Fundam Clin Pharmacol (1992) 6 , 5-9
5
0 Elsevier. Paris
The comparison of the effects of multi and single doses of buspirone, chlordiazepoxide and hydroxyzine on psychomotor function and EEG MW Blom', PR Barte12, DK Sommers', CH Van Der Meyden2, PJ Becker 'Department of Pharmacology. University of Pretoria; =Department of Neurology, University of Pretoria and HF Verwoerd Hospital; JInstitutefor Biostatbrics Medical Research Council, Pretoria, South Africa
(Received 30 August 1990; accepted 24 September 1991)
Summary - This study compares the effects of buspirone ( 5 mg). chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo on psychomotor function and EEG, when taken thrice daily for a period of two weeks, with those after a single dose administration. Nine healthy volunteers participated in the study. The battery of psychomotor tests included peak velocity of saccadic eye movements (SEM). a Sternberg memory scanning and choice reaction time test (SMS-CRT) and critical flicker fusion frequency (CFFF). The peak velocity of saccadic eye movements was significantly impaired by the single dose of hydroxyzine (P = 0.03) in comparison to the multidose results. A similar comparison regarding buspirone only approached significance (P = 0.07). The SMS-CRT and CFFF did not reveal any difference between the multi and single dose regimens. Spectral analysis of the EEG did not distinguish between the multi and single dosage schedules regarding the respective drugs in the low doses administered. buspirone I chlordiazepoxide I hydroxyzine I multi and single dose studies I psychomotor tests and EEC
Introduction
It is generally accepted that multi and single dosage regimens have different psychomotor and EEG effects. Buspirone is only effective as anxiolytic after a lag period of at least two weeks (Jacobson et al, 1985; Jann, 1988). Reportedly it causes significantly less sedation and psychomotor impairment than the benzodiazepines (Eison and Temple, 1986; Seidel et al, 1985). After initial administration the benzodiazepines generally cause drowsiness and psychomotor impairment (Wittenborn, 1979). However, ingestion of therapeutic doses for a period of one week causes less psychomotor impairment than a single dose administration, suggesting the development of tolerance (Bornstein er al, 1985; Ghoneim et al, 1981). As the available psychomo-
tor tests primarily assess drug-induced sedation, a predominantly sedative drug such as hydroxyzine, an antihistaminic and antimuscarinic drug, was included. The aim of our study was to compare the effects of the above-mentioned drugs, taken as a single dose and thrice daily for a period of two weeks, to the effects on psychomotor function and EEG.
Materials, methods and subjects
Nine healthy, non-smoking male volunteers, aged 20 - 25 years (mass 68 - 85 kg), participated in a multidose study, as well as a follow-up single dose study. Both studies were double-blind, randomized, placebo controlled cross-over studies. Subjects signed informed consent and undertook
6
MW Blom er ol
not to drive a motor vehicle or motorcycle during the two weeks of medication. The study protocol was approved by the Ethics Committee of the University of Pretoria. Subjects were familiarized with the test procedures on one occasion, without receiving medication. They were requested to abstain from taking alcohol, tea, coffee or any other drug for 24 h prior to testing.
Multidose study Each subject took one of the following drugs thrice daily for a period of two weeks: buspirone (5 mg), chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo. Hydroxyzine was included as a positive control and the dosage schedule was chosen bearing in mind that the drugs concerned were given to ambulant volunteers. The last dose of the respective drug was taken after breakfast at 08:OO and testing started at 1290. A washout period of two weeks followed each medication session.
Single dose study .4 single dose, equivalent to the total daily dose ingested in the multidose study was administered 1.5 h before testing. Subjects were requested to have breakfast at 08:OO but to remain without food until testing started at 12:OO. A washout period of one week followed each single-dose
medication session.
