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This exploratory case-controlled study examined whether the same amount of effort leads to similar feelings of fatigue and whether feelings of fatigue decline at the same rate in people with traumatic brain injury (pwTBI) compared to controls. Twenty pwTBI and 20 healthy controls (HC) completed an adaptive n-back task to induce fatigue and reported mental effort upon task completion and state-fatigue pre-task and several times during 30-minutes rest-period post-task. Task difficulty adapted to performance allowing both groups to invest substantial amounts of mental effort. Fatigue and effort levels were higher in pwTBI compared to controls. Multiple linear regression analyses showed that effort was positively related to post-task fatigue and this relationship did not differ between groups. Pre-task fatigue was the only predictor of post-task fatigue. Multilevel models showed no significant difference in decline of fatigue over the rest-period between groups. Excessive feelings of fatigue following TBI could not be explained by a higher vulnerability to the fatigue-inducing effects of mental effort needed to perform a specific task. In pwTBI pre-task fatigue levels might be more related to the complex demands of everyday life. Future studies should investigate recovery of fatigue and applications of this knowledge to rehabilitation interventions.Implications for rehabilitationPeople with TBI experience long-term fatigue as one of the most frequent and disabling symptoms and this long-term fatigue is a risk factor for development of secondary psychiatric symptoms such as depression or anxiety.Since people with TBI did not show a higher vulnerability to the fatigue-inducing effects of mental effort, fatigue following TBI might be better explained by the complex demands of everyday life such as external (environment) and internal (emotions) factors.Rehabilitation programs should be directed to this complex and highly individual interplay of fatigue in relation to other factors. People with TBI experience long-term fatigue as one of the most frequent and disabling symptoms and this long-term fatigue is a risk factor for development of secondary psychiatric symptoms such as depression or anxiety. Since people with TBI did not show a higher vulnerability to the fatigue-inducing effects of mental effort, fatigue following TBI might be better explained by the complex demands of everyday life such as external (environment) and internal (emotions) factors. Rehabilitation programs should be directed to this complex and highly individual interplay of fatigue in relation to other factors.

INTRODUCTION: Excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) can impair vigilance/attention. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved to treat EDS associated with narcolepsy (75-150 mg/day) or OSA (37.5-150 mg/day). The analysis reported here explored the use of the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model (used in transport industries to model performance based on accumulated sleep and circadian variability) as a substitute for healthy controls using psychomotor vigilance task (PVT) data collected during clinical studies.METHODS: Data were analyzed from two phase 2 studies of solriamfetol in adults with OSA (NCT02806895, EudraCT 2015-003930-28) or narcolepsy (NCT02806908, EudraCT 2015-003931-36). Participants were randomly assigned 1:1 to solriamfetol 150 mg/day (3 days) followed by 300 mg/day (4 days), or placebo (7 days), then crossed over to the other treatment. Actual task effectiveness scores were calculated from average PVT inverse reaction time (pre-dose; 2 h post-dose; 6 h post-dose). Actigraphy-derived sleep intervals were used in SAFTE to determine modeled healthy control task effectiveness scores.RESULTS: In participants with OSA (N = 31) on placebo or solriamfetol, actual and modeled healthy control task effectiveness did not differ at any time point. In participants with narcolepsy (N = 20) on placebo, actual task effectiveness at 2 h post-dose was lower than modeled healthy control task effectiveness (nominal P = 0.03), a difference not present with solriamfetol. There was no main effect of solriamfetol on actual or modeled healthy control task effectiveness across time points.CONCLUSION: This study represents a novel application of the SAFTE biomathematical model to approximate healthy controls in sleep disorder research and provides valuable lessons that may optimize future research. Future studies should perform a priori power analyses for model-tested outcomes and use sleep measures that capture sleep fragmentation characteristic of sleep disorders for sleep input (e.g., total sleep time rather than time in bed).TRIAL REGISTRATION: NCT02806895, EudraCT 2015-003930-28: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Obstructive Sleep Apnea. NCT02806908, EudraCT 2015-003931-36: A Randomized, Double-Blind, Placebo-Controlled, Crossover On-Road Driving Study Assessing the Effect of JZP-110 on Driving Performance in Subjects With Excessive Sleepiness Due to Narcolepsy.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving in participants with excessive daytime sleepiness (EDS) associated with obstructive sleep apnoea (OSA).METHODS: Eligible participants were aged 21-75 years with OSA and EDS (Maintenance of Wakefulness Test mean sleep latency RESULTS: Solriamfetol significantly reduced SDLP at 2 (n = 34; least squares mean difference, -1.1 cm; 95% CI, -1.85, -0.32; p = 0.006) and 6 hours postdose (n = 32; least squares mean difference, -0.8 cm; 95% CI, -1.58, -0.03; p = 0.043). Two hours postdose, 4 placebo-treated and 1 solriamfetol-treated participants had incomplete driving tests; 6 hours postdose, 7 and 3 participants, respectively, had incomplete tests. Common treatment-emergent adverse events included headache, nausea, and insomnia.CONCLUSIONS: Solriamfetol 300 mg/day significantly improved on-the-road driving performance in participants with EDS associated with OSA.

OBJECTIVE: To evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on-the-road driving performance in participants with narcolepsy.METHODS: In this randomised, double-blind, placebo-controlled, crossover study, driving performance during a 1 h on-road driving test was assessed at 2 and 6 h post-dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post-dose.RESULTS: The study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post-dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, -1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post-dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, -1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence.CONCLUSIONS: Solriamfetol 300 mg/day improved on-the-road driving performance, at 2 h post-administration in participants with narcolepsy.

IntroductionExcessive Daytime Sleepiness is a core symptom of narcolepsy and idiopathic hypersomnia, which impairs driving performance. Adequate treatment improves daytime alertness, but it is unclear whether driving performance completely normalizes. This study compares driving performance of patients with narcolepsy and idiopathic hypersomnia receiving treatment to that of healthy controls.MethodsPatients diagnosed with narcolepsy type 1 (NT1, n = 33), narcolepsy type 2 (NT2, n = 7), or idiopathic hypersomnia (IH, n = 6) performed a standardized one-hour on-the-road driving test, measuring standard deviation of lateral position (SDLP).ResultsResults showed that mean SDLP in patients did not differ significantly from controls, but the 95%CI of the mean difference (+1.02 cm) was wide (-0.72 to +2.76 cm). Analysis of subgroups, however, showed that mean SDLP in NT1 patients was significantly increased by 1.90 cm as compared to controls, indicating impairment. Moreover, four NT1 patients requested to stop the test prematurely due to self-reported somnolence, and two NT1 patients were stopped by the driving instructor for similar complaints.ConclusionDriving performance of NT1 patients may still be impaired, despite receiving treatment. No conclusions can be drawn for NT2 and IH patients due to the low sample sizes of these subgroups. In clinical practice, determination of fitness to drive for these patients should be based on an individual assessment in which also coping strategies are taken into account.

