The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance

Reboxetine is a novel antidepressant that has been shown to be effective in the treatment of major depressive disorders. The present experiment was designed to assess whether it affects the cognitive and psychomotor skills necessary for optimum function in everyday life. Ten healthy male volunteers received reboxetine 0.5  mg, 1  mg or 4  mg, amitriptyline 25  mg, or matched placebo with and without alcohol (0.6  mg  kg⁻¹) in a double-blind 10-way crossover study. A psychometric test battery was administered at baseline and at 1, 2.25, 3.5, 6 and 9  h post-dose. The results showed that reboxetine had little or no effect on performance at any dose, compared with placebo. Amitriptyline, however, with and without alcohol, lowered critical flicker fusion threshold compared with placebo and/or reboxetine at all test points (e.g. at 3.5  h: 28.51   vs 30.33  Hz; P <0.05); increased reaction time (e.g. 619   vs 540  ms; P <0.05); increased tracking error (e.g. 16.34 vs 8.54 RMS units; P <0.05); and slowed short-term memory scanning (e.g. 742 vs 590  ms; P <0.05). It is concluded that reboxetine at doses of 4  mg and below is free from disruptive effects on cognitive function and psychomotor performance, and that it does not act synergistically with alcohol, in contrast to amitriptyline.     

The effects of brofaromine alone and in conjunction with alcohol on cognitive function,psychomotor performance,mood and sleep in healthy volunteers

Brofaromine is a novel antidepressant that functions by the inhibition of the A form of monoamine oxidase (MAO). This inhibition is reversible, making brofaromine both pharmacologically and structurally different from most of the currently available MAO inhibitors. The drug has been shown to be clinically effective and to have significantly fewer problems than other MAO inhibitors in terms of hepatic toxicity and interaction with tyramine and coadministered tricyclic antidepressants. The present experiment was designed to assess the behavioural toxicity of the drug. Seventeen normal volunteers received brofaromine 50 mg or 75 mg, amitriptyline 50 mg or placebo with and without alcohol in a double blind eight-way crossover study. A psychometric test battery was administered at 3, 6 and 12 h post-dose. The results show that brofaromine had little or no effect on the measures employed, compared to placebo. The amitriptyline verum (with and without alcohol) however lowered critical flicker fusion threshold compared to placebo at all test points, increased reaction time, increased tracking error, and slowed memory scanning. It is concluded that, in volunteers, acute doses of brofaromine are free from disruptive effects on cognitive function and psychomotor performance, in contrast to both amitriptyline and alcohol which showed debilitating effects on most of the measures employed.     

A double-blind, placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function

AIMS: To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Twenty-four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six-way crossover, double-blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods. RESULTS: Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0. 002) increase in the percentage of 'sleep-like' activity from actigraph records during the daytime. CONCLUSIONS: Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.     

The effects of acute and repeated doses of zolpidem on subjective sleep,psychomotor performance and cognitive function in elderly volunteers

Summary We gave 24 healthy elderly volunteers with a perceived sleep onset of at least 30 minutes zolpidem 5 mg, zolpidem 10 mg, or placebo for 7 days in a double-blind, three-way, crossover study.The morning after nocturnal dosing, psychomotor performance and cognitive ability were measured using tests which are sensitive to the residual effects of hypnotics and to the effects of drugs on various indicators of sleep quality. The tests were: Choice Reaction Time; Tracking; Critical Flicker Fusion Threshold; Memory Scanning; Word Recognition; the Leeds Sleep Evaluation Questionnaire and Line Analogue Rating Scales.Zolpidem produced a subjective improvement in sleep but did not impair performance the following day. Furthermore, during repeated administration, there was no tolerance to the effects of sleep latency and quality of sleep, nor adverse effects on task performance.     