Psychomotor tests SEM Horizontal saccadic eye movements (SEMs) were recorded by electro-oculographic (EOG) techniques. The amplified EOG was digitized at a sampling rate of 400 H z with a 12 bit resolution. SEMs were elicited by the successive illumination of red light emitting diodes mounted in a stimulator bar. Stimulus jumps at pseudo-random intervals were grouped into three batches of 14 each with a 204 rest period between batches. The initial asymmetrical jumps in each series were discarded, leaving a maximum of 36 for analysis, 6 each for the following amplitudes: 16, 20, 25, 30. 35 and 40".Each SEM was individually processed, filtered, checked for artefact and finally analysed using original algorithms based on previously described methods (Baloh et a/. 1975 ; Bittencourt era/, 1981 ; Smith el a/, 1981 ; Griffiths et a/, 1984). Each of 12 conditions had to be met by saccades before acceptance. These conditions were related to noise and artefact
levels and inappropriate reaction times, velocities and durations, among others. Peak saccadic velocity was derived from non-linear regression analysis (Baloh et a/, 1975). Linear regression analysis was used to determine the duration - amplitude relationship (msl").
SMS-CR T The Sternberg memory-scanning test and choice reaction time (SMS-CRT) followed the design of Oborne and Rogers ( I 983). After learning a memory set consisting of 1, 2, 3 or 4 digits (0 - 9), the subject was required t o indicate as quickly as possible, but with the minimum of errors, whether a digit presented on a video monitor belonged to a previously memorized set. The digits subtended a visual angle of approximately 1" 26', and were presented for 0.5 s. A micro-computer was used to present the digits and to measure positive and negative reaction times, ie the stimulus did or did not belong to the memorized set. The test session started with a practice session of 2 blocks, separated by a rest period of 1 min, of 22 trials each (stimulus plus response) consisting of 1 and then 3 memory set sizes. The test consisted of 176 trials (4 memory set sizes, each presented twice, x 22 trials each) the first two trials in each block being excluded from analysis, leaving 160 trials. If the subject did not respond to a stimulus within 3 s it was recorded as a missed trial and by informing the subject when necessary, the number of errors were kept below 5% of the total. Subjects were randomly assigned one of four parallel test versions which varied the order of the four memory set sizes. The mean reaction times (ms) of positive and negative responses (y-axis) versus the memory set size (x-axis) were plotted. The y-intercept of reaction time is regarded as representing the initial and the final stages of a four-stage information processing model, namely the stimulus detection plus registration and the execution of the response. Oborne and Rogers (1983) regarded the intercept as reflecting the more peripheral processes. The slope of the linear increase in reaction time with an increase in the size of the memory set represents memory scanning plus stimulus recognition and selection of an appropriate response (stages 2 and 3). Changes in this slope reflect changes in the more central processes. CFFF The critical flicker fusion frequency (CFFF) was determined by the forced choice method, closely following the technique of Salmi (1985). A flickering target and a constantly illuminated surround consisted of red light emitting diodes, and subtended visual angles of 3 and IS",
7
Buspirone, hydroxyzine, saccades, EEG
respectively. The target and surround were mounted at the end of a black tube and were viewed through a 2-mm artificial pupil and seen in Maxwellian view at optical infinity. The CFFF was determined with right eye stimulation in each subject. EEG Spectral analysis was performed on the EEG recorded from an 0, - C, derivation with an analogue bandpass set at 0 . 5 - 3 2 Hz. The digitizing rate was 128 Hz and power was calculated in 0.25 Hz steps by applying a Fast Fourier transform to 45 4-s epochs. Epochs contaminated by eye movement or muscle artefacts were excluded. The subject's eyes were closed during the recordings and vigilance was maintained. The spectral analysis results were summed into five frequency bands: delta (0.75 3.75 Hz), theta (4.00-7.75 Hz), alpha (8.00- 12.75 Hz), PI (13.00-21.75 Hz) and P2 (22.0-31.00 Hz). Results were expressed on an amplitude @V) scale.
