The Effects of Two Antidepressants, Imipramine and Viloxazine, upon Driving Performance

A. B. Clayton/ b P. G. Harvey and T. A. Betts

INTRODUCTION

In view o f the rapid increase in the prescription of psychotropic medication to ambulant patients, it is im portant to assess their effects upon driving skills. In the past, such research has tended to employ standard tests of psychomotor skills and generalise the results to the real-\vorld driving situation. The relative values o f such methods have been discussed else- whei'e.5

The present study was designed to compare the effects of two antidepressants: imipramine, a tricyclic compound, and viloxazine, a new non tricyclic compound, upon a num ber o f driving tasks.

METHOD

Forty male volunteers (age range 18-29 years) were obtained from the student population o f the University o f Birmingham. Before being accepted for the experiment, all the subjects were screened by means of a medical examination and psychiatric interview, together with a biochemical and haemotological profile. All gave informed consent to participating in the study. The design o f the experiment was approved by the Research Ethical Committee of the Queen Elizabeth Medical Centre.

The subjects were randomly allocated on a double-blind basis to one of four treatment groups as follows:—

1) Imipramine — 25 mg t.d.s.2) Viloxazine — 50 mg t.d.s.3) Placebo4) Control — no tabletsThe control group were obviously aware of which group they were in, but the experi­

menters were unaware o f their identity.Each drug was taken three times a day for a period of seven days. Testing was carried

out on four occasions over a period o f 12 days as follows: —Day I: pre-test, before drug administration Day 5: two hours after first dose Day 7: after seven doses Day 12: after twenty-one doses

a Department of Transportation and Environmental Planning, University of Birmingham, Birmingham, U.K.b Grateful thanks are due to Professor J. Kolbuszewski and Professor W. H. Trethowan, within whose Departments the research was undertaken, for their continued support. Invaluable assistance in the run­ning of the experiment and data collection was provided by Mrs J. Fage, Mrs K. Whalley, Mrs S. Chatter- jee, and Mr S. J. Rattenbury. The drugs and financial support were provided by I.C.I. Pharmaceuticals Division.

2 3 0

The Effects o f Two Antidepressants upon Driving Performance 231

Prior to starting the experiment, each subject completed the Eysenck Personality Inven­tory Form A.6

T E ST S

K inetic Visual A cu ity

The Kinetic Vision Tester Model AS-4A (Kowa Company Ltd, Nagoya, Japan) developed by Suzumura9 is shown in Figure 1. It measures the central or parafoveal acuity for an object approaching the eyes in a horizontal plane at a constant speed (45 km /h) from a distance of 50 m. Previous research has suggested that it may be of use in discriminating between drivers with high and low accident rates.9 It also appears to be sensitive to the effects of alcohol3 and certain tranquillisers.4

KeyA SVA/KVA Switch F Chart SwitchB Brightness Switch G KVA ScaleC O n/O ff Light H O n/O ff SwitchesD “Near” Button J Lock SwitchE “Far” Button K Power Cables

Figure 1 Kowa Kinetic Vision Tester

The stimulus was a black Landolt Ring set against an illuminated background. The gap in the Ring was adjustable to any one of the eight major points of the compass (NW, SE, and so on). By pressing a button, the experimenter allowed the stimulus to move at a constant speed towards the subject. As soon as the subject saw the position o f the gap in the Ring he pressed a footswitch whereupon the machine stopped and the light was extinguished. The value o f kinetic visual acuity, measured in terms of the decimal equivalent of the Snellen Ratio, was then read directly from the scale on the side o f the instrument.

After initial familiarisation with the apparatus, each subject was given five trials on each test session. The mean of these five trials was used as his session score.

D riving Tests

To simulate the real driving situation as far as possible, two driving tests were designed and a course was laid out on one o f the University car parks. The same vehicle, a Ford Escort saloon, was used throughout the tests.

232 A. B. Clayton, P. G. Harvey and T. A. Betts

Weaving Task. This test was designed to simulate low-speed manoeuvring coupled with response to a subsidiary auditory task (Figure 2). The subsidiary auditory task was derived from Baddeley.1 It consisted o f short logic statements o f the form ‘A precedes B — AB’ to which the subject was required to answer ‘true’ or ‘false’. The following verbs, together with their negatives were used:

precedes follows antecedes succeeds comes before comes after

With the reversing of A and B, a total o f 48 possible combinations were obtained. Four separate tapes, containing these statements in random order, were prepared, one for each o f the test sessions. Five seconds were allowed for the subject to respond and the answers were recorded on a second tape recorder.

