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Acute and subchronic effects of paroxetine 20 and 40 mg on actual driving, psychomotor performance and subjective assessments in healthy volunteers
EUROPEANNEUROPSYCHOPHARMACOLOGY ELSEVIER
European Neuropsychopharmacology 5 (1995) 35-42
Acute and subchronic effects of paroxetine 20 and 40 mg on actual driving, psychomotor performance and subjective assessments in healthy volunteers H i n d r i k W.J. R o b b e * , J a m e s F. O ' H a n l o n Institute for Human Psychopharmacology, University of Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands Received 4 May 1993; accepted 1 September 1994
Abstract
The effects of paroxetine (20 and 40 mg/day) and amitriptyline (75 mg/day, used as an active control) on car driving and psychomotor function were compared with those of placebo in a double-blind, crossover study employing 16 healthy subjects. Performance testing occurred on the first and last day of each 8-day treatment series. Side-effects, sleep duration and sleep quality were rated daily. Amitriptyline produced severe drowsiness and strikingly impaired performance on nearly every test on the first day but its effects were practically gone after 1 week of treatment. Paroxetine 20 mg, the usual antidepressant dose, had no effect on performance. Paroxetine 40 mg did not affect road tracking but slightly impaired performance in some psychomotor tests in a persistent manner. Paroxetine had no effect on sleep following the 20 mg dose but reduced quality following the 40 mg dose. Side-effects that the administered drugs have in common were milder during paroxetine than amitriptyline treatment. However, some dose-related side-effects (e.g. nausea and delayed ejaculation) were only reported during paroxetine treatment.
Keywords: Paroxetine; Amitriptyline; Driving and psychomotor performance; Sleep; Side-effects
1. Introduction
Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is as efficacious as and produces fewer and/or milder side-effects than older antidepressants such as amitriptyline (Battegay et al., 1985; Laursen et al., 1985). The usual daily dose of paroxetine is 20 mg but its therapeutic range extends to 50 mg (Dunner and Dunbar, 1991). From paroxetine's side-effect profile one might expect that the drug would not unduly interfere with patients' abilities to perform skilled tasks. Some older antidepressants do this: recent epidemiological evidence indicates that elderly ( > 65 years) patients for whom tricyclic antidepressants were prescribed in amitriptyline-equivalents equal to or higher than 125 m g / d a y drove with a risk of injurious traffic accidents that was nearly six times that of age-matched controls (Ray et al., 1992). Before con*Corresponding author. Tel.: +31.43.883305; Fax: +31. 43. 257380. 0924-977X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0924-977X(94)00130-8
cluding that patients treated with paroxetine will be at less risk of injury due to performance deficits, it seems essential to provide evidence that the drug does not impair the capacity for accomplishing tasks in a safe and efficient manner. Previous experimental research has shown that a single 30 mg paroxetine dose has itself no effect on psychomotor performance in the laboratory and generally does not potentiate impairment produced by ethanol (McClelland and Raptopoulos, 1985; Hindmarch and Harrison, 1988), amylobarbitone (McClelland and Raptopoulos, 1986), oxazepam (McClelland et al., 1987a), or haloperidol (McClelland et al., 1987b). Yet one interactive effect of paroxetine 30 mg and ethanol was significant in a test of divided attention (Hindmarch and Harrison, 1988). Paroxetine 20 mg, administered to healthy elderly volunteers for 1 week, had little or no effect on performance, and did not interact with ethanol in a series of conventional psychomotor tests (Kerr et al., 1992). Yet it is always questionable to conclude that any drug has no effects
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H.W.J. Robbe. J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
upon skilled performance in real-life tasks solely on the basis of results obtained from laboratory tests. Their predictive validity has yet to be shown (O'HanIon et al., 1986). The present study was designed to determine if paroxetine has any adverse effect on performance in a real-life task, i.e. actual car driving. It compared the effects of two doses of paroxetine (20 and 40 mg) on healthy volunteers' performance relative to those of placebo, after 1 and 8 days of treatment. The subjects' performance was also measured with laboratory tests to determine whether their measures of drug-induced impairment correlate with those of actual car driving in a manner confirming the predictive validity of laboratory tests. Amitriptyline was chosen as the active control. The usual starting dose, 75 mg/day, was given. Recognising the drug's strong sedative activity, the daily dose was divided between 50 mg at night and 25 mg in the morning. This regimen was employed to achieve enough of an impairing effect for establishing test sensitivity but not so much as to seriously interfere with the volunteers' normal activities during this treatment period.
2. Experimental procedures 2.1. Subjects
Sixteen healthy male subjects completed the study. Four were replacements for earlier drop-outs. Three of the original group dropped out for reasons unrelated to treatments. One did so after completing the first treatment period wherein he experienced persistent adverse reactions to paroxetine 20 mg/day. He reported concentration problems, tiredness, severe drowsiness and unpleasant feelings in the left chest as well as headache throughout the treatment period. Furthermore, he experienced memory disturbances and diarrhoea during the last 3 days. He undertook four driving tests wherein his performance was generally poor. On one occasion it was bad enough to cause a premature termination. Subjects who completed the study ranged in age from 21 to 28 years ( m e a n - SD = 2 3 . 6 - 1.8). All held valid driving licences and had driven at least 5000 km per year for the previous 3 years. They refrained from any form of oral medication during periods of participation. Caffeine-containing beverages were only allowed at breakfast time on test days and alcohol consumption was not permitted for 24 h beforehand. At other times subjects were required to limit their alcohol consumption to one glass of beer or wine per day. They were strongly advised not to operate their own vehicles during any treatment period, including placebo (costs of public transport were reimbursed).
Before selection, subjects underwent a medical examination including ECG and haematological and blood chemistry screening. No abnormalities of clinical importance were found. Subjects gave their written informed consent and were paid for their participation. The study was approved by the Medical Ethics Review Committee of the University of Limburg, Maastricht.
2.2. Design
Daily oral doses of paroxetine 20 mg (P20), paroxetine 40 mg (P40), amitriptyline 75 mg (AMI) and placebo (PLA) were given for 8 days apiece in a four-period, double-blind, crossover design. Treatment orders were randomly assigned from those residing in four, 4 x 4 Latin squares. A washout period of at least 13 days occurred between treatments. Subjects ingested capsules containing drug or placebo at night and 10 h later the next morning, 30 min before breakfast. The entire paroxetine dose was contained in the morning capsules. The amitriptyline dose was divided between 50 mg at night and 25 mg in the morning. Subjects were thoroughly trained in all psychomotor performance tests and performed a complete 'dress rehearsal' of the entire procedure, including driving, prior to testing. They were tested on days 1 and 8 of each treatment period. They performed an alternating series of driving and psychomotor tests, lasting 60 and 75 min, respectively. The driving tests began at 1.5 h and 5 h, the psychomotor tests at 3.25 h and 6.75 h after the morning dose.
2.3. Driving test
This test has been standardised and repeatedly applied for measuring the sedative effects of drugs (O'Hanlon et al., 1986; Ramaekers et al., 1992). It was performed over a 100-km circuit on a primary highway in traffic. Subjects were instructed to drive in the right (slower) traffic lane, while maintaining a constant speed (95 km/h) and steady lateral position between delineated lane boundaries. They could, however, deviate from these instructions in order to pass a slower vehicle. Subjects were instructed not to converse with the experimenters except to announce their decision to terminate the test if doubting their ability to continue driving in a safe manner. Subjects were accompanied during all the tests by a licensed driving instructor, who could intervene if necessary by using dual controls. The test vehicle was instrumented to continuously sample lateral position, speed and steering wheel angle at a rate of 4 Hz. The primary
H.W.J. Robbe. J.F, O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42 measure of road tracking ability was the standard deviation of lateral position (SDLP).
