Association between road traffic accidents and drugs belonging to the antiseizure medications class: A pharmacovigilance analysis in VigiBase.

AIMS: Due to their central mechanism of action, antiseizure medications (ASMs) could lead to adverse effects likely to impair driving skills. Their extended use to neuropsychiatric disorders makes it a class of drugs to monitor for their road traffic accidental (RTA) potential. We aimed to assess the reporting association between ASMs and RTAs using the World Health Organization pharmacovigilance database (VigiBase). METHODS: We performed a disproportionality analysis to compute adjusted reporting odds ratios to evaluate the strength of reporting association between ASMs and RTAs. A univariate analysis using the reporting odds-ratio was used to assess drug-drug interactions between ASMs and RTAs. RESULTS: There were 1 341 509 reports associated with at least 1 ASM in VigiBase of whom 2.91‰ were RTAs reports. Eight ASMs were associated with higher reporting of RTAs compared to others (ranging from 1.35 [95% confidence interval 1.11-1.64] for lamotrigine to 4.36 [95% confidence interval 3.56-5.32] for cannabis). Eight significant drug-drug interactions were found between ASMs and the onset of RTA, mainly involving CYP450 induction. CONCLUSION: A significant safety signal between RTAs and some ASMs was identified. Association of several ASMs might further increase the occurrence of RTA. ASMs prescription in patients with identified risk factors of RTA should be considered with caution. Study number: ClinicalTrials.gov, NCT04480996.

Primary insomnia patients' performances during simulated car following and urban driving in the afternoon.

According to epidemiological studies, insomnia is associated with an increase in risk of traffic accidents. Recent investigations revealed that patients with insomnia had driving performance impairment under monotonous conditions. However, it is unclear whether other driving abilities may be impacted by insomnia, especially those needing more attentional resources than those involved in monotonous driving. Other findings revealed that impaired performances are more likely to occur with the increase of cognitive demands. However, such tests did not reflect difficulties in situations of everyday life expressed by patients with insomnia, such as driving in an urban environment with traffic and critical situations. Therefore, behaviour in situations encountered in everyday life has to be explored. The aim of the present study was to assess driving performances of patients with insomnia in daily routine tasks such as urban and car-following tests. For this purpose, 15 patients with insomnia and 16 good sleepers performed an urban test of driving with original risk scenarios and a car-following test during the middle afternoon. No significant behavioural difference between patients with insomnia and good sleepers has been found in both the urban test and the car-following test, showing that patients with insomnia have no impairment in behaviour implicated in daily contexts driving tasks of short period of time performed in the late afternoon. Although our results provide a first step towards knowledge of behavioural performance during daily routine driving tasks in patients with insomnia, future studies are needed using on-the-road driving tests and/or different population of patients with insomnia before generalisation.

Psychotropic Polypharmacy in Adults 55 Years or Older: A Risk for Impaired Global Cognition, Executive Function, and Mobility.

OBJECTIVES: With their broad spectrum of action, psychotropic drugs are among the most common medications prescribed to the elderly. Consequently, the number of older adults taking multiple psychotropic drugs has more than doubled over the last decade. To improve knowledge about the deleterious effects of psychotropic polypharmacy, we investigated whether there is a threshold number of psychotropic molecules that could lead to impairment of global cognition, executive function, or mobility. Furthermore, relationships between the number of psychotropic molecules and cognitive and mobility impairment were examined. DESIGN: Cross-sectional study. SETTING: University Hospital of Caen (France) and advertisements in medical offices. PARTICIPANTS: Community-dwelling older adults 55 years and older (n = 177; 69.8 ± 9.3 years; 81% women). MEASUREMENTS: Number of psychotropic molecules taken daily, global cognition assessed with the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), processing speed with the Trail Making Test (TMT) A, executive function with the TMT B and TMT B-A, and mobility with the Time Up and Go (TUG). The threshold numbers of psychotropic molecules were determined by ROC curves analysis. Based on these threshold values, multinomial logistic regression adjusting for covariates was then performed. RESULTS: Logistic regressions showed that the threshold of two daily psychotropic molecules, identified by the ROC curves analysis, increases the risk of impaired executive function (p = .05 and.005 for the TMT B and TMT B-A, respectively), global cognition (p = .006 and.001 for the MMSE and MoCA, respectively), and mobility (p = .005 for the TUG), independent of confounding factors, including comorbidities. Furthermore, psychotropic polypharmacy would affect mobility through executive functions. CONCLUSION: Impairment of global cognition, executive function, and mobility when as few as two psychotropic molecules are consumed in relatively healthy young older adults should alert physicians when prescribing combinations of psychotropic medications.

