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Introduction: Literature suggests pilots experience fatigue differently. So-called fatigue-resistant or -vulnerable individuals might also respond differently to countermeasures or stimulants. This study, which is part of a larger randomized controlled clinical trial, aims to investigate the effect of caffeine and modafinil on fatigue-resistant and -vulnerable pilots. Methods: This study included 32 healthy employees of the Royal Netherlands Air Force, who completed three test days, separated by at least 7 days. After a regular work day, the subjects were randomly administered either 300 mg caffeine, 200 mg modafinil or placebo at midnight. Hereafter the subjects performed the psychomotor vigilance test (PVT), vigilance and tracking test (VigTrack) and Stanford sleepiness scale (SSS) six times until 8 a.m. the next day. Subjects were ranked on the average number of lapses on the PVT during the placebo night and divided into three groups: fatigue-vulnerable (FVUL), -intermediate (FINT) and -resistant (FRES), with 11, 10 and 11 subjects in each group, respectively. Area under the curve (AUC) of the PVT, VigTrack and SSS during the test nights were calculated, which were used in univariate factorial analysis of variance (ANOVA). Tukey's HSD post hoc tests were used to differentiate between the groups. Results: A significant effect of treatment was found in the ANOVA of both PVT parameters, VigTrack mean reaction time and SSS. There was a statistically significant effect of fatigue group on all PVT parameters and VigTrack mean percentage omissions, where FINT and FRES scored better than FVUL. There was a significant interaction effect between treatment and fatigue group for PVT number of lapses. This is congruent for the AUC analyses in which for all parameters (except for the SSS) the performance of the FVUL group was consistently worse than that of the FINT and FRES groups. Discussion: This study demonstrates that the performance of individuals with different fatigue tolerances are differently affected by simulants after a limited period of sleep deprivation. The classification of fatigue tolerance through PVT lapses when sleep deprived seems to be able to predict this. [ABSTRACT FROM AUTHOR]

Background: Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to caffeine. However, the effect of a single dose of modafinil after a limited period of sleep deprivation remains unknown. Aims: This study aims to determine the effect of 200 mg modafinil on vigilance during a limited period of sleep deprivation compared to 300 mg caffeine and placebo. Methods: Thirty-two volunteers of the Royal Netherlands Air Force (RNLAF) were double-blindly administered modafinil, caffeine, and placebo on three non-consecutive trial days after being awake for median 17 h. Afterwards, subjects completed six series of the Vigilance and Tracking test (VigTrack), psychomotor vigilance task (PVT), and Stanford Sleepiness Scale (SSS), yielding six primary endpoints. Results: This study revealed statistically significant effects of caffeine and modafinil compared with placebo on all endpoints, except for VigTrack mean tracking error. PVT results were less impaired 2 h after administration, followed by VigTrack parameters and SSS scores 2 h thereafter. Compared with caffeine, modafinil significantly improved PVT and SSS scores at 8 h after administration. Conclusions: The present study demonstrates that 200 mg modafinil and 300 mg caffeine significantly decrease the effects of a limited period of sleep deprivation on vigilance compared with placebo. Although PVT parameters already improved 2 h after administration, the most notable effects occurred 2–4 h later. Modafinil seems to be effective longer than caffeine, which is consistent with its longer half-life. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Fatigue has negative effects on flight safety, especially in military aviation, where missions are often performed under challenging conditions. Modafinil is a relatively new pharmaceutical able to counter the symptoms of fatigue, but efficacy has not yet been studied in operational military aviation. This study aims to establish effectiveness and safety of modafinil in military operations. METHODS: T his field study was conducted during deployment in the Middle East by the Royal Netherlands Air Force fighter pilots. Prior to use operationally, pilots had to complete a 24-h ground test in which modafinil was administered during a nonflying period using a questionnaire to screen for duty-relevant side effects. If no side effects were reported, operational usage was allowed. In addition to registration of modafinil's effects, relevant data prior to and after administration were recorded, including caffeine consumption and sleep afterwards. RESULTS: Of the 75 pilots who completed ground testing, only one experienced duty-relevant side effects. Modafinil was used in 192 operational flights, mostly during nighttime. In 128 (67%) of the flights, modafinil was used preventively, in 64 (33%) because of fatigue. In 182 (95%) of the flights, positive effects of modafinil were reported, with a maximum effect 2--3 h after administration. There was no statistical correlation between modafinil's beneficial effects and prior administration of caffeine or sleep medication, nor was sleep afterwards negatively affected. DISCUSSION: T his study indicates modafinil is a suitable pharmaceutical countermeasure to minimize the effects of fatigue during real-life fighter operations, without signs of negative impact on flight safety or sleep quality afterwards. [ABSTRACT FROM AUTHOR]

