Europ.J.clin.Pharmacol. i0, 331-335 (1976) @ by Springer-Verlag 1976
Long-Term Lithium Treatment" Effect on Simulated Driving and Other Psychological Tests P. Bech, J. Thomsen and O. J. Rafaelsen ENT Department,
Received: accepted:
Rigshospitalet,
Copenhagen,
Denmark
January 15, 1976, and in revised form: April May 7, 1976
30, 1976,
Summary. The effect of lithium administered for six months on simulated car driving and other psychological tests was studied in patients with Meni~re's disease. The dose of lithium was adjusted every two weeks to maintain the serum level between 0.7 and 1.O mmol/l. The trial was double-blind and cross-over in type, the effect of lithium being compared with a placebo. The subjects were within the normal range of Beck's depression scale and Marke-Nyman's temperament scale. Lithium was found neither to influence the simulated driving nor to affect the scores in the two rating scales. The only specific complaints observed during lithium treatment were tremor and increased thirst. Key words: Lithium, driving, Beck's depression scale, side effects, Meni~re's disease.
The effect of lithium on psychomotor skills related to driving has been studied by Linnoila et al. (10). The subjects in that study were healthy students and the results showed that two weeks of lithium treatment increased choice reaction time, whereas co-ordinative skills, as well as the subjects' self-ratings, were unaffected. As the prevention of relapses by lithium in manic-melancholic patients is often apparent only after months of treatment (17), the effect of lithium on simulated driving has been examined after six months of treatment. Amongst the parameters measured during the simulated driving, special attention was paid to brake time, partly because brake time had been found previously (3, 13) to be a reliable parameter when testing the effect of alcohol on driving behaviour, and in part because brake time is a choice reaction time, and so would be comparable with the study of Linnoila et al. (10). The subjects in the study were patients who suffered from Meni~re's
scale, Marke-Nyman's
temperament
disease, The limitations of using healthy subjects in the evaluation of psychopharmacological drugs have been discussed previously (2), and in the present study any possible effect of lithium on mood swings has been taken into account by including Beck's depression scale (6). Furthermore, the subjects were evaluated by the Marke-Nyman temperament scale (11), as psychological vulnerability has been found in a subgroup of patients with Meni~re's disease (7). The procedure also included a general side-effect questionnaire, which was identical to the scale used, in a previous study of lithium maintenance treatment in manic-melancholic patients (5).
MATERIAL AND METHODS Subjects
The subjects were patients with Meni~re's disease, who took part in a double-blind, cross-over trial of the
332 effect of lithium against placebo in Meni~re's disease. The test periods were six months, lithium appeared to have no influence on the disease, but the otological results will be discussed elsewhere (18). From this study 22 patients (11 men and 11 women; aged 36 to 71 years, median 54.5) were tested with various rating scales. Only 8 of the 22 patients participated in the car simulator part of the study, as it was essential for it that the subject held a driver's license. The 8 subjects were all men between 39 and 58 years of age (median 53), and their driving experience ranged between 1,000 and 30,000 km/ year (median 9,400).
2. Start time was defined as the interval from when a green light appeared until the accelerator was activated by the subject (unit: 0.1 sec.) The red signals appeared at random time intervals. During the drive the subject was presented with 10 red and 10 green signals. The brake and start time values for each subject were the mean of the 10 observations. 3. The number of gear changes was the total number recorded electronically during the driving period. 4. Mean speed was calculated from the distance (unit: 10 m) covered during the ten minute drive.
Car Simulator Test
based on a standard driving period of 6 minutes, during which the subjects drove for 3 minutes with a speed limit of 40 km/h, and 3 minutes with a speed limit of 70 km/h. After the end of the standard period, each subject estimated the duration of the two test periods. The subjects estimated time in two different ways: a. "Objectively" using intellectual clues: "How long do you really think yOU have been driving?" b. "Subjectively" using emotional or intuitive clues: How long do you really feel you have been driving?"
Apparatus The car simulator was a modification of an instrument (Redifon-Auto-Tutor) used in driving schools. The simulator was shaped like the front half of a small European car. The driver had access to steering wheel, accelerator, brake, clutch, and ordinary controls. The mileometer in the instrument panel was always concealed, but the speedometer was visible during part of the driving program. The simulator had 4 forward gears; first gear, O-10 km/h; second gear, 10-30 km/h; third gear, 30-50 km/ h; and fourth gear, 50-80 km/h. Changing gears was recorded electronically. A rotating cyclorama was placed above the hood. A landscape was painted on the cyclorama and during driving the landscape was continuously projected onto the windscreen. The speed of the movable landscape, and thus the apparent speed of the car, was determined by the driver's use of the accelerator. Turning the steering wheel resulted in a corresponding movement of the landscape on the wind-screen and of the supposed position of the car on the road, so that the driver would have the impression of driving on a real road.
