Plasma amitriptyline level after acute administration, and driving performance in healthy volunteers

Psychiatry and Clinical Neurosciences 2008; 62: 610–616
Regular Article
Plasma amitriptyline level after acute administration, anddriving performance in healthy volunteers Kunihiro Iwamoto, MD,1 Yukiko Kawamura, MS,2 Masahiro Takahashi, MD,1Yuji Uchiyama, PhD,3 Kazutoshi Ebe, ME,3 Keizo Yoshida, MD, PhD,1*Tetsuya Iidaka, MD, PhD,1 Yukihiro Noda, PhD2 and Norio Ozaki, MD, PhD11Department of Psychiatry, Nagoya University, Graduate School of Medicine, 2Meijyo University, Graduate School ofPharmacy, Division of Clinical Science and Neuropsychopharmacology and 3Toyota Central R&D Labs., Aichi, Japan Aims: Amitriptyline triggers the impairment of cog- plasma amitriptyline concentrations were measured nitive and motor functions and has been confirmed on high-performance liquid chromatography.
to have harmful effects on driving performance.
Results: A significant positive correlation was ob- Although interindividual differences in plasma served between the plasma amitriptyline concen- concentration may cause variations in driving tration and road-tracking performance (r = 0.543, P < 0.05). There was no significant correlation amitriptyline concentration and its effect on driving between the plasma amitriptyline concentration and performance has not been completely elucidated.
other driving performance, cognitive functions, and Thus, the aim of the present study was to assess the influence of individual pharmacokinetic dif-ferences on driving performance and cognitive Conclusions: Amitriptyline produces a concentration- related impairment on road-tracking performance.
Therapeutic monitoring of amitriptyline would be Methods: In this double-blinded study, 17 healthy useful for predicting the difficulties involved while male volunteers were given an acute, single, 25-mg dose of amitriptyline. The subjects were assignedthree driving simulator tasks, three cognitive tasks, Key words: amitriptyline, antidepressants, automo-
and the questionnaire of the Stanford Sleepiness bile driving, cognition, drug monitoring.
Scale at the baseline and at 4 h after dosing. The INTERINDIVIDUAL DIFFERENCES IN drug re- case of antidepressants, tricyclic antidepressants sponses occur even when the same dosage of a drug (TCA) are repeatedly recommended to be monitored is prescribed to different individuals. Therapeutic for blood concentration1–5 because these drugs have drug monitoring (TDM) is one of the most valid tools shown a fairly large interindividual variance in clini- utilized to minimize interindividual differences in cal response. The relationship between the blood drug responses. TDM enables a clinician to adjust the TCA concentration and adverse effects, such as drug dosage and enhance efficacy and safety.1 In the dropout rate, central nervous system toxicity, and car-diovascular toxicity has been reported.4,6 Among TCA, there is no consensus regarding the *Correspondence: Keizo Yoshida, MD, PhD, Department of relationship between plasma amitriptyline concen- Psychiatry, Nagoya University, Graduate School of Medicine, 65 tration and therapeutic response, in contrast to that Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan. Email: for imipramine, desipramine, and nortriptyline.2,3 Previous studies reported different results regard- Received 14 April 2008; revised 11 June 2008; accepted 25 June2008. ing the relationship between plasma amitriptyline Journal compilation 2008 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2008; 62: 610–616
concentration and common adverse effects such as cal Interview for DSM-IV, the subjects were found to drowsiness and dry mouth. For example, although be free from any physical or psychiatric disorders and these adverse events were attributed to high plasma were not taking medication. All subjects had been in concentration of amitriptyline, correlation for low– possession of a driving license for at least 10 years moderate concentrations of amitriptyline was not and had been driving a car daily (minimum, 5000 km/year). The study was approved by the ethics Epidemiological data indicate that TCA users are committee of the Nagoya University School of Medi- twice as likely to be involved in traffic accidents as cine, and written informed consent was obtained compared to non-users.8,9 Various studies have dem- from each subject prior to participation.