Abstract Speech disturbances are well-known symptoms contributing to the diagnosis of schizophrenia. Subanesthetic doses of the N-methyl-D-aspartate (NMDA) antagonist ketamine have been reported to produce positive and negative symptoms and [...]

Fatigue poses an important safety risk to civil and military aviation. In addition to decreasing performance in-flight (chronic) fatigue has negative long-term health effects. Possible causes of fatigue include sleep loss, extended time awake, circadian phase irregularities and work load. Despite regulations limiting flight time and enabling optimal rostering, fatigue cannot be prevented completely. Especially in military operations, where limits may be extended due to operational necessities, it is impossible to rely solely on regulations to prevent fatigue. Fatigue management, consisting of preventive strategies and operational countermeasures, such as pre-flight naps and pharmaceuticals that either promote adequate sleep (hypnotics or chronobiotics) or enhance performance (stimulants), may be required to mitigate fatigue in challenging (military) aviation operations. This review describes the pathophysiology, epidemiology and effects of fatigue and its impact on aviation, as well as several aspects of fatigue management and recommendations for future research in this field. [ABSTRACT FROM AUTHOR]

Abstract Serotonergic hypofunction may underlie at least part of the symptoms that are experienced by women with premenstrual complaints, including memory deficits. In the current study we investigated changes in [...]

Abstract It has frequently been demonstrated that acute tryptophan depletion (ATD) induces a transient depressed mood in some patients who are in remission from depression. However, the effects of ATD [...]

Abstract Subchronic treatment with the selective serotonergic reuptake inhibitors (SSRIs) fluoxetine, venlafaxine and paroxetine, but not sertraline, were previously shown to specifically impair vigilance performance. The current study was designed [...]

In a recent issue of the Journal of Psychopharmacology (JoP), Dawson and Goodwin (2005) identified the British Association of Psychopharmacology (BAP) as well as pharmaceutical industries as the strongest supporters [...]

The article discusses the benefits of using muscarinic type 1 (M1) antagonist as a pharmacological model to induce memory impairment in healthy subjects as compared to scopolamine and mentions topics such as the need for caution while using scopolamine, and the M1 agonist improves memory.

Dopamine is well known for involvement in reinforcement, motor control and frontal lobe functions, such as attention and memory. Tyrosine/ phenylalanine depletion (TPD) lowers dopamine synthesis and can therefore be used as a model to study the effects of low dopamine levels. This is the first study to assess the effect of TPD on memory performance and its electrophysiological correlates. In a double blind placebo (PLA)-controlled crossover design, 17 healthy volunteers (six males, 11 females) aged between 18 and 25 were tested after TPD and PLA. Working memory was assessed using a Sternberg memory scanning task (SMS) and episodic memory using the Visual Verbal Learning Test (VVLT). Simultaneously, event-related potentials (ERPs) were measured. The tyrosine and phenylalanine ratio was significantly reduced after TPD and increased after PLA. Working memory performance was not affected by TPD. However, ERP measures were affected by the treatment, indicating that TPD impaired stimulus processing during working memory performance. Episodic memory was not impaired after TPD. Again, alterations in ERP measures suggested adverse effects of TPD on memory-related processing. These results suggest that dopamine is involved in both working memory and episodic memory-related processing, although the effects are too small to be detected by performance measures. [ABSTRACT FROM PUBLISHER]

5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT1A and 5-HT3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT1A agonists ameliorate memory deficits in depression.Neuropsychopharmacology (2006) 31, 712–720. doi:10.1038/sj.npp.1300869; published online 31 August 2005 [ABSTRACT FROM AUTHOR]