Analysis of data The multidose as well as the single dose study were performed as a randomized blocks design and analysed as such, where volunteers were taken as blocks. After establishing from the appropriate analysis of variance (ANOVA) that the treatments were significantly differ-
ent with respect to a parameter, the specific differences were determined by making use of Duncan's multiple range test. Non-parametric analysis was performed using the Mann-Whitney test statistics for the comparison of multi and single dose studies. Testing was done at the 5% level of singnificance (P = 0.05).
Results Psychomotor tests
Results of all tests after buspirone multidose administration did not differ significantly from those after the single dose administration. Memory scanning time was not affected at all by multi or single dose regimens. However, the decrease in SEM-K, caused by a single dose buspirone (15 mg), approached significance ( P = 0.07) (table I). Spectral analysis of the EEG revealed no significant differences between multi and single dose regimens of buspirone, regarding the five frequency bands of the EEG (table 11). Results after chlordiazepoxide multi versus single dose administration did not attain significance
Table I. Mean rt standard error of the mean (SEM) for the psychomotor tests.
Buspirone Multidose Singledose CFFF (Hz) SRT-C (ms) SEM-K ( ' I S )
Chlordiazepoxide Multidose Singledose
Hydroxyzine Multidose Singledose
31.3i1.2 32.2k0.8 30.9k1.0 31.5i0.9 31.3k1.1 32.1*0.9 316.8rt22.2 333.4rt31.7 338.9k22.8 325.7rt30.0 320.9k 17.6 331.3k25.8 518.8k22.1 414.0k54.5 474.1 rt31.0 445.6k 14.5 505.5rt9.9 392.0**52.8
Placebo
Training session
31.9k0.9 29.8i0.8 318.0k 19.3 328.9i20.0 519.2rt21.3 564.3k20.9
P c 0.05
Table II. Mean
f
standard error of the mean (SEM) for EEG amplitudes (CCV).
Multidose Delta Theta Alpha Beta, Beta,
Buspirone Singledose
71.3k4.9 65.1rt1.4 160.2k25.4 18.5 rt 6.5 34.1 f 2.1
14.3k5.6 12.1k6.4 163.2rt 21.4 8 1 . 8 i 5.6 36.0k2.2
Chlordiazepoxide Multidose Singledose
Hydroxyzine Multidose Singledose
68.3i6.2 59.1rt1.5 144.Oi 31.5 91.2k9.8 4 2 . 6 i 3.5
73.3k6.1 13.1k8.8 161.6i25.1 84.4 f 1.1 35.6rt2.4
15.3k5.1 61.5rt5.1 145.2 k26.0 82.2 rt 6.0 39.1 f 1.8
82.1 k 3.9 18.0rt 7.3 140.2rt26.4 81.8+1.2 39.3 f 2.2
Placebo
12.1 i4.6 61.6 i 6.6 164.4k22.0 84.2k1.6 31.0rt2.5
8
MW Blom el a/ DEG / S E C
500 400
300
200 100
0
BUSPIRONE
CHLORDIAZEPOXIDE
HYDROXYZINE
Fig 1. Effect of buspirone. chlordiazepoxide and hydroxyzine on peak saccadic velocity of saccadic eye movements (SEM-K): ; single dose, EBii ; Blank blocks represent stanmultidose, dard error of the mean (E).O. Hydroxyzine (30me) single dose decreased SEM-K significantly (P = 0.03)compared to the multidose regimen.
for any of the psychomotor tests used (table I). Spectral analysis of the EEG, similarly, revealed no significant difference between multi and single dose regimens (table 11). Hydroxyzine was the only drug which decreased peak velocity of saccadic eye movements significantly when given as a single dose (30mg), compared to the multidose study (P = 0.03) (fig 1). Spectral analysis of the EEG revealed non significant differences regarding multi versus single dose studies (table 11).