B. Phenc~enological Measurements, Including Estimation of Time. Time estimation was
Questionnaire Data
The method included the following questionnaires: was used as an inventory to measure the degree of depression on the test day (6). Total score and a subscore of 12 valid items (4) were calculated. a. Beck's self-rating scale
A. B e h a ~ o u r a l Measurements~ The subjects
This scale was identical to the scale used in the study of maintenance lithium treatment in manic-melancholic patients (5). The scale consisted of 14 items, including headache, vertigo, tremor, palpitation, perspiration, mouth dryness, difficulty in urination, constipation, difficulty in concentration and memory, disturbed accomodation, tension, ]~ausea, increased appetite and increased thirst. Each item was defined on the principle of Beek's scale, i.e. the statements had increasing severity, and the patient picked out the statement he considered most applicable to himself.
were instructed to drive as usual, without speed limits and following ordinary traffic rules. This part of the drive lasted 10 minutes. I. Brake time was defined as the interval from when the experimenter switched on a red light until the brake pedal was activated by the subject (unit: O.1 see.) .
c. The Marke-Nyman self-rating scale was used as an inventory for measuring personality traits (8, 11, 12). This questionnaire is based on SjSbring's theory of personality structure (16), including the three variables: validity, stability and solidity. Validity is a measure of available and effective energy,
Measurements The equipment of the car simulator permitted various behavioural and phenomenological measurements.
b. A general side-effect questionnaire.
333 Table i. Simulator data: eight subjects after 6 months on placebo and lithium, respectively. Median and range Measurement
Placebo
Lithium
P
ist-5th observation
1.O5 (O.60-1.26)
0.88 (O.64-i.O2)
> O.O5
6th-lOth observation
1.O5 (O.60-1.20)
0.96 (O.58-1.60)
> 0.05
All iO observations
1.O4 (0.69-1.20)
0.93 (O.61-1.31)
> 0.05
ist-Sth observation
1.06 (0.64-1.58)
0.84
(0o64-1.56)
> 0.05
6th-lOth observation
0.85 (O.60-1.50)
0.80 (0.76-1.70)
> 0.05
All IO observations
0.93 (O.69-1.54)
O.81
(O.50-1.63)
> 0.05
Speed (km/h)
38.0 (24.0-44.4)
39.8 (20.4-45.0)
> 0.05
68.4 (54.O-129)
53.4 (32.0-96.0)
> 0.05
3 rain. at 40 km/h
4.5 (3.0-8.0)
3.0 (2.0-8.0)
> 0.05
3 rain. at 70 km/h
5.0 (3.0-9.0)
4.0 (2.O-10.O)
> 0°05
Brake time (seconds)
Start time (seconds)
Gear changes
(number)
aTime estimation
(min.)
a There was no difference between the objective and subjective estimates
s t a b i l i t y is a m e a s u r e of e m o t i o n a l c o n trol, a n d s o l i d i t y is a m e a s u r e of maturity, so t h a t s u b v a l i d i t y , substability, and subsolidity largely c o r r e s p o n d to p s y c h o a s t h e n i a , syntony, and hysteroidy. T h e i t e m s c o r e on t h i s s c a l e w a s c a l c u l a t e d b o t h a c c o r d i n g to N y m a n a n d M a r k e (11) a n d to P e r r i s (12). In the o r i g i n a l s t u d y (11), t h e t o t a l of 60 i t e m s w a s m a d e up of 20 i t e m s for e a c h of the t h r e e v a r i a b l e s , the s c o r e s for w h i c h r a n g e d f r o m O to 40. P e r r i s (12) s e l e c t e d 10 items for e a c h v a r i a b l e , a n d the t o t a l s c o r e on e a c h s u c h s u b s c a l e r a n g e d f r o m 0 to 20.
a d j u s t m e n t of the t a b l e t i n t a k e w e r e p e r f o r m e d by p h y s i c i a n s w h o d i d n o t u n d e r t a k e the t e s t s r e p o r t e d here; thus, the d e s i g n w a s d o u b l e - b l i n d . In t y p e it was a c r o s s - o v e r trial, a n d t h e t r e a t ment order (lithium - placebo and p l a c e b o - lithium) w a s p r e - d e t e r m i n e d by u s e of r a n d o m n u m b e r t a b l e s . T h e test period was 6 months, and the tests t o o k p l a c e d u r i n g the l a s t 2 w e e k s of each treatment period. Other drugs were not allowed and the patients' practit i o n e r s w e r e i n f o r m e d of the study. The c a r s i m u l a t o r s e s s i o n s a l w a y s t o o k p l a c e b e t w e e n 2 . 0 0 a n d 4 . 0 0 p.m. statistical Analysis
Treatment and Experimental Procedure Lithium carbonate was administered as t a b l e t s , the a m o u n t b e i n g a d j u s t e d to give serum concentrations between 0.7 and 1.0 m m o l / l , m e a s u r e d 12 h o u r s a f t e r t h e l a s t dose. S e r u m l i t h i u m w a s det e r m i n e d by f l a m e p h o t o m e t r y (1), and the p a t i e n t s w e r e e x a m i n e d e v e r y 2 w e e k s t h r o u g h o u t the study, i n c l u d i n g the placebo period. Placebo and active drug were administered as t a b l e t s w i t h a n i d e n t i c a l c o a t i n g . W h e n t h e d o s e of l i t h i u m g i v e n to a n y p a t i e n t w a s adj u s t e d , a s i m i l a r a d j u s t m e n t of t a b l e t intake was made for a placebo partner, preselected by u s e of r a n d o m n u m b e r tables. Examination of the p a t i e n t s a n d
Non-parametric statistics, Wilcoxon's m a t c h e d pairs' t e s t a n d S p e a r m a n ' s c o r r e l a t i o n test, w e r e e m p l o y e d t h r o u g h o u t the s t u d y (15). T h e m e d i a n w a s u s e d to e x p r e s s the c e n t r a l t e n d e n c y a n d the r a n g e to e x p r e s s d i s p e r s i o n .
