Joris Cornelis Verster

A psychoneuroimmunological review on cytokines involved in antidepressant treatment response

The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines.

Acute Alcohol Effects on Inhibitory Control and Implicit Cognition: Implications for Loss of Control Over Drinking

Alcohol impairs inhibitory control, and it alters implicit alcohol cognitions including attentional bias and implicit associations. These effects are seen after doses of alcohol which do not lead to global impairments in cognitive performance. We review studies which demonstrate that the effects of alcohol on inhibitory control are associated with the ability of alcohol to prime alcohol-seeking behavior. We also hypothesize that alcohol-induced changes in implicit alcohol cognitions may partially mediate alcohol-induced priming of the motivation to drink. Based on contemporary theoretical models and conceptualizations of executive function, impulsivity, and the motivational salience of alcohol-related cues, we speculate on other aspects of cognition that may underlie alcohols effects on alcohol seeking. Inconsistencies in existing research and priorities for future research are highlighted, including dose effects and the potential interactions between chronic heavy drinking and the acute effects of alcohol on these cognitive processes.

Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance

Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual impairment when used in the middle of the night.

Antihistamines and driving ability: evidence from on-the-road driving studies during normal traffic

BACKGROUND All antihistamines are capable of crossing the blood-brain barrier and thus may cause sedation. Most antihistamine users are ambulatory patients and therefore presumably drive a car. OBJECTIVE To summarize the effects of antihistamine drugs on driving ability. DATA SOURCES AND STUDY SELECTION A literature search (MEDLINE and cross-references) was performed using the keywords driving and antihistamine. Sixteen studies using the on-the-road driving test during normal traffic were included in the review. Studies were double-blind and placebo-controlled and included a positive control. RESULTS First-generation antihistamines (diphenhydramine, triprolidine, terfenadine, dexchlorpheniramine, clemastine) significantly impair driving performance after both one-time and repeated (daily) administration. Second-generation antihistamines (cetirizine, loratadine, ebastine, mizolastine, acrivastine, emedastine, mequitazine) may also impair driving performance, but the magnitude and extent of impairment depend on the administered dose, sex, and time between testing and treatment administration. Tolerance develops after 4 to 5 days of administration, but impairment is not absent. Third-generation antihistamines (fexofenadine and levocetirizine) have been shown to produce no driving impairment after both one-time and repeated administration. CONCLUSIONS First- and second-generation antihistamines may significantly impair driving performance. In the context of driving safety but also taking into account the cardiotoxic properties of some of the second-generation antihistamines, we advise treating patients with third-generation antihistamines such as fexofenadine and levocetirizine.

Standard operation procedures for conducting the on-the-road driving test, and measurement of the standard deviation of lateral position (SDLP)

This review discusses the methodology of the standardized on-the-road driving test and standard operation procedures to conduct the test and analyze the data. The on-the-road driving test has proven to be a sensitive and reliable method to examine driving ability after administration of central nervous system (CNS) drugs. The test is performed on a public highway in normal traffic. Subjects are instructed to drive with a steady lateral position and constant speed. Its primary parameter, the standard deviation of lateral position (SDLP), ie, an index of ‘weaving’, is a stable measure of driving performance with high test–retest reliability. SDLP differences from placebo are dose-dependent, and do not depend on the subject’s baseline driving skills (placebo SDLP). It is important that standard operation procedures are applied to conduct the test and analyze the data in order to allow comparisons between studies from different sites.

Effects of Alprazolam on Driving Ability, Memory Functioning and Psychomotor Performance: A Randomized, Placebo-controlled Study

Alprazolam is prescribed for the treatment of anxiety and panic disorder. Most users are presumably involved in daily activities such as driving. However, the effects of alprazolam on driving ability have never been investigated. This study was conducted to determine the effects of alprazolam (1 mg) on driving ability, memory and psychomotor performance. Twenty healthy volunteers participated in a randomized, double-blind, placebo-controlled crossover study. One hour after oral administration, subjects performed a standardized driving test on a primary highway during normal traffic. They were instructed to drive with a constant speed (90 km/h) while maintaining a steady lateral position within the right traffic lane. Primary performance measures were the Standard Deviation of Lateral Position (SDLP) and the Standard Deviation of Speed (SDS). After the driving test, subjective driving quality, mental effort, and mental activation during driving were assessed. A laboratory test battery was performed 2.5 h after treatment administration, comprising the Sternberg Memory Scanning Test, a Continuous Tracking Test, and a Divided Attention Test. Relative to placebo, alprazolam caused serious driving impairment, as expressed by a significantly increased SDLP (F1,19 = 97.3, p < .0001) and SDS (F1,19 = 30.4, p < .0001). This was confirmed by subjective assessments showing significantly impaired driving quality (F1,19 = 16.4, p < .001), decreased alertness (F1,19 = 43.4, p < .0001), decreased mental activation (F1,19 = 5.7, p < .03) and increased mental effort during driving (F1,19 = 26.4, p < .0001). Furthermore, alprazolam significantly impaired performance on the laboratory tests. In conclusion, alprazolam users must be warned not to drive an automobile or operate potentially dangerous machinery.

