Critical Flicker Fusion Threshold Research Articles

The effects of D- and L-fenfluramine (and their interactions with D-amphetamine) on psychomotor function and mood

This study reports the results on psychomotor functioning of D- and L-fenfluramine alone, and in combination with D-amphetamine, in a placebo-controlled trial on 12 normal male volunteers, in order to investigate their CNS activity in humans. The major findings were that D-amphetamine increased alertness, L-fenfluramine increased unhappiness whilst D-fenfluramine decreased hunger and increased the critical flicker fusion threshold. D-Amphetamine in combination with D-fenfluramine increased the critical flicker fusion threshold and in combination with L-fenfluramine the alerting action was diminished. The differing actions of the fenfluramine isomers and their interactions with D-amphetamine suggest that D-fenfluramine is predominantly serotonergic in its activity, whereas L-fenfluramine may be causing dopamine blockade, reducing certain actions of amphetamine possibly mediated by dopamine receptors. The significance of these results in relationship to the psychopharmacology of serotonin, dopamine, and noradrenaline is discussed.

Effects of fluvoxamine and dothiepin on psychomotor abilities in healthy volunteers

We gave 12 healthy male volunteers single doses of 50 mg fluvoxamine, 100 mg fluvoxamine, 75 mg dothiepin, and placebo in a double-blind crossover study. Subjects completed a test battery that was sensitive to the behaviourally toxic effects of psychoactive drugs prior to dosing, and then at 1, 2, 3, 4, and 6 h after dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold, and memory scanning. Subjective feelings were assessed using the line analogue rating scales and the Milford-Epworth sleepiness scale. Daytime activity was recorded by means of wrist actigraphy. The results show that the positive internal control (dothiepin) had a sedative effect in that it impaired performance in the majority of the tests and also reduced daytime activity. Both doses of fluvoxamine remained relatively neutral throughout and did not impair psychomotor performance or cognitive ability in any of the tests. These results indicate that fluvoxamine may be a safe and efficacious antidepressant for outpatients who wish to carry on with the tasks of everyday life without being sedated.

Critical flicker fusion threshold and anticholinergic effects of chronic antidepressant treatment in remitted depressives

The persistence of deficits in cognitive performance in major depressive patients taking maintenance antidepressant medication was assessed by examining groups of patients in clinical remission, stable on one of a range of tricyclics or selective serotonin re-uptake inhibitors (SSRIs) for at least 3 months, compared with controls. Measures of critical flicker fusion (CFF), choice reaction time (CRT), subjective sedation, and anticholinergic side-effect score were made. Tricyclic antidepressants (TCAs) produce a significant deficit in critical flicker fusion threshold compared both to controls and SSRIs. Similar effects were seen with choice reaction times which were significantly affected by age. Sedation scores were significantly higher with TCAs than SSRIs. Anticholinergic side effects were strongly related to CFF, less so to visual analogue sedating scales and not significantly to CRT. The effect measured by CFF is different from sedation, and may be related to the anticholinergic potency of the drug; it may be considered a drug-induced pseudodementia. This effect represents a risk factor for accidents during maintenance therapy and may impair work and leisure performance. The relative risk of weight gain with TCAs compared to SSRIs in women was 5.92 (95% CI 1.79-19.50).

Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers

Potential interactions between the imidazopyridine anxiolytic alpidem and the full benzodiazepine agonist lorazepam were assessed in a randomized, double-blind, four-way cross-over, placebo-controlled study in 16 healthy young male volunteers. Each volunteer received alpidem, 50 mg, or a placebo twice daily for 8 days with a 1- week wash-out interval. The interaction between alpidem, at the steady state, and a single oral dose of lorazepam 2 mg or a placebo was assessed after concomitant administration on days 7 or 9 of each treatment period. Psycho motor performance and cognitive function were evaluated before and 2, 4, 6 and 8 h post-dose, using objective tests [critical flicker fusion threshold (CFF), choice reaction time (CRT), digit-symbol substitution (DSST), body sway and short-term memory (Sternberg memory scanning)] and self-ratings [line analogue rating scales: (LARS)]. Long-term memory (delayed free recall and recognition of pictures) was assessed before the dose and 2 and 4 h post-dose. Pharmacodynamic interactions were evaluated by applying repeated measures ANOVA to a 2 x 2 factorial interaction model. Alpidem, 50 mg twice daily at the steady state, was free of any clinically relevant detrimental effects on skilled performance, information processing or memory. In contrast, a single 2 mg dose of lorazepam induced marked impairment of psychomotor performance and cognitive function (significant reductions in CFF and DSST and increases in CRT and body sway), as well as subjective sedation from 2 to 8 h post-dose, depending on the test used. In addition, lorazepam induced anterograde amnesia, characterized by a decrease in delayed free recall and recognition, and a deficit in short-term memory. Finally, alpidem 50 mg did not potentiate the detrimental effects of lorazepam 2 mg. On the contrary, alpidem significantly antagonized the lorazepam-induced CRT increase and anterograde amnesia, and produced similar trends on most of the other cognitive parameters; thus, the results obtained with the combination of alpidem and lorazepam consistently indicated less impairment than those measured after lorazepam alone. These results are consistent with the suggested partial agonsist properties of alpidem at the benzodiazepine receptor and indicate that such properties can be assessed in humans based on antagonism of the effects of a full agonist.

The behavioural toxicity of the selective serotonin reuptake inhibitors

The serotonin reuptake inhibitors (SSRIs) are generally better tolerated than the traditional tricyclic antidepressants (TCAs) in the treatment of major depression. In particular the SSRIs are relatively free from cognitive and psychomotor effects likely to cause behavioural toxicity. Behavioural toxicity is studied using a battery of psychometric assessments. This paper discusses the effects of the TCAs and SSRIs on two such assessments, choice reaction time (CRT) and critical flicker fusion threshold (CFFT). CRT measures psychomotor speed, and CFFT assesses the information processing capacity of the CNS. The behavioural toxicity associated with the traditional TCAs can lead to an increased accident risk, whereas the SSRIs are not associated with such effects. Clinically relevant differences in the behavioural toxicity of the SSRIs are highlighted.

Lack of interaction between a new antihistamine, mizolastine, and lorazepam on psychomotor performance and memory in healthy volunteers.

1. The possible interaction between a new H1 antihistamine, mizolastine, and lorazepam was assessed in a randomised, double-blind, cross-over, placebo-controlled study involving 16 healthy young male volunteers who received mizolastine 10 mg or placebo once daily for 8 days with a 1 week wash-out interval. The interaction of mizolastine, at steady-state, with a single oral dose of lorazepam or placebo was assessed on days 6 or 8 of each treatment period. 2. Psychomotor performance and cognitive function were evaluated using objective tests (critical flicker fusion threshold, choice reaction time, tapping, arithmetic calculation, body sway) and self-ratings (visual analogue scale, ARCI) before and at 2, 4, 6 and 8 h after dosing. Short-term memory (Sternberg memory scanning immediate free recall of a word list) and long-term memory (delayed free recall and recognition of words and pictures) were assessed before and at 3 h after dosing. Pharmacodynamic interactions were evaluated by repeated measures ANOVA in a 2 x 2 factorial interaction model. 3. Mizolastine, 10 mg once daily, at steady-state, was devoid of sedation and detrimental effect on skilled performance and memory. 4. In contrast, a single 2 mg dose of lorazepam produced marked impairment of psychomotor performance, cognitive functions (significant reduction in flicker fusion threshold, tapping and arithmetic calculation and increase in reaction times and body sway) and subjective sedation from 2 to 8 h after dosing. In addition, lorazepam induced an anterograde amnesia, characterised by a decrease in delayed free recall and recognition, and a deficit in short term memory.(ABSTRACT TRUNCATED AT 250 WORDS)

Indomethacin and cognitive function in healthy elderly volunteers.