The effects of repeated doses of clomipramine and alprazolam on physiological,psychomotor and cognitive functions in normal subjects

Summary The effects of a 10 day administration of clomipramine (25–50 mg t.i.d.), alprazolam (0.25–0.75 mg t.i.d.) and placebo were assessed in normal volunteers in a double-blind cross-over study. A battery of physiological, psychomotor and cognitive tests was administered both before and 3 h after drug on days 1, 5 and 10.The effects of alprazolam on EEG and evoked potentials were characteristic of benzodiazepines; clomipramine had little effect. In contrast, reaction speed was markedly slowed by clomipramine but little affected by alprazolam.Neither drug produced any accumulation of effect on a verbal recall task but neither did tolerance develop to the acute impairments produced by active treatments. Alprazolam produced an increase in levels of forgetting, especially on day 5. Subjective ratings for mood and bodily symptoms were adversely affected by clomipramine but little altered by alprazolam.It is suggested that some of the differences between drug treatments may be due to differences in the speed of onset of tolerance.     

Evaluation of the efficacy of metaclazepam and its effects on sleep,psychomotor performance and cognitive function in anxious patients

The effects of single and multiple doses of metaclazepam were investigated in 60 anxious patients. A 15 mg nocturnal dose of metaclazepam was compared to two daily doses (5 mg in the morning and 10 mg at bedtime) in terms of efficacy and effects on various aspects of sleep, cognitive function and psychomotor performance. Anxiolytic efficacy was assessed by means of questionnaires, including the Self Rating Anxiety Scale of Zung, State Trait Anxiety Inventory of Spielberger, and a modified version of the Hamilton Anxiety Rating Scale. Hypnotic activity was evaluated using a clinical rating of insomnia questionnaire. The psychometric battery consisted of tests of Critical Flicker Fusion, Choice Reaction Time and Digit Span. In terms of clinical efficacy, metaclazepam administered in either dosage regimen demonstrated a good anxiolytic activity profile. Both dosage regimens were effective in improving the quality and quantity of sleep, however the number of intermittent awakenings were significantly higher with the daily divided dose. In addition, the nocturnal administration of metaclazepam did not appear to be associated with any undesirable side effects or decrements in psychomotor performance the following morning. In conclusion, it appears that a 15 mg bedtime dose of metaclazepam is efficacious in relieving anxiety without impairing psychomotor performance the following morning. © 1998 John Wiley & Sons, Ltd.     

Nomifensine,clobazam and HOE 8476: Effects on aspects of psychomotor performance and cognitive ability

Summary The effects of a combination of nomifensine and clobazam (HOE 8476) were compared, on a variety of psychometric measures, with those of its separate monosubstances in a placebo controlled double-blind study with twelve normal volunteers. Assessments comprised a range of psychomotor performance tests, measures of cognitive processing ability and visual analogue rating scales — previously shown to be sensitive to the effects of psychotropic drugs. Subjects acted as their own control and were tested in the morning and afternoon following subchronic pre-dosing with each of the four treatments. When compared with placebo, nomifensine showed no significant change on any of the performance measures. HOE 8476 produced no significant changes in performance but significantly reduced self-rated anxiety. Clobazam significantly improved subjective ratings of the ease of getting to sleep and impaired choice reaction time and concept identification performance in the morning. No significant changes in the test measures were found in the afternoon following any treatment. The findings were in broad agreement with those of previous studies and demonstrated that clobazam and nomifensine, both alone and in combination, tended not to impair performance on a wide range of psychological test assessments.     

The cognitive and psychomotor effects of opioid analgesics

Twelve subjects (8 male) took part in a randomised double blind four way crossover design study comparing four treatments: (i) morphine sulphate 10 mg, (ii) morphine sulphate 15 mg, (iii) lorazepam 1 mg (positive control) and (iv) placebo. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment. Lorazepam produced a marked impairment in the tests of attention and memory. CFFT was reduced from 1–4 h but this only reached significance at 4 hours. The subjective measures suggested impaired alertness but this did not reach significance. The effects of morphine were less dramatic; both doses of morphine produced significant impairment at 1 hour on tests of secondary memory retrieval (delayed word recall and picture recognition sensitivity). CFFT was reduced for the whole observation period (6 h) achieving statistical significance at 4 hours. Morphine 15 mg produced a significant improvement in accuracy on the choice reaction time test at the 2, 4 and 6 h assessments. These results show minimal impairment of cognitive and psychomotor function after single oral doses of morphine and with possible improvement in one test. Further studies are required to examine the effect of repeated doses.     