There is evidence for a specific impairment of human vigilance following enhancement of serotonergic activity by antidepressant drugs. In the present study, we investigated the putative role of serotonergic-dopaminergic interactions in diminished vigilance by comparing the attentional effects of sertraline, a selective serotonin reuptake inhibitor (SSRI) with additional mild dopamine stimulating effects, with those of paroxetine, a SSRI without dopamine activity, using a placebo-controlled, double-blind, three-way cross-over design. Twenty-one (of 24) healthy middle-aged subjects completed the three treatment periods of 2 weeks in which sertraline (50 mg, days 1-7; 100 mg, days 8-14), paroxetine (20 mg, days 1-7; 40 mg, days 8-14) and placebo were administered. Vigilance (Mackworth Clock Test), selective (Stroop, Dichotic Listening) and divided attention (Dichotic Listening) were assessed at baseline and on days 7 and 14 of each treatment period. Selective and divided attention were unaffected by SSRI treatment. Subchronic administration of paroxetine impaired vigilance performance at each investigated dose. Sertraline did not produce a significant decline in vigilance performance, presumably due to its concomitant effects on dopamine activity, counteracting the negative effects of serotonin on dopamine neurotransmission. It is concluded that a serotonergically mediated reduction of dopamine activity plays an important role in the reduction of human vigilance following SSRI administration. [ABSTRACT FROM AUTHOR]

The current study was carried out to investigate the cognitive effects of two serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, with special reference to differences in their affinity for other neurotransmitter systems, i.e. anticholinergic activity of paroxetine and putative dopamine reuptake activity of sertraline. The study was conducted according to a double-blind, three-way cross-over design. During three treatment periods of 2 weeks, 24 healthy middle-aged (aged 30-50 years) subjects of both sexes received sertraline (50 mg on days 1-7, 100 mg on days 8-14), paroxetine (20 mg on days 1-7, 40 mg on days 8-14) and placebo. Paroxetine specifically impaired delayed recall in a word learning test at a dose of 20 and 40 mg. Sertraline did not affect word learning but improved performance on a verbal fluency task at a dose of 50 and 100 mg. Neither drug affected performance on a short-term memory scanning task. These subtle but significant changes in cognitive performance can be explained by subtle differences in pharmacological profiles of these SSRIs. The additional anticholinergic effects of paroxetine could account for its induction of long-term memory impairment. Similarly, the additional dopaminergic effects of sertraline could account for its induction of slightly improved verbal fluency. The impairing and facilitating cognitive effects of paroxetine and sertraline, respectively, may be more pronounced in the elderly depressed patient. [ABSTRACT FROM AUTHOR]

Eight patients suffering from major depression were treated with trazodone 150 or 200 mg bid (non-responders) over 5 weeks, preceded and followed by a placebo week. Cognitive functioning was tested in the morning at the end of each treatment week. Before trazodone treatment commenced, patients' cognitive performance was compared with non-depressed controls. The depressed group showed significantly slower reaction times on the memory scanning test, but did not differ from the control group on five other tests including word learning, Critical Flicker/Fusion frequency (CFF), vigilance, tracking and divided attention. CFF threshold decreased significantly during trazodone treatment. CFF returned to its initial baseline level at the end of the placebo withdrawal. During the trazodone treatment period, recall from long-term memory of a previously learnt word list significantly improved, but at the end of the placebo withdrawal period memory performance returned to its initial baseline level. These results indicated that the subchronic influence of trazodone on cognitive functions is at least of a two-dimensional nature: decreased CFF threshold can be interpreted in terms of lowered CNS arousal, whereas a higher cognitive function, memory, improved, possibly related to the relief of depressive symptoms. Copyright © 1999 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A response by S. Sobczak, A. Honig and Wim J. Riedel to a letter to the editor about their article "Pronounced Cognitive Deficits Following an Intravenous L-Tryptophan Challenge in First-Degree Relatives of Bipolar Patients Compared to Healthy Controls," in the 2003 issue is presented.

Presents a response to a letter to the editor about dissociable hormonal, cognitive and mood responses to neuroendocrine challenge.