2. 4. Psychomotor tests The battery comprised seven different tests. Its total duration was 1.25 h. Each test in the following succession was started at a fixed time. Critical Flicker~Fusion Frequency (CFF). The method of 'successive approximation' was used to measure CFF (Rey and Rey, 1964). Ultimately, the CFF was defined within a 0.5-Hz interval between frequencies that were reliably judged as leading to the respective perceptions of flicker and fusion (test duration: 5 min). Critical Tracking Test (CTT, Jex et al., 1966). This test measured the subject's ability to control a displayed error signal in a first-order compensatory tracking task. Error appeared as horizontal deviation of a cursor from midpoint on a horizontal, linear scale. Compensatory joystick movements nulled the error by returning the cursor to the midpoint. The frequency of cursor deviations, and therefore its velocity, increased as a stochastic, linear function of time. The frequency at which the subject lost control was the critical frequency (Ac, expressed in rad/s). Theoretically, Ac is the reciprocal of the operating delay lag in human closed-loop manual control. The test included five trials of which the lowest and highest score were removed; the average of the remaining scores was taken as the final score (5 min). Continuous Recall (CONT, Hunter, 1975). A series of fractions, each presented with two digits in both the numerator and denominator, were presented on a display at a rate of one per 3.5 s. The task was to memorise the denominator and decide whether it was the same as or different than the numerator shown two presentations later. Dichotomous responses were made as rapidly as possible with corresponding push buttons. The percentage of correct responses (CONTPC) and the mean reaction time (CONT-RT) for yielding the same were separate dependent variables for measuring treatment effects on working memory (3.5 min). Divided Attention (DAT, Moskowitz and Burns, 1977). This test required simultaneous performance of two tasks, a central tracking task and a peripheral visual search-and-detection task. The central task was the compensatory tracking task described above but with a constant difficulty level set at 50% of subject's maximum capacity, as determined during training trials. Tracking error was measured as the difference in mm between the position of the cursor and the midpoint of the scale. The mean absolute tracking error (DAT-TE) over the entire test was the dependent variable for this sub-task. The secondary task was
37
to monitor each of 24 peripheral LED displays, showing the numerals 0-9, and react to the appearance of the target ('2') by removing the foot from a pedal. The numerals changed asynchronously at intervals of 5 s. Inter-target intervals varied randomly between 5 and 25 s. Mean reaction time (DAT-RT) was the dependent variable for this sub-task (12 min). Sternberg Test (ST, Sternberg, 1969). Subjects were briefly (3 s) shown a set of letters and told to memorise them. They then saw a series of 90 letters, presented one per 2 s. Their task was to decide and respond as rapidly as possible by pressing respective push-buttons to indicate whether or not each successive letter was one of those contained in the memory set. This task was performed three times, with memory sets of one, two and four letters, respectively. Mean reaction time of both correct 'yes' and 'no' responses were the dependent variables (12 min). Constant Tapping (TAP, Michon, 1966). This test provides a measure of fine motor control during repetitive movement. Variability of tapping rate is thought to directly vary with adverse treatment effects on fine motor control. Subjects were instructed to tap at a constant rate of twice per second. The standard deviation of intertap interval times (TAP-SD) was recorded (3 min). Visual Discrimination (DIS, Nuechterlein et al., 1983). A digit appeared on the display for 34 ms every second. Stimuli were digits (0, 2, 3, 5, 6, 8 and 9) of which zero was defined as a target and the others as non-targets. The ratio of targets to non-targets was 1:3. Stimuli were optically degraded by a diffusion screen in front of the display. Signal detection theory (Green and Swets, 1966) was applied for calculating perceptual sensitivity, d', and decision criterion, /3, as the dependent variables.
2.5. Subjective assessments Subjects completed a standardised clinical questionnaire (Mulder-Hajonides van der Meulen, 1981) for assessing their sleep quality and estimating its total duration each morning throughout every treatment period. They also retrospectively indicated the occurrence and severity of possible side-effects- drowsiness, loss of concentration, memory disturbance, fatigue and n a u s e a - o n separate 10-cm visual analogue scales in the evenings of the same days. If a subject experienced any other side-effect, he was urged to report it also. On test days only, they used Zijlstra and Van Doorn's (1985) scale to indicate effort required for performing all tests at the conclusions of both the morning and afternoon sessions. They also rated quality of their own driving performance on visual analogue scales at the conclusions of both tests.
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H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
2.6. Blood samples Blood samples were drawn from subjects' antecubital vein on test days, 8 h after ingestion of the morning dose, and the plasma fraction was assayed to confirm presence of the administered drug. An additional sample was taken on day 8 to measure haematological and biochemical parameters. Subjects were not allowed to enter the next treatment period unless these parameters were within normal clinical limits.
33 31 29
~27 ~. 25
~23 21 19
2.7. Statistical analysis All variables were separately analysed by repeatedmeasures analysis of variance (ANOVA). With one exception, psychomotor and driving data were partitioned according to a 4 (treatment)x 2 (day)× 2 (time of day, ToD) factorial model to test main effects and the interaction. Subjective ratings of driving quality and mental effort were also analysed in this manner. The exception occurred as the factors of set size ( x 3) and response category ( x 2) were added for analysing data from the Sternberg test. Sleep quality and duration were analysed according to a 4 (treatment) x 6 (days 2-7) factorial model. Data from days 1 and 8 were not included in these analyses since subjects awoke earlier than normal on test days. Subjective ratings of side-effects were analysed according to a 4 (treatment) × 8 (day) factorial model. If ANOVA revealed a significant (P ~<0.05) main effect of treatment, or a significant interaction of treatment and another factor, data obtained in P20, P40 and AMI were separately compared with those from PLA using parallel, repeated-measures ANOVAs. Such comparisons allow identification of the specific drugplacebo differences that contribute most to the overall effect.
3. Results
3.1. Driving tests Thirteen driving tests (i.e. 5%) were terminated prematurely: two in PLA and P40 and seven in AMI on day 1; and one in PLA and P40 on day 8. One test in P40 was terminated at the subject's request when he felt incapable of driving safely. All other rides were terminated by the driving instructor. These subjects appeared very drowsy though not all had begun to perform deficiently. Standard deviation of lateral position. Fig. 1 shows mean ( + SE) SDLP in all conditions, on both days and in both tests on the same days. ANOVA revealed a significant overall treatment effect (F3,45 = 11.12; P ~< 0.001). Univariate tests demonstrated only a signifi-
17
Day 1 (am)
Day 1 (pro)
Day 8 (am)
Day 8 (pm)
Study Day and Time of Day (am/pro) Fig. 1. Mean ( + SE) standard deviation of lateral position (SDLP) in the driving test by treatment, day and time of day.
cant effect of amitriptyline (F1,15 = 39.60; P <~0.001) and none due to either dose of paroxetine. The day effect was significant (FL15 = 18.94; P ~<0.001): on the average SDLPs were lower on day 8. The ToD effect was also significant: subjects drove worse in the second test than the first (F1,~5 = 28.07; P ~<0.001). The treatment × day interaction was significant (F3,45 = 11.75; P~<0.001) due to the improvement in performance which occurred in AMI over days (F~,~5 = 18.10; P ~<0.001). Speed. Mean speed ranged from 95.5 to 97.7 km/h among conditions. ANOVA revealed a significant overall treatment effect upon mean speed (F3,45 = 3.24; P~<0.031). Subjects drove significantly slower on AMI than PLA (F1,~5=4.66; P~<0,047) but the reduction in speed was small in absolute terms (1.2 km/h). Main effects of day and ToD were also significant (F1,15=4.91; P<~0.043 and F~,ts=10.00; P ~<0.006, respectively) but, again, the changes were small. Standard deviation of speed. Standard deviation of speed ranged among conditions from 2.08 to 2.55 km/h and was significantly affected by day (F1,15 = 7.94; P~<0.013) and ToD (/71,15=18.17; P~<0.001). All of the mean differences in SD speed, whether significant or not, were small in absolute terms, i.e. less than 0.25 km/h or about 0.25% of mean speed. No particular importance is attached to these results.