The effects of alcohol on the cognitive function of males and females and on skills relating to car driving

Nine male and nine female subjects received one of four doses of alcohol (0-25, 0-5, 0-75 or 1 g per kg of bodyweight for male subjects: females received 92% of these values) or placebo. Similar blood alcohol concentrations (BAC) for males and females were reached. Subjects were then tested on two batteries of psychological tests related to skills involved in driving. These included psychomotor, cognitive and subjective assessment tasks. The results showed a linear increase in the disruption of performance with dose for many of the tests, particularly those involving psychomotor function. In addition it was demonstrated that on certain tasks males were affected more by alcohol than females. It is concluded that moderate doses of alcohol (resulting in BACs of 0-05 to 0-08 g/100 ml) can produce significant deficits in perceptual and motor skills related to driving a vehicle.     

The effects of acute and repeated doses of moclobemide on psychomotor performance and cognitive function in healthy elderly volunteers

The effects of moclobemide, a new selective and reversible MAO-A inhibitor, on cognitive function and psychomotor performance were measured in 12 healthy elderly male volunteers (with a mean age of 72.5 years). Subjects received moclobemide 200 mg, amitriptyline (positive internal control) 25 mg or placebo twice daily and were assessed on a battery of psychometric tests on the mornings following the first (acute) day and seventh (sub-chronic) day. The tests were: Choice Reaction Time; Tracking; Critical Flicker Fusion Threshold; Memory Scanning; Continuous Attention Task; the Leeds Sleep Evaluation Questionnaire and a Visual Line Analogue Rating Scale. The results show that amitriptyline produced impairment of cognitive and psychomotor functions. Moclobemide, however, did not disrupt sleep or cause daytime sedation, and remained neutral in the assessment of behavioural toxicity.     

The effects of acute doses of dothiepin (25, 50, and 75 mg) versus placebo on psychomotor performance and cognitive function

Sixteen healthy volunteers received dothiepin 25 mg, 50 mg, 75 mg and placebo in a double-blind crossover study. Each subject received the four treatments once, with a 6-day washout period between test days. On each occasion psychomotor performance and cognitive function were measured 30 min before dosing and 1, 2, 4, 6 and 8 h after drug administration. The test battery comprised: Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking and Short Term Memory. Subjective ratings of sedation were measured using Line Analogue Rating Scales. Dothiepin at the subtherapeutic dose of 75 mg was shown to produce statistically significant impairment (p<0·05) on several of the variables investigated. These included CFF at the 2- and 4-h test points, TRT at the 2-h test point and LARS at the 2- and 4-h test points. Lower doses also produced impairment of cognitive function and psychomotor performance as measured by the present test battery. © 1997 John Wiley & Sons, Ltd.     

The psychomotor and cognitive effects of a new antihistamine,mizolastine, compared to terfenadine,triprolidine and placebo in healthy volunteers

Eighteen healthy volunteers received mizolastine 5 mg, 15 mg or 45 mg, terfenadine 60 mg, triprolidine 10 mg or placebo in a 6-way crossover, double blind study. Following each dose, subjects performed a series of tests of cognitive function and psychomotor performance at 1, 3, 5, 8 and 24 hours post-dose. The test battery included critical flicker fusion, choice reaction time, tracking, Stroop and Sternberg memory tests and assessment of subjective sedation.Sedative effects and a concomitant reduction in psychomotor and cognitive function were observed following triprolidine, terfenadine and the highest dose of mizolastine, 45 mg, e.g. triprolidine reduced CFF threshold by 1.5 Hz and increased reaction time by 50 ms, impairments comparable to those caused by blood alcohol concentrations of 50 mg%, the legal limit in many countries. Mizolastine 5 mg did not differ significantly from placebo and at 15 mg differed only at one test point at one time.It may be concluded that mizolastine (5 mg and 15 mg) is free from disruptive effects on cognitive function and psychomotor performance, in contrast to terfenadine 60 mg, triprolidine 10 mg and mizolastine 45 mg.     