Background: Methylphenidate improves motor response inhibition, typically assessed with the stop-signal task. The exact underlying mechanism for this, however, remains unknown. In addition, recent studies highlight that stop signals can have a confounding attentional-capture effect because of their low frequency in the task. In the current study, we assessed the effects of methylphenidate on neural networks of inhibitory control and attentional-capture within the context of two inhibitory control tasks. Methods: The effects of methylphenidate (40 mg) were assessed using functional magnetic resonance imaging in 16 healthy volunteers in a within-subject, double-blind, placebo-controlled design. Results: Methylphenidate significantly reduced activation of different regions within the right inferior frontal gyrus/insula to infrequent stimuli associated with successful inhibition, failed inhibition, and attentional capture. These inferior frontal gyrus regions showed different interregional connections with inhibitory and attention networks. For failed inhibitions, methylphenidate increased activation within performance-monitoring regions, including the superior frontal, anterior cingulate, and parietal-occipital cortices, but only after controlling for attentional capture. Conclusions: Our findings suggest that the improvement of response inhibition seen following methylphenidate administration is due to its influence on underlying attentional mechanisms linked to response control requirements. [ABSTRACT FROM AUTHOR]

Abstract: Background: It has frequently been demonstrated that experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50–60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression. In unmedicated depressed patients, ATD has no immediate effect on symptoms. The effects in currently depressed medicated patients have not been investigated. Methods: Fourteen currently depressed patients (seven patients treated with a selective serotonin–noradrenalin reuptake inhibitor (SSNRI); seven other treatment, non-SSNRI) received ATD in a double-blind, crossover design. Different strengths of the ATD mixture (aimed at 50% and 90% reduction of tryptophan) were used on separate days. Psychiatric symptoms were assessed at both sessions prior to, at +6.5 h, and at +24 h after ATD. Results: The ATD mixtures induced the expected reductions of plasma tryptophan levels. Full but not partial depletion improved mood and other psychiatric symptoms at +24 h in patients who received SSNRI treatment, as indicated by clinical ratings and self-report. Subjective sleep quality also improved. Conclusions: The effects of ATD on psychiatric symptoms in currently depressed patients are remarkably different from the results in recently remitted SSRI-treated patients. ATD in currently depressed patients treated with serotonergic antidepressants possibly provides important information about the mechanism of action of SSRIs. [Copyright &y& Elsevier]

Background: We evaluated the cognitive profile of 48 patients with major depression following their first myocardial infarction (MI). Methods: The cognitive performance of the patients was compared with the performance of 48 non-depressed MI patients and 48 healthy controls. Results: Depressed MI patients performed slower on a simple cognitive speed related measure compared with non-depressed MI patients and healthy controls. Attention and speed-related aspects of cognitive functioning were not affected. Surprisingly, (depressed) MI patients showed even better performances with respect to memory function. Limitation: No patients with non-MI-related depression were included. Conclusions: The cognitive profile of major depression after MI differs from that of non-cardiac-related depressive disorder, as described in the literature. This may reflect a different etiology of post MI depression from non-cardiac-related depression. [Copyright &y& Elsevier]

Declarative Memory consists of memory for events (episodic memory) and facts (semantic memory). Methods to test declarative memory are key in investigating effects of potential cognition-enhancing substances--medicinal drugs or nutrients. A number of cognitive performance tests assessing declarative episodic memory tapping verbal learning, logical memory, pattern recognition memory, and paired associates learning are described. These tests have been used as outcome variables in 34 studies in humans that have been described in the literature in the past 10 years. Also, the use of episodic tests in animal research is discussed also in relation to the drug effects in these tasks. The results show that nutritional supplementation of polyunsaturated fatty acids has been investigated most abundantly and, in a number of cases, but not all, show indications of positive effects on declarative memory, more so in elderly than in young subjects. Studies investigating effects of registered anti-Alzheimer drugs, cholinesterase inhibitors in mild cognitive impairment, show positive and negative effects on declarative memory. Studies mainly carried out in healthy volunteers investigating the effects of acute dopamine stimulation indicate enhanced memory consolidation as manifested specifically by better delayed recall, especially at time points long after learning and more so when drug is administered after learning and if word lists are longer. The animal studies reveal a different picture with respect to the effects of different drugs on memory performance. This suggests that at least for episodic memory tasks, the translational value is rather poor. For the human studies, detailed parameters of the compositions of word lists for declarative memory tests are discussed and it is concluded that tailored adaptations of tests to fit the hypothesis under study, rather than "off-the-shelf" use of existing tests, are recommended.