Figure 2 Plan o f Driving Course

The subject was given four trials on each test session and the subsidiary task was given on two of the four trials.

The following scores were derived from this test:—W T T - mean time (seconds) to complete the weaving courseWTB - total num ber o f bollards hitSTP - proportion o f correct responses to auditory taskS T T m e a n response time (seconds) for correct answers on auditory task

Gap Acceptance Task. This test was designed to measure any changes in the level of risk or hazard incurred by the subjects under drug conditions (Figure 2). The subjects were required to assess whether or not they could successfully drive the car through a series of gaps (-7.5 cm, -2.5 cm, +2.5 cm, +7.5 cm, +12.5 cm, difference from the width o f the car), the decision being made at a distance of 25 m from the gap. In those cases where they considered it to be possible, the subjects then attempted to do so without hitting either board. Each gap was presented four times in random order, a total of 20 trials. The test was continuous.

The Effects o f Two Antidepressants upon Driving Performance 233

TABLE 1 A djusted drug x trial means fo r task scores.

Task Score Trial Imipramine Viloxazine Control Placebo

Kinetic Decimal 1 0.50 0.53 0.50 0.48Visual Snellen 2 0.51 0.52 0.50 0.44Acuity Ratio 3 0.57 0.48 0.51 0.47

Weaving Time taken 1 35.98 33.23 32.75 32.08Task (sec) 2 32.23 31.33 30.97 29.84

3 31.14 30.09 29.37 29.74

No. of bollards 1 1.46 1.23 0.94 1.20hit* 2 1.50 1.19 1.21 1.22

3 1.78 1.41 1.26 1.29

Subsidiary Proportion of 1 46.04 59.63 58.05 54.10Task correct responses 2 50.29 60.48 51.53 55.66

** 3 58.51 63.99 61.47 63.32

Mean response 1 3.70 3.96 4.00 4.14time (sec) 2 3.63 4.19 3.87 3.77

3 3.58 3.69 3.72 3.72

Gap Task Time taken 1 10.63 10.17 10.42 11.05(min) 2 11.27 9.78 9.93 10.13

3 11.11 10.02 935 10.53

No. of false 1 1.69 1.90 1.84 1.80positives* 2 1.75 1.75 1.80 1.44

3 1.93 1.63 1.47 1.48

No. of false 1 1.35 1.21 1.17 1.14negatives* 2 1.02 1.23 1.53 1.46

3 1.05 1.09 1.39 1.25_

No. of 1 3.66 3.82 3.80 3.75acceptances* 2 3.82 3.75 3.66 3.50

3 3.88 3.75 3.59 3.59

Proportion of 1 59.19 65.50 57.97 63.92successes** 2 60.69 76.57 68.62 71.05

3 65.34 67.58 71.90 65.36

*Data transformed using X 1 = \/X + 1**Data transformed using X 1 = arcsin \/Proportion.

234 A. B. Clayton, P. G. Harvey and T. A. Betts

The following scores were derived from this test:—GTT - total time (minutes) to complete the taskGT + - num ber of false positives (acceptance of a gap narrower than the width of the

vehicle)G T - - num ber of false negatives (rejection of a gap wider than the width of the ve­

hicle)GTA - total num ber o f gaps accepted irrespective o f sizeGTP - proportion of successful negotiations through gaps wider than the width of the

vehicleThe individual task scores were analysed using an analysis of covariance repeated

measures design using the pre-test scores as the covariate.10 Certain o f the data were transfor­med prior to the analysis. In the case o f the frequency scores (WTB, GT + , G T-, GTA), the transformation X 1 = \/X + % was used. In the case o f the proportion scores (STP, GTP), the transformation X 1 = arcsin \/Proportion was employed. To assess the effects o f neuroticism upon the drug performance interaction, each treatment group was divided into two equal sub-groups about the group median score on the Neuroticism scale of the Eysenck Personality Inventory.