RESULTS Simulator Data N o o r d e r e f f e c t w a s found. As s h o w n in T a b l e I, t h e r e s u l t s for b o t h b r a k e a n d s t a r t t i m e w e r e a n a l y s e d on t h e b a s i s of the f i r s t f i v e (nos. I-5) and t h e l a s t f i v e (nos. 6-10) o b s e r v a t i o n s , as
334 Table 2. Questionnaire data: all 22 subjects after 6 months on placebo and lithium respectively. Median and (range values) Rating scales
Placebo
Lithium
P
General scale
3 (0-16)
4 (0-24)
> O.05
Subscale
2 (0-9)
2 (O-13)
> 0.05
17 (4-36)
18 (4-36)
> 0.05
8 (2-18)
8 (0-17)
> 0.05
17 (6-36)
15 (8-32)
> O.O5
8 (2-20)
8 (2-20)
> 0.05
General scale
23 (12-32)
26 (12-34)
> 0.05
Subscale
ii (2-16)
12 (2-18)
> 0.05
Beck's depression scale
Marke-Nyman's temperament scale Validity General scale Subscale
Stability General scale Subscale
Solidity
well as of all 10 o b s e r v a t i o n s . T h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r ence b e t w e e n l i t h i u m and p l a c e b o p e r i o d s in brake time or start time, or the other m e a s u r e m e n t s d u r i n g s i m u l a t e d driving. However, in some items a trend to s l i g h t l y lower v a l u e s on l i t h i u m was observed, but it n e v e r r e a c h e d statistical s i g n i f i c a n c e .
Questionnaire Data A g a i n no o r d e r e f f e c t was found. T h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t difference b e t w e e n l i t h i u m and p l a c e b o p e r i o d s in B e c k ' s d e p r e s s i o n scale, n e i t h e r on the g e n e r a l scale nor on the s u b s c a l e (Tab. 2). There was no s i g n i f i cant difference, either, b e t w e e n l i t h i u m and p l a c e b o in the three v a r i a b l e s of the M a r k e - N y m a n scale. T h e t e s t - r e t e s t c o e f f i c i e n t of corr e l a t i o n s r s for the B e c k scale was 0.77 and 0.78 (P < O.O1) on the g e n e r a l scale and subscale, r e s p e c t i v e l y . On the M a r k e - N y m a n scale the c o e f f i c i e n t of c o r r e l a t i o n for v a l i d i t y was 0 . 8 5 and 0.87 (P ~ O.O1) on the g e n e r a l scale and the subscale, r e s p e c t i v e l y ; for s t a b i l i t y 0.84 and 0.83 (P < 0.01); and for s o l i d i t y 0.59 (P < 0.01) and 0.48 (P < 0.01). The scores for each of the 14 items of the g e n e r a l side effects scale w e r e
c a l c u l a t e d b o t h for i n t e n s i t y (no = O, m i l d = 1, m o d e r a t e = 2, and severe = 3) and for f r e q u e n c y (the ratio of p o s i t i v e item scores). The r e s u l t s s h o w e d that only two items ("tremor" and " i n c r e a s e d thirst") w e r e s c o r e d s i g n i f i c a n t l y h i g h e r (P ~ 0.O1 and P ! 0.02, respectively) in i n t e n s i t y in the l i t h i u m than in the p l a c e b o periods. For "tremor", 59% of the 22 p a t i e n t s s c o r e d p o s i t i v e l y w h i l s t on lithium, as a g a i n s t 18% on placebo, and for "inc r e a s e d thirst" 64% s c o r e d p o s i t i v e l y on l i t h i u m as a g a i n s t 32% on placebo. The r e m a i n i n g 12 items of the g e n e r a l s i d e - e f f e c t scale showed no s t a t i s t i c a l ly s i g n i f i c a n t d i f f e r e n c e b e t w e e n l i t h i u m and placebo. The score p a t t e r n of the 8 p a t i e n t s in the car s i m u l a t o r s t u d y was s i m i l a r to the r e s u l t s for all 22 p a t i e n t s in the v a r i o u s q u e s t i o n n a i r e s .