Rationale The mechanisms underlying impaired sleep quality in insomnia are not fully known, but an important role for sleep fragmentation has been proposed. Objectives The aim of this study is to explore potential mechanisms of sleep fragmentation influencing alterations of perceived sleep quality. Methods We analyzed polysomnography (PSG) recordings from a double-blind crossover study with zopiclone 7.5 mg and placebo, in elderly participants with insomnia complaints and age-matched healthy controls. We compared survival dynamics of sleep and wake across group and treatment. Subsequently, we used a previously proposed model to estimate the amount of sleep onset latency (SOL) misperception from PSG-defined sleep fragmentation. Self-reported and model-estimated amount of SOL misperception were compared across group and treatment, as well as model prediction errors. Results In the zopiclone night, the average segment length of NREM sleep was increased (group F = 1.16, p = 0.32; treatment F = 8.89, p< 0.01; group x treatment F = 0.44, p = 0.65), while the segment length of wake was decreased (group F = 1.48, p = 0.23; treatment F = 11.49, p< 0.01; group x treatment F = 0.36, p = 0.70). The self-reported and model-estimated amount of SOL misperception were lower during the zopiclone night (self-reported group F = 6.08, p< 0.01, treatment F = 10.8, p< 0.01, group x treatment F = 2.49, p = 0.09; model-estimated F = 1.70, p = 0.19, treatment F = 16.1, p< 0.001, group x treatment F = 0.60, p = 0.55). The prediction error was not altered (group F = 1.62, p = 0.20; treatment F = 0.20, p = 0.65; group x treatment F = 1.01, p = 0.37). Conclusions Impaired subjective sleep quality is associated with decreased NREM stability, together with increased stability of wake. Furthermore, we conclude that zopiclone-induced changes in SOL misperception can be largely attributed to predictable changes of sleep architecture.

Study objectiveTo study sleep EEG characteristics associated with misperception of Sleep Onset Latency (SOL).MethodsData analysis was based on secondary analysis of standard in-lab polysomnographic recordings in 20 elderly people with insomnia and 21 elderly good sleepers. Parameters indicating sleep fragmentation, such as number of awakenings, wake after sleep onset (WASO) and percentage of NREM1 were extracted from the polsysomnogram, as well as spectral power, microarousals and sleep spindle index. The correlation between these parameters during the first sleep cycle and the amount of misperceived sleep was assessed in the insomnia group. Additionally, we made a model of the minimum duration that a sleep fragment at sleep onset should have in order to be perceived as sleep, and we fitted this model to subjective SOLs of both subject groups.ResultsMisperception of SOL was associated with increased percentage of NREM1 and more WASO during sleep cycle 1. For insomnia subjects, the best fit of modelled SOL with subjective SOL was found when assuming that sleep fragments shorter than 30 min at sleep onset were perceived as wake. The model indicated that healthy subjects are less sensitive to sleep interruptions and perceive fragments of 10 min or longer as sleep.ConclusionsOur findings suggest that sleep onset misperception is related to sleep fragmentation at the beginning of the night. Moreover, we show that people with insomnia needed a longer duration of continuous sleep for the perception as such compared to controls. Further expanding the model could provide more detailed information about the underlying mechanisms of sleep misperception.

De vraag of het gebruik van tweedegeneratieantidepressiva effect heeft op de rijvaardigheid van patiënten met een klinische depressie is nog niet beantwoord. De conclusies uit epidemiologisch onderzoek zijn niet eenduidig. Experimentele studies laten weinig invloed zien van tweedegeneratieantidepressiva op de rijvaardigheid, maar deze studies wijken vaak methodologisch af van de klinische praktijk. Dit artikel beschrijft de uitkomsten van een onderzoek naar de effecten van een langdurige behandeling (6–52 weken) met tweedegeneratieantidepressiva in een steekproef van klinisch depressieve patiënten. Patiënten die werden behandeld met een medicijn uit deze groep (n = 24) werden vergeleken met patiënten die chronisch behandeld werden met een benzodiazepine (n = 31), een onbehandelde patiëntengroep (n = 10) en een controlegroep van gezonde vrijwilligers (n = 24). De uitkomsten tonen aan dat de eerste groep significant beter presteerde op een gestandaardiseerde rijtest op de weg dan de andere twee patiëntengroepen, maar dat deze groep het nog steeds slechter deed dan de controlegroep. Een correlatieanalyse liet een verband zien tussen de ernst van de depressie en de prestatie op de rijtest. De conclusie is dan ook dat depressieve klachten een probleem vormen voor de rijveiligheid en dat een behandeling met een tweedegeneratieantidepressivum dit risico kan doen afnemen.

Background: Excessive daytime sleepiness (EDS) in people with obstructive sleep apnoea (OSA) is associated with increased driving accident risk. Solriamfetol [Sunosi™] is a dopamine/norepinephrine reuptake inhibitor approved in the EU and US to treat EDS in adults with OSA (37.5–150mg/d). Aim: Evaluate solriamfetol’s effects on on-road driving performance in adults with EDS associated with OSA. Methods: In a randomised, double-blind, crossover study (NCT02806895/EudraCT 2015-003930-28), an on-road driving test was conducted at 2h and 6h postdose after 7d of treatment with solriamfetol (150mg/d×3d, then 300mg/d×4d) or placebo. Primary endpoint: standard deviation of lateral position (SDLP), a measure of weaving, at 2h postdose. Results: Baseline characteristics (N=34): 88% male; mean age, 52y; mean Epworth Sleepiness Scale, 14.4; Maintenance of Wakefulness Test, 14.3 min. At 2h and 6h, mean SDLP was significantly lower with solriamfetol vs placebo (Fig.). At 2h, 1 participant on solriamfetol and 4 on placebo had incomplete driving tests; at 6h, 3 and 7 participants, respectively, had incomplete driving tests. Common adverse events with solriamfetol: headache, nausea, insomnia, dizziness, and agitation. Conclusion: Solriamfetol (300mg/d) improved SDLP, an important measure of driving performance, at 2h and 6h postdose in participants with EDS associated with OSA.

Sleep and physical activity are both modifiable behavioural factors that are associated with better health and are potentially related. Following traumatic brain injury, damage to the brain caused by an external force, sleep disturbances are common. Exploring bidirectional relationships between sleep and physical activity might provide insight into whether increasing physical activity could decrease these sleep disturbances. The current study, therefore, examined inter‐ and intra‐individual temporal associations between sleep and daytime physical activity in 64 people with traumatic brain injury reporting sleep problems or fatigue (47 males; mean age, 40 years). Sleep and physical activity were measured using actigraphy with corroborating sleep diaries over 14 consecutive days. Multilevel models were used to examine inter‐ and intra‐individual associations between physical activity and sleep. Inter‐individual variations showed that earlier bedtimes, earlier wake‐up times and lower sleep efficiency were associated with more physical activity. Intra‐individual temporal variations showed no significant association of daytime physical activity with sleep duration or continuity. However, shorter sleep time and less wake after sleep onset than usual were associated with more time spent in light‐intensity activity the next day. Therefore, sleep may have more of an influence on physical activity than physical activity has on sleep in people with traumatic brain injury. In conclusion, the results do not confirm a potential beneficial effect of physical activity on sleep but suggest that improving sleep quality might be relevant to support of a physically active lifestyle in people with traumatic brain injury. Further research is necessary to confirm these results.

