The effects of repeated nocturnal doses of clobazam, dipotassium chlorazepate and placebo on subjective ratings of sleep and early morning behaviour and objective measures of arousal, psychomotor performance and anxiety.

1. Repeated nocturnal doses of 30 mg clobazam and dipotassium chlorazepate 15 mg showed no significant effects compared to matching placebo on tests of psychomotor performance and serial subtraction of numbers given in the morning and afternoon of the day following treatment. 2. Both active preparations improved the perceived quality of sleep compared to placebo. 3. A reduction in rated anxiety scores was found with clobazam on the afternoon of the day following treatment together with an elevation of critical flicker fusion thresholds. 4. Dipotassium chlorazepate was found to impair performance of a low level conceptual task but not to influence performance at a more difficult level.     

The effect of a sub-chronic administration of three dose levels of a 1,5-benzodiazepine derivative, clobazam, on subjective assessments of sleep and aspects of psychomotor performance the morning following night time medication.

The effect of repeated doses of a 1,5-benzodiazepine derivative, clobazam, at doses of 20, 30, and 40 mg taken at night was assessed the morning following medication on a variety of subjective and objective measures of sleep and psychomotor performance. None of the three dose levels of the drug produced any significant changes in critical flicher fusion thresholds or in complex reaction time tasks. Conceptual learning ability was not impaired by any of the doses of clobazam administered. Clobazam was rated on a self-scoring analogue rating scale as an effective sleep inducer, which also improved the perceived quality of sleep. There was also a reduction in the perceived integrity of early morning behaviour commensurate with the reported ease of getting to sleep.     

Clobazam, a 1,5-benzodiazepine, and car-driving ability.

1 The effects of clobazam, a new anxiolytic agent (a 1,5-benzodiazepine) on car-driving ability and other tests of psychomotor performance were investigated in a double-blind, cross-over study v. placebo in normal volunteers. 2 Clobazam (20 mg) or placebo was given nightly for six nights to ten volunteers and subjective ratings of sleep and subjective and objective assessments of behaviour and psychomotor performance on the morning following drug ingestion were recorded. 3 Clobazam significantly improved the subjective ratings of sleep induction and quality of induced sleep. 4 Clobazam did not significantly impair performance in a variety of psychomotor tests and car-driving ability. 5 The validity of the measures used and the relevance of the findings to real life car-driving situations are discussed.     

The effects of clobazam and lorazepam on aspects of psychomotor performance and car handling ability.

1 Laboratory tests of psychomotor performance and 'on road' assessments of car handling ability were made following repeated doses of clobazam 10 mg three times daily, lorazepam 1 mg three times daily and matching placebo 1 capsule three times daily. 2 Both active compounds produced on impairment, compared to placebo, in some mental arithmetic and letter cancellation tasks, but these effects were neither widespread nor consistent. 3 Lorazepam produced a significant impairment of car driving tasks and analogue rating scales of subjective alertness. The pronounced sedative activity of the drug was also shown in the verbal reports of side effects and in indices of early morning sedation derived from the Leeds Sleep Evaluation Questionnaire. 4 Clobazam did not produce either the objective, or the subjective impairment of performance and alertness found with lorazepam. 5 The results taken as a whole show important differences between the 1,4 benzodiazepine, lorazepam, and the 1,5 benzodiazepine, clobazam, in their effects on the integrity of psychomotor performance related to car driving ability.     

Pharmacodynamic effects of buspirone and clobazam.

1. The pharmacodynamic effects of buspirone and clobazam were compared in two volunteer studies. Acute doses of buspirone 5 mg, 10 mg and clobazam 10 mg were contrasted with placebo and a verum (lorazepam 1 mg), in a repeated measures design with 10 subjects assessed on a battery of psychometric tests at 1.5, 3.5, and 5.5 h post dose. For the combined results clobazam and the lower dose of buspirone (5 mg) were significantly contrasted with lorazepam on measures of subjective sedation, memory and choice reaction time (CRT). The higher dose of buspirone was not statistically different from lorazepam for all measures except memory; whilst contrasting significantly with placebo and clobazam on movement and total reaction time components respectively. Though failing to achieve significance, a similar trend was seen for critical flicker fusion (CFF) with buspirone 10 mg and lorazepam producing the lowest scores indicative of increased sedation. 2. Repeated doses of buspirone 5 mg twice daily, clobazam 10 mg twice daily, or placebo twice daily for 8 consecutive days were compared on the same battery of psychometric tests in a repeated measures design. Nine subjects were assessed on days 1, 3, and 8 of the study. Overall, memory performance significantly decreased with buspirone 5 mg in contrast to both clobazam and placebo whilst the opposite trend was seen with CFF. Clobazam significantly improved TRT in contrast to both placebo and buspirone. 3. These results indicate improved reaction time and memory performance with repeated dosing of clobazam in contrast to buspirone. Impairment following acute administration of buspirone appears limited to the higher (10 mg) dose.     