DISCUSSION In p r e v i o u s studies (3, 13) p a r t i c u l a r l y brake time in the car s i m u l a t o r was found to be a r e l i a b l e p a r a m e t e r w h e n t e s t i n g the e f f e c t of a l c o h o l on driving behaviour. In the p r e s e n t study the t e s t - r e t e s t interval was 6 months, and the r e s u l t s showed no order effect, w h i c h i n d i c a t e s no g e n e r a l e f f e c t of practice. No e f f e c t of l i t h i u m on b r a k e time or on the o t h e r car s i m u l a t o r m e a s u r e m e n t s was found on c o m p a r i s o n w i t h placebo. As brake time is a c o m p l e x r e a c t i o n time, these results are in c o n t r a s t w i t h the findings of L i n n o i l a et al. (10), w h o found that l i t h i u m treatment, p r o d u c i n g c o m p a r a b l e s e r u m levels, a f f e c t e d c o m p l e x r e a c t i o n time after 2 w e e k s of treatment. However, the p r o l o n g a t i o n of the r e a c t i o n time values was o n l y 15-20% on l i t h i u m c o m p a r e d w i t h placebo, and they found no e f f e c t on c o - o r d i n a t e d skills; nor did l i t h i u m a p p e a r to have any e f f e c t on the subjects' s e l f - r e p o r t s , m o r e than 50% c o n s i d e r e d the l i t h i u m t r e a t m e n t as placebo. The subjects in the p r e s e n t e x p e r i m e n t rated as s p e c i f i c c o m p l a i n t w h i l s t on l i t h i u m only t r e m o r and inc r e a s e d thirst, w h e r e a s there was no d i f f e r e n c e b e t w e e n l i t h i u m and p l a c e b o in such items as d i f f i c u l t y in c o n c e n t r a t i o n and memory. This is in a c c o r d ance w i t h f i n d i n g s from l i t h i u m m a i n t e n a n c e t r e a t m e n t of m a n i c - m e l a n c h o l i c p a t i e n t s (5), and w i t h the study of S c h o u et al. (14) on n o r m a l subjects. The latter o b s e r v e d that a r e l a t i v e l y low a v e r a g e d o s a g e of l i t h i u m (25 meq/ 24 hours) had little or no e f f e c t on p s y c h i a t r i c f u n c t i o n s after 3 to 6 w e e k s of treatment, w h e r e a s on a h i g h e r d o s e
335
(50 m e q / 2 4 h o u r s ) " i n t e l l e c t u a l i n i t i a tive was diminished, and there was a f e e l i n g o f l o w e r e d a b i l i t y to c o n c e n trate and memorize". Similar results after high lithium dosage have been reported by Demers and Heninger (9). T h e s u b j e c t s in t h e p r e s e n t s t u d y s c o r e d within the normal range on Beck's dep r e s s i o n s c a l e (4,6) a n d o n M a r k e N y m a n ' s p e r s o n a l i t y s c a l e (11). L i t h i u m w a s n o t f o u n d to i n f l u e n c e t h e s e r a t i n g scores. T h e b a c k g r o u n d to t h i s i n v e s t i g a t i o n was a positive effect of lithium on M e n i @ r e ' s d i s e a s e in a n o p e n p i l o t study, but the preliminary result could not be confirmed (18). I r r e s p e c t i v e of t h e c l i n i c a l e f f e c t , six months of treatment with lithium had no detectable influence on psychic o r p s y c h o m o t o r f u n c t i o n s in t h o s e n o n melancholic patients.
8.
9.
i0.
ii.
12.
13.
Acknowledgements. The study was supported in part by a grant from Dansk Esso Fond. 14.
REFERENCES i. Amdisen, A.: Serum lithium determination for clinical use. Scand. J. clin. Lab. Invest. 20, 104 (1967) 2. Bech, P.: Mental illness and simulated driving before and during treatment. Pharmakopsychiat. 8, 143-150 (1975) 3. Bech, P., Rafaelsen, L., Rafaelsen, O.J.: Cannabis: A psychopharmacological review. Dan. med. Bull. 21, 106-120 (1974) 4. Bech, P., Gram, L.F., Dein, E., Jacobsen, 0., Vitger, J., Bolwig, T.G.: Quantitative rating of depressive states. Acta psychiat. scand. 51, 161-170 (1975) 5. Bech, P., Vendsborg, P.B., Rafaelsen, O.J.: Lithium maintenance treatment of manicmelancholic patients: Its role in the daily routine. Acta psychiat, scand. 53, 70-81 (1976) 6. Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbaugh, J.: An inventory for measuring depression. Arch. gen. Psychiat. 4, 561-571 (1961) 7. Brightwell, D.R., Abramson, M.: Personality
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characteristics in patients with vertigo° Arch. Otolaryng. 101, 364-366 (1975) Coppen, A.: The Marke-Nyman temperament scale: An English translation. Brit. J. med. Psychol. 39, 55-59 (1966) Demers, R.G., Heminger, G.R.: Visual-motor performance during lithium treatment. J. clin. Pharmaeol. 11, 274-279 (1971) Linnoila, M., Saarie, I., Maki, M.: Effect of treatment with diazepam or lithium and alcohol on psychomotor skills related to driving. Europ. J. clin. Pharmacol. 7, 337342 (1974) Nyman, G.E., Marke, S.: Sj~brings differentiella psykologi. (The differential psychology of Sj6bring). Lund: Glee,ups 1962 Perris, C.: A study of bipolar (manicdepressive) and unipolar (recurrent depressive) psychoses. IV. A multi-dimensional study of personality traits. Aeta psychiat. scand., Suppl. 