In the first column of table 2, it says: 'REM Weibull scale, 1/ʎ'. NREM Weibull scale 1/ʎ, and Wake Weibull scale 1/ʎ.

OBJECTIVE: To evaluate the construct validity of Psychomotor Vigilance Test performance for measuring fatigue in people with acquired brain injury.DESIGN: Observational cross-sectional study.PARTICIPANTS: Fifty-four people with acquired brain injury and 61 healthy controls.METHODS: Participants performed the Psychomotor Vigilance Test and reported momentary fatigue before and after this test and general fatigue. Associations between performance and fatigue in patients were tested by correlational and hierarchical multiple linear regression analyses, controlling for sleep quality, daytime sleepiness, and mood.RESULTS: Patients performed worse on the test compared with controls. Within the patient group, worse test performance was associated with increases in momentary post-test fatigue and general fatigue, indicating convergent validity, but also with daytime sleepiness, and mood complaints, indicating a lack of divergent validity. When controlling for sleepiness and mood, the association between performance and general fatigue was no longer significant, whereas the association between performance and post-test fatigue remained.CONCLUSION: Performance on the Psychomotor Vigilance Test cannot be used as a specific measure for fatigue, but it appears to be a more general measure of severity of symptoms including fatigue, mood, and sleepiness. Therefore, the Psychomotor Vigilance Test may be a useful measure to examine the effects of interventions aimed at reducing these symptoms.

Study Objectives To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23–78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug–placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Mean drug–placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated. Clinical Trial Registration clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

BACKGROUND: Fatigue and sleep problems are common after a traumatic brain injury (TBI) and are experienced as highly distressing symptoms, playing a significant role in the recovery trajectory, and they can drastically impact the quality of life and societal participation of the patient and their family and friends. However, the etiology and development of these symptoms are still uncertain.OBJECTIVE: The aim of this study is to examine the development of fatigue and sleep problems following moderate to severe TBI and to explore the changes in underlying biological (pain, brain damage), psychological (emotional state), and social (support family, participation) factors across time.METHODS: This study is a longitudinal multicenter observational cohort study with 4 measurement points (3, 6, 12, and 18 months postinjury) including subjective questionnaires and cognitive tasks, preceded by 7 nights of actigraphy combined with a sleep diary. Recruitment of 137 moderate to severe TBI patients presenting at emergency and neurology departments or rehabilitation centers across the Netherlands is anticipated. The evolution of fatigue and sleep problems following TBI and their association with possible underlying biological (pain, brain damage), psychological (emotional state), and social (support family, participation) factors will be examined.RESULTS: Recruitment of participants for this longitudinal cohort study started in October 2017, and the enrollment of participants is ongoing. The first results are expected at the end of 2020.CONCLUSIONS: To the authors' knowledge, this is the first study that examines the development of both post-TBI fatigue and sleep longitudinally within a biopsychosocial model in moderate to severe TBI using both subjective and objective measures. Identification of modifiable factors such as mood and psychosocial stressors may give direction to the development of interventions for fatigue and sleep problems post-TBI.TRIAL REGISTRATION: Netherlands Trial Register NTR7162; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=7162 (Archived by WebCite at http://www.webcitation.org/6z3mvNLuy).INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/11295.

Acute benzodiazepine intoxication produces severe impairment of neurocognitive skills related to driving. It is less clear whether such impairments also occur in patients who use benzodiazepines chronically. The current review evaluated neurocognitive skills of long-term benzodiazepine users and addressed 2 major questions: do long-term users develop tolerance for the impairing effects of benzodiazepines on neurocognitive performance, and if so, does tolerance warrant a change in driver fitness classification systems that currently deem users of benzodiazepines unfit to drive? Neurocognitive impairments were reported in patients who on average used benzodiazepines for 5–15 years. In addition, sensitivity to acute benzodiazepine impairment decreased in long-term users, suggesting (partial) tolerance. Definitions of clinical relevance of neurocognitive impairments in long-term users and how these were affected by duration of benzodiazepine use were generally lacking. Also, sensitivity of neurocognitive tasks to drug effects and their validity to predict fitness to drive were generally unknown. Because of these limitations, no firm conclusion can be drawn regarding a re-classification of long-term benzodiazepine effects on driver fitness.

Introduction Depression is a mental disorder likely to affect everyday functions. The present study aimed to assess actual driving performance of depressed patients who were without specific antidepressant treatment or received long-term antidepressant treatment. Methods A standardized on-the-road driving test was used to assess standard deviation of lateral position (SDLP) in 3 patient groups receiving either no antidepressant treatment (with or without benzodiazepine medication) or treatment with selective serotonin/noradrenalin reuptake inhibitors for a period of 6–52 weeks. Severity of depression was assessed using Beck’s Depression Inventory and the Hamilton Depression Rating Scale. The performance of patient groups was compared to healthy controls. Results The mean SDLP of untreated and treated patients was significantly higher than that of healthy controls. Driving impairment in the long-term treated group was significantly less than in the untreated groups. SDLP was positively correlated to severity of depression across all groups. Discussion It is concluded that symptoms of depression are a major cause of driving impairment. Reductions in severity of depression through antidepressant treatment reduce severity of driving impairment.

OBJECTIVES: There is no consensus yet on how to determine which patients with cognitive impairment are able to drive a car safely and which are not. Recently, a strategy was composed for the assessment of fitness to drive, consisting of clinical interviews, a neuropsychological assessment, and driving simulator rides, which was compared with the outcome of an expert evaluation of an on-road driving assessment. A selection of tests and parameters of the new approach revealed a predictive accuracy of 97.4% for the prediction of practical fitness to drive on an initial sample of patients with Alzheimer's dementia. The aim of the present study was to explore whether the selected variables would be equally predictive (i.e. valid) for a closely related group of patients, i.e. patients with Mild Cognitive Impairment (MCI).METHODS: Eighteen patients with mild cognitive impairment completed the proposed approach to the measurement of fitness to drive, including clinical interviews, a neuropsychological assessment and driving simulator rides. The criterion fitness to drive was again assessed by means of an on-road driving evaluation. The predictive validity of the fitness to drive assessment strategy was evaluated by Receiver Operating Characteristic (ROC) analyses.RESULTS: Twelve patients with mild cognitive impairment (66.7%) passed and 6 patients (33.3%) failed the on-road driving assessment. The previously proposed approach to the measurement of fitness to drive achieved an overall predictive accuracy of 94.4% in these patients. The application of an optimal cut-off resulted in a diagnostic accuracy of 100% sensitivity towards unfit to drive, and 83.3% specificity towards fit to drive. Further analyses revealed that the neuropsychological assessment and the driving simulator rides produced rather stable prediction rates, whereas clinical interviews were not significantly predictive for practical fitness to drive in the MCI patient sample.CONCLUSIONS: The selected measures of the previously proposed approach revealed adequate accuracy in identifying fitness to drive in patients with Mild Cognitive Impairment. Furthermore, a combination of neuropsychological test performance and simulated driving behaviour proved to be the most valid predictors of practical fitness to drive.