Background: Enantioselective analysis of amphetamine (AM), methamphetamine (MA), 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) helps interpret toxicological results. Methods have been described for various matrices, but so far not for oral fluid, a matrix of increasing importance in testing for drugs of abuse, especially in the context of driving under the influence of drugs (DUID)., Methods: After dilution with 200 microL carbonate buffer (pH 9), oral fluid samples (10-50 microL) were derivatized with S-heptafluorobutyrylprolyl chloride. The resulting diastereomers were extracted into 100 microL of cyclohexane, separated by gas chromatography (HP-5MS column), and detected by mass spectrometry in the negative-ion chemical ionization mode (GC-NICI-MS). The method was validated and applied to samples from a controlled study with MDMA and from authentic DUID cases., Results: The derivatized AM, MA, MDA, MDMA, and MDEA enantiomers were well separated from each other. The method was linear from 5-250 microg/L per enantiomer of MDA and from 25-1250 microg/L per enantiomer of AM, MA, MDMA, and MDEA. With the exception of MDEA, analytical recoveries, repeatability, and intermediate precision were within required limits. The analyte concentrations and enantiomer ratios in the application samples correlated only weakly with corresponding published plasma data., Conclusions: This sensitive, reliable, and fast GC-NICI-MS assay enantioselectively measures AM, MA, MDA, and MDMA in oral fluid samples. Prediction of plasma concentrations and enantiomer ratios from respective oral fluid data is not possible.

In this article cognition assessments as outcome measures in CNS drug development research are described. An outline is given of the various choices that can be made and the reasons for them, depending on the approach followed. First, a brief historical context is provided of the psychological sciences that have contributed to today's psychopharmacology of cognition assessment. Subsequently, the focus is on identifying cognitive domains and criteria for selecting appropriate tests. In applied cognitive performance assessment in human psychopharmacology, a number of approaches can be recognised, each associated with models that connect cognitive functions with physiological functions and neural structures. The product-oriented approach of cognition assessment is usually characterised by the use of a battery of several cognitive tasks as an assessment instrument and aims to demonstrate an effect of a pharmaceutical substance without much attempt to determine which cognitive process is primarily influenced by a drug. The process-oriented approach precisely defines the cognitive process in terms of at least a single factor linear model of a process (e.g. by manipulating levels of difficulty) and then compares how diseases and drugs modify the parameters of that process. The associated factor analytical-, resource-strategy- and staged information processing models respectively are described. Finally a brief review is presented on possible physiological markers or biomarkers of human cognitive functions.

The ascending dopamine system of the mammalian brain has been associated with motor, mnemonic and goal-directed or reward-related behaviour. The most progress in understanding the cortical mechanisms of dopaminergic modulation of function has been made with regards to short-term mnemonic (or working memory) function. Research in experimental animals strongly suggests that stimulation of dopamine D1 receptors in the prefrontal cortex can ameliorate spatial working memory related cognitive deficits, and may even enhance cognitive function in healthy animals. Research in humans has not been able to clearly replicate these findings, partly due to the lack of available agents that can safely be used. Low doses of dopamine D2 receptor agonists such as bromocriptine and pergolide may be able to enhance working memory and executive functions, but these effects may be dependent on the nature of the tasks used and the baseline performance levels of the subjects. Thus, the effects of dopaminergic cognitive enhancers may not be simple, or uniform across subjects. Systematic studies in humans carefully controlling task parameters are needed in order to specify the potential cognitive processes open to enhancement with dopaminergics. However, since the DA receptor subtypes in different brain regions appear to differentially influence similar functions, carefully defining the cognitive processes to be tested against potential therapeutics is an equally important goal. Studies in patients groups using selective dopaminergics are rather restricted, but show promise for designing large-scale clinical trials into the cognitive enhancing properties of potential therapeutic agents that act through the dopamine system.