For each task score, adjusted trial x drug means (adjusted to control for differences in the pre-test performance) were calculated (Table 1).

RESULTS

(1) Kinetic visual acuity (KVA)

No significant effects were obtained.

(2) Weaving task-time (WTT)

A significant learning effect was obtained with the overall means on trials 2 and 3 (after7 and 21 doses) being less than that on Trial 1 (p<0.001). No significant drug effects were obtained.

(3) Weaving task — number o f bollards hit (WTB)

A significant drug effect was obtained with the imipramine group having a higher total num­ber o f bollards hit than either the control or placebo group (p<0.05). There was also a sig­nificant trials effect with a higher total num ber o f bollards hit on Trial 3 than on Trial 1 (p<0.05).

(4) Subsidiary task — proportion of correct responses (STP)

A significant drug x Neuroticism interaction was obtained. For the low Neuroticism group only, the viloxazine group had a higher proportion o f correct responses than either the control or im ipramine groups (p<0.05). There was also a significant learning effect with the overall mean proportion o f correct responses on Trial 3 being significantly higher than on Trials 1 and 2 (p<0.01).

(5) Subsidiary task — response time (STT)

There was a significant learning effect with the overall mean response time for correct answers being lower on Trial 3 than on Trial 1 (p<0.05).

(6) Gap Acceptance task — time (GTT)

A significant ‘trials x drug’ effect was obtained. On Trial 2 (after 7 doses), the imipramine group took longer to complete the task than the control and viloxazine groups (p<0.05). On trial 3 (after 21 doses), the imipramine and placebo groups took longer than the control group (p<0.05).

(7) Gap Acceptance task no. o f false positives (GT + )

A significant ‘trials x drug’ interaction was obtained. On trial 3 (after 21 doses) the imipramine group accepted more gaps narrower than the width o f the car than both the placebo and control groups (p<0.05).

A significant learning effect was also obtained. The overall mean number of falxe posi­tives on Trial 3 was less than on Trial 1 (p<0.05).

(8) Gap Accectance task no. of false negatives (GT-)

A significant ‘trials x drugs’ interaction was obtained. On Trial 2 (after 7 doses), the imipramine group rejected fewer gaps wider than the width o f the car than the placebo and control groups (p<0.05).

(9) Gap Acceptance task 3# no. of acceptances (GTA)

A significant ‘trials x drugs’ interaction was obtained. On Trials 2 and 3 (after 7 and 21 doses), the placebo group accepted fewer gaps irrespective o f size than the imipramine group (p<0.05). On Trial 2 only, the placebo group accepted fewer gaps than the viloxazine group and on Trial 3, the control group accepted fewer gaps than the imipramine group (p<0.05).

(10) Gap Acceptance task — proportion of successes (GTP)

A significant learning effect was obtained. On Trial 2 (after 7 doses), the overall proportion o f successful negotiations through attempted gaps wider than the width of the vehicle was significantly higher than on Trial 1 (p<0.05).

The Effects o f Two Antidepressants upon Driving Performance 235

DISCUSSION

The use o f the analysis of covariance allows the maximum use to be made of the available data. In particular, it controls for differences in pre-test levels o f performance. Although random assignment o f individuals to treatm ent groups should ensure base-line equality, it does not always occur, particularly when the size of the groups is relatively small.

In overall terms, the influence of Neuroticism as a main effect or as an interaction with the drugs appears to be negligible. In only one case (subsidiary task — proportion of correct responses) was there a significant interaction. However the size of the sub-samples (N = 5) reduces the likelihood of such interactions being shown.

There was only one significant drug main effect (no. o f bollards hit) but there were four ‘trials x drug’ interactions, all in the gap acceptance task. In these latter interactions, the significant effects were confined to Trials 2 and 3 (after 7 and 21 doses). It would appear therefore that neither of the active drugs produced any effect two hours after the adm inistrat­ion of the first dose. This lack o f effect on Trial 1 would tend to reduce the likelihood o f any drug main effects achieving statistical significance.

The major drug effects were observed on the gap acceptance task which was designed to measure any changes in the level of acceptable risk to the subject. If a drug increases the risk level, then it follows that it would produce

(1) an increase in the number of false positives,

(2) a reduction in the number of false negatives,

(3) an increase in the overall number of gaps accepted, irrespective of size, and

(4) an increase in the time taken to complete the task (because of the slow speed at which the actual gap was negotiated).