3.2. Psychomotor tests Means (SEs) and significant results from psychomotor tests are summarised in Tables 1 and 2, respectively. The results of all tests except continuous recall and constant tapping were consistent in showing gross impairing effects of amitriptyline on day 1. However, that general impairment was virtually gone by day 8. These observations were statistically confirmed by
H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
39
Table 1 M e a n (SE) values of psychomotor task variables by treatment and day N = 16) Values were averaged across ToD since there were no significant interactions between this and other factors. Variable
C F F (Hz) CTT-A c (rad/s) C O N T - R T (ms) fONT-PC (%) D A T - T E (mm) D A T - R T (ms) S T 1 - R T ~ (ms) S T 2 - R T a (ms) S T 4 - R T a (ms) T A P - S D (ms) DIS-d' b DIS-/3 b
PLA
P20
P40
AMI
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
54.3 (1.0) 5.61 (0.16) 873 (77) 97.4 (0.6) 16.9 (1.4) 2030 (158) 470 (17) 534 (20) 594 (18) 27.2 (2.0) 2.63 (0.23) 5.25 (0.86)
54.8 (1.1) 5.60 (0.18) 831 (83) 98.6 (0.3) 15.3 (1.5) 1982 (167) 476 (16) 536 (22) 599 (20) 26.8 (1.3) 2.35 (0.20) 5.30 (0.86)
54.5 (1.3) 5.48 (0.17) 926 (89) 96.8 (0.78) 17.2 (1.1) 2035 (195) 489 (18) 549 (21) 619 (24) 27.1 (2.7) 2.34 (0.25) 4.83 (1.14)
54.3 (1.4) 5.55 (0.16) 881 (76) 98.1 (0.4) 17.6 (1.2) 2052 (213) 485 (21) 542 (23) 625 (30) 26.3 (2.2) 2.44 (0.22) 5.74 (1.33)
55.3 (1.1) 5.38 (0.14) 898 (77) 96.2 (1.2) 18.3 (1.3) 2116 (201) 503 (17) 549 (15) 612 (17) 27.0 (2.2) 2.44 (0.21) 3.94 (0.78)
55.3 (1.3) 5.35 (0.15) 882 (83) 97.1 (1.0) 18.4 (1.5) 2022 (165) 494 (18) 556 (20) 615 (16) 26.9 (2.3) 2..29 (0.17) 6.07 (1.90)
51.7 (1.2) 4.75 (0.25) 915 (90) 96.2 (0.9) 22.6 (1.8) 2432 (229) 527 (19) 624 (27) 694 (24) 33.7 (2.7) 1.98 (0.22) 6.02 (1.72)
53.7 (0.8) 5.53 (0.20) 831 (82) 97.0 (1.0) 16.4 (1.3) 2110 (165) 478 (16) 540 (17) 606 (20) 27.5 (2.7) 2.52 (0.18) 7.22 (2.12)
ST1-, ST2- and ST4-RT are m e a n reaction times in the Sternberg paradigm with m e m o r y set sizes of one, two and four, respectively. Values are averaged across response category ('yes', ' n o ' ) since there were no significant interactions between this and other factors. b N = 14, due to the impossibility to calculate d' a n d / 3 for two subjects who failed to m a k e false alarms in one or m o r e conditions.
significant treatment and treatment × day interaction effects for the AMI vs PLA comparisons. Paroxetine 20 mg was devoid of significant effects in the psychomotor test battery. The 40 mg dose, however, produced significant performance decrements in some tasks (CTT, D A T and ST). These effects were much less than those produced by amitriptyline (Fig.
2), but more stable over time as shown by the lack of treatment × day interaction for P40 relative to PLA. ANOVA showed the expected significant effect of set size in the Sternberg test (F2.30 = 155.08; P~< 0,001): greater memory sets prolonged reaction times. The effect of response category was also significant (F~,15=37.73; P~<0.001) indicating that 'no' re-
Table 2 M a j o r results from r e p e a t e d - m e a s u r e s A N O V A of the psychomotor variables Factor
Treatment ( d f = 3,45)
CFF
CTT•t c
3.61" 4.93** A M I vs P L A (1,15) 4.39* 9.66** P40 vs P L A 5.48* P20 vs P L A . . Day (1,15) 19.36"* ToD (1,15) 8.01" Treatment x day (3,45) 10.88"* A M I vs P L A (1,15) 13.49"* P40 vs P L A . . . P20 vs P L A . . . (All other interactions were non-significant)
CONTRT
fONTPC
DATTE
DATRT
STRT
TAPSD
DISd' a
DIS/3 a
-
-
3.66* 15.81"* 4.53*
-
5.00** 12.81"* 6.43* . 6.51" . 11.47"* 20.32** . .
3.19" -
-
-
. -
-
-
7.33** 14.26"*
-
. 8.15" . . .
.
.
.
. . .
20.36** . 10.69"* 9.30** . . . .
.
. 6.17" .
. . .
.
. .
Significant F-ratios are shown with the associated P value ( * P ~<0.05; **P ~<0.01). a N = 14 and degrees of freedom for the error term 39 and 13 instead of 45 and 15, respectively, due to the impossibility to calculate d' a n d / 3 for two subjects who failed to m a k e false alarms in one or more conditions.
H.W,J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
40
treatment × day interaction was also significant (F3.45 = 6.26.6 t
I I P L A ].JP20 [~P40 ~ A M I
5.8-
4.2
Day 1 (am)
Day 1 (pro)
Day 8 (am)
Day 8 (pro)
Study Day and Time of Day (am/pm) Fig. 2. Mean ( + SE) h~ in the critical tracking test by treatment, day and time of day.
sponses took more time than 'yes' responses. The set size × response category interaction was not significant, i.e., the difference in reaction time between 'yes' and 'no' responses was similar for all set sizes. The set size × treatment interaction was significant (F6.90 = 2.81; P ~<0.015) and mainly due to AMI (F2,30 = 3.67; P~<0.037). This means that amitriptyline, but not paroxetine 40 mg, retarded the memory search process. Therefore, paroxetine's slowing of reaction time probably occurred at an earlier or later stage of information processing, i.e. perception or response selection and execution. Average intrasubject correlations were calculated for determining if changes in SDLP covaried with changes in the psychomotor test variables. Individual correlations were based upon 16 pairs (4 treatments × 2 days x 2 repetitions). The individual correlations for the combination of SDLP and a particular psychomotor variable were transformed into corresponding Fisher z scores and then averaged across subjects. This Zav was tested for significant deviation from zero by t-test and then retransformed to Pearson's r. Correlations between SDLP and the other measures were modest, which confirms the results from a previous study employing similar tests (Robbe et al., 1988). Highest correlations (r = 0.45; P ~<0.001) were found between SDLP and the two measures of laboratory tracking performance, i.e. CTY and DAT-TE.
10.65; P ~<0.001), again due to amitriptyline (F1,15 = 11.68; P~<0.004). Performing the tests after amitriptyline required more effort on day 1 than on day 8. Mean perceived driving quality, indicating awareness of impairment, varied in parallel with SDLP across tests in all conditions. Significant effects were shown by ANOVA for treatment (F3,45 = 10.89; P~<0.001), day (F~.15= 11.59; P ~<0.004) and treatment × day interaction (F3,45 = 10.36; P~<0.001). Amitriptyline was again responsible for these effects (F~,~5 = 42.10; P<~0.001 for treatment effect and F1,15 = 11.99; P 0.003 for treatment ~
•
g~ 50%
P40
4. P20
"¢.
PLA
40% .y~ 30%
3.3. Subjective assessments Mental effort and driving quality. Mental effort ratings were significantly affected by t r e a t m e n t (F3,45 = 7.14; P~<0.001) and ToD (F1,~5=8.43; P<~0.011). The latter indicates that the second session on both days required more mental effort than the first. The overall treatment effect was mainly due to increased effort ratings in AMI (F~,~5 = 16.75; P~<0.001). The
20%
I
0%t 0
_
L 1
_~ 2
~ 3
J 4
t 5
. • 6
~ 7
_1 8
Study Day Fig. 3. Mean ( + SE) ratings of drowsiness by treatment and day, presented as percentage of full scale.
H.W..J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
the week, whereas paroxetine 40 mg's initially smaller effect was more persistent. Mean ratings of fatigue, concentration loss and memory disturbances were generally lower than for drowsiness. Nonetheless, all of the former followed similar profiles over the respective treatment periods as the latter and these differed significantly in the same ways. Mean nausea ratings followed an entirely different pattern. There were significant overall treatment (F3,45 : 6.26; P ~ 0.001) and day (F7,105 = 2.62; P~<0.016) effects but no significant treatment x day interaction. Nausea ratings were significantly higher in both P20 and P40 than in PLA (F1,15 = 5.15 and 11.64; P~<0.038 and 0.004, respectively). The maximum amplitudes of these mean ratings were low, however, i.e., 7% and 22% of full scale in P20 and P40, respectively. Adverse experiences. Side-effects that were spontaneously reported by the 16 subjects were analysed by Cochran's Q-test to determine whether the incidence differed significantly (P~<0.05) between treatments. This was the case for the following side-effects: dry mouth (4 in P40, 8 in AMI), tremor (1 in P20, 7 in P40, 5 in AMI), headache (3 in PLA, 5 in P20, 8 in P40, 2 in AMI), delayed ejaculation or anorgasmia (3 in P20, 5 in P40) and jaw trembling or pain (1 in PLA, 4 in P20, 4 in P40).