International audience; The present study mainly aimed to assess whether and how sleepiness due to sleep deprivation interacts with Time on Task (ToT) effects both on electroencephalography (EEG) measures and driving performance in real driving conditions. Healthy participants performed a one hour on-the-road monotonous highway driving task while EEG was recorded continuously after one night of normal sleep and after one night of total sleep deprivation. The main outcome parameter in the highway driving test was the Standard Deviation of Lateral Position (SDLP). SDLP and EEG indices (i.e alpha and theta power spectra) increased after sleep deprivation and varied with ToT. The latter was more pronounced after sleep deprivation. Beta power spectra did not differ between conditions but increased with ToT. Changes in SDLP and EEG did not correlate significantly. We conclude that driving performance as well as fatigue and sleepiness fluctuations with ToT were more evident after sleep deprivation as compared to normal sleep.

BACKGROUND/OBJECTIVE: Neurodegenerative disorders impact fitness to drive of older drivers, but on-road driving studies investigating patients with different neurodegenerative disorders are scarce. A variety of driving errors have been reported in patients with Alzheimer's disease (AD), but it is unclear which types of driving errors occur most frequently. Moreover, patients with other neurodegenerative disorders than AD typically present with different symptoms and impairments, therefore different driving errors may be expected.METHODS: Patients with AD (n = 80), patients with other neurodegenerative disorders with cognitive decline (i.e., vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease, n = 59), and healthy older drivers (n = 45) participated in a fitness-to-drive assessment study including on-road driving.RESULTS: Patients with AD performed significantly worse than healthy older drivers on operational, tactical, visual, and global aspects of on-road driving. In patients with AD, on-road measures were significantly associated with 'off-road' measures. Patients with neurodegenerative disorders other than AD showed large overlap in the types of driving errors. Several driving errors were identified that appear to be characteristic for patients with particular neurodegenerative disorders.CONCLUSION: Patients from each group of neurodegenerative disorders commonly display tactical driving errors regarding lane positioning, slow driving, observation of the blind spot, and scanning behavior. Several other tactical and operational driving errors, including not communicating with cyclists and unsteady steering, were more frequently observed in patients with non-AD neurodegenerative disorders. These findings have implications for on-road and 'off-road' fitness-to-drive assessments for patients with neurodegenerative disorders with cognitive decline.

Study Objectives To assess potential effects of lemborexant on next-morning driving performance in adult and elderly healthy volunteers. Methods Randomized, double-blind, double-dummy, placebo and active-controlled, four period incomplete crossover study in 48 healthy volunteers (22 females), 23–78 years old. Participants were treated at bedtime for eight consecutive nights with two of three dose levels of lemborexant (2.5, 5, or 10 mg), zopiclone 7.5 mg (on the first and last night with placebo on intervening nights), or placebo. Driving performance was assessed in the morning on days 2 and 9 using a standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug–placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Mean drug–placebo differences in SDLP following lemborexant 2.5, 5, and 10 mg on days 2 and 9 were 0.74 cm or less. The upper bound of the 95% confidence intervals (CIs) for lemborexant treatment groups were all below 2.4 cm and the 95% CIs included zero, indicating that the effects were neither clinically meaningful nor statistically significant. Symmetry analysis further supported the lack of clinically meaningful impairment with lemborexant. Conclusions When assessed starting ~9 h after lemborexant administration at bedtime the previous night, there was no statistically significant or clinically meaningful effect on driving performance in healthy adults and elderly, as assessed by either mean differences in SDLP relative to placebo or symmetry analysis. In this study, lemborexant at doses up to 10 mg was well-tolerated. Clinical Trial Registration clinicaltrials.gov, NCT02583451. https://clinicaltrials.gov/ct2/show/NCT02583451.

Laboratory tests assessing driving related skills can be useful as initial screening tools to assess potential drug induced impairment as part of a standardized behavioural assessment. Unfortunately, consensus about which laboratory tests should be included to reliably assess drug induced impairment has not yet been reached. The aim of the present review was to evaluate the sensitivity of laboratory tests to the dose dependent effects of alcohol, as a benchmark, on performance parameters. In total, 179 experimental studies were included. Results show that a cued go/no-go task and a divided attention test with primary tracking and secondary visual search were consistently sensitive to the impairing effects at medium and high blood alcohol concentrations. Driving performance assessed in a simulator was less sensitive to the effects of alcohol as compared to naturalistic, on-the-road driving. In conclusion, replicating results of several potentially useful tests and their predictive validity of actual driving impairment should deserve further research. In addition, driving simulators should be validated and compared head to head to naturalistic driving in order to increase construct validity.

Introduction Excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA) is associated with an increased risk of driving accidents. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the US (Sunosi®) for EDS associated with OSA (37.5-150 mg/day). This study evaluated solriamfetol’s effects on on-road driving performance in participants with EDS associated with OSA. Methods In each period of this randomized, double-blind, placebo-controlled, crossover study (NCT 02806895; EudraCT 2015-003930-28), driving performance during an on-road driving test was assessed at 2 hours and 6 hours postdose following 7 days of treatment with solriamfetol (150mg/day × 3, then 300mg/day × 4) or placebo. The primary endpoint—standard deviation of lateral position (SDLP), a measure of “weaving,” at 2 hours postdose—was compared between solriamfetol and placebo per time point using a repeated mixed-effects analysis of variance model. Results The study included 34 participants. Baseline characteristics reflected the broader OSA population (88% male; mean age=52 years; mean Epworth Sleepiness Scale score=14.4). SDLP at 2 hours postdose was statistically significantly lower following solriamfetol (least squares [LS] mean [standard error; SE], 18.83cm [0.63]) compared with placebo (19.92cm [0.63]): LS mean difference, -1.08cm; 95% confidence interval (CI), -1.85, -0.32; P=0.0062 (incomplete driving tests: solriamfetol, n=1; placebo, n=4), indicating better performance with solriamfetol. At 6 hours postdose, SDLP following solriamfetol (LS mean[SE], 19.24cm [0.63]) was statistically significantly lower compared with placebo (20.04cm [0.63]): LS mean difference, -0.80cm; 95% CI, -1.58, -0.03; P=0.0432 (incomplete driving tests: solriamfetol, n=3; placebo, n=7). Common adverse events (≥5%) with solriamfetol were headache, nausea, insomnia, dizziness, and agitation. Conclusion Solriamfetol (300mg/day) improved SDLP, an important measure of driving performance, at 2 and 6 hours in participants with EDS associated with OSA. Support Jazz Pharmaceuticals