onstrated the harmful effects of TCA on driving per-formance.10 As for amitriptyline, impairment of road Procedure
tracking performance and increase in brake reactiontime have been reported.11,12 Amitriptyline also has All subjects were tested at approximately 09.30 hours been linked to impairment of cognitive functions as using the Stanford Sleepiness Scale (SSS),21 driving well as driving performance. A single low dose of tests, and cognitive tests. The entire testing lasted amitriptyline impaired cognitive functions as mea- approximately 1 h for each person. Following base- sured on cognitive tests such as auditory vigilance line assessment, the subjects were given capsules test, tapping test, arithmetic test, digit symbol substi- containing 25 mg amitriptyline in a double-blind tution test, short term memory test, flicker-fusion manner. The dose of 25 mg was selected because it test, and choice reaction time test.13–19 is a recommended starting dose in Japan, and also In our recent study we used simulator scenarios to because the higher dose of amitriptyline might cause examine car-following performance in the context severe side-effects, possibly interrupting the experi- of crowded urban roads and driving at relatively low ments. Blood samples (10 mL) were collected 4 h speeds as well as other driving tasks routinely inves- after administration, because that is when maximum tigated in other previous studies. Furthermore, cog- plasma drug concentration occurs.22 The patients nitive function was evaluated using the Wisconsin were subjected to all the aforementioned tests Card-Sorting Test (WCST), Continuous Performance again after blood drawing. The blood samples were Test (CPT), and N-back test. At 4 h after amitrip- immediately centrifuged at 1700 g. for 10 min, and the plasma was frozen at -30°C. Plasma ami- following performance was significantly impaired, triptyline concentrations were determined on high- vigilance was reduced, and subjective somnolence performance liquid chromatography, as described previously.23 Five-point calibration curves were set up Although the adverse effects of amitriptyline on for the range 2–200 ng/mL. A linear response func- driving performance and cognitive functions differ tion was obtained, and the limit of quantification across individuals, to the best of our knowledge there was 2 ng/mL. The interday coefficient of variation have been no studies reported on the relationship for 4 days for plasma amitriptyline at 20 ng/mL between plasma amitriptyline concentration on the was 11.2%. The intraday coefficients of variation one hand, and driving performance and cogni- were 1.1–1.2% (n = 2). Amitriptyline has an active tive functions on the other. Considering the afore- metabolite, nortriptyline. Both amitriptyline and mentioned factors, we examined the influence of nortriptyline undergo benzylic hydroxylation, and individual pharmacokinetic differences on driving the hydroxylated nortriptyline metabolites are still performance and cognitive functions using the same active.24 Jiang et al. reported that the plasma concen- tration of nortriptyline was considerably lower thanthat of amitriptyline after a single dose of amitrip-tyline.22 The plasma concentrations of nortriptyline and its metabolites were not analyzed because thepresent study used only single low dosing and a short Subjects
sampling interval after administration.
The sample consisted of 17 healthy male volunteers The subjects received substantial training in driving aged 30–42 years (mean Ϯ SD, 35.8 Ϯ 3.3 years).
and cognitive tests 1 or 2 weeks prior to the first Based on health interviews and the Structured Clini- testing; and in order to minimize the learning effects Journal compilation 2008 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2008; 62: 610–616
the subjects were trained until they reached the tion was used, and the performance was measured plateau level. Furthermore, the subjects were prohib- as the percentage of correct responses (accuracy, ited from consuming alcohol or beverages contain- ing caffeine for 12 h before taking the tests andwere requested to sleep adequately on the previousevening. On the test days the subjects were also pro- Statistical analysis
hibited from ingesting substances that may induce None of the outcome variables of the driving tests, wakefulness, such as caffeine, supplement drinks, cognitive tests, and subjective scales, except BRT chewing gum, or candies because these substances (harsh-braking test) and d’ (CPT), had a normal dis- could exert a stimulating effect on their performance.