3.4. Drug plasma concentrations In P20, the mean (-+ SD) paroxetine plasma concentrations were 6.7 ( -+ 6.0) and 33.0 ( _ 16.1) ng/ml on days 1 and 8, respectively; and in P40 21.6 ( -+ 9.4) and 99.1 ( -- 38.9) ng/ml. In AMI, the mean ( _+SD) amitriptyline and nortriptyline concentrations were 14.5 (___6.9) and 7.6 (-+ 3.2) ng/ml, respectively, on day 1; and 22.5 (--_ 10.8) and 22.1 (---9.3) ng/ml on day 8.
4. Discussion
Plasma concentrations of both drugs were found to be in the expected range for the doses given (Lader et al., 1986; Allen et al., 1988; Raptopoulos and McClelland, 1987; Kaye et al., 1989) indicating that the subjects complied with the dosing regimen. Amitriptyline fulfilled its function as the active control. Its acute effects on road tracking ability confirmed the results of an earlier study (Louwerens et al., 1986). Furthermore, seven driving tests (i.e. 22%) were terminated on the first day of treatment in an early stage of the ride because subjects were judged unable to continue safely. It was again obvious that amitriptyline has severe acute effects on driving performance. It also produced severe drowsiness, loss of
41
concentration and fatigue and significantly impaired performance in every laboratory test except continous recall and constant tapping. However, nearly all of these adverse effects tended to dissipate with repeated dosing and were practically gone after a week. Apparently, young healthy volunteers rapidly develop tolerance to amitriptyline's sedative activities which result in psychomotor impairment when the drug is administered in this dose and regimen. Previous studies with amitriptyline in young healthy volunteers provided similar indications of the ameliorating effects of tolerance on psychomotor impairment (Allen et al., 1988; Lader et al., 1986; Seppfilfi, 1977; Seppfilfi et al., 1984). Whether the same would occur in patients treated with higher daily doses, divided in the same or a different manner, is unknown. Paroxetine 20 mg was devoid of any adverse effects on group performance, both in the laboratory and on the road. Compared to placebo, it had no disturbing effect on sleep and the few side-effects it produced were of a mild nature. There was, however, one subject who dropped out of the study after experiencing more severe side-effects and driving poorly during treatment with paroxetine 20 mg. The possibility that his reaction might occur in some patients cannot be easily dismissed. Paroxetine 40 mg did not alter driving performance relative to placebo. Although three subjects failed to complete one of the four driving tests they undertook during treatment with paroxetine 40 mg, no particular importance is attached to these results because the same number of rides were prematurely terminated following placebo. Paroxetine 40 mg slightly impaired performance in several laboratory tests, i.e., critical tracking, divided attention and the Sternberg test. Earlier reports of similar increases in reaction times following paroxetine 20 mg (Kerr et al., 1992) and paroxetine 30 mg in combination with alcohol (Hindmarch and Harrison, 1988) suggest that the present study's results were not accidental. That they were small in magnitude and no similarly significant effects emerged from the driving test probably indicates that they are of little practical relevance. That they did not dissipate over the treatment period may be of greater importance. It means that if some impairment of practical relevance ever occurs (e.g. in sensitive patients or after doses higher than 40 mg) it may persist for a prolonged period. Several side-effects were observed during treatment with paroxetine 40 mg. Sleep quality was reduced, especially in the beginning of the treatment period, which agrees with a previous report of disturbed sleep with paroxetine (Oswald and Adam, 1986). Ratings for drowsiness, loss of concentration, fatigue, nausea and memory disturbance were increased, although less than with amitriptyline. However, except for memory
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H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
d i s t u r b a n c e , the statistical analyses p r o v i d e d n o evid e n c e for d e v e l o p i n g t o l e r a n c e to these side-effects. I n c o n c l u s i o n , this study c o n f i r m e d p r e v i o u s findings w h i c h show that p a r o x e t i n e 20 m g is g e n e r a l l y d e v o i d of a d v e r s e effects o n p s y c h o m o t o r p e r f o r m a n c e . It e x t e n d e d t h e m by p r o v i d i n g direct e v i d e n c e that p a t i e n t s who take this dose w i t h o u t e x p e r i e n c i n g severe side-effects are c a p a b l e of driving safely. It also s h o w e d that adverse r e a c t i o n s to p a r o x e t i n e are dose related and might influence psychomotor performance at doses higher t h a n or e q u a l to 40 r a g / d a y . T h e i n d i c a t i o n t h a t adverse effects of higher doses persist for at least a w e e k w a r r a n t s f u r t h e r a t t e n t i o n .
Acknowledgement This r e s e a r c h was s u p p o r t e d by S m i t h K l i n e Beecha m P h a r m a c e u t i c a l s , H a r l o w , Essex, U K .
References Allen, D., Lader, M. and Curran, H.V. (1988) A comparative study of the interactions of alcohol with amitriptyline, fluoxetine and placebo in normal subjects. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 12, 63-80. Battegay, R., Hager, M. and Rauchfleisch, U. (1985) Double-blind comparative study of paroxetine and amitriptyline in depressed patients of a university psychiatric outpatient clinic (pilot study). Neuropsychobiology 13, 31-37. Dunner, D.L. and Dunbar, G.C. (1991) Paroxetine-the optimal dosing regimen for this new antidepressant. Eur. Neuropsychopharmacol. 1, 437. Green, D.M. and Swets, J.A. (1966) Signal Detection and Psychophysics. Wiley, New York. Hindmarch, I. and Harrison, C. (1988) The effects of paroxetine and other antidepressants in combination with alcohol in psychomotor activity related to car driving. Hum. Psychopharmacol. 3, 13-20. Hunter, D.R. (1975) Development of an enlisted psychomotor/ perceptual test battery. Technical Report AFHRL-TR-75-60, Air Force Human Resources Laboratory, Dayton, OH. Jex, H.R., McDonell, J.D. and Phatak, A.V. (1966) Critical tracking task for manual control research. IEEE Trans. Hum. Fac. Electron. 7, 138-145. Kaye, C.M., Haddock, R.E., Langley, P.F., Mellows, G., Tasker, T.C.G., Zussman, B.D. and Greb, W.H. (1989) A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psychiatr. Scand. 80 (Suppl. 350), 60-75. Kerr, J.S., Fairweather, D.B., Mahendran, R. and Hindmarch, I, (1992) The effects of paroxetine, alone and in combination with alcohol on psychomotor performance and cognitive function in the elderly. Int. Clin. Psychopharmacol. 7, 101-108. Lader, M., Melhuish, A., Freka, G., Fredricson OverO, K. and Christensen, V. (1986) The effects of citalopram in single and repeated doses and with alcohol on physiological and psychological measures in healthy subjects. Eur, J. Clin. Pharmacol. 31, 183-190. Laursen, A.L., Mikkelsen, P.L., Rasmussen, S. and LeFevre, H.P. (1985) Paroxetine in the treatment of depression: a randomized comparison with amitriptyline. Acta Psychiatr. Scand. 71, 249255.