Introduction Patients with narcolepsy have an increased risk of automobile accidents. Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the US (Sunosi®) for adults with excessive daytime sleepiness (EDS) associated with narcolepsy (75-150 mg/day). This study evaluated the effects of solriamfetol on on-road driving performance in participants with narcolepsy. Methods In each period of this randomized, double-blind, placebo-controlled, crossover study (NCT 02806908; EudraCT 2015-003931-36), driving performance during an on-road driving test (a 1-hour drive on a public highway) was assessed at 2 hours and 6 hours postdose following 7 days of treatment with solriamfetol (150 mg/day × 3, then 300 mg/day × 4) or placebo. For assessment of driving performance, the primary endpoint was standard deviation of lateral position (SDLP), a measure of “weaving,” at 2 hours postdose. Comparisons (solriamfetol vs placebo) used a Wilcoxon signed-rank test. Results The study included 24 participants (54% male; mean age, 40 years); 22 were included in the analyses of SDLP data. At 2 hours postdose, SDLP for solriamfetol (median, 19.08 cm) was statistically significantly lower than that for placebo (median, 20.46 cm; P=0.0022; incomplete driving tests: solriamfetol, n=4; placebo, n=7), indicating a better performance with solriamfetol. At 6 hours postdose, SDLP for solriamfetol (median, 19.59 cm) was not statistically significantly different from that for placebo (median, 19.78 cm; P=0.1245; incomplete driving tests: solriamfetol, n=3; placebo, n=10). Common adverse events (≥5%) were headache, decreased appetite, somnolence, sleep disorder, agitation, nausea, and palpitations. Conclusion Solriamfetol (300 mg/day) improved SDLP, an important measure of driving performance, at 2 hours after administration in participants with narcolepsy. Support Jazz Pharmaceuticals

Since Alzheimer's disease may affect driving performance, patients with Alzheimer's disease are assessed on fitness to drive. On-road driving assessments are widely used, and attempts have also been made to develop strategies to assess fitness to drive in a clinical setting. Preferably, a first indication of fitness to drive is obtained quickly after diagnosis using a single test such as the Mini-Mental State Examination (MMSE). The aim of this study is to investigate whether the MMSE can be used to predict whether patients with Alzheimer's disease will pass or fail an on-road driving assessment. Patients with Alzheimer's disease (n = 81) participated in a comprehensive fitness-to-drive assessment which included the MMSE as well as an on-road driving assessment [PLoS One 11(2):e0149566, 2016]. MMSE cutoffs were applied as suggested by Versijpt and colleagues [Acta Neurol Belg 117(4):811-819, 2017]. All patients with Alzheimer's disease who scored below the lower cutoff (MMSE ≤ 19) failed the on-road driving assessment. However, a third of the patients with Alzheimer's disease who scored above the upper cutoff (MMSE ≥ 25) failed the on-road driving assessment as well. We conclude that the MMSE alone has insufficient predictive value to correctly identify fitness to drive in patients with very mild-to-mild Alzheimer's disease implicating the need for comprehensive assessments to determine fitness to drive in a clinical setting.

Als automobilisten dementie krijgen, rijst de vraag of zij nog rijgeschikt zijn. Dit dient per patient onderzocht te worden met een rijtest van het Centraal Bureau Rijvaardigheidsbewijzen (CBR). De stap van de dementiediagnose naar de rijtest op de weg is echter groot, daarom is er recentelijk een klinisch rijgeschiktheidsonderzoek ontwikkeld. Met behulp van klinische interviews, verkeersneuropsychologisch onderzoek en rijsimulatorritten kan in een klinische setting voorspeld worden of iemand met de ziekte van Alzheimer de rijtest van het CBR zou halen. Deze aanpak is deels gevalideerd in een groep patienten met lichte cognitieve stoornissen (mild cognitive impairment; MCI). Voor mensen met andere vormen van dementie zijn echter nieuwe modellen nodig om hun rijgeschiktheid te kunnen voorspellen in een klinische setting.

Sedating cns-active drugs are typically studied for the potential to impair next-morning driving. Data from an on-road driving performance study are presented for lemborexant (lem), a dual orexin receptor antagonist under development for insomnia disorder.

OBJECTIVE: Screening of drug-induced performance impairment is needed to provide meaningful information for users and prescribers regarding the impact of drugs on driving. The main objective was to assess the effects of oxazepam 10 mg (OXA10), oxazepam 30 mg (OXA30), and diazepam 10 mg (DIA10) on standard deviation of lateral position (SDLP) in a highway driving test in actual traffic and to determine the ability of eight neurocognitive tests to detect comparable effects.METHODS: Twenty-three healthy volunteers participated in a four-way double-blind, placebo-controlled, crossover study. The highway driving test was conducted between 4 and 5 h after drug intake. A range of neurocognitive tests was conducted before and after driving, 2 and 6 h post-treatment, respectively.RESULTS: Mean SDLP increased by 1.83, 3.03, and 7.57 cm after OXA10, DIA10, and OXA30, respectively. At 2 h post-treatment, all neurocognitive tests, except the useful field of view, showed performance impairment in all active treatments. Effect sizes (ES) were moderate for OXA10, large ES for DIA10, and largest ES for OXA30. Modest correlations were found between changes in SDLP and performance in the attention network test (ANT), the divided attention test (DAT), and the psychomotor vigilance test (PVT).CONCLUSION: OXA10 caused minor, DIA10 moderate, and OXA30 severe driving impairment. No neurocognitive test was both dose dependently sensitive and able to be associated with driving impairment. No neurocognitive test can replace the on-the-road highway driving test.

Dementia is a risk factor for unsafe driving. Therefore, an assessment strategy has recently been developed for the prediction of fitness to drive in patients with the Alzheimer disease (AD). The aim of this study was to investigate whether this strategy is also predictive of fitness to drive in patients with non-AD dementia, that is, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies. Predictors were derived from 3 types of assessment: clinical interviews, neuropsychological tests, and driving simulator rides. The criterion was the pass-fail outcome of an official on-road driving assessment. About half of the patients with non-AD dementia (n=34) failed the on-road driving assessment. Neuropsychological assessment [area under the curve (AUC)=0.786] was significantly predictive of fitness to drive in patients with non-AD dementia, however, clinical interviews (AUC=0.559) and driving simulator rides (AUC=0.404) were not. The fitness-to-drive assessment strategy with the 3 types of assessment combined (AUC=0.635) was not found to significantly predict fitness to drive in non-AD dementia. Different types of dementia require different measures and assessment strategies.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Study Objective: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. Design: Double-blind, placebo-controlled, 4-period crossover study. Setting: Maastricht University, The Netherlands. Participants: 28 healthy volunteers (15 females), aged 23 to 64 years. Interventions: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. Measurements: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. Results: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests-all following suvorexant-stop prematurely due to self-reported somnolence. Conclusions: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests.