Se,f ratings of sedation and sleep Hydroxyzine caused more daytime drowsiness and induced sound sleep at night relative to chlordiazepoxide whilst buspirone had no sedative effects during the day and did not affect sleep at night. However, these findings were non-significant.
et al, 1982). N o reference could be found regarding a multidose regimen of buspirone and saccadic eye movements, but Schaffler and Klausnitzer (1988) demonstrated that a single 5-mg dose of buspirone did not decrease the mean angular velocity of saccades. However, the single 15-mg dose of buspirone given in our study decreased peak velocity of saccades, approaching significance (P < 0.07). Hindmarch (1979) demonstrated that chlordiazepoxide given in a 10-mg dose thrice daily for 5 days, decreased CFFF and choice reaction time, whilst in our study the low dose of 5 mg thrice daily had no deleterious effects on the abovementioned tests. Peak velocity of saccadic eye movement is a sensitive measure of benzodiazepine induced sedation (Griffiths et al, 1984) and the development of tolerance to benzodiazepines has been described (Tedeschi e? al, 1985). The lack of effect on saccadic eye movements in the multidose study could be due to the development of tolerance to the sedative action of chlordiazepoxide over a period of two weeks. Hydroxyzine did not impair CFFF, a finding which is in accordance with the study of Pishkin et al(l983). Only a few studies have addressed the issue to tolerance to continuous antihistamine therapy. Most of these studies have demonstrated the development of varying degrees of tolerance to long term antihistamine treatment via skin wheal and flare reactions (Kemp, 1989). The present study is the first using saccadic eye movements, to demonstrate tolerance to the psychomotor effects of an antihistaminic drug. The EEG results of our study regarding buspirone and chlordiazepoxide are similar to the findings of Bond et al (1983), whilst hydroxyzine displayed central effects characteristic of classical antihistamines (Pechadre el al, 1988).
Discussion References
The minimal impairment of psychomotor function and memory after the multi or single dose administration of buspirone are in agreement with previous studies (Moskowitz and Smiley, 1982; Seppda
Baloh RW, Sills AW, Kumley WE, Honrubia V (1975) Quantitative measurement of saccade amplitude, duration and velocity. Neurology 25, 1065-1070
Buspirone. hydroxyzine, saccades, EEG Bittencourt PRM, Wade P , Smith AT, Richens A (1981) The relationship between peak velocity of saccadic eye movements and serum benzodiazepine concentration. Br J Clin Pharmacol 12, 523-533 Bond A, Lader M, Shrotriya R (1983) Comparative effects of a repeated dose regime of diazepam and buspirone on subjective ratings, psychological tests and the EEG. Eur J Clin Parmacol24, 463-467 Bornstein RA, Watson GD, Pawluk LK (1985) Effects of chronic benzodiazepine administration on neuropsychological performance. CIin Neuropharmacol 8, 357-361 Eison AS, Temple DL (1986) Buspirone: review of its pharmacology and current perspectives on its mechanism of action. A m J Med 80, (suppl 3B 1-9) Ghoneim MM, Mewaldt SP, Berie JL, Hinrichs JV (1981) Memory and performance effects of single and 3-week administration of diazepam. Psychopharmacology 73, 147-151 Griffiths AN, Marshall RW, Richens A (1984) Saccadic eye movement analysis as a measure of drug effects on human psychomotor performance. Br J Clin Pharmacol (suppl) 18, 73s-82s Hindmarch I (1979) Some aspects of the effects of clobazam on human psychomotor performance. Br J Clin Pharmacol7, 77s-82s Jacobson AF, Dominguez RA, Goldstein BJ, Steinbock RM (1985) Comparison of buspirone and diazepam in generalized anxiety disorder. Pharmacotherapy 5, 290- 296 Jann MW (1988) Buspirone: an update on a unique anxiolytic agent. Pharmacotherapy 8, 100- 116 Kemp JP (1989) Tolerance to antihistamines: is it a problem? Ann Allergy 63, 621-623 Moskowitz H , Smiley A (1982) Effects of chronically administered buspirone and diazepam on driving-related
9