194, 68-82 (1966) Rafaelsen, O.J., Bech, P., Rafaelsen, L.: Simulated car driving influenced by cannabis and alcohol. Pharmakopsychiat. 6, 71-83 (1973) Schou, M., Amdisen, A., Thomsen, K.: The effect of lithium on the normal mind. In: De psychiatria pregrediente II (eds. P. Baudis, E. Peterova, V. Sedivec), pp. 712721. Plzen: 1968 Siegel, S.: Non-parametric statistics. New York: McGraw Hill 1956 Sj~bring, H.: Personality structure and development. Acta psychiat, scand. Suppl. 244, 115-157 (1973) Stallone, F., Shelley, E.M., Mendlewicz, J., Fieve, R.B.: The use of lithium in affective disorders, III. A double-blind study of prophylaxis in bipolar illness. Amer. J. Psychiat. 130, 1OO6-1010 (1973) Thomsen, J., Bech, P., Geisler, A~, Prytz, S., Rafaelsen, O.J., Vendsborg, P.B., Zilstorff, K.: Lithium treatment of Meni~re's disease. Results of a doubleblind cross-over trial. Acta oto-laryng. (Stockh.), (in press 1976) Dr. P. Bech Psychochemistry Institute Rigshospitalet 9, Blegdamsvej DK-21OO Copenhagen Denmark
Long-Term Lithium Treatment" Effect on Simulated Driving and Other Psychological Tests P. Bech, J. Thomsen and O. J. Rafaelsen ENT Department,
Received: accepted:
Rigshospitalet,
Copenhagen,
Denmark
January 15, 1976, and in revised form: April May 7, 1976
30, 1976,
Summary. The effect of lithium administered for six months on simulated car driving and other psychological tests was studied in patients with Meni~re's disease. The dose of lithium was adjusted every two weeks to maintain the serum level between 0.7 and 1.O mmol/l. The trial was double-blind and cross-over in type, the effect of lithium being compared with a placebo. The subjects were within the normal range of Beck's depression scale and Marke-Nyman's temperament scale. Lithium was found neither to influence the simulated driving nor to affect the scores in the two rating scales. The only specific complaints observed during lithium treatment were tremor and increased thirst. Key words: Lithium, driving, Beck's depression scale, side effects, Meni~re's disease.
The effect of lithium on psychomotor skills related to driving has been studied by Linnoila et al. (10). The subjects in that study were healthy students and the results showed that two weeks of lithium treatment increased choice reaction time, whereas co-ordinative skills, as well as the subjects' self-ratings, were unaffected. As the prevention of relapses by lithium in manic-melancholic patients is often apparent only after months of treatment (17), the effect of lithium on simulated driving has been examined after six months of treatment. Amongst the parameters measured during the simulated driving, special attention was paid to brake time, partly because brake time had been found previously (3, 13) to be a reliable parameter when testing the effect of alcohol on driving behaviour, and in part because brake time is a choice reaction time, and so would be comparable with the study of Linnoila et al. (10). The subjects in the study were patients who suffered from Meni~re's
scale, Marke-Nyman's
temperament
disease, The limitations of using healthy subjects in the evaluation of psychopharmacological drugs have been discussed previously (2), and in the present study any possible effect of lithium on mood swings has been taken into account by including Beck's depression scale (6). Furthermore, the subjects were evaluated by the Marke-Nyman temperament scale (11), as psychological vulnerability has been found in a subgroup of patients with Meni~re's disease (7). The procedure also included a general side-effect questionnaire, which was identical to the scale used, in a previous study of lithium maintenance treatment in manic-melancholic patients (5).
MATERIAL AND METHODS Subjects
The subjects were patients with Meni~re's disease, who took part in a double-blind, cross-over trial of the
332 effect of lithium against placebo in Meni~re's disease. The test periods were six months, lithium appeared to have no influence on the disease, but the otological results will be discussed elsewhere (18). From this study 22 patients (11 men and 11 women; aged 36 to 71 years, median 54.5) were tested with various rating scales. Only 8 of the 22 patients participated in the car simulator part of the study, as it was essential for it that the subject held a driver's license. The 8 subjects were all men between 39 and 58 years of age (median 53), and their driving experience ranged between 1,000 and 30,000 km/ year (median 9,400).
2. Start time was defined as the interval from when a green light appeared until the accelerator was activated by the subject (unit: 0.1 sec.) The red signals appeared at random time intervals. During the drive the subject was presented with 10 red and 10 green signals. The brake and start time values for each subject were the mean of the 10 observations. 3. The number of gear changes was the total number recorded electronically during the driving period. 4. Mean speed was calculated from the distance (unit: 10 m) covered during the ten minute drive.