International audience; Insomniacs report decreased performance in daily routines, which may have detrimental consequences for car driving. We compared changes over time in driving performance (measured as Standard Deviation of Lateral Position – SDLP) and background EEG between 20 untreated insomnia patients (52–70 years old) and 21 normal sleepers (54–73 years old) during a 1 h on-the-road driving test after a normal night of sleep, in the morning. SDLP did not differ between groups and increased slightly over time to similar degrees in both groups. EEG alpha and beta power were lower in insomniacs as compared to normal sleepers. Alpha and beta power slightly reduced during driving in normal sleepers but remained at a constant low level in insomniacs. Changes in EEG power and SDLP were not related. It is concluded that on-the-road driving performance does not differ between older insomniacs and older normal sleepers and that changes in spectral EEG measures of cortical arousal and in driving performance are not related.

IntroductionThe on-the-road highway driving test is generally regarded as a gold standard for assessing drug-induced driving impairment. The primary outcome measure is the standard deviation of lateral position (SDLP), a measure of road tracking error or “weaving”. The test has been calibrated for incremental doses of alcohol almost 30 years ago in order to define the impact of drug-induced impairment in terms of blood alcohol concentration (BAC) equivalents. Drug-induced changes in SDLP exceeding 2.4 cm have been evaluated as clinically relevant ever since. The present analysis was conducted to assess the robustness of the alcohol effect in a range of on-the-road driving studies which have been conducted since the initial alcohol calibration study.MethodsThe present study pooled data of 182 participants from nine placebo-controlled crossover studies who performed the highway driving test, while their BAC was at or just below the legal limit for drivers (i.e., 0.5 g/L).ResultsOverall, mean SDLP increased with 2.5 cm (95% CI 2.0–2.9 cm). Equivalence testing showed that the clinical relevance criterion value of 2.4 cm fell well within the 95% CI in each individual study. Gender did not affect alcohol-induced changes in SDLP.DiscussionThese results demonstrate the robustness and validity of the clinical relevance criterion for SDLP as measured during on-the-road driving.

Narcolepsie en idiopathische hypersomnie (IH) zijn slaapaandoeningen die worden gekenmerkt door een dagelijks aanwezige verhoogde slaapneiging. In de Nederlandse regelgeving (regeling eisen geschiktheid 2000) zijn criteria vastgelegd voor de rijgeschiktheidsbeoordeling van narcolepsie en IH. De criteria zijn: • een Epworth Sleeping Scale (ESS) score van kleiner dan 11 • een Maintenance of Wakefulness Test (MWT) met een gemiddelde latentie van meer dan acht minuten • beoordeling door een specialist met ervaring op het gebied van slaapgerelateerde stoornissen. Er zijn argumenten om de MWT bij rijbewijskeuringen van personen met narcolepsie en IH te vervangen. De Sustained Attention to Response Task (SART) is voorgesteld als een mogelijk alternatief voor de MWT. Beide testen zijn niet eerder met elkaar vergeleken in een keuringssituatie. De doelstelling van dit onderzoek is vast te stellen of de MWT kan worden vervangen door de SART bij rijbewijskeuringen van personen met narcolepsie en IH. Om dit te onderzoeken werd bij een grote groep van 96 proefpersonen een reguliere rijbewijskeuring uitgevoerd, aangevuld met 4 afnames van de SART steeds voorafgaand aan de MWT. MWT resultaten werden vergeleken met prestaties op de SART. Bij 45 van de 96 proefpersonen werden de resultaten op MWT en SART vergeleken met de prestaties bij een rijtest op de snelweg. Prestaties in de snelwegrit werden ook vergeleken met die van gezonde controles. De gemiddelde Standaard Deviatie van Laterale Positie (SDLP in centimeters), of in andere woorden de mate van slingeren, was de primaire onderzoeksvariabele van de snelwegrit. Verwacht werd dat een korte(re) MWT latentietijd gepaard zou gaan met meer fouten op de SART (hypothese 1). Daarnaast werd tussen SART en rijprestatie een minstens even sterk verband verwacht als tussen MWT en rijprestatie (hypothese 2). Ten slotte werd verwacht dat de SART een beter onderscheid kon maken in slechte en goede rijprestaties dan de MWT (hypothese 3). Er werd geen significante correlatie gevonden tussen gemiddeld SART foutenaantal en gemiddelde slaaplatentie op de MWT. Dit betekent dat een kortere MWT latentietijd niet gepaard ging met meer fouten op de SART. Er werd een zwakke significante correlatie gevonden tussen MWT en SDLP en tussen SART op testdag 2 en SDLP. De absolute correlatie tussen SART op testdag 2 en SDLP was alleen hoger dan de correlatie tussen MWT en SDLP in de subgroep narcolepsie met kataplexie en niet voor de hele groep proefpersonen. Er werd gevonden dat de SART de slechtste prestaties op de slingermaat beter onderscheidt dan de MWT bij personen met narcolepsie en IH. De meeste proefpersonen die uitzonderlijk veel slingerden tijdens de snelwegrit, hadden meer dan 7 fouten op de SART, maar niet de kortste latentietijden op de MWT. Tenslotte kwam naar voren naar dat prestaties in de snelwegrit niet significant verschilden van die van gezonde controles, maar dat er grote individuele spreiding was binnen de patiëntengroep. Samengevat werd gesteld dat de SART een bruikbare test is ter vervanging van de MWT bij rijbewijskeuringen van personen met narcolepsie en IH. De SART is niet alleen goedkoper en minder belastend voor de patiënt, ook detecteert de SART extreem slingergedrag beter. Een belangrijke vereiste van een test voor de bepaling van rijgeschiktheid is om risicovolle bestuurders te kunnen identificeren en daarmee verkeersveiligheid te waarborgen. Op dit punt is de SART dus bruikbaarder dan de MWT. De SART en MWT zijn echter geen ideale objectieve testen voor het beoordelen van rijgeschiktheid, mede gezien de zwakke correlaties met de onderzochte indices van rijvaardigheid, dus blijft het meewegen van andere, subjectieve criteria van belang.