A comparative study of on-the-road and simulated driving performance after nocturnal treatment with lormetazepam 1 mg and oxazepam 50 mg

The main purpose of this study was to compare the sensitivity of a driving simulator test model (TS2) with a standard on-the-road driving test, after one night treatment with lormetazepam 1 mg, oxazepam 50 mg (as a verum) and placebo. The secondary purpose was to measure the effects of the intended drugs and placebo in the same subject sample, after two treatment nights in the morning and in the afternoon, on on-the-road driving performance. Eighteen healthy male volunteers received the three treatments (2 consecutive nights each) according to a double-blind, three-way crossover design. Time of administration was set at 22.00 hours each night. An on-the-road driving test and a simulator driving test were conducted in the morning following the first night. After the second treatment night, on-the-road driving tests were performed in the morning and in the afternoon. The on-the-road driving test consisted of operating an instrumental automobile over a 100 km highway circuit at a constant speed (90 km/h) and constant steady lateral position between the right lane boundaries. Primary performance measure was the SD of lateral position (SDLP). The simulator test consisted of repeatedly performing ‘curve-following’ manoeuvres, which was the main tracking control task, while simultaneously reacting to secondary visual signs. Test parameters were the number of correctly executed manoeuvres (TC) and reaction time (RT). Oxazepam 50 mg seriously impaired, and lormetazepam 1 mg slightly impaired, on-the-road driving performance in the morning, both after the first and second treatment night. The drugs produced no significant effects in the afternoon test following the second night. In contrast with these results, neither oxazepam 50 mg nor lormetazepam 1 mg affected simulator tracking control after one night. No deterioration was found for reaction time. Correlational and multiple regression analyses were applied to determine relationships between SDLP, TC and RT. The major conclusion of this study was that the TS2 driving simulator test does not predict residual drug effects in the on-the-road driving test, and seems to be a less sensitive measure of sedative drug-induced impairment in contrast to the on-the-road driving test.     

Repeated dose effects of lormetazepam and flurazepam upon driving performance

Summary The residual effects of lormetazepam 1 mg and 2 mg in soft gelatine capsules on driving performance were assessed and compared to those of flurazepam 30 mg, which is also a powerful hypnotic, but possesses a far less favourable pharmacokinetic profile with a longacting sedative metabolite. Driving performance was tested 10 to 11 h and 16 to 17 h post administration, after 2 days on placebo (baseline), and 2,4 and 7 days of drug treatment (active), and after 1 and 3 days following the resumption of placebo (washout). The driving test consisted of operating an instrumented motor-vehicle over a 72 km highway circuit in light traffic. Flurazepam 30 mg significantly impaired the ability to control the lateral position of the vehicle compared to placebo baseline measurements. The degree of impairment was substantial in the female subjects and was greater in the morning than in the afternoon. Lormetazepam 1 mg showed no residual effect on driving performance. Lormetazepam 2 mg impaired driving performance to some extent on the following morning, 10 to 11 h post administration, but no residual effect was found in the afternoon. All drugs improved sleep quality and prolonged sleep duration to more or less the same extent.     

Cognitive sequelae of 1,4- and 1,5-benzodiazepines

Two studies were carried out comparing the effects of clobazam (a 1,5-benzodiazepine), and clonazepam (a 1,4-benzodiazepine), with placebo, in a double-blind crossover design. Ten and nine healthy male volunteers, respectively, participated in each study. Performance on a series of automated psychological tests was assessed on four occassions: prior to any treatment; at the end of the first 2-week treatment period; following a 2-week washout phase, and again at the end of a second 2-week treatment period. Blood samples were collected at the last three occasions for analysis of drug levels. Minimal impairment in cognitive functioning was found with clobazam, only two of the more complex tasks being affected. In contrast, the pattern of findings with clonazepam suggests that it may have adverse affects on a broader range of functions. A relationship was found between performance on three measures and serum level of clobazam, such that response latency decreased with increasing serum level. In contrast, for clonazepam, a significant correlation was found on one task, in the direction of increased response latency with increasing drug level. These findings are discussed in the light of clinical literature about the use and efficacy of these two benzodiazepines, as antiepileptic agents.     

