Cognitive toxicity of pharmacotherapeutic agents used in social anxiety disorder.

OBJECTIVE: To compare cognitive impairment of medications used in social anxiety disorder (SAD). METHODS: Data from peer-reviewed publications (1975-2007) of controlled, crossover design, pharmacodynamic studies on SAD medications in healthy volunteers were analysed. The number of objective psychometrics for each drug/dose level at all time points after dosing, and of instances of statistically significant impairment of cognitive function, enabled calculation of drug-induced cognitive impairment. The magnitude of impairment between drugs was compared using proportional impairment ratios (PIRs). RESULTS: Olanzapine, oxazepam, lorazepam and mianserin had twice the average cognitive toxicity of other treatments. Selective serotonin reuptake inhibitors (SSRIs) impaired cognition to a lesser extent than other pharmacological groupings. There was extensive intra-class variation: fluvoxamine (PIR = 0.08) possessed little detrimental cognitive activity, whereas sertraline (PIR = 5.33) caused impairment over five times the SSRI group average. Benzodiazepines caused noticeable cognitive impairment. CONCLUSIONS: Substantial differences exist, both between and within therapeutic classes, in the behavioural toxicity of medications used for SAD.

Investigation into the suitability of a portable psychometric device to be used in the field: an illicit drugs field investigation.

RATIONALE: Driving performance is easily disrupted as a direct consequence of the use of alcohol, licit and illicit drugs. The use of such drugs has a high degree of correlation with increased accident risk. Europe wide research projects into drugged driving have called for the development of a portable objective device capable of screening those impaired through drug use which can be used at the roadside. OBJECTIVE: This study investigated the cognitive and psychomotor performance of a cohort of polydrug drug users in field conditions. Volunteers completed a psychometric test battery on a hand held device in music festival conditions. The test battery comprised a critical tracking task (CTT) and a sustained attention to response task (SART). Volunteers also took a breathanalyser and provided a saliva sample for a DOA screen. RESULTS: On the CTT significance was observed for tracking error following response to a peripheral stimulus in the high alcohol (>80 mg/100 ml) illicit drug group (p=0.0090) and approached significance for the low alcohol (<80 mg/100 ml) illicit drug group (p=0.088). For the SART, incorrect presses to the target stimulus was impaired for volunteers in both the low (<80 mg/100 ml) alcohol illicit drug group (p=0.0080) and the high alcohol (>80 mg/100 ml) illicit drug group (p=0.0415). Discrimination analysis demonstrated that the impairment device was able to discriminate between those individuals who had consumed neither alcohol nor drugs (94.12%), those in the low alcohol drug group (46.67%) and those in the high alcohol drug group (60.00%). CONCLUSION: It is possible to derive an impairment ratio. Further research will demonstrate whether this device could significantly contribute to drug driving detection and road traffic safety.

Factor analysis of the St. Mary's Hospital Sleep Questionnaire.

The St. Mary's Hospital Sleep Questionnaire was designed to evaluate the sleep of hospital patients. To gain an understanding of possible underlying factors, the questionnaire was factor analysed using data collected from 222 hospitalised rheumatic patients. The analysis did not produce a completely clear factor structure. Two factors relating to "sleep latency" and "sleep quality" emerged more clearly than the other factors produced. These factors correspond with two sleeping state factors (ease of getting to sleep; quality of sleep) that were extracted by a previous factor analysis of the Leeds Sleep Evaluation Questionnaire. This suggests that the two most important aspects of subjectively perceived sleep are the process of going to sleep and the quality of sleep.

Residual effects of hypnotics: an update.

The sedative/hypnotic benzodiazepines introduced worldwide in the early 1960s were acclaimed for their low chemical toxicity and safety in clinical use. A decade later, some researchers and clinicians found that while all the drugs had undoubted potency and efficacy as sleep inducers and maintainers, the trade-off in residual effects (e.g., excessive daytime tiredness, poor concentration, impaired psychomotor performance, lowered mental abilities) was cause for concern. These sequelae not only affected patients' safety and ability to perform daytime tasks, but were also counter-therapeutic; the daytime sleep that was produced interfered with the natural nocturnal sleep. In a recent study, the degree to which patient abilities were impaired was measured by a number of psychomotor tests. Benzodiazepines with a duration of clinical effect of less than 8 to 10 hours produced fewer, less frequent residual effects than those with a measurable activity in excess of the normal nocturnal sleep period.