Rationale Residual effects of hypnotics on driving performance have been mainly determined in studies using a standardized driving test with healthy good sleepers. Responses to effects may differ, however, between insomniacs and healthy volunteers due to the underlying sleep disorder. In addition, a majority of insomniacs uses hypnotics chronically resulting in the development of tolerance to impairing effects. Impaired driving performance in healthy volunteers may then be an overestimation of the actual effects in insomniacs. Objectives The present study aims to compare the residual effects of zopiclone 7.5 mg on on-the-road driving performance of 16 middle-aged insomniacs chronically using hypnotics (chronic users), 16 middle-aged insomniacs not or infrequently using hypnotics (infrequent users), and 16 healthy, age matched, good sleepers (controls). Methods The study was conducted according to a 3 × 2 double-blind, placebo controlled crossover design, with three groups and two treatment conditions. Treatments were single oral doses of zopiclone 7.5 mg and placebo administered at bedtime (2330 hours). Between 10 and 11 h after administration subjects performed a standardized highway driving test. Results Zopiclone 7.5 mg significantly impaired on-the-road driving performance in both insomnia groups and healthy controls. The magnitude of impairment was significantly less in the chronic users group as compared with the controls. Conclusions The smaller magnitude of effects suggests that investigating residual effects of hypnotics in healthy volunteers may yield a minor overestimation of the actual effects in insomnia patients

Rationale Medication and illicit drugs can have detrimental side effects which impair driving performance. A drug’s impairing potential should be determined by well-validated, reliable, and sensitive tests and ideally be calibrated by benchmark drugs and doses. To date, no consensus has been reached on the issue of which psychometric tests are best suited for initial screening of a drug’s driving impairment potential. Objective The aim of this alcohol calibration study is to determine which performance tests are useful to measure drug-induced impairment. The effects of alcohol are used to compare the psychometric quality between tests and as benchmark to quantify performance changes in each test associated with potentially impairing drug effects. Methods Twenty-four healthy volunteers participated in a double-blind, four-way crossover study. Treatments were placebo and three different doses of alcohol leading to blood alcohol concentrations (BACs) of 0.2, 0.5, and 0.8 g/L. Results Main effects of alcohol were found in most tests. Compared with placebo, performance in the Divided Attention Test (DAT) was significantly impaired after all alcohol doses and performance in the Psychomotor Vigilance Test (PVT) and the Balance Test was impaired with a BAC of 0.5 and 0.8 g/L. The largest effect sizes were found on postural balance with eyes open and mean reaction time in the divided attention and the psychomotor vigilance test. Conclusions The preferable tests for initial screening are the DAT and the PVT, as these tests were most sensitive to the impairing effects of alcohol and being considerably valid in assessing potential driving impairment.

STUDY OBJECTIVE: To evaluate next-morning driving performance after middle-of-the-night use of zolpidem 3.5 mg in a buffered sublingual formulation (ZST). DESIGN: Single-center, four-period, randomized, double-blind, placebo-controlled, crossover study. SETTING: Maastricht University, The Netherlands. PARTICIPANTS: Forty healthy volunteers (20 females). INTERVENTIONS: Single dose of ZST administered in the middle of the night at 3 and 4 h before driving, zopiclone 7.5 mg at bedtime 9 h before driving, and placebo. MEASUREMENTS: Performance in a 100-km standardized highway driving test in normal traffic measuring standard deviation of lateral position (SDLP) - an index of weaving. Drug-placebo changes in SDLP > 2.5 cm were considered to reflect clinically relevant driving impairment. RESULT: For ZST, Max McNemar symmetry analyses showed that the proportion of drivers classified as impaired was increased 3 h after dosing (P < 0.012), but not 4 h after dosing. Mean increases in SDLP from placebo, although statistically significant, were small (1.46 cm [P < 0.0001] at 3 h and 0.83 cm [P = 0.0174] at 4 h). The morning after zopiclone, 45% of the drivers were classified as impaired with a mean increase in SDLP of 2.46 cm (P < 0.0001). There were no significant sex differences in effects of ZST and zopiclone. CONCLUSION: Zolpidem 3.5 mg in a buffered sublingual formulation has a minimal risk of impairing driving performance in the morning >/= 4 hours after middle-of-the night use. When taken 3 hours before driving, the drug may have impairing effects so caution should be exercised if medication is taken other than as indicated. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01106859; Trial Name: Driving Performance After Middle of the Night Administration of 3.5 mg Zolpidem Tartrate Sublingual Tablet; http://clinicaltrials.gov/ct2/show/NCT01106859. CITATION: Vermeeren A; Vuurman EF; Leufkens TR; Van Leeuwen CJ; Van Oers AC; Laska E; Rico S; Steinberg F; Roth T. Residual effects of low-dose sublingual zolpidem on highway driving performance the morning after middle-of-the-night use. SLEEP 2014;37(3):489-496.

The histaminergic involvement in selective processes underlying its role in human sensori-motor performance is largely unknown. Recently, selective effects of central H₁-inverse agonism on sensory visual processes were observed in electrophysiological--but not behavioral data; a discrepancy suggested to result from speeded response-choice related processes. This study attempts to establish the effects on visual processes and identify putative compensatory mechanisms related to increased visual and response-choice task demands by assessing H₁-inverse agonism induced changes in blood oxygenation level dependent (BOLD) response. Twelve participants received oral doses of dexchlorpheniramine 4 mg, lorazepam 1 mg, and placebo in a three-way crossover designed study. Brain activity was assessed for choice reaction time task performance in a 3 T magnetic resonance scanner 2 h after drug administration. Participants responded with their left or right hand and index or middle finger as indicated by the laterality of stimulus presentation and identity of the stimulus, respectively. Stimuli were intact or visually degraded and responses were compatible or incompatible with the laterality of stimulus presentation. Both dexchlorpheniramine and lorazepam affected the BOLD response in the occipital cortex indicating affected visual information processing. Dexchlorpheniramine decreased BOLD response in the dorsal precuneus and left precentral gyrus as part of a motor network, which however might not be interpreted as a compensatory mechanism, but may be the upstream consequence of impaired visual processing.

Z-drugs such as zopiclone are increasingly involved in forensic cases. Its degradation occurs in solvents and biological fluids. It is assumed that hydrolysis largely accounts for the breakdown of zopiclone in aqueous media. Therefore, a stability study in blood at different storage conditions (-20, 4, 20, and 40A degrees C) was performed to establish changes of the drug's concentration with time, also including its degradation product 2-amino-5-chloropyridine (ACP). As removal of the aqueous phase may stabilize molecules that are prone to hydrolysis, it was assessed whether the use of dried blood spots (DBS) may be an alternative for storing and analyzing zopiclone and ACP. Spiked and authentic blood samples and corresponding DBS were analyzed using fully validated LC-MS/MS assays. There was agreement between the measurement of zopiclone from either blood or matching DBS in freshly prepared samples. Results showed that zopiclone was unstable in blood at all storage temperatures except at -20A degrees C. Stability of zopiclone in spiked and authentic blood was increased in DBS compared to matching blood samples stored at the same condition. About 85 % of the initial concentration of zopiclone was still intact in DBS on day 8 at 20A degrees C. ACP was formed from zopiclone in equimolar amounts in both media. Therefore, determination of both zopiclone and ACP may be helpful to estimate the initial concentration in both media. Pre-analytical conditions have a major impact on the recovery of zopiclone from blood. With respect to its known advantages, DBS can be recommended as a valuable alternative for the determination of zopiclone from blood.