Louwerens, J.W., Brookhuis, K.A. and O'Hanlon, J.F. (1986) Several antidepressants' acute effects upon actual driving performance and subjective mental activation. In: O'Hanlon, J.F. and De Gier, J.J. (Eds.), Drugs and Driving. Taylor and Francis, London, pp. 203-212. McClelland, G.R. and Raptopoulos, P. (1985) Psychomotor effects of paroxetine and amitriptyline, alone and in combination with ethanol. Br. J. Clin. Pharmacol. 19, 578P. McClelland, G.R. and Raptopoulos, P. (1986) Paroxetine and amylobarbitone: effects on psychomotor performance. Br. J. Clin. PharmacoL 22, 227P-228P. McClelland, G.R., Loudon, J.M. and Raptopoulos, P. (1987a) Paroxetine and oxazepam: effects on psychomotor performance. Br. J. Clin. Pharmacol. 23, l17P. McClelland, G.R., Cooper, S.M. and Raptopoulos, P. (1987b) Paroxetine and baloperidol: effects on psychomotor performance. Br. J. Clin. Pharmacol. 24, 268P-269P. Michon, J.A. (1966) Tapping regularity as a measure of perceptual motor load. Ergonomics 9, 401-412. Moskowitz, H. and Burns, M. (1977) The effects of alcohol and Valium, singly and in combination, upon driving-related skills performance. In: Hulke, D. (Ed.), Proceedings of the 21st Conference of the American Association for Automotive Medicine. AAAM, Morton Grove, IL. Mulder-Hajonides van der Meulen, W.R.E.H. (1981) Measurements of subjective sleep quality. Proceedings of the International European Sleep Congress, Elsevier, Amsterdam. Nuechterlein, K.H., Parasuraman, R. and Jiang, Q. (1983) Visual sustained attention: Image degradation produces rapid sensitivity decrement over time. Science 220, 327-329. O'Hanlon, J.F., Brookhuis, K.A., Louwerens, J.W. and Volkerts, E.R. (1986) Performance testing as part of drug registration. In: O'Hanlon, J.F. and De Gier, J.J. (Eds.), Drugs and Driving. Taylor and Francis, London, pp. 311-330. Oswald, I. and Adam, K. (1986) Effects of paroxetine on human sleep. Br. J. Clin. Pharmacol. 22, 97-99. Ramaekers, J.G., Swijgman, H.F. and O'Hanlon, J.F. (1992) Effects of moclobemide and mianserin on highway driving, psychometric performance and subjective parameters, relative to placebo. Psychopharmacology 106, $62-$67. Raptopoulos, P. and McClelland, G.R. (1987) Effects of 28-day repeated oral administration of paroxetine to normal volunteers. Int. J. Neurosci. 32, 435. Ray, W.A., Fought, R.L. and Decker, M.D. (1992) Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Am. J. Epidemiol. 136, 873-883. Rey, P. and Rey, J.P. (1964) La frrquence de fusion optique subjective: comparaison de trois mrthodes de mesure avant et apr~s le travail. Travail Hum. 26, 135-145. Robbe, H.W.J., Schoenmakers, E.A.J.M. and O'Hanlon, J.F. (1988) Attempt to assess the predictive validity of laboratory tests from the results of a subchronic study of new and old antidepressants (i.e. levoprotiline and doxepin, respectively). Psychopharmacology 96, S156. Sepp/il~i, T. (1977) Psychomotor skills during acute and two-week treatment with mianserin (Org GB 94) and amitriptyline, and their combined effects with alcohol. Ann. Clin. Res. 9, 66-72. Sepp~il~i, T., Str6mberg, C. and Bergman, I. (1984) Effects of zimeldine, mianserin and amitriptyline on psychomotor skills and their interaction with ethanol: a placebo controlled cross-over study. Eur. J. Clin. Pharmacol. 27, 181-189. Sternberg, S. (1969) Memory-scanning: mental processes revealed by reaction-time experiments. Am. Scientist 57, 421-457. Zijlstra, F.R.H. and Van Doorn, L. (1985) The Construction of a Scale to Measure Perceived Effort. Technical Report, Delft University, Delft.
European Neuropsychopharmacology 5 (1995) 35-42
Acute and subchronic effects of paroxetine 20 and 40 mg on actual driving, psychomotor performance and subjective assessments in healthy volunteers H i n d r i k W.J. R o b b e * , J a m e s F. O ' H a n l o n Institute for Human Psychopharmacology, University of Limburg, P.O. Box 616, 6200 MD Maastricht, The Netherlands Received 4 May 1993; accepted 1 September 1994
Abstract
The effects of paroxetine (20 and 40 mg/day) and amitriptyline (75 mg/day, used as an active control) on car driving and psychomotor function were compared with those of placebo in a double-blind, crossover study employing 16 healthy subjects. Performance testing occurred on the first and last day of each 8-day treatment series. Side-effects, sleep duration and sleep quality were rated daily. Amitriptyline produced severe drowsiness and strikingly impaired performance on nearly every test on the first day but its effects were practically gone after 1 week of treatment. Paroxetine 20 mg, the usual antidepressant dose, had no effect on performance. Paroxetine 40 mg did not affect road tracking but slightly impaired performance in some psychomotor tests in a persistent manner. Paroxetine had no effect on sleep following the 20 mg dose but reduced quality following the 40 mg dose. Side-effects that the administered drugs have in common were milder during paroxetine than amitriptyline treatment. However, some dose-related side-effects (e.g. nausea and delayed ejaculation) were only reported during paroxetine treatment.
Keywords: Paroxetine; Amitriptyline; Driving and psychomotor performance; Sleep; Side-effects
1. Introduction
Paroxetine, a selective serotonin reuptake inhibitor (SSRI), is as efficacious as and produces fewer and/or milder side-effects than older antidepressants such as amitriptyline (Battegay et al., 1985; Laursen et al., 1985). The usual daily dose of paroxetine is 20 mg but its therapeutic range extends to 50 mg (Dunner and Dunbar, 1991). From paroxetine's side-effect profile one might expect that the drug would not unduly interfere with patients' abilities to perform skilled tasks. Some older antidepressants do this: recent epidemiological evidence indicates that elderly ( > 65 years) patients for whom tricyclic antidepressants were prescribed in amitriptyline-equivalents equal to or higher than 125 m g / d a y drove with a risk of injurious traffic accidents that was nearly six times that of age-matched controls (Ray et al., 1992). Before con*Corresponding author. Tel.: +31.43.883305; Fax: +31. 43. 257380. 0924-977X/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0924-977X(94)00130-8
cluding that patients treated with paroxetine will be at less risk of injury due to performance deficits, it seems essential to provide evidence that the drug does not impair the capacity for accomplishing tasks in a safe and efficient manner. Previous experimental research has shown that a single 30 mg paroxetine dose has itself no effect on psychomotor performance in the laboratory and generally does not potentiate impairment produced by ethanol (McClelland and Raptopoulos, 1985; Hindmarch and Harrison, 1988), amylobarbitone (McClelland and Raptopoulos, 1986), oxazepam (McClelland et al., 1987a), or haloperidol (McClelland et al., 1987b). Yet one interactive effect of paroxetine 30 mg and ethanol was significant in a test of divided attention (Hindmarch and Harrison, 1988). Paroxetine 20 mg, administered to healthy elderly volunteers for 1 week, had little or no effect on performance, and did not interact with ethanol in a series of conventional psychomotor tests (Kerr et al., 1992). Yet it is always questionable to conclude that any drug has no effects
36
H.W.J. Robbe. J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
upon skilled performance in real-life tasks solely on the basis of results obtained from laboratory tests. Their predictive validity has yet to be shown (O'HanIon et al., 1986). The present study was designed to determine if paroxetine has any adverse effect on performance in a real-life task, i.e. actual car driving. It compared the effects of two doses of paroxetine (20 and 40 mg) on healthy volunteers' performance relative to those of placebo, after 1 and 8 days of treatment. The subjects' performance was also measured with laboratory tests to determine whether their measures of drug-induced impairment correlate with those of actual car driving in a manner confirming the predictive validity of laboratory tests. Amitriptyline was chosen as the active control. The usual starting dose, 75 mg/day, was given. Recognising the drug's strong sedative activity, the daily dose was divided between 50 mg at night and 25 mg in the morning. This regimen was employed to achieve enough of an impairing effect for establishing test sensitivity but not so much as to seriously interfere with the volunteers' normal activities during this treatment period.
2. Experimental procedures 2.1. Subjects
Sixteen healthy male subjects completed the study. Four were replacements for earlier drop-outs. Three of the original group dropped out for reasons unrelated to treatments. One did so after completing the first treatment period wherein he experienced persistent adverse reactions to paroxetine 20 mg/day. He reported concentration problems, tiredness, severe drowsiness and unpleasant feelings in the left chest as well as headache throughout the treatment period. Furthermore, he experienced memory disturbances and diarrhoea during the last 3 days. He undertook four driving tests wherein his performance was generally poor. On one occasion it was bad enough to cause a premature termination. Subjects who completed the study ranged in age from 21 to 28 years ( m e a n - SD = 2 3 . 6 - 1.8). All held valid driving licences and had driven at least 5000 km per year for the previous 3 years. They refrained from any form of oral medication during periods of participation. Caffeine-containing beverages were only allowed at breakfast time on test days and alcohol consumption was not permitted for 24 h beforehand. At other times subjects were required to limit their alcohol consumption to one glass of beer or wine per day. They were strongly advised not to operate their own vehicles during any treatment period, including placebo (costs of public transport were reimbursed).