Car Simulator Test
based on a standard driving period of 6 minutes, during which the subjects drove for 3 minutes with a speed limit of 40 km/h, and 3 minutes with a speed limit of 70 km/h. After the end of the standard period, each subject estimated the duration of the two test periods. The subjects estimated time in two different ways: a. "Objectively" using intellectual clues: "How long do you really think yOU have been driving?" b. "Subjectively" using emotional or intuitive clues: How long do you really feel you have been driving?"
Apparatus The car simulator was a modification of an instrument (Redifon-Auto-Tutor) used in driving schools. The simulator was shaped like the front half of a small European car. The driver had access to steering wheel, accelerator, brake, clutch, and ordinary controls. The mileometer in the instrument panel was always concealed, but the speedometer was visible during part of the driving program. The simulator had 4 forward gears; first gear, O-10 km/h; second gear, 10-30 km/h; third gear, 30-50 km/ h; and fourth gear, 50-80 km/h. Changing gears was recorded electronically. A rotating cyclorama was placed above the hood. A landscape was painted on the cyclorama and during driving the landscape was continuously projected onto the windscreen. The speed of the movable landscape, and thus the apparent speed of the car, was determined by the driver's use of the accelerator. Turning the steering wheel resulted in a corresponding movement of the landscape on the wind-screen and of the supposed position of the car on the road, so that the driver would have the impression of driving on a real road.
B. Phenc~enological Measurements, Including Estimation of Time. Time estimation was
Questionnaire Data
The method included the following questionnaires: was used as an inventory to measure the degree of depression on the test day (6). Total score and a subscore of 12 valid items (4) were calculated. a. Beck's self-rating scale
A. B e h a ~ o u r a l Measurements~ The subjects
This scale was identical to the scale used in the study of maintenance lithium treatment in manic-melancholic patients (5). The scale consisted of 14 items, including headache, vertigo, tremor, palpitation, perspiration, mouth dryness, difficulty in urination, constipation, difficulty in concentration and memory, disturbed accomodation, tension, ]~ausea, increased appetite and increased thirst. Each item was defined on the principle of Beek's scale, i.e. the statements had increasing severity, and the patient picked out the statement he considered most applicable to himself.
were instructed to drive as usual, without speed limits and following ordinary traffic rules. This part of the drive lasted 10 minutes. I. Brake time was defined as the interval from when the experimenter switched on a red light until the brake pedal was activated by the subject (unit: O.1 see.) .
c. The Marke-Nyman self-rating scale was used as an inventory for measuring personality traits (8, 11, 12). This questionnaire is based on SjSbring's theory of personality structure (16), including the three variables: validity, stability and solidity. Validity is a measure of available and effective energy,
Measurements The equipment of the car simulator permitted various behavioural and phenomenological measurements.
b. A general side-effect questionnaire.
333 Table i. Simulator data: eight subjects after 6 months on placebo and lithium, respectively. Median and range Measurement
Placebo
Lithium
P
ist-5th observation
1.O5 (O.60-1.26)
0.88 (O.64-i.O2)
> O.O5
6th-lOth observation
1.O5 (O.60-1.20)
0.96 (O.58-1.60)
> 0.05
All iO observations
1.O4 (0.69-1.20)
0.93 (O.61-1.31)
> 0.05
ist-Sth observation
1.06 (0.64-1.58)
0.84
(0o64-1.56)
> 0.05
6th-lOth observation
0.85 (O.60-1.50)
0.80 (0.76-1.70)
> 0.05
All IO observations
0.93 (O.69-1.54)
O.81
(O.50-1.63)
> 0.05
Speed (km/h)
38.0 (24.0-44.4)
39.8 (20.4-45.0)
> 0.05
68.4 (54.O-129)
53.4 (32.0-96.0)
> 0.05
3 rain. at 40 km/h
4.5 (3.0-8.0)
3.0 (2.0-8.0)
> 0.05
3 rain. at 70 km/h
5.0 (3.0-9.0)
4.0 (2.O-10.O)
> 0°05
Brake time (seconds)
Start time (seconds)
Gear changes
(number)
aTime estimation
(min.)
a There was no difference between the objective and subjective estimates
s t a b i l i t y is a m e a s u r e of e m o t i o n a l c o n trol, a n d s o l i d i t y is a m e a s u r e of maturity, so t h a t s u b v a l i d i t y , substability, and subsolidity largely c o r r e s p o n d to p s y c h o a s t h e n i a , syntony, and hysteroidy. T h e i t e m s c o r e on t h i s s c a l e w a s c a l c u l a t e d b o t h a c c o r d i n g to N y m a n a n d M a r k e (11) a n d to P e r r i s (12). In the o r i g i n a l s t u d y (11), t h e t o t a l of 60 i t e m s w a s m a d e up of 20 i t e m s for e a c h of the t h r e e v a r i a b l e s , the s c o r e s for w h i c h r a n g e d f r o m O to 40. P e r r i s (12) s e l e c t e d 10 items for e a c h v a r i a b l e , a n d the t o t a l s c o r e on e a c h s u c h s u b s c a l e r a n g e d f r o m 0 to 20.