skills performance. J Clin Psychiatry 43, 12 (sec 2) 44-55 Oborne DJ, Rogers Y (1983) Interactions of alcohol and caffeine on human reaction time. Aviat Space Environ Med 54, 528-534 Pechadre JC, Vernay D, Trolese JF, Bloom M, Dupond P , Rihoux J P (1988) Comparison of the central and peripheral effects of cetirizine and terfenadine. Eur J Clin Pharmacol 35, 255-259 Pishkin V, Sengel RA, Lovallo WR, Shurley J T (1983) Cognitive and psychomotor evaluation of clemastinefumarate, diphenhydramine HCL and hydroxyzine HCL : Double-blind study. Curr Ther Res vol33,2, 230-237 Salmi T (1985) Critical flicker frequencies in MS patients with normal or abnormal pattern VEP. Acta Neurol Scand 71, 354-358 Schaffler K, Klausnitzer W (1988) Single dose study on buspirone versus diazepam in volunteers. Drug Res 38 (I), 2, 282-287 Seidel WF. Cohen SA, Bliwise NG, Dement WC (1985) Buspirone : an anxiolytic without sedative effect. Psychopharmacology 87, 371 -373 Seppala T , Aranko K, Mattila MJ, Shrotriya RC (1982) Effects of alcohol on buspirone and lorazepam actions. CIin Pharmacol Ther vol 32, 2, 201-201 Smith AT, Bittencourt PRM, Lloyd DSL, Richens A (198 1) An efficient technique for determining characteristics of saccadic eye movements using a mini computer. J Biomed Eng 3, 39-43 Tedeschi G,Griffiths AN, Smith AT, Richens A (1985) The effect of repeated doses of temazepam and nitrazepam on human psychomotor performance. Br J CIin Pharmacol20, 36 1 -367 Wittenborn JR (1979) Effects of benzodiazepines on psychomotor performance. Br J CIin Pharmacol (suppl) 7, 61s-67s
5
0 Elsevier. Paris
The comparison of the effects of multi and single doses of buspirone, chlordiazepoxide and hydroxyzine on psychomotor function and EEG MW Blom', PR Barte12, DK Sommers', CH Van Der Meyden2, PJ Becker 'Department of Pharmacology. University of Pretoria; =Department of Neurology, University of Pretoria and HF Verwoerd Hospital; JInstitutefor Biostatbrics Medical Research Council, Pretoria, South Africa
(Received 30 August 1990; accepted 24 September 1991)
Summary - This study compares the effects of buspirone ( 5 mg). chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo on psychomotor function and EEG, when taken thrice daily for a period of two weeks, with those after a single dose administration. Nine healthy volunteers participated in the study. The battery of psychomotor tests included peak velocity of saccadic eye movements (SEM). a Sternberg memory scanning and choice reaction time test (SMS-CRT) and critical flicker fusion frequency (CFFF). The peak velocity of saccadic eye movements was significantly impaired by the single dose of hydroxyzine (P = 0.03) in comparison to the multidose results. A similar comparison regarding buspirone only approached significance (P = 0.07). The SMS-CRT and CFFF did not reveal any difference between the multi and single dose regimens. Spectral analysis of the EEG did not distinguish between the multi and single dosage schedules regarding the respective drugs in the low doses administered. buspirone I chlordiazepoxide I hydroxyzine I multi and single dose studies I psychomotor tests and EEC
Introduction
It is generally accepted that multi and single dosage regimens have different psychomotor and EEG effects. Buspirone is only effective as anxiolytic after a lag period of at least two weeks (Jacobson et al, 1985; Jann, 1988). Reportedly it causes significantly less sedation and psychomotor impairment than the benzodiazepines (Eison and Temple, 1986; Seidel et al, 1985). After initial administration the benzodiazepines generally cause drowsiness and psychomotor impairment (Wittenborn, 1979). However, ingestion of therapeutic doses for a period of one week causes less psychomotor impairment than a single dose administration, suggesting the development of tolerance (Bornstein er al, 1985; Ghoneim et al, 1981). As the available psychomo-
tor tests primarily assess drug-induced sedation, a predominantly sedative drug such as hydroxyzine, an antihistaminic and antimuscarinic drug, was included. The aim of our study was to compare the effects of the above-mentioned drugs, taken as a single dose and thrice daily for a period of two weeks, to the effects on psychomotor function and EEG.