1. Cognitive function was studied after single and multiple doses of indomethacin (I) and matched placebo (P) in 20 healthy elderly volunteers using a double-blind crossover design. 2. Arousal, attention, integration, coordination, memory and mood were investigated using a battery of psychomotor tests and the Hospital Anxiety and Depression Scale. Assessments were performed before and after the first and last doses of a 7 day course of medication. 3. Critical flicker fusion threshold fell by a mean of 1.96% on indomethacin compared with a 1.13% rise on placebo 5 h after the first dose (P = 0.029). A beneficial effect on choice reaction time latency (P = 0.012) was seen both after acute and continuing administration of indomethacin. Performance at the most discriminating level (level 3) of the paired word association test was significantly better following 8 days of treatment with indomethacin in the younger (55-65 year-old) age group (P = 0.001). 4. There was no significant difference in performance on the symbol-digit substitution test and the continuous attention task. No change was seen in hospital anxiety and depression scale scores. 5. These results suggest that performance on tests of sensorimotor coordination and short term memory may improve in healthy volunteers following indomethacin administration, whereas tests of attention and psychomotor speed remain unaffected. However, further controlled studies in rheumatic patients are needed to evaluate fully the psychomotor effects of indomethacin and other NSAIDs in clinical practice.

Instrumental assessment of psychomotor functions and the effects of psychotropic drugs.

The basic assumption underlying psychopharmacology is that the effects of psychoactive drugs can be assessed by measuring the changes produced on aspects of human behaviour and cognitive function. This review concentrates on 3 established psychometric tests that have been shown over a long period of time to be not only valid and reliable measures of aspects of behaviour relevant to the daily activities of patients taking such drugs but also appropriate indicators of any countertherapeutic effects or side effects of medication. Choice reaction time (CRT) is a reliable index of sedation directly related to accident risk situations at home, on the road or at work. Critical flicker fusion threshold (CFFT), a direct measure of the capacity for processing cognitive information, is an accurate measure of various aspects of mental illness and drug effects, and the continuous daytime EEG (c-EEG) is a truly objective measure of CNS activity on a continuous 24-h basis. The judicious use of CRT, CFFT, CFFT and c-EEG not only demonstrates the inherent potential of certain molecules to adversely affect the performance of certain daily activities but also helps identify the drugs with profiles of activity or side effects that are likely to be countertherapeutic.

Relevant psychometric tests for antidepressants and anxiolytics.

Psychometric tests can provide a sensitive and objective measure of drug effects which are of relevance to the clinical situation. Two tests, critical flicker fusion threshold and choice reaction time, used alone or as a part of a battery of tests, have been shown to be useful in detecting differences between drugs in their effect on cognitive and psychomotor functions. They provide important information on the activity and safety of drugs as they are used in practice.

A comparison of the psychometric effects of remoxipride with those of haloperidol, thioridazine, and lorazepam in healthy volunteers

AbstractIn this placebo and verum (lorazepam 2 mg) controlled double‐blind crossover study the acute effects of Remoxipride 50 mg and 100 mg; Haloperidol 2·5 mg; and Thioridazine 50 mg were examined in 18 healthy volunteers. CNS function was assessed using a battery of psychometric measures, viz: Critical Flicker Fusion Threshold (CFFT); Choice Reaction Time (CRT); Tracking Accuracy (RMS) and Peripheral Reaction Time (PRT); Sternberg Memory Scanning (SMS); Word Memory (WM) as well as Line Analogue Ratings of subjective sedation (LARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ). Both doses of remoxipride were associated with a reduction of CFFT: 0·9 Hz for 50 mg and 1·3 Hz for 100 mg. The 100 mg dose caused an increase (impairment) in CRT total time of 38 msec. Haloperidol reduced CFFT, while thioridazine and lorazepam impaired performance on the majority of objective measures, as expected for known sedative drugs. Thioridazine led to hypotension in three subjects, and to subjective sedation (LARS), but no treatment affected responses on the LSEQ administered the morning of the day following treatment. These results show that remoxipride has some depressant effects on CNS function, but that these are less prominent than those of sedative neuroleptics such as thioridazine.

Precision of measures of saccadic eye movements and conventional psychomotor function tests

AbstractMeasures of variability are rarely quoted in drug studies of psychomotor function. Five recent studies were therefore analysed to calculate the coefficients of variation for different tests of psychomotor function, both during and between study days. Saccadic eye movement analysis and critical flicker fusion threshold were found to have low coefficients of variation (ranging from 2·7 to 7·5 per cent) while visual analogue rating scales and the digit symbol substitution test were found to have much higher coefficients of variation (ranging from 7·9 to 17·6 per cent). It is suggested that measures of test variability be routinely assessed in psychomotor studies as a check on test methodology.