a d j u s t m e n t of the t a b l e t i n t a k e w e r e p e r f o r m e d by p h y s i c i a n s w h o d i d n o t u n d e r t a k e the t e s t s r e p o r t e d here; thus, the d e s i g n w a s d o u b l e - b l i n d . In t y p e it was a c r o s s - o v e r trial, a n d t h e t r e a t ment order (lithium - placebo and p l a c e b o - lithium) w a s p r e - d e t e r m i n e d by u s e of r a n d o m n u m b e r t a b l e s . T h e test period was 6 months, and the tests t o o k p l a c e d u r i n g the l a s t 2 w e e k s of each treatment period. Other drugs were not allowed and the patients' practit i o n e r s w e r e i n f o r m e d of the study. The c a r s i m u l a t o r s e s s i o n s a l w a y s t o o k p l a c e b e t w e e n 2 . 0 0 a n d 4 . 0 0 p.m. statistical Analysis
Treatment and Experimental Procedure Lithium carbonate was administered as t a b l e t s , the a m o u n t b e i n g a d j u s t e d to give serum concentrations between 0.7 and 1.0 m m o l / l , m e a s u r e d 12 h o u r s a f t e r t h e l a s t dose. S e r u m l i t h i u m w a s det e r m i n e d by f l a m e p h o t o m e t r y (1), and the p a t i e n t s w e r e e x a m i n e d e v e r y 2 w e e k s t h r o u g h o u t the study, i n c l u d i n g the placebo period. Placebo and active drug were administered as t a b l e t s w i t h a n i d e n t i c a l c o a t i n g . W h e n t h e d o s e of l i t h i u m g i v e n to a n y p a t i e n t w a s adj u s t e d , a s i m i l a r a d j u s t m e n t of t a b l e t intake was made for a placebo partner, preselected by u s e of r a n d o m n u m b e r tables. Examination of the p a t i e n t s a n d
Non-parametric statistics, Wilcoxon's m a t c h e d pairs' t e s t a n d S p e a r m a n ' s c o r r e l a t i o n test, w e r e e m p l o y e d t h r o u g h o u t the s t u d y (15). T h e m e d i a n w a s u s e d to e x p r e s s the c e n t r a l t e n d e n c y a n d the r a n g e to e x p r e s s d i s p e r s i o n .
RESULTS Simulator Data N o o r d e r e f f e c t w a s found. As s h o w n in T a b l e I, t h e r e s u l t s for b o t h b r a k e a n d s t a r t t i m e w e r e a n a l y s e d on t h e b a s i s of the f i r s t f i v e (nos. I-5) and t h e l a s t f i v e (nos. 6-10) o b s e r v a t i o n s , as
334 Table 2. Questionnaire data: all 22 subjects after 6 months on placebo and lithium respectively. Median and (range values) Rating scales
Placebo
Lithium
P
General scale
3 (0-16)
4 (0-24)
> O.05
Subscale
2 (0-9)
2 (O-13)
> 0.05
17 (4-36)
18 (4-36)
> 0.05
8 (2-18)
8 (0-17)
> 0.05
17 (6-36)
15 (8-32)
> O.O5
8 (2-20)
8 (2-20)
> 0.05
General scale
23 (12-32)
26 (12-34)
> 0.05
Subscale
ii (2-16)
12 (2-18)
> 0.05
Beck's depression scale
Marke-Nyman's temperament scale Validity General scale Subscale
Stability General scale Subscale
Solidity
well as of all 10 o b s e r v a t i o n s . T h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r ence b e t w e e n l i t h i u m and p l a c e b o p e r i o d s in brake time or start time, or the other m e a s u r e m e n t s d u r i n g s i m u l a t e d driving. However, in some items a trend to s l i g h t l y lower v a l u e s on l i t h i u m was observed, but it n e v e r r e a c h e d statistical s i g n i f i c a n c e .