Materials, methods and subjects
Nine healthy, non-smoking male volunteers, aged 20 - 25 years (mass 68 - 85 kg), participated in a multidose study, as well as a follow-up single dose study. Both studies were double-blind, randomized, placebo controlled cross-over studies. Subjects signed informed consent and undertook
6
MW Blom er ol
not to drive a motor vehicle or motorcycle during the two weeks of medication. The study protocol was approved by the Ethics Committee of the University of Pretoria. Subjects were familiarized with the test procedures on one occasion, without receiving medication. They were requested to abstain from taking alcohol, tea, coffee or any other drug for 24 h prior to testing.
Multidose study Each subject took one of the following drugs thrice daily for a period of two weeks: buspirone (5 mg), chlordiazepoxide (5 mg), hydroxyzine (10 mg) and placebo. Hydroxyzine was included as a positive control and the dosage schedule was chosen bearing in mind that the drugs concerned were given to ambulant volunteers. The last dose of the respective drug was taken after breakfast at 08:OO and testing started at 1290. A washout period of two weeks followed each medication session.
Single dose study .4 single dose, equivalent to the total daily dose ingested in the multidose study was administered 1.5 h before testing. Subjects were requested to have breakfast at 08:OO but to remain without food until testing started at 12:OO. A washout period of one week followed each single-dose
medication session.
Psychomotor tests SEM Horizontal saccadic eye movements (SEMs) were recorded by electro-oculographic (EOG) techniques. The amplified EOG was digitized at a sampling rate of 400 H z with a 12 bit resolution. SEMs were elicited by the successive illumination of red light emitting diodes mounted in a stimulator bar. Stimulus jumps at pseudo-random intervals were grouped into three batches of 14 each with a 204 rest period between batches. The initial asymmetrical jumps in each series were discarded, leaving a maximum of 36 for analysis, 6 each for the following amplitudes: 16, 20, 25, 30. 35 and 40".Each SEM was individually processed, filtered, checked for artefact and finally analysed using original algorithms based on previously described methods (Baloh et a/. 1975 ; Bittencourt era/, 1981 ; Smith el a/, 1981 ; Griffiths et a/, 1984). Each of 12 conditions had to be met by saccades before acceptance. These conditions were related to noise and artefact
levels and inappropriate reaction times, velocities and durations, among others. Peak saccadic velocity was derived from non-linear regression analysis (Baloh et a/, 1975). Linear regression analysis was used to determine the duration - amplitude relationship (msl").