Loprazolam (HR158) and flurazepam with ethanol compared on tests of psychomotor ability

Summary 1. Twelve healthy female volunteers were given either loprazolam 1 mg, flurazepam 15 mg or placebo in conjunction with ethanol for 3 consecutive nights in a double-blind crossover study with each subject acting as her own control. 2. Neither of the test compounds, in conjuction with ethanol, showed any statistically significant impairment of performance on tests of psychomotor ability the morning following 3 nights administration. 3. Subjective evaluations of the ease of getting to sleep and the perceived quality of sleep were improved by both drugs in conjunction with ethanol. However, flurazepam with ethanol produced a greater impairment of subjects' ratings of early morning behaviour than either loprazolam or placebo taken with ethanol. 4. Subjective reports of sedation were more prevalent the morning following flurazepam and ethanol than those after loprazolam and ethanol and placebo and ethanol.     

Clobazam and diazepam: The differential effects on psychomotor performance and subjective feelings in normal volunteers with high neuroticism level

The purpose of this study was to investigate the possible differences between diazepam and clobazam with regard to their effects on psychomotor performance and subjective feeling in normal volunteers with high neuroticism levels. The study was designed as a double-blind, crossover, single-dose comparison of clobazam, diazepam, and placebo. Using the Maudsley Personality Inventory (MPI), 12 healthy male volunteers exhibiting high neuroticism scores were selected. Clobazam 10 mg, diazepam 5 mg, and placebo were administered orally. Measurements of psychomotor performance and subjective ratings of mood states were performed before and 1.5 and 6 hr after administration. Prior to the experiment the subjects were trained with the performance tests to minimize interference of learning effects with drug effects. Between the three treatments there were 1-wk intervals. Both clobazam and diazepam significantly lowered choice-reaction task performance as compared to placebo. Only clobazam lowered mirror-drawing task performance significantly differently from placebo. Significant changes in subjectively rated mood states were also seen after clobazam only. These mood changes appeared to indicate some disinhibitory or stimulant effects. The demonstrated differences between the effects of both anxiolytics are discussed in the context of experimental design characteristics and the subjects' high level of neuroticism. Some of the observed effects may be due to an interaction of drug effects with neurotic tendencies rather than to generalized drug effects per se.     

The effect of clobazam and lorazepam on the psychomotor performance of anxious patients

1 Psychomotor performance and anxiety were measured in 70 anxious outpatients in a randomized double-blind, placebo-controlled trial comparing the 1,5-benzodiazepine clobazam (10 mg twice a day) to lorazepam (1 mg twice a day). Carefully selected tests were administered pre-treatment and at 2 and 9 days after treatment. Compliance was checked by blood assays.

2 All three treatment groups (clobazam, lorazepam and placebo) showed a significant improvement in anxiety over the course of the trial. There were no significant differences between the groups in terms of anxiety reduction.

3 All three groups improved over the course of the trial in choice reaction time, digit symbol substitution test, Purdue pegboard test (both hands) and in the Inglis paired-associate learning test: there were no significant differences between the groups with regard to these tests. There was no change in critical flicker fusion threshold over the trial period in any of the three groups.

4 The placebo and clobazam groups showed a significant improvement in two of the Purdue pegboard tests (preferred hand and assembly) from pre-treatment to 2 days but no further improvement at 9 days. The lorazepam group, however, showed no improvement in these two tests from pre-treatment to 2 days; a significant improvement only emerged between the 2-day and 9-day assessments. This might reflect an initial, transient sedation in the lorazepam-treated patients.

5 Generally, we failed to demonstrate any consistent impairment in psychomotor performance with either clobazam or lorazepam in our anxious patients. These findings contrast with those obtained after administration of 1,4-benzodiazepines (e.g., lorazepam) to normal volunteers and they suggest that data from the latter cannot necessarily be extrapolated to anxious patients.

     

Effect of midazolam and sleep deprivation on day-time sleep propensity

The combined effect of midazolam (Ro 21-3981, Dormicum) and sleep deprivation on day-time sleep propensity was investigated in young, healthy adults. The oral administration of midazolam (15 mg) or placebo at bedtime was followed either by a sleep period of 7 or 4 h, or by no sleep at all. Sleep propensity was recorded at 2-h intervals throughout the following day by the multiple sleep latency test and self-ratings of tiredness. Performance was assessed in the morning and afternoon by a psychomotor test. Partial and total sleep deprivation caused a marked and significant increase of day-time sleep propensity. However, there was no significant difference between the midazolam and placebo condition after 7 or 4 h of sleep. After total sleep deprivation, sleep propensity was higher after placebo than after midazolam. Neither the treatment nor sleep duration had a significant effect on performance. The results show that a bedtime dose of 15 mg midazolam followed by normal or restricted sleep does not significantly affect day-time alertness.     