Questionnaire Data A g a i n no o r d e r e f f e c t was found. T h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t difference b e t w e e n l i t h i u m and p l a c e b o p e r i o d s in B e c k ' s d e p r e s s i o n scale, n e i t h e r on the g e n e r a l scale nor on the s u b s c a l e (Tab. 2). There was no s i g n i f i cant difference, either, b e t w e e n l i t h i u m and p l a c e b o in the three v a r i a b l e s of the M a r k e - N y m a n scale. T h e t e s t - r e t e s t c o e f f i c i e n t of corr e l a t i o n s r s for the B e c k scale was 0.77 and 0.78 (P < O.O1) on the g e n e r a l scale and subscale, r e s p e c t i v e l y . On the M a r k e - N y m a n scale the c o e f f i c i e n t of c o r r e l a t i o n for v a l i d i t y was 0 . 8 5 and 0.87 (P ~ O.O1) on the g e n e r a l scale and the subscale, r e s p e c t i v e l y ; for s t a b i l i t y 0.84 and 0.83 (P < 0.01); and for s o l i d i t y 0.59 (P < 0.01) and 0.48 (P < 0.01). The scores for each of the 14 items of the g e n e r a l side effects scale w e r e
c a l c u l a t e d b o t h for i n t e n s i t y (no = O, m i l d = 1, m o d e r a t e = 2, and severe = 3) and for f r e q u e n c y (the ratio of p o s i t i v e item scores). The r e s u l t s s h o w e d that only two items ("tremor" and " i n c r e a s e d thirst") w e r e s c o r e d s i g n i f i c a n t l y h i g h e r (P ~ 0.O1 and P ! 0.02, respectively) in i n t e n s i t y in the l i t h i u m than in the p l a c e b o periods. For "tremor", 59% of the 22 p a t i e n t s s c o r e d p o s i t i v e l y w h i l s t on lithium, as a g a i n s t 18% on placebo, and for "inc r e a s e d thirst" 64% s c o r e d p o s i t i v e l y on l i t h i u m as a g a i n s t 32% on placebo. The r e m a i n i n g 12 items of the g e n e r a l s i d e - e f f e c t scale showed no s t a t i s t i c a l ly s i g n i f i c a n t d i f f e r e n c e b e t w e e n l i t h i u m and placebo. The score p a t t e r n of the 8 p a t i e n t s in the car s i m u l a t o r s t u d y was s i m i l a r to the r e s u l t s for all 22 p a t i e n t s in the v a r i o u s q u e s t i o n n a i r e s .
DISCUSSION In p r e v i o u s studies (3, 13) p a r t i c u l a r l y brake time in the car s i m u l a t o r was found to be a r e l i a b l e p a r a m e t e r w h e n t e s t i n g the e f f e c t of a l c o h o l on driving behaviour. In the p r e s e n t study the t e s t - r e t e s t interval was 6 months, and the r e s u l t s showed no order effect, w h i c h i n d i c a t e s no g e n e r a l e f f e c t of practice. No e f f e c t of l i t h i u m on b r a k e time or on the o t h e r car s i m u l a t o r m e a s u r e m e n t s was found on c o m p a r i s o n w i t h placebo. As brake time is a c o m p l e x r e a c t i o n time, these results are in c o n t r a s t w i t h the findings of L i n n o i l a et al. (10), w h o found that l i t h i u m treatment, p r o d u c i n g c o m p a r a b l e s e r u m levels, a f f e c t e d c o m p l e x r e a c t i o n time after 2 w e e k s of treatment. However, the p r o l o n g a t i o n of the r e a c t i o n time values was o n l y 15-20% on l i t h i u m c o m p a r e d w i t h placebo, and they found no e f f e c t on c o - o r d i n a t e d skills; nor did l i t h i u m a p p e a r to have any e f f e c t on the subjects' s e l f - r e p o r t s , m o r e than 50% c o n s i d e r e d the l i t h i u m t r e a t m e n t as placebo. The subjects in the p r e s e n t e x p e r i m e n t rated as s p e c i f i c c o m p l a i n t w h i l s t on l i t h i u m only t r e m o r and inc r e a s e d thirst, w h e r e a s there was no d i f f e r e n c e b e t w e e n l i t h i u m and p l a c e b o in such items as d i f f i c u l t y in c o n c e n t r a t i o n and memory. This is in a c c o r d ance w i t h f i n d i n g s from l i t h i u m m a i n t e n a n c e t r e a t m e n t of m a n i c - m e l a n c h o l i c p a t i e n t s (5), and w i t h the study of S c h o u et al. (14) on n o r m a l subjects. The latter o b s e r v e d that a r e l a t i v e l y low a v e r a g e d o s a g e of l i t h i u m (25 meq/ 24 hours) had little or no e f f e c t on p s y c h i a t r i c f u n c t i o n s after 3 to 6 w e e k s of treatment, w h e r e a s on a h i g h e r d o s e
335
(50 m e q / 2 4 h o u r s ) " i n t e l l e c t u a l i n i t i a tive was diminished, and there was a f e e l i n g o f l o w e r e d a b i l i t y to c o n c e n trate and memorize". Similar results after high lithium dosage have been reported by Demers and Heninger (9). T h e s u b j e c t s in t h e p r e s e n t s t u d y s c o r e d within the normal range on Beck's dep r e s s i o n s c a l e (4,6) a n d o n M a r k e N y m a n ' s p e r s o n a l i t y s c a l e (11). L i t h i u m w a s n o t f o u n d to i n f l u e n c e t h e s e r a t i n g scores. T h e b a c k g r o u n d to t h i s i n v e s t i g a t i o n was a positive effect of lithium on M e n i @ r e ' s d i s e a s e in a n o p e n p i l o t study, but the preliminary result could not be confirmed (18). I r r e s p e c t i v e of t h e c l i n i c a l e f f e c t , six months of treatment with lithium had no detectable influence on psychic o r p s y c h o m o t o r f u n c t i o n s in t h o s e n o n melancholic patients.
8.
9.
i0.
ii.
12.
13.
Acknowledgements. The study was supported in part by a grant from Dansk Esso Fond. 14.
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