tribution. To clarify the correlations between plasma During the intervals between the test series, the sub- amitriptyline concentration and percent change in jects were assigned certain light tasks to prevent them performance, the Spearman rank-order correlation coefficients (non-parametric) were calculated. PENand DMS were analyzed as difference not percent Driving and cognitive tests
change, because their baseline values could be 0and percent change could not be calculated. BRT We used a driving simulator (Toyota Central R&D and d’ were analyzed using the Pearson product- Labs, Nagakute, Japan) to examine three driving skills moment correlation. In order to analyze the drug that appeared to be associated with the recent traffic effect, the baseline values were compared to that accidents. The road-tracking test in the present study obtained at 4 h after dosing using the Wilcoxon was based on a road-tracking test that was developed signed-rank test. A paired t test was used to analyze previously.25,26 The subjects were instructed to drive at the BRT and d’ data. All statistical tests were con- a constant speed of 100 km/h and stabilize their ducted using SPSS version 11 for Windows (SPSS vehicles at the center of a gently winding road. The Japan, Tokyo, Japan). Significance levels were set at standard deviation of the lateral position (SDLP; cm), which indicates weaving, was considered a perfor-mance measure. The car-following test required thesubjects to maintain a constant distance between the cars (targeted distance of 5 m) in the contextof crowded urban roads driving at a speed of Correlations between plasma amitriptyline
40–60 km/h. The coefficient of variation (CV) was concentration and driving performance,
obtained by dividing the standard deviation of the cognitive function, and
car-following distance (m) between the cars by the subjective assessments
mean value, and it was considered a performancemeasure.27 Therefore, a smaller value of distance The mean Ϯ SD plasma amitriptyline concentration CV (DCV) would indicate a better performance. The was 15.3 Ϯ 6.4 ng/mL (range, 8.5–32.9 ng/mL). The harsh-braking test required the subjects to avoid relationships between the plasma amitriptyline con- crashing into the humanoid models that randomly centration and driving performance, cognitive func- ran on the road by harsh braking. The brake reaction tion, and subjective assessments are shown in Fig. 1.
time (BRT; ms) was considered a performance Data that indicate the coefficient of correlation of measure. Each test lasted for 5 min and the details -0.1 < r < 0.1 are not shown. A significant correlation was observed between plasma amitriptyline con- The three cognitive tests were examined using a centration and percent change in SDLP (Fig. 1a).
computer. In the WCST the performance was mea- No significant correlations were detected between sured using the following indices: category achieve- plasma amitriptyline concentration and the remain- ment (CA), perseverative errors of Nelson (PEN), ing driving, cognitive, and subjective variables and difficulty of maintaining set (DMS).28,29 In (Fig. 1b–f). Percent change in CA, difference of PEN the CPT the performance was measured using the and percent change in SSS showed no significant cor- signal detection index d-prime (d’), which is a relations as follows: r = -0.070, P = 0.789 for CA, measure of discriminability computed from hits and r = 0.048, P = 0.855 for PEN and r = 0.035, P = 0.893 false alarms.30 In the N-back test a two-back condi- 2008 The AuthorsJournal compilation 2008 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2008; 62: 610–616
Plasma Amitriptyline Concentration (ng/mL) Figure 1. Relationship between plasma amitriptyline concentration and percent changes in the variables of driving performance,
cognitive functions, and subjective somnolence. (Difference rather than percent change was used for (e) difficulty of maintaining set
[DMS], because the baseline values of DMS can be 0 and hence, percent changes cannot be calculated.) (a) Percent change in
standard deviation of the lateral position (SDLP; r = 0.543, P = 0.045); (b) percent change in distance coefficient of variation (DCV;
r = -0.110, P = 0.673); (c) percent change in brake reaction time (BRT; r = -0.163, P = 0.532); (d) percent change in signal detection
index d-prime (d’) in the Continuous Performance Test (r = 0.209, P = 0.420); (e) difference of DMS in the Wisconsin Card-Sorting
Test (r = 0.132, P = 0.614); (f) percent change in accuracy in the N-back test (r = 0.260, P = 0.370). Due to non-completion of the
assigned task and technical malfunctions, three subjects were excluded from statistical analyses for SDLP and N-back test.