RATIONALE: P-glycoprotein (P-gp) is a drug efflux pump expressed, amongst others, on the luminal surface of the cerebral endothelial cells forming the blood-brain barrier. Studies in rodents have demonstrated that antihistamines that are substrates of the P-gp transporter display no or minor central nervous system (CNS) effects as compared to antihistamines that are not P-gp transporter substrates. OBJECTIVES: The present study explored whether P-gp contributes in similar ways to the occurrence of sedative effects of antihistamines in humans. METHODS: An fMRI study was conducted according to a double-blind, randomized, placebo-controlled, cross-over design in 13 healthy volunteers. Participants received cetirizine 15 mg (an antihistamine), verapamil 120 mg (a P-gp blocker), a combination of cetirizine + verapamil, and a placebo. Brain activity was assessed while conducting the attention network test (ANT) in a 3T magnetic resonance scanner. The ANT measures three independent attention domains: i.e., alerting, orienting, and executive attention. It was expected that the combined treatment of cetirizine with verapamil would prevent efflux of cetirizine from the CNS, thus increasing attentional impairment, as compared to cetirizine administered alone. RESULTS: The present study provides evidence that the P-gp transporter is involved in central antihistamine effects in humans. Participants were less alert during the combined treatment of cetirizine and verapamil as indicated by longer reaction times and decreased blood oxygen level-dependent response in the right superior temporal gyrus. CONCLUSION: It is concluded that the affinity for the P-gp transporter may contribute to the lower incidence of CNS side effects of certain antihistamines.

Rationale Suvorexant is a first-in-class orexin receptor antagonist for treating insomnia. There is a general concern that hypnotics may impair next-morning driving ability. Objective The objective of this study was to evaluate next-morning driving performance in older adults after single and repeated doses of suvorexant. Methods Double-blind, randomized, placebo-controlled, 4-period crossover study in 24 healthy volunteers (10 females), aged 65–80 years. Subjects were treated with suvorexant (15 and 30 mg) for eight consecutive nights, zopiclone 7.5 mg nightly on days 1 and 8, and placebo. Driving performance was assessed on days 2 and 9 (9 h after dosing) using a 1-h standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo differences in SDLP >2.4 cm were considered to reflect clinically meaningful driving impairment. Results Driving performance as measured by SDLP was not impaired following suvorexant. Mean drug–placebo differences in SDLP following suvorexant 15 and 30 mg on day 2 and 9 were 0.6 cm or less. Their 90 % CIs were all below the threshold of 2.4 cm for clinical relevance and included zero, indicating effects were not clinically meaningful or statistically significant. Symmetry analysis showed no significant differences between the number of participants who had SDLP differences >2.4 cm and those who had SDLP differences

The number of patients with Alzheimer's disease (AD) is increasing and so is the number of patients driving a car. To enable patients to retain their mobility while at the same time not endangering public safety, each patient should be assessed for fitness to drive. The aim of this study is to develop a method to assess fitness to drive in a clinical setting, using three types of assessments, i.e. clinical interviews, neuropsychological assessment and driving simulator rides. The goals are (1) to determine for each type of assessment which combination of measures is most predictive for on-road driving performance, (2) to compare the predictive value of clinical interviews, neuropsychological assessment and driving simulator evaluation and (3) to determine which combination of these assessments provides the best prediction of fitness to drive. Eighty-one patients with AD and 45 healthy individuals participated. All participated in a clinical interview, and were administered a neuropsychological test battery and a driving simulator ride (predictors). The criterion fitness to drive was determined in an on-road driving assessment by experts of the CBR Dutch driving test organisation according to their official protocol. The validity of the predictors to determine fitness to drive was explored by means of logistic regression analyses, discriminant function analyses, as well as receiver operating curve analyses. We found that all three types of assessments are predictive of on-road driving performance. Neuropsychological assessment had the highest classification accuracy followed by driving simulator rides and clinical interviews. However, combining all three types of assessments yielded the best prediction for fitness to drive in patients with AD with an overall accuracy of 92.7%, which makes this method highly valid for assessing fitness to drive in AD. This method may be used to advise patients with AD and their family members about fitness to drive.

It is well known that the sedative properties of antihistamines can differ considerably between individual drugs. Several factors have been suggested to determine the presence, absence, and/or magnitude of sedation by antihistamines. Research has suggested that the sedative effects caused by central H1 blockade partly depend on the availability of histamine competing for the same receptor and that this competition is affected by a mechanism related to sleep. Consequently, the present study was designed to compare the effects of evening and morning doses of the first-generation antihistamine hydroxyzine on cognition. It was expected that the sedative effect of hydroxyzine would be apparent in the evening after an evening dose but would be smaller in the morning after a morning dose owing to the greater release of histamine shortly after awakening. Eighteen participants (9 females) participated in a placebo-controlled, randomized, double-blind 3-way crossover design. Performance was assessed using several psychomotor tests: that is, divided attention task, critical tracking task, stop signal task, the attention network test, and the experimental attention switch task. Results demonstrated that evening doses of hydroxyzine impaired performance on the divided attention and the attention network test. Impairment after morning doses was generally larger in magnitude and affected performance measures in all tasks. It is concluded that hydroxyzine-induced impairment at t(max) is more prominent after morning doses compared with evening doses and that the present study could not present direct evidence to substantiate the hypothesis that histamine availability inversely affects the magnitude of antihistamine impairment.

The neurotransmitter histamine has been suggested to be involved in cognitive functioning. Generally, studies in animals have shown a decrease in performance after decreasing histamine neurotransmission and improved performance after increasing histamine neurotransmission. It is unclear, however, what role histamine plays in cognition in humans. Up until now, most data are derived from studies and reviews that aimed to assess the sedative potential of H(1)-antagonists and not the effects on cognition in particular. The objective of this paper is specifically to review which cognitive domains are affected by H(1)-antagonists. Taken together, 90 experimental studies on the performance effects of sedative H(1)-antagonists published between 1973 and 2009 were reviewed. Results showed that psychomotor skills and attention are most frequently impaired and memory the least. Tasks assessing memory that were affected usually required rapid responses. It was concluded that both the complexity of the task as well as the demand for information processing speed determines the sensitivity to the effects of central H(1)-antagonism. The importance of the sensitive cognitive domains to histaminergic dysfunction, as well as the relation between histamine related decrease in arousal and task performance deserve further research.