The effects of cimetidine and ranitidine on psychomotor function in healthy volunteers

Summary

Single oral doses of cimetidine (400?mg), ranitidine (150?mg), promethazine (25?mg) or placebo were administered to 8 healthy volunteers in a double-blind study. Cimetidine and ranitidine did not cause any significant change in critical flicker frequency (c.f.f.), reaction time, pursuit rotor or the visual analogue scale scores for sedation. Promethazine significantly lowered c.f.f., prolonged reaction time and increased sedation when compared with placebo. It is concluded that in this study cimetidine and ranitidine had little, if any, effect on psychomotor function.     

The impact of sertraline,desipramine, and placebo on psychomotor functioning in depression

Impairment of psychomotor performance is a common adverse effect of many antidepressants, particularly tricyclics. Desipramine is thought to be an exception, with possible performance enhancing effects on psychomotor function. This multicentre study examined the relative effects on psychomotor function of sertraline versus desipramine versus placebo in mild to moderate depression. Fifty-eight patients who satisfied DSM-III-R criteria for major depression and had a minimum HAM-D score of 15 (17 items) completed eight weeks of treatment. They underwent a standardized assessment which included depression and anxiety rating scales (HAM-D, HAM-A, MADRS) and a battery of psychomotor performance tests (The Simple and Choice Reaction Time, The Digit Symbol Substitution and The Trail Making Test), before, during, and after eight weeks of treatment with sertraline, desipramine, or placebo. At baseline, there was a trend for both the sertraline and placebo groups to exhibit better psychomotor performance than desipramine. No significant differences were found between groups after treatment nor between groups for the change from baseline to week 8. However, at week 3, the sertraline group performed significantly better in the trail making test than the placebo patients (p<0.05). Within each treatment group, there was a trend towards improvement in performance for all four parameters from baseline to the end of the study, with these improvements being most obvious in the desipramine group. Sertraline, however, was found to be associated with significantly fewer other adverse effects than the desipramine group, i.e. sweating, dry mouth, anorexia. These results suggest that desipramine and sertraline do not adversely affect psychomotor performance and may even enhance it in mild to moderately depressed patients.     

The effects of single doses of lorazepam on event-related potentials and cognitive function

Twelve healthy participants received double-blind single doses of lorazepam 1 mg, 2 mg and placebo at weekly intervals using a Latin square design. Prior to administration and 2 h afterwards, a battery of tests was used to assess psychomotor and cognitive function and to elicit event-related potentials (ERPs), concentrating on the P300 wave. This wave, elicited reliably using two paradigms (Rugg– Nagy and ‘oddball’), was prolonged in latency and reduced in amplitude in a dose-related manner by lorazepam. Cognitive and psychomotor performance was impaired by the benzodiazepine. Subjective sedation was induced by the drug. However, no relationships were found between drug effects and the ERPs and on psychological functioning. It was concluded that the lack of correlation could reflect relatively low participant numbers or carry-over effects of the medication.     

A double blind comparison of the effects of fluoxetine and amitriptyline on cognitive function in elderly depressed patients

Sixty-six elderly depressed patients received fluoxetine 20 mg (FLU) or amitriptyline 75 mg (AMI) for 42 days in a double blind parallel group study. Each week, subjects completed a test battery which is sensitive to the residual effects of psychoactive drugs. The results show that FLU and AMI were equally effective in relieving depression. However, the psychometric test battery showed that, compared to FLU, AMI, as expected, produced impairments in cognitive function and psychomotor performance. The relative impairment of cognitive and psychomotor skills following the tricyclic AMI and the lack of such activity after administration of the selective serotonin reuptake inhibition, FLU are important considerations when prescribing antidepressants, especially when the safety and well being of ambulant patients is essential.     

Evaluation of the cognitive, psychomotor and pharmacokinetic profiles of rupatadine, hydroxyzine and cetirizine, in combination with alcohol, in healthy volunteers