The effects of sertraline on psychomotor performance in elderly volunteers.

The psychopharmacologic effects of sertraline, a new antidepressant drug, are reviewed. A double-blind, placebo-controlled crossover study was conducted, investigating the effects of 9 days' administration of sertraline and mianserin on cognitive and psychomotor performance of elderly volunteers. The two antidepressants were given on a rising dose schedule for the first five days of treatment (sertraline 100 mg Day 1 and 2, 150 mg Days 3 and 4, and 200 mg Day 5; mianserin 10 mg Days 1 and 2, 20 mg Days 3 and 4, and 30 mg Day 5) with the highest dose (mianserin 30 mg and sertraline 200 mg) being intended for the rest of the study. To assess the effect of concomitant alcohol administration, alcohol (0.5 g/kg body weight) was given 6 hours after the last dose of each treatment. There was a severe intolerance to the effects of mianserin in this group of patients even at the lowest dose and, as many subjects were withdrawn, there was no formal analysis because of the missing data. However, the available evidence showed the expected sedative effects on a number of psychometric tests. Single or multiple doses of sertraline did not affect objective measures of performance. The addition of alcohol did not affect these results. The results indicate that sertraline has a neutral psychomotor profile in the elderly and appears to have no additive depressant effects when taken with moderate amounts of alcohol.

Behavioural toxicity of antidepressants with particular reference to moclobemide.

The clinical decision to use a particular antidepressant should be made with reference to the behavioural toxicity profiles of substances in current use. Antidepressants can be cardiotoxic, proconvulsant, able to cause weight gain and sleep disturbance, and also impair psychological functions necessary for everyday living. Behavioural toxicity (reduction in psychomotor activity or cognitive ability) tends to augment levels of psychomotor and cognitive retardation; meta-analysis of controlled studies of antidepressants shows that some tricyclics can disrupt these functions. In comparison with these, moclobemide is relatively free from significant behavioural toxicity within the dose-ranges used. No relevant differences were found between placebo and 200 mg moclobemide on a battery of psychomotor and cognitive tests: with 400 mg, there was a significant impairment of peripheral reaction time, but no other measure of the test battery was impaired. In comparison, amitriptyline 50 mg, produced a noticeable and significant impairment of psychomotor and cognitive skills on most test measures. On the whole moclobemide has been found to be free from any behavioural toxicity likely to interfere with the well-being of patients or their performance of the tasks of everyday living.

Effects of tianeptine and mianserin on car driving skills.

RATIONALE: Tianeptine is a novel antidepressant which enhances the reuptake of serotonin (5-HT). Previous studies suggest that tianeptine has a non-sedative side-effect profile, but its effects on everyday activities including car driving have not been fully explored. OBJECTIVES: To assess the effects of tianeptine on tests related to car driving performance. METHOD: Sixteen healthy volunteers received acute doses of tianeptine 12.5 mg and 37.5 mg, mianserin 30 mg and placebo in a double blind four-way crossover study. The effects of treatment on self assessed ratings of sedation (LARS), two valid and reliable laboratory performance measures, critical flicker fusion (CFF) and choice reaction time (CRT) and an "on-the-road" measure of one aspect of car driving performance, brake reaction time (BRT) were examined. The BRT test was administered at baseline and at 1.5, 3, 4.5 and 6 h post-dose, while LARS, CFF and CRT were administered at baseline and at 1, 2, 4 and 5 h post-dose. For all data, the maximum change from baseline was calculated and used in the analysis. RESULTS: Tianeptine had no measurable effect on performance, compared to placebo, on any of the variables investigated. Compared to placebo, mianserin was shown to lower CFF thresholds (P = 0.01), increase reaction times on both the CRT (P = 0.001) and the BRT (P = 0.01) tests and was subjectively rated as more sedative than placebo (P = 0.01). CONCLUSION: The apparent lack of counter-therapeutic side-effects produced by an acute dose of tianeptine suggest that it may be a suitable antidepressant for use in an ambulant population.