EFFECTS OF SMALL CONCENTRATIONS OF ISOFLURANE ON SOME PSYCHOMETRIC MEASUREMENTS

We have investigated the effects of 9.5% and 14.1% MAC concentrations of isoflurane on some psychometric measurements. Both concentrations depressed peak saccadic velocity (P < 0.01), choice reaction time (P < 0.05) and visual analogue scores for sedation (P < 0.05), but not the critical flicker fusion threshold. The incidence of errors in saccade tasks increased in a dose-related fashion, which made analysis of peak saccadic velocity less accurate at more than 10% MAC. The percentage error itself was an indicator of the depth of sedation. All the objective measures correlated highly with the estimated brain tension of isoflurane (r2 = 0.86-0.96), but not the visual analogue score for sedation (r2 = 0.51). This suggests that a combination of peak saccadic velocity, percentage error and choice reaction time is a potentially useful batch of tests to measure recovery from anaesthesia.

Concentration-Effect Relationships of Propofol After Total Intravenous Anesthesia

To evaluate the concentration-effect relationships of propofol during recovery after total intravenous anesthesia, 20 female patients undergoing lower abdominal surgery were studied. In 10 patients (Group B) the propofol infusion was supplemented with an epidural block with bupivacaine to evaluate the relation between the blood concentration of propofol and various pharmacodynamic end-points. The remaining 10 patients (Group A) received an alfentanil infusion intravenously instead of the epidural block to assess the dynamic interactions of alfentanil and propofol. Postoperative performances (drowsiness, amnesia, cooperation, and orientation) were evaluated by means of scoring scales. Critical flicker fusion threshold (CFF) also was used to assess the level of postoperative alertness. A propofol blood concentration of 2.5 micrograms/mL was required for satisfactory hypnosis during surgery and at 0.8 +/- 0.4 microgram/mL, the patients were considered fully awake. A concomitant alfentanil infusion reduced the propofol concentration required by 0.2-0.4 microgram/mL for the same degree of effect. Rapid recovery was seen in all patients, but in the group receiving alfentanil infusion there was a shift to the left of the concentration-effect curve in regard to drowsiness and a statistically significant prolongation of recovery by CFF-measurement which suggests a possible dynamic interaction with alfentanil. We conclude that there is a good correlation between the blood concentration of propofol and the pharmacodynamic responses during recovery.

Computerised psychomotor performance testing: a comparative study of the single dose pharmacodynamics of minaprine and amitriptyline in young and elderly subjects

The psychomotor and cardiovascular effects of minaprine 100 mg, a novel antidepressant, were compared with amitriptyline 25 mg, as a positive control, and placebo in a single dose randomised double-blind crossover trial using an automated psychomotor test battery (APT), postural sway (PS), blood pressure (BP) and pulse in nine young and nine elderly healthy subjects. Analysis of variance, taking into account baseline values, showed that continuous attention test (CAT), critical flicker fusion threshold (CFFT), decision making test (DMT) and paired word association (PWA) were significantly impaired with amitriptyline compared with minaprine and placebo. Minaprine did not differ from placebo. Amitriptyline significantly lowered supine systolic blood pressure (BP) and all treatments produced significant decreases in heart rate in young and elderly. No age effect on psychomotor performance was seen. Minaprine compared favourably with amitriptyline using the APT with the doses used. The APT is useful in the evaluation of new drugs on psychomotor performance.

A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study

Subjective and objective measures of daytime sleepiness and psychomotor function were determined in normal control subjects and in epileptic patients on chronic monotherapy with phenobarbital or valproate ( n = 10 in each group). All patients had primary generalized epilepsy with a normal resting EEG and were seizure-free for at least 1 year. After nocturnal polysomnographic recording, each subject was evaluated at 2 h intervals between 10:00 and 16:00 h by using multiple sleep latency tests (MSLT), a visual analogue rating scale for alertness (VARS), an anxiety scale (STAI-X1) and a battery of psychomotor tests. Nocturnal sleep parameters before daytime assessment were comparable in the 3 groups. At MSLT, patients on phenobarbital showed a shorter mean sleep latency (9.0 ± 1.7 min) compared with the valproate group (12.5 ± 1.3 min) and controls (12.9 ± 1.2 min), though within-group variability was considerable. Compared with controls, patients on phenobarbital showed longer motor movement times, impaired attention (cancellation test, CT), reduced processing speed (digit-symbol substitution, DSS) and a trend towards lower critical flicker fusion threshold. Patients on valproate showed some impairment in attention and a trend towards longer motor movement time. In patients, no correlation was found between assessed parameters and serum drug concentrations, which were 19.3 ± 1.7 μg/ml for phenobarbital and 85.7 ± 4.7 μg/ml for valproic acid.