SMS-CR T The Sternberg memory-scanning test and choice reaction time (SMS-CRT) followed the design of Oborne and Rogers ( I 983). After learning a memory set consisting of 1, 2, 3 or 4 digits (0 - 9), the subject was required t o indicate as quickly as possible, but with the minimum of errors, whether a digit presented on a video monitor belonged to a previously memorized set. The digits subtended a visual angle of approximately 1" 26', and were presented for 0.5 s. A micro-computer was used to present the digits and to measure positive and negative reaction times, ie the stimulus did or did not belong to the memorized set. The test session started with a practice session of 2 blocks, separated by a rest period of 1 min, of 22 trials each (stimulus plus response) consisting of 1 and then 3 memory set sizes. The test consisted of 176 trials (4 memory set sizes, each presented twice, x 22 trials each) the first two trials in each block being excluded from analysis, leaving 160 trials. If the subject did not respond to a stimulus within 3 s it was recorded as a missed trial and by informing the subject when necessary, the number of errors were kept below 5% of the total. Subjects were randomly assigned one of four parallel test versions which varied the order of the four memory set sizes. The mean reaction times (ms) of positive and negative responses (y-axis) versus the memory set size (x-axis) were plotted. The y-intercept of reaction time is regarded as representing the initial and the final stages of a four-stage information processing model, namely the stimulus detection plus registration and the execution of the response. Oborne and Rogers (1983) regarded the intercept as reflecting the more peripheral processes. The slope of the linear increase in reaction time with an increase in the size of the memory set represents memory scanning plus stimulus recognition and selection of an appropriate response (stages 2 and 3). Changes in this slope reflect changes in the more central processes. CFFF The critical flicker fusion frequency (CFFF) was determined by the forced choice method, closely following the technique of Salmi (1985). A flickering target and a constantly illuminated surround consisted of red light emitting diodes, and subtended visual angles of 3 and IS",
7
Buspirone, hydroxyzine, saccades, EEG
respectively. The target and surround were mounted at the end of a black tube and were viewed through a 2-mm artificial pupil and seen in Maxwellian view at optical infinity. The CFFF was determined with right eye stimulation in each subject. EEG Spectral analysis was performed on the EEG recorded from an 0, - C, derivation with an analogue bandpass set at 0 . 5 - 3 2 Hz. The digitizing rate was 128 Hz and power was calculated in 0.25 Hz steps by applying a Fast Fourier transform to 45 4-s epochs. Epochs contaminated by eye movement or muscle artefacts were excluded. The subject's eyes were closed during the recordings and vigilance was maintained. The spectral analysis results were summed into five frequency bands: delta (0.75 3.75 Hz), theta (4.00-7.75 Hz), alpha (8.00- 12.75 Hz), PI (13.00-21.75 Hz) and P2 (22.0-31.00 Hz). Results were expressed on an amplitude @V) scale.
Analysis of data The multidose as well as the single dose study were performed as a randomized blocks design and analysed as such, where volunteers were taken as blocks. After establishing from the appropriate analysis of variance (ANOVA) that the treatments were significantly differ-
ent with respect to a parameter, the specific differences were determined by making use of Duncan's multiple range test. Non-parametric analysis was performed using the Mann-Whitney test statistics for the comparison of multi and single dose studies. Testing was done at the 5% level of singnificance (P = 0.05).
Results Psychomotor tests
Results of all tests after buspirone multidose administration did not differ significantly from those after the single dose administration. Memory scanning time was not affected at all by multi or single dose regimens. However, the decrease in SEM-K, caused by a single dose buspirone (15 mg), approached significance ( P = 0.07) (table I). Spectral analysis of the EEG revealed no significant differences between multi and single dose regimens of buspirone, regarding the five frequency bands of the EEG (table 11). Results after chlordiazepoxide multi versus single dose administration did not attain significance
Table I. Mean rt standard error of the mean (SEM) for the psychomotor tests.
Buspirone Multidose Singledose CFFF (Hz) SRT-C (ms) SEM-K ( ' I S )
Chlordiazepoxide Multidose Singledose
Hydroxyzine Multidose Singledose
31.3i1.2 32.2k0.8 30.9k1.0 31.5i0.9 31.3k1.1 32.1*0.9 316.8rt22.2 333.4rt31.7 338.9k22.8 325.7rt30.0 320.9k 17.6 331.3k25.8 518.8k22.1 414.0k54.5 474.1 rt31.0 445.6k 14.5 505.5rt9.9 392.0**52.8
Placebo
Training session
31.9k0.9 29.8i0.8 318.0k 19.3 328.9i20.0 519.2rt21.3 564.3k20.9
P c 0.05
Table II. Mean
f
standard error of the mean (SEM) for EEG amplitudes (CCV).