Background: The enantiomers of the designer drugs 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA), and 3,4-methylenedioxyethylamphetamine (MDEA) differ in their pharmacologic and toxicologic potency. The aim of this study was to develop an assay for measuring these enantiomers in small plasma volumes and to analyze samples from a controlled study with MDMA., Methods: The analytes were extracted from < or = 0.2 mL of plasma by mixed-mode solid-phase extraction. After derivatization with S-(-)-heptafluorobutyrylprolyl chloride, the resulting diastereomers were separated by gas chromatography (HP-5MS) within 17 min and detected by mass spectrometry in the negative-ion chemical ionization mode. The method was fully validated and applied to samples from a controlled study in which a single dose of racemic MDMA (75 mg) was administered., Results: The derivatized enantiomers were well separated and detected with good sensitivity. The assay was linear (per enantiomer) at 1-50 microg/L for MDA and 5-250 microg/L for MDMA and MDEA. Analytical recovery, accuracy, repeatability, and intermediate precision data were within required limits. Extraction yields were 82.1%-95.3%. In the study samples, concentrations of R-(-)-MDMA significantly exceeded those of S-(+)-MDMA. Their ratios (R vs S) were always >1.0 and increased over time. Concentrations of S-(+)-MDA exceeded those of R-(-)-MDA, their ratios (R vs S) also increasing over time but remaining <1.0., Conclusions: This assay enables sensitive, reliable, and fast enantioselective measurement of MDA, MDMA, and MDEA in small volumes of plasma. The controlled study data confirm previous findings of MDMA and MDA enantiomer ratios (R vs S) increasing over time after ingestion of racemic MDMA.

The interest in the function of the serotonergic system in relation to cognition stems from three sources: (1) the association of depression, cognitive dysfunction and 5-HT dysregulation; (2) the association of drug-induced 5-HT dysregulation and cognitive dysfunction; and (3) the association of cognitive performance and serotonergic function per se. We performed several experiments in subjects at risk for cognitive impairment and in healthy volunteers, in which 5-HT was manipulated by means of either tryptophan depletion or tryptophan loading. The results show that tryptophan and cognitive performance are associated in a complex non-linear fashion. Dissociations are observed between cognitive functions: tryptophan depletion impairs memory consolidation but improves focussed attention; as well as between subject groups: tryptophan depletion impairs problem solving in healthy 1st degree relatives of bipolar depressed patients but improves it in healthy volunteers without such a family history. It was demonstrated that the mood- and memory effects of tryptophan-depletion were specifically mediated by the depletion of tryptophan and also that the observed memory and cognitive deficits were emotionally biased in a manner consistent with depressive symptoms. We conclude that experimental manipulations of tryptophan mediate temporal and frontal cognitive functions such as memory consolidation and working memory respectively, in an opposite manner.

Study Objectives: To compare residual effects of zaleplon 10 mg, zopiclone 7.5 mg, and placebo, and a social dose of alcohol on car driving, memory, and psychomotor performance., Design: Two-part placebo controlled, crossover study. Part 1 was single blind, Part 2 double blind., Setting: University research institute., Participants: Thirty healthy volunteers (15 men and 15 women, mean age 32 +/- 7 years), Interventions: In Part 1 alcohol and alcohol-placebo drinks were administered around noon. In Part 2 single oral doses of zaleplon 10 mg, zopiclone 7.5 mg and placebo were administered at bedtime., Measurement and Results: A highway driving test, laboratory tests of word learning, critical tracking and divided attention, and subjective assessments of sleep, mood, and effects of treatments on driving. Driving started 40 minutes after a second alcohol dose in Part 1, and 10 hours after drug intake in Part 2. The results demonstrated that alcohol, at average plasma concentrations of approximately 0.030 g/dl, significantly impaired performance in all tests. Zaleplon's residual effects did not differ significantly from those of placebo in any test. In contrast, zopiclone had significant residual effects on driving, divided attention, and memory. The magnitude of impairment in the driving test observed the morning after zopiclone 7.5 mg was twice that observed with alcohol., Conclusion: Zaleplon 10 mg has no residual effects on driving when taken at bedtime, 10 hours before driving. In contrast, zopiclone 7.5 mg can cause marked residual impairment. Patients should be advised to avoid driving the morning after zopiclone administration.