The results suggested such an effect with imipramine after 7 and 21 doses in comparison to the placebo and control groups. Such an effect was not gererally found with viloxazine except that, on Trial 2 only, the placebo group accepted less gaps irrespective of size than the viloxazine group.

Examination of the data from the weaving and subsidiary auditory tasks also suggested that the imipramine group performed worse than the control and placebo groups (in terms of the num ber o f bollards hit) and worse than the viloxazine group in terms of the proportion o f correct responses in the subsidiary task (Low Neuroticism group only).

Previous research into the effects of imipramine and viloxazine upon psychomotor skills has tended to examine the effects o f a single acute dose only. From the results of the present study, therefore, it would not be expected that significant differences would be obtained. Landauer and M ilner8 using a dose o f 0.8 mg imipramine per kg body weight (equivalent to 50-60 mg) found no differences compared with placebo on tapping task, tracking task, pursuit rotor, and choice reaction time. Bayliss and Duncan2 found that, four hours after a single dose o f 50 mg imipramine, reaction time was increased. Studies on viloxazine2- 7 have suggested that doses o f 50 mg or 80 mg have no effect upon the psychomotor skills tested (reaction time, disc dotting, serial subtraction task).

236 A. B. Clayton, P. G. Harvey and T. A. Betts

CONCLUSIONS

The results o f the present study suggest that a semi-chronic administration of clinical doses o f imipramine to normal healthy males results in a deterioration in performance on a number o f basic driving skills as compared to placebo or control. Imipramine appears to increase the level o f risk acceptable to the individual or conversely to reduce normal caution. This effect was shown both in the gap acceptance task and the weaving task (no. of bollards hit, proportion o f correct responses to the subsidiary task). If this effect were to be transferred from the admittedly rather simulated test situation to actual driving performance on the road, then an increase in the risk of accident-involvement would occur. Viloxazine, on the other hand, appears generally to be little different from placebo and control. Whilst driving under the influence o f any drug should not be condoned, it would appear that viloxazine would be a less hazardous drug then im ipram ine under such circumstances.

The Effects o f Two Antidepressants upon Driving Performance 237

R E F E R E N C E S

1. Baddeley, A. C., A 3 minute Reasoning Test Based Upon Grammatical Transformation, Psychonomic Science, 10: 341-342, 1968.

2. Bayliss, P. F. C. and Duncan, S. M., The Clinical Pharmacology of Viloxazine hydrochloride— A New Antidepressant of Novel Chemical Structure, British Journal o f Clinical Pharmacology, 1: 431-437, 1974.

3. Clayton, A. B., Kinetic Visual Acuity as a Driving-related Function, Paper presented at 1st Inter­national Conference on Vision and Traffic Safety, Paris, February, 1975.

4. Clayton, A. B., Mackay, G. M. and Betts, T. A., The Effects of Certain Tranquillisers and Small Amounts of Alcohol upon Kinetic Visual Acuity, Proceedings 16th Annual Conference American Association for Automotive Medicine, Chapel Hill, N.C., 1972.

5. Clayton, A. B., The Effects of Psychotropic Drugs upon Driving-related Skills. Human Factors, 18: 241-252, 1976.

6. Eysenck, H. J. and Eysenck, S. B. G., Manual of the Eysenck Personality Inventory. University of London Press, London, 1964.

7. Kirby, M. and Turner, P., Some Preliminary Observations on ICI 58, 834, a New Psychotropic Agent, in Man, British Journal of Clinical Pharmacology, 1: 169, 1974.

8. Landauer, A. A. and Milner, G., Desipramine and Imipramine, Alone and Together with Alcohol in Relation to Driving Safety, Pharmakopsychiatrie Neuro-Psychopharmakologie, 4: 265-275, 1971.

9. Suzumura, A., The Trial Production of a Kinetic Vision Tester (Type AS-4A) and its Application, Annual Report of Research Institute of Environmental Medicine, 16: 77-89, Nagoya University, Japan, 1968.

10. Winer, B. J., Statistical Principles in Experimental Design, McGraw Hill, New York, U.S.A., 1971.