. The following distance is important for psychomotor elements, and the simultaneous appli- avoiding car crashes (Brookhuis et al., 1994); cation of these functions is required for safe driving.
however, it was hitherto difficult to measure the Regression analyses revealed that the negative effects following distance in actual driving tests and the same of antidepressants on driving performance were setting was not investigated in previous simulator associated with diminished sustained attention, execu- driving tests. Therefore, our simulator test may be tive impairment, and increased somnolence, although considered complementary to actual driving tests. In the low correlation coefficients warrant further addition, the results of the present 5-min simulator investigations. Previous findings that are consistent road-tracking test were similar to those of previous with ours also show that somnolence or sedation is the actual driving tests, which may require more time and most important cause of driving impairment in patients treated with antidepressants (Ramaekers, The present simulator scenarios were different from actual driving tests in terms of course configuration Differences in the pharmacological properties of and driving settings. Therefore, it is difficult to SSRIs and TCAs may provide a reasonable expla- compare the parameters between simulator testing and nation for our results. Amitriptyline, unlike parox- actual driving. The gently winding road resulted in etine, has strong antagonistic effects on cholinergic, difficulties in stabilizing the vehicle in the center of the adrenergic (a1), and histaminergic (H1) receptors, road, thereby yielding considerably higher SDLP causing cognitive impairment, balance disturbance, values than actual driving tests, even under the placebo and sedation, respectively. These common character- condition. The non-normal distributions of the driving istics of TCAs may impair driving performance variables could be attributed to the small sample size, (Hindmarch et al., 1983; Robbe and O’Hanlon, 1995; complicated by the inability of some subjects to van Laar et al., 1995; Wingen et al., 2005). In the complete the task and by some outliers related to present study, amitriptyline did not significantly differences in the drug metabolizing capacities of impair driving performance and cognitive function subjects. Although the effects of antidepressants on at 1 h post-dosing; this is not consistent with the the DCV were similar to those on the SDLP, no previous results obtained using amitriptyline. How- significant differences in BRT were observed among ever, most of the previous studies administered 25 mg the three conditions. It was assumed that the other amitriptyline 2 or 3 times daily. Although several driving tasks were more complex than the harsh- studies showed impaired performance 1–2 h after a braking task and might have therefore caused the single administration of 25 mg or less amitriptyline significant differences. In the present study, there were (Bye et al., 1978), the results obtained at the low doses no significant differences in executive function and varied with the tasks or subjects’ ages (Crome and working memory performance between baseline and Newman, 1978; Kinirons et al., 1993; Nathan et al., post-dosing values. Although amitriptyline adminis- 2000; Ogura et al., 1983; Peck et al., 1979; Tiller, tration has been repeatedly associated with negative 1990). The absence of amitriptyline effects at 1 h effects (Hindmarch et al., 1983; Kerr et al., 1996; post-dosing could be chiefly due to the present tests Richardson et al., 1994; van Laar et al., 2002), the employing single low doses. Furthermore, the low variables measured in the WCST and N-back test sensitivity of the driving simulator to the drug effects could be considered to have high SD values that may might also have contributed to the absence of have potentially influenced the present outcome.
amitriptyline effects at 1 h post-dosing.
Copyright # 2008 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2008; 23: 399–407.
Correlation between driving tests, cognitive tests, and We sincerely thank the healthy volunteers for parti- cipating in our study. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan andthe Ministry of Health, Labor and Welfare of Japan.
This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Ministry of Health, Labor and Welfare of Japan.
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