INTRODUCTION: The Central Nervous System (CNS) impairment induced by moderate alcohol (ALC) ingestion may be enhanced if other drugs are taken simultaneously. Rupatadine (RUP) is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release in inflammatory reactions. OBJECTIVE: The main aim of the study was to assess the effects of ALC 0.8 g/Kg on RUP (10 mg and 20 mg) CNS effects. An evaluation of alcohol and RUP pharmacokinetics was also attained. METHODS: Eighteen healthy young volunteers of both sexes participated in a phase I, randomised, crossover, double-blind, placebo-controlled study. At 2-week intervals they received six treatments: (a) placebo (PLA), (b) ALC alone and ALC in combination with: (c) hydroxyzine 25 mg (HYD), (d) cetirizine 10 mg (CET), (e) RUP 10 mg or (f) RUP 20 mg. At baseline and several times thereafter, seven psychomotor performance tests (finger tapping, fine motoric skills, nystagmus, temporal estimation, critical-flicker-fusion frequency, 'd2' cancellation, simple reaction) and eleven subjective self-reports (drunkenness, sleepiness, alertness, clumsiness, anger, inattentiveness, efficiency, happiness, hostility, interest and extraversion) were carried out. Two-way (treatment, time) ANOVAs for repeated measures to each variable together with a multivariate non-parametric approach were applied. Plasma concentrations of alcohol, and of RUP and its metabolites, were quantified by validated immunofluorescence and LC/MS/MS methods, respectively. Plasma-time curves for all compounds were analysed by means of model-independent methods. RESULTS: The combination of alcohol with HYD, CET and RUP 20 mg produced more cognitive and psychomotor impairment as compared to alcohol alone, being the combination of alcohol and HYD the one which induced the greatest deterioration. The combination of alcohol and RUP 10 mg could not be differentiated from ALC alone. Subjective self-reports reflect effects on metacognition after the combination of alcohol with HYD and CET i.e. the increased objective impairment observed was not subjectively perceived by the subjects. No significant differences were obtained when comparing alcohol plasma concentrations assessed after the treatments evaluated. RUP showed a lineal kinetic relationship after 10 and 20 mg with a higher exposition to both metabolites assayed. CONCLUSIONS: Present results showed that single oral doses of rupatadine 10 mg in combination with alcohol do not produce more cognitive and psychomotor impairment than alcohol alone. Higher doses of rupatadine, in combination with alcohol, may induce cognitive and psychomotor deterioration as hydroxyzine and cetirizine at therapeutic doses.     

Acute and subacute effects on psychomotor performance of femoxetine alone and with alcohol

Summary The effects on human psychomotor performance of femoxetine (FEMO), a 5-hydroxytryptamine-selective antidepressant, alone and in combination with alcohol (EtOH) were compared with those of amitriptyline (AMI) and placebo in a controlled double-blind crossover trial in 11 student volunteers. Objective measurements (body sway, choice reaction, flicker fusion, tracking, nystagmus, digit symbol substitution, backwards recall) and subjective self-assessment (visual analogue scales, reporting of side-effects) were done after single doses of FEMO, AMI and placebo, and subacute administration of FEMO and placebo. Single doses of 200 mg FEMO did not impair psychomotor performance, but 50 mg AMI did so in several respects. AMI but not FEMO increased the objective and subjective effects of EtOH. After FEMO 600 mg/d for 10 days almost no objective difference from placebo was noted, although mild sedation at home was reported as a side-effect. FEMO either did not increase or slightly decreased the effect of EtOH on reactive and co-ordination skills. The plasma concentrations of FEMO varied widely from 0 to 156 ng/ml, as in previous clinical trials but reduced a blood 5-hydroxytryptamine concentration in each subject indicating an effect of FEMO on serotoninergic mechanisms.     

The effects of alcohol alone or in combination with other drugs on information processing,task performance and subjective responses

This paper reviews the effects of alcohol on human psychomotor performance and cognitive function. It concentrates particularly on effects on reaction time and on skills related to car driving. The effects of alcohol on performance are very variable at low doses (under 1 g per kg body weight). The variability is due to the different measures and methods employed by the researchers and to the large interindividual and interoccasional differences in the effects of alcohol. That is, alcohol affects different people in different ways and it affects the same person differently on separate occasions. Greater performance deficits are observed as the dose increases and as the tasks become more complex. Although results vary, both nicotine and caffeine appear to antagonize the detrimental effects of alcohol on performance. Many other drugs interact with alcohol, the most important of which are sedative agents that can combine synergistically with alcohol to produce profound psychomotor and cognitive impairment. © 1998 John Wiley & Sons, Ltd.