Hypnotics and driving safety: Meta-analyses of randomized controlled trials applying the on-the-road driving test

BACKGROUND Many people who use hypnotics are outpatients and are likely to drive a car the day after drug intake. The purpose of these meta-analyses was to determine whether or not this is safe. METHODS Placebo-controlled, randomized, double-blind trials were selected if using the on-the-road driving test to determine driving ability the day following one or two nights of treatment administration. Primary outcome measure of the driving test was the Standard Deviation of Lateral Position (SDLP); i.e., the weaving of the car. Fixed effects model meta-analyses were performed. Effect size (ES) was computed using mean standardized (weighted) difference scores between treatment and corresponding placebo SDLP values. RESULTS Ten studies, published from 1984 to 2002 (207 subjects), were included in the meta-analyses. The morning following bedtime administration, i.e. 10-11 hours after dosing, significant driving impairment was found for the recommended dose of various benzodiazepine hypnotics (ES=0.42; 95% Confidence Interval (CI)=0.14 to 0.71). Twice the recommended dose impaired driving both in the morning (ES=0.68; CI=0.39 to 0.97) and afternoon, i.e. 16-17 hours after dosing (ES=0.57; CI=0.26 to 0.88). Zopiclone 7.5 mg also impaired driving in the morning (ES=0.89; CI=0.54 to 1.23). Zaleplon (10 and 20 mg) and zolpidem (10 mg) did not affect driving performance the morning after dosing. Following middle-of-the-night administration, significantly impaired driving performance was found for zopiclone 7.5 mg (ES=1.51, CI=0.85 to 2.17), zolpidem 10 mg (ES=0.66, CI=0.13 to 1.19) and zolpidem 20 mg (ES=1.16, CI=0.60 to 1.72). Zaleplon (10 and 20 mg) did not affect driving performance. CONCLUSIONS The analyses show that driving a car the morning following nocturnal treatment with benzodiazepines and zopiclone is unsafe, whereas the recommended dose of zolpidem (10 mg) and zaleplon (10 mg) do not affect driving ability.

Sleep disorders, sleepiness and traffic safety: a public health menace

Sleep disorders are not uncommon and have been widely reported throughout the world. They have a profound impact on industrialized 24-h societies. Consequences of these problems include impaired social and recreational activities, increased human errors, loss of productivity, and elevated risk of accidents. Conditions such as acute and chronic insomnia, sleep loss, excessive sleepiness, shift-work, jet lag, narcolepsy, and sleep apnea warrant public health attention, since residual sleepiness during the day may affect performance of daily activities such as driving a car. Benzodiazepine hypnotics and zopiclone promote sleep, both having residual effects the following day including sleepiness and reduced alertness. In contrast, the non-benzodiazepine hypnotics zolpidem and zaleplon have no significant next-day residual effects when taken as recommended. Research on the effects of wakefulness-promoting drugs on driving ability is limited. Countermeasures for excessive daytime sleepiness have a limited effect. There is a need for a social awareness program to educate the public about the potential consequences of various sleep disorders such as narcolepsy, sleep apnea, shift-work-related sleep loss, and excessive daytime sleepiness in order to reduce the number of sleep-related traffic accidents.

Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking.

The impairing effects on memory functioning after acute alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. A total of 48 healthy volunteers participated in a single-blind study comprising an evening (baseline) session, followed by a treatment administration (ethanol 1.4 g/kg or placebo), and a morning session. Memory was tested with a word-learning test (including immediate and delayed recall, and recognition). Further, a 45-min Mackworth clock test for measuring vigilance was included (parameters: number of hits and false alarms) and subjective alertness was assessed, to infer whether word-learning test findings reflect sedation or specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol group when compared to the placebo group (F1,42=6.0, p<0.02). In contrast, immediate recall and recognition were unimpaired in the alcohol group. In the morning session, relative to the placebo group, subjective alertness was significantly reduced in the alcohol group before and after the tests (F1,44=8.7, p<0.005; F1,44=13.3, p<0.001, respectively). However, in the Mackworth clock test, the alcohol group and placebo group did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. Vigilance performance was not significantly affected, indicating that this memory impairment does not reflect sedation.

Drugs of Abuse, Driving and Traffic Safety

Roadside studies indicate that 1-15% of drivers drive under the influence of one or more drugs of abuse. After drug use, drivers are more often culpable for an accident than non-users. Information on drugs and traffic safety comes from roadside studies, epidemiological research, experimental studies on driving-related skills, and on-the-road driving tests. Road-side studies show that drivers most frequently test positive for the use of alcohol and/or cannabis. These two drugs affect driving ability in a dose-dependent matter and result in poor vehicle control, especially when used in combination. Drivers on cocaine, ecstasy and amphetamine show no impairment on basic driving skills, but often overestimate their driving skills. In combination with impaired decision making, this increases risk taking during driving. Only few studies looked at the effects on driving of other drugs of abuse, such as ketamine, inhalants and anabolic steroids, but suggest a negative effect on driving performance. In conclusion, most drugs of abuse negatively affect driving ability, especially when used in combination with alcohol or another drug. It is of concern that a substantial number of drug users are not aware that their driving is impaired.