Before selection, subjects underwent a medical examination including ECG and haematological and blood chemistry screening. No abnormalities of clinical importance were found. Subjects gave their written informed consent and were paid for their participation. The study was approved by the Medical Ethics Review Committee of the University of Limburg, Maastricht.
2.2. Design
Daily oral doses of paroxetine 20 mg (P20), paroxetine 40 mg (P40), amitriptyline 75 mg (AMI) and placebo (PLA) were given for 8 days apiece in a four-period, double-blind, crossover design. Treatment orders were randomly assigned from those residing in four, 4 x 4 Latin squares. A washout period of at least 13 days occurred between treatments. Subjects ingested capsules containing drug or placebo at night and 10 h later the next morning, 30 min before breakfast. The entire paroxetine dose was contained in the morning capsules. The amitriptyline dose was divided between 50 mg at night and 25 mg in the morning. Subjects were thoroughly trained in all psychomotor performance tests and performed a complete 'dress rehearsal' of the entire procedure, including driving, prior to testing. They were tested on days 1 and 8 of each treatment period. They performed an alternating series of driving and psychomotor tests, lasting 60 and 75 min, respectively. The driving tests began at 1.5 h and 5 h, the psychomotor tests at 3.25 h and 6.75 h after the morning dose.
2.3. Driving test
This test has been standardised and repeatedly applied for measuring the sedative effects of drugs (O'Hanlon et al., 1986; Ramaekers et al., 1992). It was performed over a 100-km circuit on a primary highway in traffic. Subjects were instructed to drive in the right (slower) traffic lane, while maintaining a constant speed (95 km/h) and steady lateral position between delineated lane boundaries. They could, however, deviate from these instructions in order to pass a slower vehicle. Subjects were instructed not to converse with the experimenters except to announce their decision to terminate the test if doubting their ability to continue driving in a safe manner. Subjects were accompanied during all the tests by a licensed driving instructor, who could intervene if necessary by using dual controls. The test vehicle was instrumented to continuously sample lateral position, speed and steering wheel angle at a rate of 4 Hz. The primary
H.W.J. Robbe. J.F, O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42 measure of road tracking ability was the standard deviation of lateral position (SDLP).
2. 4. Psychomotor tests The battery comprised seven different tests. Its total duration was 1.25 h. Each test in the following succession was started at a fixed time. Critical Flicker~Fusion Frequency (CFF). The method of 'successive approximation' was used to measure CFF (Rey and Rey, 1964). Ultimately, the CFF was defined within a 0.5-Hz interval between frequencies that were reliably judged as leading to the respective perceptions of flicker and fusion (test duration: 5 min). Critical Tracking Test (CTT, Jex et al., 1966). This test measured the subject's ability to control a displayed error signal in a first-order compensatory tracking task. Error appeared as horizontal deviation of a cursor from midpoint on a horizontal, linear scale. Compensatory joystick movements nulled the error by returning the cursor to the midpoint. The frequency of cursor deviations, and therefore its velocity, increased as a stochastic, linear function of time. The frequency at which the subject lost control was the critical frequency (Ac, expressed in rad/s). Theoretically, Ac is the reciprocal of the operating delay lag in human closed-loop manual control. The test included five trials of which the lowest and highest score were removed; the average of the remaining scores was taken as the final score (5 min). Continuous Recall (CONT, Hunter, 1975). A series of fractions, each presented with two digits in both the numerator and denominator, were presented on a display at a rate of one per 3.5 s. The task was to memorise the denominator and decide whether it was the same as or different than the numerator shown two presentations later. Dichotomous responses were made as rapidly as possible with corresponding push buttons. The percentage of correct responses (CONTPC) and the mean reaction time (CONT-RT) for yielding the same were separate dependent variables for measuring treatment effects on working memory (3.5 min). Divided Attention (DAT, Moskowitz and Burns, 1977). This test required simultaneous performance of two tasks, a central tracking task and a peripheral visual search-and-detection task. The central task was the compensatory tracking task described above but with a constant difficulty level set at 50% of subject's maximum capacity, as determined during training trials. Tracking error was measured as the difference in mm between the position of the cursor and the midpoint of the scale. The mean absolute tracking error (DAT-TE) over the entire test was the dependent variable for this sub-task. The secondary task was
37
to monitor each of 24 peripheral LED displays, showing the numerals 0-9, and react to the appearance of the target ('2') by removing the foot from a pedal. The numerals changed asynchronously at intervals of 5 s. Inter-target intervals varied randomly between 5 and 25 s. Mean reaction time (DAT-RT) was the dependent variable for this sub-task (12 min). Sternberg Test (ST, Sternberg, 1969). Subjects were briefly (3 s) shown a set of letters and told to memorise them. They then saw a series of 90 letters, presented one per 2 s. Their task was to decide and respond as rapidly as possible by pressing respective push-buttons to indicate whether or not each successive letter was one of those contained in the memory set. This task was performed three times, with memory sets of one, two and four letters, respectively. Mean reaction time of both correct 'yes' and 'no' responses were the dependent variables (12 min). Constant Tapping (TAP, Michon, 1966). This test provides a measure of fine motor control during repetitive movement. Variability of tapping rate is thought to directly vary with adverse treatment effects on fine motor control. Subjects were instructed to tap at a constant rate of twice per second. The standard deviation of intertap interval times (TAP-SD) was recorded (3 min). Visual Discrimination (DIS, Nuechterlein et al., 1983). A digit appeared on the display for 34 ms every second. Stimuli were digits (0, 2, 3, 5, 6, 8 and 9) of which zero was defined as a target and the others as non-targets. The ratio of targets to non-targets was 1:3. Stimuli were optically degraded by a diffusion screen in front of the display. Signal detection theory (Green and Swets, 1966) was applied for calculating perceptual sensitivity, d', and decision criterion, /3, as the dependent variables.
2.5. Subjective assessments Subjects completed a standardised clinical questionnaire (Mulder-Hajonides van der Meulen, 1981) for assessing their sleep quality and estimating its total duration each morning throughout every treatment period. They also retrospectively indicated the occurrence and severity of possible side-effects- drowsiness, loss of concentration, memory disturbance, fatigue and n a u s e a - o n separate 10-cm visual analogue scales in the evenings of the same days. If a subject experienced any other side-effect, he was urged to report it also. On test days only, they used Zijlstra and Van Doorn's (1985) scale to indicate effort required for performing all tests at the conclusions of both the morning and afternoon sessions. They also rated quality of their own driving performance on visual analogue scales at the conclusions of both tests.
38
H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
2.6. Blood samples Blood samples were drawn from subjects' antecubital vein on test days, 8 h after ingestion of the morning dose, and the plasma fraction was assayed to confirm presence of the administered drug. An additional sample was taken on day 8 to measure haematological and biochemical parameters. Subjects were not allowed to enter the next treatment period unless these parameters were within normal clinical limits.
33 31 29
~27 ~. 25
~23 21 19
2.7. Statistical analysis All variables were separately analysed by repeatedmeasures analysis of variance (ANOVA). With one exception, psychomotor and driving data were partitioned according to a 4 (treatment)x 2 (day)× 2 (time of day, ToD) factorial model to test main effects and the interaction. Subjective ratings of driving quality and mental effort were also analysed in this manner. The exception occurred as the factors of set size ( x 3) and response category ( x 2) were added for analysing data from the Sternberg test. Sleep quality and duration were analysed according to a 4 (treatment) x 6 (days 2-7) factorial model. Data from days 1 and 8 were not included in these analyses since subjects awoke earlier than normal on test days. Subjective ratings of side-effects were analysed according to a 4 (treatment) × 8 (day) factorial model. If ANOVA revealed a significant (P ~<0.05) main effect of treatment, or a significant interaction of treatment and another factor, data obtained in P20, P40 and AMI were separately compared with those from PLA using parallel, repeated-measures ANOVAs. Such comparisons allow identification of the specific drugplacebo differences that contribute most to the overall effect.