A comparison of the effect of imipramine,nomifensine, and placebo on the psychomotor performance of normal males

Imipramine (50 mg), nomifensine (50 mg), or placebo was administered early morning, late morning, and mid-afternoon to normal volunteers. The program of hourly tests included: the Digit Symbol Substitution, Perceptual Reversal, Time Estimation Test, and Simple and Complex Continuous Performances tests both of which required recognition of briefly exposed letters of the alphabet.It was found that relative to placebo or nomifensine, imipramine had a clearly detracting effect on most of the tests. Drowsiness was reported more often in the imipramine group than in the placebo and nomifensine groups combined.     

EEG-Brain mapping,psychometric and psychophysiological studies on central effects of kavain - a kava plant derivative

In a double-blind, placebo-controlled study the encephalotropic and psychotropic effects of kavain-a synthetic kava plant derivative as compared with clobazam were investigated, utilizing EEG brain mapping, psychometric and psychopysiological analyses. 15 normal volunteers received randomized in weekly intervals single oral doses of placebo, 200 mg, 400 mg and 600 mg kavain as well as 30 mg clobazam as reference compound. EEG recordings, psychometric tests, evaluations of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6 and 8. Brain maps of drug induced pharmaco-EEG changes (pharmaco-EEG maps) demonstrated that kavain exerted a significant action on the human brain function as compared with placebo characterized by a dose-dependent increase of delta, theta and alpha 1 activity while alpha 2, beta activity and the centroid of the total activity decreased. These findings are indicative of a sedative effect which was, however, in type quite different from that of the 1·5 benzodiazepine. The latter produced a decrease of delta, theta, alpha 1 and alpha 2 and an increase of beta activity while the total centroid was accelerated. Interestingly, 200 mg kavain induced with a decrease of delta and beta activity and an increase of alpha activity and of total power also vigilance promoting effects. Psychometric investigations demonstrated also clear differences between the two compounds at the behavioural level. Kavain improved the noopsyche as compared with placebo in all 3 doses as there was a significant improvement in intellectual performance (Pauli test), attention, concentration, reaction time and motor speed (rigidity test), while opposite findings were observed after 30 mg clobazam. In regard to thymopsychic variables such as drive, wakefulness, affectivity, mood, well-being, 200 mg kavain produced an improvement as compared with placebo while 600 mg kavain produced sedation as did 30 mg clobazam. Psychophysiological evaluations resulted in only minimal findings. Time efficacy calculations demonstrated after kavain a pharmacodynamic peak in the 1st to the 2nd hour then a drop and a second peak in the 8th hour while clobazam produced maximal central effects in the 1st hour which declined thereafter to show a second peak in the 6th hour. Topographically, most encephalotropic effects were found after kavain in the frontal, after clobazam in the central and parietal areas. Evaluations of pulse, blood pressure and side effect demonstrated good tolerability of both compounds with 30 mg clobazam producing more sedation than kavain.     

A comparison of the pharmacodynamic profiles of nomifensine and amitriptyline in normal subjects.

1 Six healthy male volunteers participated in a double-blind placebo crossover comparison of the pharmacodynamic profiles of single oral doses of 75 mg nomifensine and 50 mg amitriptyline. 2 Nomifensine treatment did not influence salivary flow and did not significantly affect psychomotor performance (critical flicker fusion, pursuit rotor and reaction time): in addition nomifensine had no significant effect on subjective measurements of sedation and concentration. 3 By contrast, amitriptyline treatment significantly reduced salivary flow and was associated with significant sedation and reduced concentration: significant changes in psychomotor performance were also noted. 4 Plasma concentrations of amitriptyline and nomifensine were measured at 2 h. The respective median concentration values were 55.0 ng/ml and 52.0 ng/ml. 5 Ex vivo platelet amine uptake of dopamine (DA) and 5-hydroxytryptamine (5HT) was measured 2 h after each treatment. Both nomifensine and amitriptyline treatment significantly inhibited DA uptake to a similar extent. Amitriptyline treatment additionally inhibited 5-HT uptake.     

Clobazam versus diazepam--a double-blind study in anxiety neurosis.