Effect of sleep deprivation after a night shift duty on simulated crisis management by residents in anaesthesia. A randomised crossover study.

BACKGROUND: Sleep deprivation has been associated with an increased incidence of medical errors and can jeopardise patients' safety during medical crisis management. The aim of the study was to assess the effect of sleep deprivation on the management of simulated anaesthesia crisis by residents in anaesthesiology. METHODS: A randomised, comparative, monocentric crossover study involving 48 residents in anaesthesia was performed on a high fidelity patient simulator. Each resident was evaluated in a sleep-deprived state (deprived group, after a night shift duty) and control state (control group, after a night of sleep). Performance was assessed through points obtained during crisis scenario 1 (oesophageal intubation followed by anaphylactic shock) and scenario 2 (anaesthesia-related bronchospasm followed by ventricular tachycardia). Sleep periods were recorded by actigraphy. Two independent observers assessed the performances. The primary endpoint of the study was the score obtained for each scenario. RESULTS: Resident's crisis management performance is associated with sleep deprivation (scenario 1: control=39 [33-42] points vs. deprived=26 [19-40] points, P=0.02; scenario 2: control=21 [17-24] vs. deprived=14 [12-19], P=0.01). The main errors observed were: error in drug administration and dose, delay in identification of hypotension, and missing communication with the surgical team about situation. CONCLUSIONS: The present study showed that sleep deprivation is associated with impairment of performance to manage crisis situations by residents in anaesthesia.

Polypharmacy Cut-Off for Gait and Cognitive Impairments.

BACKGROUND: Polypharmacy is a well-established risk factor for falls, and these are one of the major health problems that affect the quality of life as people age. However, the risk of mobility and cognitive impairments consecutive to polypharmacy has been little addressed, despite the association between these adverse outcomes and falls. Moreover, the rare polypharmacy cut-offs were all but one arbitrarily determined. OBJECTIVE: Studying relationships between polypharmacy and both mobility and cognitive impairments, and statistically determining a cut-off point in the number of medicinal molecule beyond which polypharmacy has deleterious consequences with respect to mobility and cognitive impairment. METHODS: We enrolled 113 community-dwelling adults aged 55 years and older with a fall history, with or without injury, in the previous year. We carefully collected information about daily medicinal molecules taken. We assessed basic mobility and global cognition with the Time-Up-and-Go and the Montreal Cognitive Assessment (MoCA) test, respectively (clinicaltrials.gov NCT02292316). RESULTS: Timed-Up and Go test and MoCA scores were both significantly correlated with the number of molecule, used. Receiver Operating Characteristic curves indicate, with high prediction (p < 0.002), that daily consumption of five or more molecules is associated with risk for both impaired mobility and global cognition. These relationships were independent of the number of comorbidities and of the pharmacological class. CONCLUSION: Community-dwelling adults aged 55 years and older who take five or more daily medicinal molecules are at high risk for both mobility and cognitive impairments. Physicians and patients should be aware of these new findings, especially when there are multiple prescribers involved in the care of the patient.

Effects of acute administration of melatonin on attentional, executive, and working memory processes in rats.

Melatonin is a potential candidate for additive therapy in cancer, neurodegenerative, and mental disorders requiring administration during the activity phase. Nevertheless, because melatonin has mostly been used as a hypnotic, less is known about its cognitive effects. In this study, we investigated the effects of acute administration of melatonin on executive, attentional, and working memory processes in rats during the activity phase. Three doses of melatonin (6, 18, or 36 mg/kg) were tested and compared to a saline control group in two behavioral tests: the Attentional Set Shifting task (for attentional and executive processes assessment) and the Spontaneous Alternation test in a Y-maze (for working memory assessment). Our results revealed that, up to 36 mg/kg, the acute administration dose of melatonin did not alter the attentional or executive processes, nor the working memory in rats. Consequently, this result may be encouraging for the use of melatonin in additive therapy during the activity phase.

Specific EEG sleep pattern in the prefrontal cortex in primary insomnia.

