Pencil and paper tests- sensitivity to psychotropic drugs

Transcription

1 Br. J. clin. Pharmac. (1984), 18, 15S-20S Pencil and paper tests- sensitivity to psychotropic drugs BARBARA M. STONE Royal Air Force Institute of Aviation Medicine, Farnborough, Hampshire 1 The literature on pencil and paper tests and the effects of psychotropic drugs is reviewed. 2 Performance at digit symbol substitution, symbol copying, letter cancellation, arithmetic, logic and cognitive processing with a relatively constant level of triazolam was compared with placebo. 3 Analysis of variance, covariance analysis and principal component analysis were applied to the data. 4 Pencil and paper tests which measure various skills are useful for detecting drug effects. Letter cancellation, arithmetic and DSST appear to be most sensitive, although logic and symbol copying may be useful. Keywords psychotropic drugs pencil and paper tests Introduction The effects of drugs on performance have been investigated using a variety of techniques, and in this context pencil and paper tests are attractive because they do not need complex equipment, they are easy to administer and replicate. However, the apparent simplicity of the techniques may be deceptive. They have in common with other tests practice and learning effects, and it is necessary to ensure that parallel examples are used to prevent the subjects remembering the test from one session to the next. There have been several reviews on performance and psychotropic drugs (Hindmarch, 1980; Johnson & Chernik, 1982; Vogel, 1979; Wittenborn, 1979) and these have included analyses of pencil and paper tests. It would appear that cancellation and digit symbol substitution have been used more often than any other test. Both measure processing of sensory information although there is also a motor component in each task. Two other tasks which have been used frequently are symbol copying and arithmetic or number handling. There is however, no clear consensus about the relative usefulness of each task, or of its sensitivity. Vogel (1981) considered that cancellation was more sensitive than digit symbol substitution (DSS), whereas Johnson & Chernik (1982) suggested that DSS and symbol copying were more sensitive than cancellation. Hindmarch (1980) considered arithmetic to be a most sensitive skill, and reported that such tests were not only impaired by sedative drugs but also showed improvement with stimulant drugs. However, there have been few, if any, studies where these tasks have been compared, and from the few studies where more than one test was used it is unclear whether one test is more sensitive than another. In a recent study which we carried out jointly with the University of Leiden, performance at letter cancellation, DSS, symbol copying and mathematics was measured, together with a 15S logic test and cognitive processing test (Hindmarch & Parrott, 1978). A relatively constant plasma concentration of triazolam was maintained over a period of 36 h by means of a rectal

2 16S Barbara M. Stone osmotic pump and performance on the various tests was measured and compared with placebo (Breimer et al., 1984, unpublished data). Methods The experimental protocol is illustrated in Figure 1. At each performance session eight different tests were given. Two-letter and six-letter cancellation tests 50 (two-letter test) or 40 (six-letter test) sheets, with 1200 randomised letters arranged in 40 columns. Each sheet had either two or six target letters printed at the top. Subjects were given either 2 min (two-letter test) or 5 min (six-letter test) to cancel as many target letters as possible, working down each column in turn. The number of columns completed, and the number of correct cancellations/possible cancellations were scored. Logic test 50 different sheets of 100 problems. Each problem took the form: If B>A: A=F: F>E: E>D Then B>D Subjects were required to respond to the final statement with True (T), False (F) or Indeterminate (?), and were given 3 min to complete as many problems as possible. The number correct/ number attempted was scored. Digit symbol substitution test (DSST) 50 sheets, with 200 randomised digits (0-9) arranged in 10 rows on each side. In the space below each digit subjects were required to insert the corresponding symbol, indicated by a code at the top of each page. Subjects were given 2 min per side to complete as many substitutions as possible. The number correct on each sheet was scored. Mental arithmetic 50 different sheets, with 192 sums on each. Each sum required the addition/subtraction of three three-digit numbers, and written calculation was not permitted. In 10 min, subjects completed as many sums as possible, and the number correct/number attempted was recorded. Symbol copying test (SCT) 50 sheets, with 200 randomised symbols (those used in the DSST) arranged in 10 rows on each side. Subjects were required to copy each symbol in the space provided. Subjects were allowed 1 min per side to copy as many symbols as possible. The number correct on each sheet was scored. Concept identity test Cognitive processing ability was measured 23t00 I Sleep 1 Pump in o o I Pump out -L 2300 Time (h) I Sleep Time (h) Sleep 2 (cont) H ffl isep Figure 1 Design of the experiment in which central effects were studied. The subjects slept from to h before, during and after infusion of triazolam. Performance tests (hatched rectangles) were carried out from h each day. The pump (indicated by an arrow) was inserted at h on day 1 and taken out at h on day 2. Sle