A placebo controlled double‐blind evaluation of the pharmacodynamics of fengabine vs amitriptyline following single and multiple doses in elderly volunteers.

1. The effects of fengabine were compared with those of amitriptyline in healthy elderly volunteers. Doses were administered double-blind and assessments were made before and after ingestion. 2. Psychomotor performance and cognitive ability were measured using tests of choice reaction time, tracking, critical flicker fusion threshold, memory scanning and word recognition. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic data suggest that fengabine may induce its own metabolism following repeated dosing. 4. The findings of this study show that fengabine 200 mg and 400 mg does not produce any noticeable behavioural toxicity in elderly volunteers, in contrast to amitriptyline which had a disruptive effect throughout.

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

AbstractBrofaromine 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.

Effects of lofepramine and dothiepin on memory and psychomotor function in healthy volunteerso

The effects of single doses of lofepramine (70 mg), dothiepin (50 mg) and placebo on memory and psychomotor function were compared in a cross-over study with 12 healthy volunteers. Dothiepin produced a differential pattern of effects across the range of memory assessments used, impairing episodic memory and slowing learning in a procedural task but not affecting working, semantic or implicit memory. Dothiepin also impaired performance on two attentional tasks, slowed down reaction times and increased subjective sedation. Lofepramine was similar to placebo on nearly all objective measures, but produced effects similar to dothiepin on critical flicker fusion threshold, salivary flow and most EEG wavebands. It is concluded that, unlike lofepramine, acute dosage with dothiepin is associated with sedative effects and impairments of concentration and memory.

STUDIES ON THE CHRONOPHARMACOLOGY OF ETHANOL

Male subjects (n = 10) were given ethanol (0.75 g/kg) at four equally spaced times in the 24 hr cycle (9 am, 3 pm, 9 pm 3 am) in random order. Blood ethanol concentrations were monitored by breath analysis and measurements were made of the blood or plasma levels of ethanol, acetaldehyde, acetate, pyruvate, lactate and cortisol. Blood pressure, heart rate and body temperature were measured before and at 60 and 120 min after ethanol administration and the effects of ethanol on a number of behavioural parameters and mood were studied. After ethanol ingestion, there was a significant decrease in body temperature, systolic blood pressure, plasma cortisol and pyruvate levels, whilst acetate levels and the lactate:pyruvate ratio were significantly increased. Standing steadiness, critical flicker fusion threshold and divided attention tracking control were significantly impaired under ethanol and self-report data indicated a significant decrease in alertness, co-ordination, concentration and attentiveness. Although a significantly higher peak blood ethanol concentration was attained at the 9 am session, other time-of-day differences did not reach significance and the pharmacokinetics of ethanol were essentially unchanged. Since the only significant diurnal variations in the response to ethanol identified in this study (apart from the subjective results) were for plasma cortisol concentrations and body temperature (both of which are well known to exhibit diurnal rhythmicity), it appears that major circadian variability in the metabolic and/or behavioural effects of ethanol is unlikely to occur.

The effects of moclobemide on psychomotor performance and cognitive function

Sixteen young male volunteers received single doses of moclobemide 200 mg, moclobemide 400 mg, amitriptyline 50 mg and placebo in a double-blind crossover study. Subjects then completed a test battery which is sensitive to the effects of psychoactive drugs at 1, 2, and 4 h post-dose. The test battery included tasks of choice reaction time, tracking, critical flicker fusion threshold and memory scanning. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). The results show that the positive internal control (amitriptyline) has a sedative effect in that it increased critical flicker fusion threshold, reaction time and tracking error. Moclobemide 400 mg increased reaction time in the tracking task but neither dose of moclobemide impaired psychomotor performance or cognitive ability in any of the other tests.