OBJECTIVE: To assess the specific prefrontal activity in comparison to those in the other main cortical areas in primary insomnia patients and in good sleepers. METHODS: Fourteen primary insomnia patients and 11 good sleepers were included in the analysis. Participants completed one night of polysomnography in the sleep lab. Power spectra were calculated during the NREM (Non-rapid eyes movements) and the REM (Rapid eyes movements) sleep periods at prefrontal, occipital, temporal and central electrode positions. RESULTS: During the NREM sleep, the power spectra did not differ between groups in the prefrontal cortex; while primary insomnia patients exhibited a higher beta power spectrum and a lower delta power spectrum compared to good sleepers in other areas. During the REM sleep, the beta1 power spectrum was lower in the prefrontal cortex in primary insomnia patients compared to good sleepers; while no significant difference between groups was obtained for the other areas. CONCLUSIONS: The present study shows a specific prefrontal sleep pattern during the whole sleep period. In addition, we suggest that primary insomnia patients displayed a dysfunction in the reactivation of the limbic system during the REM sleep and we give additional arguments in favor of a sleep-protection mechanism displayed by primary insomnia patients.

Impaired driving performance associated with effect of time duration in patients with primary insomnia.

STUDY OBJECTIVES: To evaluate driving performance and psychomotor vigilance in patients with primary insomnia. DESIGN: After 1 night of polysomnography, participants performed a 1-h simulated monotonous driving task and a psychomotor vigilance task (PVT). Self-ratings of sleepiness, mood, and driving performance were completed. SETTING: This study was conducted at the CHU of Caen Sleep Unit and the University of Caen. PARTICIPANTS: Twenty-one primary insomnia patients and 16 good sleepers. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: Results revealed a larger standard deviation of lateral position (P = 0.023) and more lane crossings (P = 0.03) in insomnia patients than in good sleepers. Analyses of effect of time on task performance showed that the impairment in patients occurred after 20 min of driving, which was not the case for good sleepers. No difference between groups was found for the PVT, neither for the mean reaction time (RT) (P = 0.43) nor the number of lapses (P = 0.21) and the mean slowest 10% 1/RT (P = 0.81). Patients rated their sleepiness level higher (P = 0.06) and their alertness level lower (P = 0.007) than did good sleepers (P = 0.007). The self-evaluation of the driving performance was not different between groups (P = 0.15). CONCLUSIONS: These findings revealed that primary insomnia is associated with a performance decrement during a simulated monotonous driving task. We also showed that patients are able to drive safely only for a short time. It appears advisable for clinicians to warn patients about their impaired driving performance that could lead to an increased risk of driving accidents.

Effects of three therapeutic doses of codeine/paracetamol on driving performance, a psychomotor vigilance test, and subjective feelings.

RATIONALE: Some recent pharmacoepidemiological studies revealed an elevated risk of driving accidents after opioid analgesics uses. Among analgesics, codeine is often associated with paracetamol in numerous pharmaceutical specialties. OBJECTIVES: The objective of this study was to evaluate the dose-effect relationship of three usual therapeutic doses of codeine/paracetamol on driving ability, psychomotor performance, subjective alertness, in link with blood concentrations in healthy young volunteers. METHODS: Driving performance, responses to psychomotor vigilance tests, and scales reflecting alertness were evaluated during the morning after drug intake in a double-blind, randomized, placebo-controlled study. Sixteen healthy volunteers (23.4 ± 2.7 years old, 8 men and 8 women) participated in this balanced, cross-over study. Three doses of codeine/paracetamol (20/400, 40/800, 60/1200 mg) were evaluated against placebo. Two blood samples were collected, 1 and 4 h after drug intake. In serum, codeine and morphine concentrations were determined in serum using high-performance liquid chromatography electrospray ionization-tandem mass spectrometry, and paracetamol concentrations using fluorescence polarization immunoassay. RESULTS: Driving and psychomotor performance were not affected by any of the three codeine/paracetamol doses. However, significant, though modest, correlations were observed between the driving parameters and both morphine and codeine blood concentrations. CONCLUSIONS: This study did not reveal any significant impairment in performance due to the three therapeutic doses used in healthy young volunteers. However, the relationships between drug blood concentration and behavioral measures suggest that an inter-subject variability in blood concentration may influence the power of the observed drug effect.

Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects.