The Leeds Sleep Evaluation Questionnaire in psychopharmacological investigations - a review.

The Leeds Sleep Evaluation Questionnaire comprises ten self-rating 100-mm-line analogue questions concerned with aspects of sleep and early morning behaviour. The questionnaire has been used to monitor subjectively perceived changes in sleep during psychopharmacological investigations involving a variety of psychoactive agents, including sedative-hypnotics, antidepressants, anxiolytics, CNS stimulants, and antihistamines. Dose-related improvements in the self-reported ratings of getting to sleep and perceived quality of sleep were generally associated with reductions in the self-reported levels of alertness and behavioural integrity the morning following the nocturnal administration of sedative hypnotic and anti-anxiety agents. Psychostimulants on the other hand, impaired subjective ratings of sleep and produced increases in early morning assessments of alertness. Certain antidepressant and antihistaminic agents produced effects similar to the sedative-hypnotics, while others did not affect self-reported aspects of sleep and early morning behaviour.

Separate and combined effects of the social drugs on psychomotor performance.

Ten female subjects (five smokers and five non-smokers) performed a choice reaction time task (CRT), a compensatory tracking task (CTT), a short-term memory task (STM) and were tested for their critical flicker fusion threshold (CFF) at set points over 4 h after the administration of each possible combination of nicotine (2 mg gum or placebo), caffeine (250 mg capsule or placebo) and alcohol (30 g or placebo). Memory and motor function were shown to be facilitated by nicotine or caffeine, and the debilitating effects of alcohol were frequently antagonised by either drug. In spite of the differences in their neuropharmacological actions, combinations of nicotine, caffeine and alcohol may be compared through their effects on common information processing mechanisms involved in psychomotor performance.

Psychomotor performance in smokers following single and repeated doses of nicotine gum.

The psychomotor effects of single and repeated doses of 2 mg nicotine gum were investigated in 13 regular smokers who had abstained from tobacco overnight. In comparison to baseline, a first dose of nicotine led to significantly raised critical flicker fusion thresholds, faster motor reaction times, improved compensatory tracking performance, and faster short-term memory reaction times. Performance after a second and third dose of nicotine remained significantly improved on all measures in comparison to baseline, and absolutely improved when comparing first and third nicotine doses on measures of sensorimotor performance. Throughout, comparisons with a placebo gum condition confirmed that these effects were genuine and not subject to the development of acute nicotine tolerance, suggesting that the enhancement of psychomotor performance experienced by smokers after a first cigarette may be maintained by repeated smoking.

Effects of nicotine gum on psychomotor performance in smokers and non-smokers.

Two experiments were conducted to investigate the effects of nicotine on human performance. In the first study six smokers, who had been allowed to smoke normally prior to testing, completed a battery of psychometric tests (choice reaction time, memory scanning, tracking and flicker fusion threshold) at set points over 4 h after chewing 0, 2, or 4 mg nicotine polacrilex gum. A second study followed a similar design, but used five non-smoker volunteers who were required to chew only the 0 or 2 mg nicotine gum. Blood nicotine levels following the gum were measured in all subjects. The results indicate that additional nicotine improved both the speed and accuracy of motor activity among the smokers, but did not enhance central cognitive processes. No drug effects were found in the non-smoker study.

The effects of black tea and other beverages on aspects of cognition and psychomotor performance.