3. Results
3.1. Driving tests Thirteen driving tests (i.e. 5%) were terminated prematurely: two in PLA and P40 and seven in AMI on day 1; and one in PLA and P40 on day 8. One test in P40 was terminated at the subject's request when he felt incapable of driving safely. All other rides were terminated by the driving instructor. These subjects appeared very drowsy though not all had begun to perform deficiently. Standard deviation of lateral position. Fig. 1 shows mean ( + SE) SDLP in all conditions, on both days and in both tests on the same days. ANOVA revealed a significant overall treatment effect (F3,45 = 11.12; P ~< 0.001). Univariate tests demonstrated only a signifi-
17
Day 1 (am)
Day 1 (pro)
Day 8 (am)
Day 8 (pm)
Study Day and Time of Day (am/pro) Fig. 1. Mean ( + SE) standard deviation of lateral position (SDLP) in the driving test by treatment, day and time of day.
cant effect of amitriptyline (F1,15 = 39.60; P <~0.001) and none due to either dose of paroxetine. The day effect was significant (FL15 = 18.94; P ~<0.001): on the average SDLPs were lower on day 8. The ToD effect was also significant: subjects drove worse in the second test than the first (F1,~5 = 28.07; P ~<0.001). The treatment × day interaction was significant (F3,45 = 11.75; P~<0.001) due to the improvement in performance which occurred in AMI over days (F~,~5 = 18.10; P ~<0.001). Speed. Mean speed ranged from 95.5 to 97.7 km/h among conditions. ANOVA revealed a significant overall treatment effect upon mean speed (F3,45 = 3.24; P~<0.031). Subjects drove significantly slower on AMI than PLA (F1,~5=4.66; P~<0,047) but the reduction in speed was small in absolute terms (1.2 km/h). Main effects of day and ToD were also significant (F1,15=4.91; P<~0.043 and F~,ts=10.00; P ~<0.006, respectively) but, again, the changes were small. Standard deviation of speed. Standard deviation of speed ranged among conditions from 2.08 to 2.55 km/h and was significantly affected by day (F1,15 = 7.94; P~<0.013) and ToD (/71,15=18.17; P~<0.001). All of the mean differences in SD speed, whether significant or not, were small in absolute terms, i.e. less than 0.25 km/h or about 0.25% of mean speed. No particular importance is attached to these results.
3.2. Psychomotor tests Means (SEs) and significant results from psychomotor tests are summarised in Tables 1 and 2, respectively. The results of all tests except continuous recall and constant tapping were consistent in showing gross impairing effects of amitriptyline on day 1. However, that general impairment was virtually gone by day 8. These observations were statistically confirmed by
H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
39
Table 1 M e a n (SE) values of psychomotor task variables by treatment and day N = 16) Values were averaged across ToD since there were no significant interactions between this and other factors. Variable
C F F (Hz) CTT-A c (rad/s) C O N T - R T (ms) fONT-PC (%) D A T - T E (mm) D A T - R T (ms) S T 1 - R T ~ (ms) S T 2 - R T a (ms) S T 4 - R T a (ms) T A P - S D (ms) DIS-d' b DIS-/3 b
PLA
P20
P40
AMI
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
Day 1
Day 8
54.3 (1.0) 5.61 (0.16) 873 (77) 97.4 (0.6) 16.9 (1.4) 2030 (158) 470 (17) 534 (20) 594 (18) 27.2 (2.0) 2.63 (0.23) 5.25 (0.86)
54.8 (1.1) 5.60 (0.18) 831 (83) 98.6 (0.3) 15.3 (1.5) 1982 (167) 476 (16) 536 (22) 599 (20) 26.8 (1.3) 2.35 (0.20) 5.30 (0.86)
54.5 (1.3) 5.48 (0.17) 926 (89) 96.8 (0.78) 17.2 (1.1) 2035 (195) 489 (18) 549 (21) 619 (24) 27.1 (2.7) 2.34 (0.25) 4.83 (1.14)
54.3 (1.4) 5.55 (0.16) 881 (76) 98.1 (0.4) 17.6 (1.2) 2052 (213) 485 (21) 542 (23) 625 (30) 26.3 (2.2) 2.44 (0.22) 5.74 (1.33)
55.3 (1.1) 5.38 (0.14) 898 (77) 96.2 (1.2) 18.3 (1.3) 2116 (201) 503 (17) 549 (15) 612 (17) 27.0 (2.2) 2.44 (0.21) 3.94 (0.78)
55.3 (1.3) 5.35 (0.15) 882 (83) 97.1 (1.0) 18.4 (1.5) 2022 (165) 494 (18) 556 (20) 615 (16) 26.9 (2.3) 2..29 (0.17) 6.07 (1.90)
51.7 (1.2) 4.75 (0.25) 915 (90) 96.2 (0.9) 22.6 (1.8) 2432 (229) 527 (19) 624 (27) 694 (24) 33.7 (2.7) 1.98 (0.22) 6.02 (1.72)
53.7 (0.8) 5.53 (0.20) 831 (82) 97.0 (1.0) 16.4 (1.3) 2110 (165) 478 (16) 540 (17) 606 (20) 27.5 (2.7) 2.52 (0.18) 7.22 (2.12)
ST1-, ST2- and ST4-RT are m e a n reaction times in the Sternberg paradigm with m e m o r y set sizes of one, two and four, respectively. Values are averaged across response category ('yes', ' n o ' ) since there were no significant interactions between this and other factors. b N = 14, due to the impossibility to calculate d' a n d / 3 for two subjects who failed to m a k e false alarms in one or m o r e conditions.
significant treatment and treatment × day interaction effects for the AMI vs PLA comparisons. Paroxetine 20 mg was devoid of significant effects in the psychomotor test battery. The 40 mg dose, however, produced significant performance decrements in some tasks (CTT, D A T and ST). These effects were much less than those produced by amitriptyline (Fig.
2), but more stable over time as shown by the lack of treatment × day interaction for P40 relative to PLA. ANOVA showed the expected significant effect of set size in the Sternberg test (F2.30 = 155.08; P~< 0,001): greater memory sets prolonged reaction times. The effect of response category was also significant (F~,15=37.73; P~<0.001) indicating that 'no' re-
Table 2 M a j o r results from r e p e a t e d - m e a s u r e s A N O V A of the psychomotor variables Factor
Treatment ( d f = 3,45)
CFF
CTT•t c
3.61" 4.93** A M I vs P L A (1,15) 4.39* 9.66** P40 vs P L A 5.48* P20 vs P L A . . Day (1,15) 19.36"* ToD (1,15) 8.01" Treatment x day (3,45) 10.88"* A M I vs P L A (1,15) 13.49"* P40 vs P L A . . . P20 vs P L A . . . (All other interactions were non-significant)
CONTRT
fONTPC
DATTE
DATRT
STRT
TAPSD
DISd' a
DIS/3 a
-
-
3.66* 15.81"* 4.53*
-
5.00** 12.81"* 6.43* . 6.51" . 11.47"* 20.32** . .
3.19" -
-
-
. -
-
-
7.33** 14.26"*
-
. 8.15" . . .
.
.
.
. . .
20.36** . 10.69"* 9.30** . . . .
.
. 6.17" .
. . .
.
. .
Significant F-ratios are shown with the associated P value ( * P ~<0.05; **P ~<0.01). a N = 14 and degrees of freedom for the error term 39 and 13 instead of 45 and 15, respectively, due to the impossibility to calculate d' a n d / 3 for two subjects who failed to m a k e false alarms in one or more conditions.
H.W,J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
40
treatment × day interaction was also significant (F3.45 = 6.26.6 t
I I P L A ].JP20 [~P40 ~ A M I
5.8-
4.2
Day 1 (am)
Day 1 (pro)
Day 8 (am)
Day 8 (pro)
Study Day and Time of Day (am/pm) Fig. 2. Mean ( + SE) h~ in the critical tracking test by treatment, day and time of day.
sponses took more time than 'yes' responses. The set size × response category interaction was not significant, i.e., the difference in reaction time between 'yes' and 'no' responses was similar for all set sizes. The set size × treatment interaction was significant (F6.90 = 2.81; P ~<0.015) and mainly due to AMI (F2,30 = 3.67; P~<0.037). This means that amitriptyline, but not paroxetine 40 mg, retarded the memory search process. Therefore, paroxetine's slowing of reaction time probably occurred at an earlier or later stage of information processing, i.e. perception or response selection and execution. Average intrasubject correlations were calculated for determining if changes in SDLP covaried with changes in the psychomotor test variables. Individual correlations were based upon 16 pairs (4 treatments × 2 days x 2 repetitions). The individual correlations for the combination of SDLP and a particular psychomotor variable were transformed into corresponding Fisher z scores and then averaged across subjects. This Zav was tested for significant deviation from zero by t-test and then retransformed to Pearson's r. Correlations between SDLP and the other measures were modest, which confirms the results from a previous study employing similar tests (Robbe et al., 1988). Highest correlations (r = 0.45; P ~<0.001) were found between SDLP and the two measures of laboratory tracking performance, i.e. CTY and DAT-TE.