Clobazam, a new antianxiety compound, was compared in a double-blind study with diazepam in 40 neurotic outpatients. Twenty-three patients completed the trial under clobazam conditions while 17 patients completed the trial under diazepam conditions. The trial was conducted for a period of four weeks of active drug administration followed by a one-week period of placebo administration. Clobazam was administered in three divided doses of 30 to 40 mg/day, while diazepam was administered in three divided doses of 15 to 20 mg/day, following a fixed dosage schedule. No significant differences were noted between the two treatment conditions during the drug trial period. The patients on clobazam maintained greater improvement during the placebo trial period for the variables "somatic anxiety" and "nights of sleep disturbance." Simultaneous motor coordination tests (hand steadiness test) showed greater improvement on clobazam throughout the trial period in patients with an initial error score greater than 50 points. This difference was significant during the second week of the trial.     

The effects of midazolam in conjunction with alcohol on sleep, psychomotor performance and car driving ability

The acute and early morning effects of midazolam 15mg and alcohol 0.5g/kg on subjective measures of CNS activity, psychomotor performance and car driving ability were investigated in eight healthy female volunteers. One hour following treatment with midazolam and midazolam + alcohol, critical flicker fusion threshold (CFFT) was significantly depressed and subjects perceived themselves as feeling more sedated when compared to treatment with placebo or alcohol alone. Perceived ease of getting to sleep (GTS) was also improved by midazolam and the midazolam + alcohol combination. Stimulus processing time was significantly increased at one hour after treatment by midazolam taken in conjunction with alcohol, thus resulting in an overall increase in total reaction time. On the morning following administration, both "on the road" assessments of car driving ability and laboratory tests of psychomotor performance were unaffected by any of the treatment conditions. Midazolam 15mg was found to be an effective sleep inducer with no evidence of residual or "hangover" effects, although the drug's hypnotic activity may be augmented by social doses of alcohol.     

Comparative efficacy of zolpidem and temazepam in transient insomnia

This study compared hypnotic effects of zolpidem 10 mg, temazepam 15 mg and placebo in healthy adults. Two factors expected to promote insomnia, the 'first night effect' and a 2-hour phase advance, were combined in a single night laboratory-based double-blinded protocol. This was a multi-center study, with data collected in 13 sleep laboratories. Subjects with normal sleep histories and without prior sleep laboratory experience were randomly assigned to treatment groups. Medications were administered 15 min before lights out, with polysomnographic monitoring for 7.5 h. Subjective questionnaires and performance tests, digit symbol substitution test (DSST) and symbol copying test (SCT), were administered at study entry and after arising. 630 subjects completed the study and provided data analyzed using repeated measures ANOVAs. Neither agent significantly reduced objective sleep latency relative to placebo. Zolpidem reduced awakenings and wake after sleep onset (WASO); temazepam did not. Both agents improved sleep efficiency and most subjective sleep measures relative to placebo, with zolpidem superior for five of six subjective outcome measures compared to temazepam. SCT, morning sleepiness and morning concentration were not altered by any treatment. Zolpidem significantly reduced morning DSST performance; temazepam did not. Zolpidem 10 mg provided greater subjective hypnotic efficacy than temazepam 15 mg in this model of transient insomnia, with reduced polysomnographic awakenings and WASO. Impairment of DSST was seen with zolpidem but not temazepam. Copyright 2001 John Wiley & Sons, Ltd.     

An investigation of the effects of lofepramine, nomifensine, amitriptyline and placebo on aspects of memory and psychomotor performance related to car driving

Ten healthy, female volunteers took part in a double-blind, placebo-controlled study to investigate the effects of lofepramine 70 mg, lofepramine 140 mg, nomifensine 100 mg, amitriptyline 50 mg and placebo on psychomotor performance related to driving. One subject failed to complete the study for reasons unrelated to the medications. Each subject received each of the treatments in random order at weekly intervals and was then assessed for psychomotor performance, sedation and quality of sleep. Amitriptyline 50 mg served as a positive control producing results consistent with its known sedative properties. In contrast, lofepramine 70 mg and 140 mg and nomifensine 100 mg were generally free from any significant effect on psychomotor performance.     

The effects of triazolam and nitrazepam on sleep quality, morning vigilance and psychomotor performance

1. Repeated doses of triazolam 0.5 mg and mitrazepam 10 mg were given to two groups of consenting volunteers. 2. Measures of choice reaction time, critical flicker fusion threshold, and mental arithmetic ability were made the morning following nocturnal medication with either the active drug or placebo. 3. The subjects' assessment of sleep and early morning behaviour were obtained on 10 cm-line visual analogue scales. 4. Both drugs were rated as effective hypnotics while, at the same time, ratings of the ease of awakening from sleep and the errors produced in a mental arithmetic task were impaired. 5. Objective measures of performance and subjective reports of "hangover" differentiated nitrazepam from triazolam. A significant impairment of early morning performance found with nitrazepam was not found following treatment with triazolam.