Nineteen healthy volunteers ingested 400 ml black tea, coffee, caffeinated water, decaffeinated tea or plain water on three occasions through the day (0900, 1400 and 1900 hours). A 2 x 2 factorial design with caffeine (0, 100 mg) and beverage type (water, tea) was employed, with coffee (100 mg caffeine) as a positive internal control, based on a five-way crossover. A psychometric test battery comprising critical flicker fusion (CFF), choice reaction time (CRT), short-term memory (STM) and subjective sedation (LARS) was performed at regular intervals throughout the day, and intensively so immediately following each beverage. Consumption of tea compared to water was associated with transient improvements in performance (CFF) within 10 min of ingestion and was not affected by the time of day. Caffeine ingestion was associated with a rapid (10 min) and persistent reduction in subjective sedation values (LARS), again independent of time of day, but did not acutely alter CFF threshold. Over the whole day, consumption of tea rather than water, and of caffeinated compared to decaffeinated beverages, largely prevented the steady decline in alertness (LARS) and cognitive capacity observed with water ingestion. The effects of tea and coffee were similar on all measures, except that tea consumption was associated with less variation in CFF over the whole day. No significant treatment effects were apparent in the data for the STM. Tea ingestion is associated with rapid increases in alertness and information processing capacity and tea drinking throughout the day largely prevents the diurnal pattern of performance decrements found with the placebo (no caffeine) condition. It appears that the effects of tea and coffee were not entirely due to caffeine per se; other factors either intrinsic to the beverage (e.g. sensory attributes or the presence of other biologically active substances) or of a psychological nature (e.g. expectancy) are likely to play a significant role in mediating the responses observed in this study.

The effects of cigarette smoking on overnight performance.

Fifteen healthy smokers and 15 non-smokers were enrolled into this study investigating the effects of smoking on overnight performance. Subjects arrived at the test centre at 1930 hours and were assessed at baseline (2000 hours) and at 2200, 0000, 0200, 0400, 0600, and 0800 hours on a battery of tests (including Critical Flicker Fusion, CFF; Choice Reaction Time, CRT; Compensatory Tracking Task, CTT; Short Term Memory Task, STM; and the Line Analogue Rating Scale, LARS). Results showed that the performance of the smokers was more consistent with baseline measures than that of the non-smokers, which became more impaired throughout the night on a number of tasks [CFF (P < 0.005), Total Reaction Time (TRT, P < 0.05), CTT (P < 0.05) and the Reaction Time (RT) aspect of the CTT task (P < 0.0005)]. The Recognition Reaction Time (RRT) aspect of the CRT task showed that the performance of the non-smokers became more impaired from baseline (P < 0.005), while that of the smokers remained at baseline levels until 0400 hours, when it deteriorated to become comparable to that of the non-smoking controls. Subjective sedation ratings (LARS) resulted in comparable levels of impairment for both study groups (P < 0.00005). Findings from the STM task failed to reach significance. These data suggest that when performance is being measured overnight, smokers show little or no impairment, whilst the performance of non-smokers showed performance decrements.

A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality.

RATIONALE: The effects of caffeine, especially caffeinated coffee, on human performance have been extensively studied. However, few studies have been naturalistic representations of how tea/coffee is normally consumed in terms of dose and time of consumption. OBJECTIVES: This study investigated the effects of day-long consumption of tea, coffee and water on cognitive and psychomotor performance, and sleep quality at night. METHODS: Thirty healthy volunteers received equal volume drinks equivalent to either 1 or 2 cups of tea (containing 37.5 mg or 75 mg caffeine), or coffee (75 mg or 150 mg caffeine), or water, in a randomised five-way crossover design. Drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours). A psychometric battery consisting of critical flicker fusion (CFF), choice reaction time (CRT) and subjective sedation (LARS) tests, was administered pre-dose and at frequent time points post-dose. The Leeds Sleep Evaluation Questionnaire (LSEQ) was completed each morning and a wrist actigraph was worn for the duration of the study. RESULTS: Caffeinated beverages maintained CFF threshold over the whole day (P<0.05), independent of caffeine dose or beverage type. During the acute phase of beverage ingestion, caffeine significantly sustained performance compared to water after the first beverage for CFF and subjective sedation (P<0.05), and after the second beverage for the Recognition component of the CRT task (P<0.05). Additionally, there were significant differences between tea and coffee at 75 mg caffeine after the first drink. Compared to coffee, tea produced a significant increase in CFF threshold between 30 and 90 min post-consumption (P<0.01). However, following the second beverage caffeinated coffee at 75 mg significantly improved reaction time (P<0.05), compared to tea at the same dose, for the Recognition component of the CRT task. Caffeinated beverages had a dose dependent negative effect on sleep onset (P<0.001), sleep time (P<0.001) and sleep quality (P<0.001). CONCLUSIONS: These results indicate that ingestion of caffeinated beverages may maintain aspects of cognitive and psychomotor performance throughout the day and evening when caffeinated beverages are administered repeatedly. This study also demonstrates that day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep. Other differences between tea and coffee were more subtle, and require further investigation.