Journal compilation 2008 Japanese Society of Psychiatry and Neurology Psychiatry and Clinical Neurosciences 2008; 62: 610–616
significant correlation was observed between plasma Effects of amitriptyline on driving
amitriptyline concentration and percent change in performance, cognitive function, and
SSS scores. These values might be influenced by subjective assessments
individual pharmacodynamic differences rather than At 4 h after receiving the single dose of 25 mg ami- individual pharmacokinetic differences. The same triptyline, SDLP (P = 0.003), DCV (P = 0.006), CA logic may be applied to the absence of correlations (P = 0.035), and SSS score (P = 0.0002) were signifi- between plasma amitriptyline concentration and cantly impaired. The effect of amitriptyline on the DCV and CA (WCST); therefore, further investiga- remaining variables was not statistically significant.
tions should be conducted in this regard.
These data have been reported in our previous study.20 Several studies indicate cognitive impairments in major depression patients.34–36 Richardson et al.
reported that amitriptyline and fluoxetine showed DISCUSSION
equal clinical improvement but patients receiving The present results demonstrated a significant linear amitriptyline did not perform as well on the verbal correlation between plasma amitriptyline concentra- learning task.37 The present results indicate that TCA tion and percent change in SDLP. Baseline SDLP including amitriptyline might affect recovered cogni- was 38.9 Ϯ 10.8 cm, and at 4 h it increased to tive function, even though clinical depressive symp- 51.3 Ϯ 12.7 cm. This increase of lateral swerving might lead to traffic accidents. The plasma amitrip- The present study has several limitations. First, it tyline concentration, however, did not show a signifi- used a single, low dose of amitriptyline. Therefore, we cant relationship with (i) other driving performance could not investigate the steady state condition, in parameters of DCV and BRT; (ii) cognitive functions which amitriptyline and its active metabolites exert measured using the WCST, CPT, and N-back test; or their influence. Second, the participants were limited (iii) subjective somnolence, determined using the SSS.
to healthy adult male volunteers; therefore, women In a previous study imipramine had a detrimental who are prone to develop depression and the elderly effect on driving performance measured as SDLP and should be included in future studies. Third, the valid- caused slight cognitive impairment as assessed on a ity and sensitivity of the driving simulator used in the memory scanning test.33 This memory test indicated present study should be considered. Finally, we found that the plasma drug concentration significantly cor- a significant linear correlation between plasma ami- related with reaction time change but not with SDLP triptyline concentration and percent change in SDLP, change. The present study found a significant corre- but it is necessary to investigate this relationship under lation between plasma concentration of amitriptyline clinical therapeutic dose and steady-state conditions.
after a single dose and driving performance measuredas SDLP. Amitriptyline may have a concentration-dependent ACKNOWLEDGMENTS
ability. Therapeutic monitoring of amitriptyline This work was supported in part by research grants would be useful for predicting the difficulties from the Ministry of Education, Culture, Sports, encountered while driving. The present results and Science and Technology of Japan, the Ministry of those of the van Laar et al. study33 do not agree, Health of Japan, Labor and Welfare, Grant-in-Aid for although both these studies used TCA. The method- Scientific Research on Pathomechanisms of Brain ological differences between the two studies might Disorders from the Ministry of Education, Culture, Sports, Science and Technology of Japan, MEXT A previous review demonstrated that somnolence Academic Frontier and the Japan Health Sciences or sedation is the most important cause of driving Foundation (Research on Health Sciences focusing impairment in patients treated with antidepres- sants.10 In our previous simulator study we also con-firmed a weak but significant association between thedetrimental effects of antidepressants on driving per- REFERENCES
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