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A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance.

ABSTRACT: N-methyl-D-aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment-resistant major depressive disorder. This phase I, randomized, multicenter, placebo-controlled, five-period, crossover, single-dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60-min 100-km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10-min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p < 0.02). Rapastinel 900 and 1800 mg did not significantly affect simulated driving performance compared to placebo (both p > 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p < 0.002); ketamine significantly impaired driving compared to placebo (p = 0.0001). Results for the additional measures were similar to the primary end point. No new safety signals were observed for any study interventions. This first study of rapastinel effects on simulated driving found that rapastinel 900 and 1800 mg did not impair driving performance, but ketamine 0.5 mg/kg resulted in significantly impaired driving performance. Ketamine's effects on driving were maintained for at least 105 min, indicating that clinicians should be vigilant to prevent or postpone driving in patients after ketamine treatment.

SUBMITTER: Su S

PROVIDER: S-EPMC8742651 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveDaily cannabis users develop tolerance to some drug effects, but the extent to which this diminishes driving impairment is uncertain. This study compared the impact of acute cannabis use on driving performance in occasional and daily cannabis users using a driving simulator.MethodsWe used a within-subjects design to observe driving performance in adults age 25 to 45 years with different cannabis use histories. Eighty-five participants (43 males, 42 females) were included in the final analysis: 24 occasional users (1 to 2 times per week), 31 daily users and 30 non-users. A car-based driving simulator (MiniSim™, National Advanced Driving Simulator) was used to obtain two measures of driving performance, standard deviation of lateral placement (SDLP) and speed relative to posted speed limit, in simulated urban driving scenarios at baseline and 30 min after a 15 min ad libitum cannabis smoking period. Participants smoked self-supplied cannabis flower product (15% to 30% tetrahydrocannabinol (THC). Blood samples were collected before and after smoking (30 min after the start of smoking). Non-users performed the same driving scenarios before and after an equivalent rest interval. Changes in driving performance were analyzed by repeated measures general linear models.ResultsMean whole blood THC cannabinoids concentrations post smoking were use THC = 6.4 ± 5.6 ng/ml, THC-COOH = 10.9 ± 8.79 ng/mL for occasional users and THC = 36.4 ± 37.4 ng/mL, THC-COOH = 98.1 ± 90.6 ng/mL for daily users. On a scale of 0 to 100, the mean post-use score of subjective high was similar in occasional users and daily users (52.4 and 47.2, respectively). In covariate-adjusted analysis, occasional users had a significant increase in SDLP in the straight road segment from pre to post compared to non-users; non-users decreased by a mean of 1.1 cm (25.5 cm to 24.4 cm) while occasional users increased by a mean of 1.9 cm (21.7 cm to 23.6 cm; p = 0.02). Daily users also increased adjusted SDLP in straight road segments from baseline to post-use (23.2 cm to 25.0 cm), but the change relative to non-users was not statistically significant (p = 0.08). The standardized mean difference in unadjusted SDLP from baseline to post-use in the straight road segments comparing occasional users to non-users was 0.64 (95% CI 0.09 - 1.19), a statistically significant moderate increase. When occasional users were contrasted with daily users, the baseline to post changes in SDLP were not statistically significant. Daily users exhibited a mean decrease in baseline to post-use adjusted speed in straight road segments of 1.16 mph; a significant change compared to slight speed increases in the non-users and occasional users (p = 0.02 and p = 0.01, respectively).ConclusionWe observed a decrement in driving performance assessed by SDLP after acute cannabis smoking that was statistically significant only in the occasional users in comparison to the nonusers. Direct contrasts between the occasional users and daily users in SDLP were not statistically significant. Daily users drove slower after cannabis use as compared to the occasional use group and non-users. The study results do not conclusively establish that occasional users exhibit more driving impairment than daily users when both smoke cannabis ad libitum.