The effects of an ergot alkaloid derivative (Hydergine) on aspects of psychomotor performance, arousal, and cognitive processing ability.

Hydergine, 12 mg per day for two weeks, has some direct activity on a variety of tasks of mental and cognitive performance. These results add support to biochemical findings that implicate the ergot alkaloids (particularly co-dergo-crine, Hydergine) in cellular activity likely to increase cortical arousal and awareness. The high dose of Hydergine used in this volunteer study was exceptionally well tolerated and did produce significant results on individual measures of central nervous system activity which might suggest the use of similar doses in patient populations. The findings of a hangover of activity after drug withdrawal and the fact that some CNS activity (serial subtraction of 17s) is not obvious until two weeks of medication would suggest the need for pharmacokinetic measures to be taken in conjunction with psychologic assessments. It would seem that a two-week schedule of repeated doses is the minimum required to produce an effect on CNS activity, but even with such a dose regimen it appears that the drug continues to exert some effect after its withdrawal.

Amnestic effects of triazolam and other hypnotics.

1. The effects of a number of hypnotics were compared to a range of results collected for triazolam on objective measures of CNS sedation (critical flicker fusion) and short-term memory function (memory scanning). 2. Assessments taken after the drugs had been administered but prior to the onset of sleep showed that in comparison to placebo most of the compounds were effective sedatives and this correlated highly (r = 0.734, p < 0.04) with amnestic effects found at the same time, suggesting that general CNS sedation is a major component of anterograde amnesia. 3. Residual effects assessed the morning after the hypnotics had been used showed a similar relationship (r = 0.896, p < 0.005). 4. The distribution of results indicates that 0.25 mg triazolam has an acute amnestic profile which is similar to other hypnotics, but possesses a distinct lack of residual effects.

The effects of antidepressants on psychomotor function with particular reference to reboxetine.

This review assesses the relative efficacy and side-effect profile of the currently available treatment options for major depression and the new selective noradrenergic agent, reboxetine. The effects of these treatments on psychomotor function are reviewed using: choice reaction time (CRT) and critical flicker fusion threshold (CFFT) measurements to compare and contrast the various antidepressants. Tricyclic antidepressant (TCA) agents are associated with an increased risk of accidents, especially in the elderly (primarily accidents related to driving or falls/fractures due to postural hypotension). In comparison, the newer noradrenergic agents such as reboxetine have demonstrated significant improvements in the incidence and severity of effects on psychomotor function. Such a lack of side-effects makes agents like reboxetine most useful for the treatment of depression in ambulant patients performing their usual activities of daily living.

The effects of the sub-chronic administration of an anti-histamine, clemastine, on tests of car driving ability and psychomotor performance.

A double-blind placebo-controlled crossover trial was carried out in 21 normal volunteers to study the effects of sub-chronic administration of clemastine on car driving ability and psychomotor performance. Subjects were assessed on 5 tests representing various aspects of everyday car driving experience, and on subjective rating scales for mood, sleep, and psychomotor integration. The results showed that repeated doses of 1 mg clemastine b.d. for 3 days had no significant consistent effect on any of the parameters measured.

The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare.

AIM: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments. METHODS: Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit. RESULTS: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4. CONCLUSIONS: In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.

A re-examination of the clinical effects of imipramine and amitriptyline in depressive illness.

A double-blind trial of amitriptyline and imipramine was conducted in patients suffering from depressive illness. The results failed to confirm the prevalent belief that amitriptyline has a greater sedative effect and superior anxiolytic properties than imipramine. The therapeutic effect of these drugs was not shown to be related to their sedative properties and with regard to anxiety the reverse appeared to be true.