3 using a concept identification task. Subjects were required to abstract the common elements from sets of line drawings. The concepts to be recognised were of two levels of difficulty. Two response measures were recorded: the time taken to complete correct identification and the number of erroneous solutions made. Several parallel forms of the task were used. Post-drug and post-placebo measurements were compared using analysis of variance. A further analysis was undertaken to determine whether the drug effect detected in one task could be predicted by another. A covariance analysis was used to correct (in all pairs) one task for another task. The drug x time interaction was then examined to determine whether the drug effect was still detectable. A principal component analysis of all the Pencil and paper tests 17S tests except the two concept identity tasks was then undertaken. The main effects of subjects and drug were removed before calculation of the components. Results The results of the analysis of variance are given in Table 1. There were impairments in maths and letter cancellation around 1 h after drug administration began. Impairments in the concept identity task were inconsistent and from the covariance analysis it was clear that the drug effect in concept identity could be predicted by the results of any one of the other tests. Further the SC results could be predicted by the DSS, Table 1 Effect of triazolam on performance measures-differences from placebo (means for six/seven subjects) Day I Time (h) DSST ** ** * ** ** SCT * * * ** ** Maths * * ** ** * ** ** Logic Canc * ** *** *** ** ** ** Canc Easy concept test Hard concept test Day 2 Time (h) DSST *** *** *** ** ** SCT *** *** *** ** * Maths *** *** *** ** * * Logic * * * * Canc *** *** *** * ** Canc ****** *** *** ** * Easy concept test ** ** ** Hard concept test * ** Significant levels: * P < 0.05; ** P < 0.01; **P <

4 18S 0.0 a) o 0 a) 10 C 10 Barbara M. Stone Pump in IJ /1000 Day / o Pump out 1000 Day \ 11o Time (h) a1).0 o C) CuQ8 u:c [ \' ' i_ 'SCT E C,, 50 [ 60 L Figure 2 Change in symbol copying with triazolam compared with placebo over the 2 day experiment (-). Change in symbol copying with triazolam compared with placebo corrected for digit symbol substitution test performance (0) (means for seven subjects). logic and maths results, and the logic performance could be predicted by mathematics performance. This is illustrated for SC corrected for DSS in Figure 2. However, with cancellation of two and six letters, DSST and maths a significant drug effect still remained when correction was made for any other task. The weightings of the various principal components are given in Table 2 in order of their percentage contribution to the total variance. Only the first, second and sixth component showed a drug x time interaction. The other three components showed a trend with time which may have been related to practice or circadian effects. The first, second and sixth component were then analysed by an analysis of variance. Comparisons for differences between placebo and drug between Ti and the other times were made using Dunnett's multiple comparison test (Tables 3 and 4). The six different tasks contributed almost equally to the first component which showed the dominant drug effect. The effect of triazolam was apparent by the third time and there was a fast recovery on the second day after the pump had been removed. Performance on the first session on day 2 was particularly low and there was a gradual recovery during day 2. The second component which was principally a contrast between the two cancellation tests and the logic test, continued to fall on the second day even after the pump containing triazolam had been removed. The sixth component was due mainly to a difference between DSS and the other tests. Although at no individual time was there a Table 2 Principal component analysis Components First Second Third Fourth Fifth Sixth DSST SCT Two-letter cancellation Six-letter cancellation Logic Maths % 13% 7% 6% 4% 3% TD ** NS NS NS * T ** NS overall cancellation DSST mean vs logic Significance levels: * P < 0.05; ** P < 0.01; *** P <

5 Table 3 Principal component analysis of performance tests Rotation I Day I T T T T ** T T T T Day 2 Tg TIo T T T T T T Day 2 Tg < T3 - T8 * Day 2 Tg - T13: Reducing drug effect, linear trend ** Significance levels: * P < 0.05; ** P < 0.01; *** P < difference from control levels, the two occasions (T3 and T14) where the component was most different from control coincided with the times when peak concentrations may not have been reached, or when concentrations were falling. Discussion Both analysis of variance and covariance analysis suggested that the concept identity test was rather insensitive to the effects of a benzodiazepine. All the other tests, on the other hand, showed the main drug effect quite strongly, although there was some duplication of information. The tasks showing the drug effects most strongly were DSS, mathematics and both cancellation tests. Six-letter cancellation appeared to be more sensitive than cancellation of two letters. However there is evidence of some differential effect on individual tasks, namely logic as opposed to cancellation showed Pencil and paper tests Table 4 Principal component analysis of performance tests Rotation 2 Difference from T, Day I T T T T T T T * T Day 2 T T1o TI, T * T T ** T * T * Significance levels: * P < 0.05; ** P < 0.01; *** P < Rotation 6 Day 1 T T T T T T T T Day 2 T T1o TI T T T T T S a continuing effect after drug removal. Furthermore DSS may be less sensitive than the other tasks at lower concentrations of triazolam. In conclusion, pencil and paper tests which measure various skills are useful for detecting impaired performance. Cancellation, maths and DSS appear to be the most sensitive in the present study, although the other tasks studied may also be useful. References Hindmarch, I. (1980). Psychomotor function and psychoactive drugs. Br. J. clin. Pharmac., 10, Hindmarch, I. & Parrott, A. C. (1978). The effect of a sub-chronic administration of three dose levels of a 1,5-benzodiazepine derivative, clobazam, on

6 20S Barbara M. Stone subjective aspects of sleep and psychomotor performance the morning after night time medication. Arzneimittel-Forsch., 28, Johnson, L. C. & Chernik, D. A. (1982). Sedativehypnotics and human performance. Psychopharmacology, 76, Vogel, J. R. (1979). Objective measurement of human performance changes produced by antianxiety drugs In Anxiolytics, eds Fielding, J. & Lal, S., pp New York: Futura. Wittenbom, J. R. (1979). Effects of benzodiazepines on psychomotor performance. Br. J. clin. Pharmac., 7, 61S-67S.