10.65; P ~<0.001), again due to amitriptyline (F1,15 = 11.68; P~<0.004). Performing the tests after amitriptyline required more effort on day 1 than on day 8. Mean perceived driving quality, indicating awareness of impairment, varied in parallel with SDLP across tests in all conditions. Significant effects were shown by ANOVA for treatment (F3,45 = 10.89; P~<0.001), day (F~.15= 11.59; P ~<0.004) and treatment × day interaction (F3,45 = 10.36; P~<0.001). Amitriptyline was again responsible for these effects (F~,~5 = 42.10; P<~0.001 for treatment effect and F1,15 = 11.99; P 0.003 for treatment ~
•
g~ 50%
P40
4. P20
"¢.
PLA
40% .y~ 30%
3.3. Subjective assessments Mental effort and driving quality. Mental effort ratings were significantly affected by t r e a t m e n t (F3,45 = 7.14; P~<0.001) and ToD (F1,~5=8.43; P<~0.011). The latter indicates that the second session on both days required more mental effort than the first. The overall treatment effect was mainly due to increased effort ratings in AMI (F~,~5 = 16.75; P~<0.001). The
20%
I
0%t 0
_
L 1
_~ 2
~ 3
J 4
t 5
. • 6
~ 7
_1 8
Study Day Fig. 3. Mean ( + SE) ratings of drowsiness by treatment and day, presented as percentage of full scale.
H.W..J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
the week, whereas paroxetine 40 mg's initially smaller effect was more persistent. Mean ratings of fatigue, concentration loss and memory disturbances were generally lower than for drowsiness. Nonetheless, all of the former followed similar profiles over the respective treatment periods as the latter and these differed significantly in the same ways. Mean nausea ratings followed an entirely different pattern. There were significant overall treatment (F3,45 : 6.26; P ~ 0.001) and day (F7,105 = 2.62; P~<0.016) effects but no significant treatment x day interaction. Nausea ratings were significantly higher in both P20 and P40 than in PLA (F1,15 = 5.15 and 11.64; P~<0.038 and 0.004, respectively). The maximum amplitudes of these mean ratings were low, however, i.e., 7% and 22% of full scale in P20 and P40, respectively. Adverse experiences. Side-effects that were spontaneously reported by the 16 subjects were analysed by Cochran's Q-test to determine whether the incidence differed significantly (P~<0.05) between treatments. This was the case for the following side-effects: dry mouth (4 in P40, 8 in AMI), tremor (1 in P20, 7 in P40, 5 in AMI), headache (3 in PLA, 5 in P20, 8 in P40, 2 in AMI), delayed ejaculation or anorgasmia (3 in P20, 5 in P40) and jaw trembling or pain (1 in PLA, 4 in P20, 4 in P40).
3.4. Drug plasma concentrations In P20, the mean (-+ SD) paroxetine plasma concentrations were 6.7 ( -+ 6.0) and 33.0 ( _ 16.1) ng/ml on days 1 and 8, respectively; and in P40 21.6 ( -+ 9.4) and 99.1 ( -- 38.9) ng/ml. In AMI, the mean ( _+SD) amitriptyline and nortriptyline concentrations were 14.5 (___6.9) and 7.6 (-+ 3.2) ng/ml, respectively, on day 1; and 22.5 (--_ 10.8) and 22.1 (---9.3) ng/ml on day 8.
4. Discussion
Plasma concentrations of both drugs were found to be in the expected range for the doses given (Lader et al., 1986; Allen et al., 1988; Raptopoulos and McClelland, 1987; Kaye et al., 1989) indicating that the subjects complied with the dosing regimen. Amitriptyline fulfilled its function as the active control. Its acute effects on road tracking ability confirmed the results of an earlier study (Louwerens et al., 1986). Furthermore, seven driving tests (i.e. 22%) were terminated on the first day of treatment in an early stage of the ride because subjects were judged unable to continue safely. It was again obvious that amitriptyline has severe acute effects on driving performance. It also produced severe drowsiness, loss of
41
concentration and fatigue and significantly impaired performance in every laboratory test except continous recall and constant tapping. However, nearly all of these adverse effects tended to dissipate with repeated dosing and were practically gone after a week. Apparently, young healthy volunteers rapidly develop tolerance to amitriptyline's sedative activities which result in psychomotor impairment when the drug is administered in this dose and regimen. Previous studies with amitriptyline in young healthy volunteers provided similar indications of the ameliorating effects of tolerance on psychomotor impairment (Allen et al., 1988; Lader et al., 1986; Seppfilfi, 1977; Seppfilfi et al., 1984). Whether the same would occur in patients treated with higher daily doses, divided in the same or a different manner, is unknown. Paroxetine 20 mg was devoid of any adverse effects on group performance, both in the laboratory and on the road. Compared to placebo, it had no disturbing effect on sleep and the few side-effects it produced were of a mild nature. There was, however, one subject who dropped out of the study after experiencing more severe side-effects and driving poorly during treatment with paroxetine 20 mg. The possibility that his reaction might occur in some patients cannot be easily dismissed. Paroxetine 40 mg did not alter driving performance relative to placebo. Although three subjects failed to complete one of the four driving tests they undertook during treatment with paroxetine 40 mg, no particular importance is attached to these results because the same number of rides were prematurely terminated following placebo. Paroxetine 40 mg slightly impaired performance in several laboratory tests, i.e., critical tracking, divided attention and the Sternberg test. Earlier reports of similar increases in reaction times following paroxetine 20 mg (Kerr et al., 1992) and paroxetine 30 mg in combination with alcohol (Hindmarch and Harrison, 1988) suggest that the present study's results were not accidental. That they were small in magnitude and no similarly significant effects emerged from the driving test probably indicates that they are of little practical relevance. That they did not dissipate over the treatment period may be of greater importance. It means that if some impairment of practical relevance ever occurs (e.g. in sensitive patients or after doses higher than 40 mg) it may persist for a prolonged period. Several side-effects were observed during treatment with paroxetine 40 mg. Sleep quality was reduced, especially in the beginning of the treatment period, which agrees with a previous report of disturbed sleep with paroxetine (Oswald and Adam, 1986). Ratings for drowsiness, loss of concentration, fatigue, nausea and memory disturbance were increased, although less than with amitriptyline. However, except for memory
42
H.W.J. Robbe, J.F. O'Hanlon / European Neuropsychopharmacology 5 (1995) 35-42
d i s t u r b a n c e , the statistical analyses p r o v i d e d n o evid e n c e for d e v e l o p i n g t o l e r a n c e to these side-effects. I n c o n c l u s i o n , this study c o n f i r m e d p r e v i o u s findings w h i c h show that p a r o x e t i n e 20 m g is g e n e r a l l y d e v o i d of a d v e r s e effects o n p s y c h o m o t o r p e r f o r m a n c e . It e x t e n d e d t h e m by p r o v i d i n g direct e v i d e n c e that p a t i e n t s who take this dose w i t h o u t e x p e r i e n c i n g severe side-effects are c a p a b l e of driving safely. It also s h o w e d that adverse r e a c t i o n s to p a r o x e t i n e are dose related and might influence psychomotor performance at doses higher t h a n or e q u a l to 40 r a g / d a y . T h e i n d i c a t i o n t h a t adverse effects of higher doses persist for at least a w e e k w a r r a n t s f u r t h e r a t t e n t i o n .
Acknowledgement This r e s e a r c h was s u p p o r t e d by S m i t h K l i n e Beecha m P h a r m a c e u t i c a l s , H a r l o w , Essex, U K .
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