Multidose Delta Theta Alpha Beta, Beta,
Buspirone Singledose
71.3k4.9 65.1rt1.4 160.2k25.4 18.5 rt 6.5 34.1 f 2.1
14.3k5.6 12.1k6.4 163.2rt 21.4 8 1 . 8 i 5.6 36.0k2.2
Chlordiazepoxide Multidose Singledose
Hydroxyzine Multidose Singledose
68.3i6.2 59.1rt1.5 144.Oi 31.5 91.2k9.8 4 2 . 6 i 3.5
73.3k6.1 13.1k8.8 161.6i25.1 84.4 f 1.1 35.6rt2.4
15.3k5.1 61.5rt5.1 145.2 k26.0 82.2 rt 6.0 39.1 f 1.8
82.1 k 3.9 18.0rt 7.3 140.2rt26.4 81.8+1.2 39.3 f 2.2
Placebo
12.1 i4.6 61.6 i 6.6 164.4k22.0 84.2k1.6 31.0rt2.5
8
MW Blom el a/ DEG / S E C
500 400
300
200 100
0
BUSPIRONE
CHLORDIAZEPOXIDE
HYDROXYZINE
Fig 1. Effect of buspirone. chlordiazepoxide and hydroxyzine on peak saccadic velocity of saccadic eye movements (SEM-K): ; single dose, EBii ; Blank blocks represent stanmultidose, dard error of the mean (E).O. Hydroxyzine (30me) single dose decreased SEM-K significantly (P = 0.03)compared to the multidose regimen.
for any of the psychomotor tests used (table I). Spectral analysis of the EEG, similarly, revealed no significant difference between multi and single dose regimens (table 11). Hydroxyzine was the only drug which decreased peak velocity of saccadic eye movements significantly when given as a single dose (30mg), compared to the multidose study (P = 0.03) (fig 1). Spectral analysis of the EEG revealed non significant differences regarding multi versus single dose studies (table 11).
Se,f ratings of sedation and sleep Hydroxyzine caused more daytime drowsiness and induced sound sleep at night relative to chlordiazepoxide whilst buspirone had no sedative effects during the day and did not affect sleep at night. However, these findings were non-significant.
et al, 1982). N o reference could be found regarding a multidose regimen of buspirone and saccadic eye movements, but Schaffler and Klausnitzer (1988) demonstrated that a single 5-mg dose of buspirone did not decrease the mean angular velocity of saccades. However, the single 15-mg dose of buspirone given in our study decreased peak velocity of saccades, approaching significance (P < 0.07). Hindmarch (1979) demonstrated that chlordiazepoxide given in a 10-mg dose thrice daily for 5 days, decreased CFFF and choice reaction time, whilst in our study the low dose of 5 mg thrice daily had no deleterious effects on the abovementioned tests. Peak velocity of saccadic eye movement is a sensitive measure of benzodiazepine induced sedation (Griffiths et al, 1984) and the development of tolerance to benzodiazepines has been described (Tedeschi e? al, 1985). The lack of effect on saccadic eye movements in the multidose study could be due to the development of tolerance to the sedative action of chlordiazepoxide over a period of two weeks. Hydroxyzine did not impair CFFF, a finding which is in accordance with the study of Pishkin et al(l983). Only a few studies have addressed the issue to tolerance to continuous antihistamine therapy. Most of these studies have demonstrated the development of varying degrees of tolerance to long term antihistamine treatment via skin wheal and flare reactions (Kemp, 1989). The present study is the first using saccadic eye movements, to demonstrate tolerance to the psychomotor effects of an antihistaminic drug. The EEG results of our study regarding buspirone and chlordiazepoxide are similar to the findings of Bond et al (1983), whilst hydroxyzine displayed central effects characteristic of classical antihistamines (Pechadre el al, 1988).
Discussion References
The minimal impairment of psychomotor function and memory after the multi or single dose administration of buspirone are in agreement with previous studies (Moskowitz and Smiley, 1982; Seppda
Baloh RW, Sills AW, Kumley WE, Honrubia V (1975) Quantitative measurement of saccade amplitude, duration and velocity. Neurology 25, 1065-1070
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