Project description:Driving is increasing across the world and road traffic accidents are a major cause of serious injuries and fatalities. The link between alcohol consumption and impaired driving has long been established and has led to legislation in many countries, with enforcement of legal limits based on blood alcohol concentration levels. Alcohol hangover research is an emerging field with a range of laboratory and naturalistic studies now clearly demonstrating the significant impairments that can result from hangover, even when alcohol levels are measured at or close to zero the day following a social drinking occasion. Driving is a commonplace activity but requires competency with a range of complex and potentially demanding tasks. Driving impaired can have serious consequences, including death and serious injury. There have been only limited alcohol hangover driving studies. The studies presented examined the consequences of alcohol hangover with a driving simulator contrasting a group with zero residual alcohol (N = 26) next day and another with residual alcohol (N = 26) assessed with breathalyzer in the morning before undertaking a 20 min commute to work. All participants completed a morning drive after a night without alcohol consumption and another after a night of social drinking. The driving scenarios were relatively demanding including traffic and pedestrians, traffic lights and other potential hazards in a mixed rural and urban journey. Subjective hangover and workload were assessed in addition to a range of driving performance variables, including divided attention, steering control and driving violations. Analyses contrasted driving in the no alcohol condition with the residual alcohol condition. The combined groups data (N = 52) was contrasted with the zero and residual alcohol groups. Significant contrasts were found for a range of driving measures, including divided attention, vehicle control, and driving violations as well as perceived workload. The pattern of impairment was broadly similar across both groups, indicating that whether or not residual alcohol was present, consistent driving impairment was seen. The relatively high number of significant variables may reflect the increased cognitive demand of the 20 min commute drive including busy and complex urban environments. This was also reflected in the significant increase in perceived workload recorded across the 6 dimensions of the National Aeronautics and Space Administration Task Load Index (NASA-TLX). Associations between subjective measures and driving performance with hangover suggested a potential lack of awareness of impairment, though were limited in number. The overall findings indicate that the levels of impairment seen reflect those seen with alcohol impaired driving, even when breath alcohol is zero.

Project description:PurposeTo compare radiologists' diagnostic accuracy and recall rates for breast tomosynthesis combined with digital mammography versus digital mammography alone.Materials and methodsInstitutional review board approval was obtained at each accruing institution. Participating women gave written informed consent. Mediolateral oblique and craniocaudal digital mammographic and tomosynthesis images of both breasts were obtained from 1192 subjects. Two enriched reader studies were performed to compare digital mammography with tomosynthesis against digital mammography alone. Study 1 comprised 312 cases (48 cancer cases) with images read by 12 radiologists; study 2, 312 cases (51 cancer cases) with 15 radiologists. Study 1 readers recorded only that an abnormality requiring recall was present; study 2 readers had additional training and recorded both lesion type and location. Diagnostic accuracy was compared with receiver operating characteristic analysis. Recall rates of noncancer cases, sensitivity, specificity, and positive and negative predictive values determined by analyzing Breast Imaging Reporting and Data System scores were compared for the two methods.ResultsDiagnostic accuracy for combined tomosynthesis and digital mammography was superior to that of digital mammography alone. Average difference in area under the curve in study 1 was 7.2% (95% confidence interval [CI]: 3.7%, 10.8%; P < .001) and in study 2 was 6.8% (95% CI: 4.1%, 9.5%; P < .001). All 27 radiologists increased diagnostic accuracy with addition of tomosynthesis. Recall rates for noncancer cases for all readers significantly decreased with addition of tomosynthesis (range, 6%-67%; P < .001 for 25 readers, P < .03 for all readers). Increased sensitivity was largest for invasive cancers: 15% and 22% in studies 1 and 2 versus 3% for in situ cancers in both studies.ConclusionAddition of tomosynthesis to digital mammography offers the dual benefit of significantly increased diagnostic accuracy and significantly reduced recall rates for noncancer cases.Supplemental materialhttp://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120674/-/DC1.

Project description:The number of older drivers is steadily increasing, and advancing age is associated with a high rate of automobile crashes and fatalities. This can be attributed to a combination of factors including decline in sensory, motor, and cognitive functions due to natural aging or neurodegenerative diseases such as HIV-Associated Neurocognitive Disorder (HAND). Current clinical assessment methods only modestly predict impaired driving. Thus, there is a need for inexpensive and scalable tools to predict on-road driving performance. In this study EEG was acquired from 39 HIV+ patients and 63 healthy participants (HP) during: 3-Choice-Vigilance Task (3CVT), a 30-min driving simulator session, and a 12-mile on-road driving evaluation. Based on driving performance, a designation of Good/Poor (simulator) and Safe/Unsafe (on-road drive) was assigned to each participant. Event-related potentials (ERPs) obtained during 3CVT showed increased amplitude of the P200 component was associated with bad driving performance both during the on-road and simulated drive. This P200 effect was consistent across the HP and HIV+ groups, particularly over the left frontal-central region. Decreased amplitude of the late positive potential (LPP) during 3CVT, particularly over the left frontal regions, was associated with bad driving performance in the simulator. These EEG ERP metrics were shown to be associated with driving performance across participants independent of HIV status. During the on-road evaluation, Unsafe drivers exhibited higher EEG alpha power compared to Safe drivers. The results of this study are 2-fold. First, they demonstrate that high-quality EEG can be inexpensively and easily acquired during simulated and on-road driving assessments. Secondly, EEG metrics acquired during a sustained attention task (3CVT) are associated with driving performance, and these metrics could potentially be used to assess whether an individual has the cognitive skills necessary for safe driving.

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A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance.

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