RATIONALE: Although hypnotics are primarily used by older people, the residual effects the morning after a single nighttime intake of the two most commonly prescribed hypnotics, zolpidem (Zp) and zopiclone (Zc), on older middle-aged drivers have not been evaluated and compared. METHODS: Sixteen healthy subjects, 55 to 65 years of age, participated in this double-blind, balanced, cross-over study. Zc (7.5 mg), Zp (10 mg) and flunitrazepam (Fln) (1 mg) or a placebo was administered at each subject's home at 11.00 pm. The next morning, at 9.00 am, the subjects had to drive in a simulated monotonous driving environment for 1 h. During each morning session, two blood samples were collected, and subjective feelings of alertness were completed three times. RESULTS: In comparison to placebo, Zp and Zc equivalently and significantly impaired the standard deviation of lateral position, the standard deviation of speed and the number of road exits. Detectable blood concentrations were found with Zp in 11 subjects at 8.30 am and at 1.30 pm. The subjective alertness factor was significantly impaired with Zp. CONCLUSIONS: This is the first study revealing residual effects of Zp on driving performance in ageing drivers which are similar to that of Zc. Studying the effects of medication in different age ranges appears useful to complete the studies on behavioural-pharmacological effects of medication. To reduce the incidence of driving accidents due to prescription drugs, patients should be warned at the time of treatment initiation that they should avoid driving.

Impaired smooth pursuit in schizophrenia results from prediction impairment only.

BACKGROUND: Oculomotor abnormality is one of the endophenotypes in schizophrenia. The predictive component of smooth pursuit can be studied by comparing the gain, i.e., the ratio of smooth eye position to target position, during predictable (pure sinusoidal) and unpredictable (pseudorandom) target motions. The aim of this experiment was to study predictive and nonpredictive components of smooth pursuit in two groups of schizophrenia patients compared with control subjects. METHODS: Fifty-one schizophrenia patients (40 nondeficit and 11 deficit) and 21 control subjects were studied. During a predictable task, subjects were asked to track a sinusoidal target (.4 Hz). For the unpredictable task, the pseudorandom target motion consisted of five superimposed sinusoidal waveforms (.1, .2, .4, .6, and .8 Hz). The smooth eye position (eye position without saccades), gain, and phase were calculated for each frequency in each participant and for both tasks. RESULTS: The mean sinusoidal smooth eye position gain was significantly lower in patients than in control subjects with no significant difference between deficit and nondeficit patients. During the pseudorandom task, all groups had a similar gain at .4 Hz. CONCLUSIONS: Our study reveals that patients have a normal nonpredictive component of smooth pursuit, regardless of their level of negative symptoms. In contrast, the predictive mechanisms involved in eye pursuit were impaired in schizophrenia patients. These results indicate that poor pursuit performance during smooth pursuit is primarily a consequence of a predictive problem and is not related to the ability to generate an accurate pursuit maintenance response.

Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study.

RATIONALE: The effects of hypnotic drugs on driving performance are most often evaluated on young healthy subjects by using a monotonous motorway driving test. The effects of drugs in urban driving situations have not yet been evaluated in any age group. Our objectives were to assess residual effects of the most prescribed hypnotics, zolpidem and zopiclone, on older middle-age drivers' capacities in an urban situation. MATERIALS AND METHODS: Sixteen healthy subjects aged 55 to 65 years underwent this double-blind, balanced, cross-over study. Zopiclone (7.5 mg), zolpidem (10 mg), and flunitrazepam (1 mg; used as positive control) or a placebo were administered at each subject's home at 11:00 PM: under the supervision of an investigator. The next morning, the subjects had to drive in a simulated urban environment where accident scenarios were introduced. Accident scenarios were implemented using data from real accident cases. RESULTS: Hypnotics did not significantly increase the number of collisions. However, significantly higher speeds were found with zopiclone and flunitrazepam; moreover, zolpidem and zopiclone induced modifications of the lateral position of the car on the road. CONCLUSIONS: This study did not reveal any major residual effects of the hypnotics studied on driving performance in aging drivers. However, the urban driving situations used here for the first time in the evaluation of drugs revealed some modifications in driving habits which could lead to risky behavior. It thus appears that urban driving simulations are useful for gaining knowledge about the effects of drugs on driving behavior.

Total sleep deprivation effect on disengagement of spatial attention as assessed by saccadic eye movements.

OBJECTIVE: Previous research has shown that total sleep deprivation (TSD) of short duration (one night) affects performance to some cognitive tasks subserved by a fronto-parietal network. The aim of our study was to assess the effects of TSD on visuo-spatial attention, which is a cognitive task involving this network. Specifically, the disengagement of spatial attention was investigated with gap and overlap paradigms of saccadic eye movements. METHODS: Ten healthy young male subjects performed the two tasks the morning after a normal night and after a TSD night. The study was conducted using a balanced, crossover design. RESULTS: TSD significantly increased the gap effect (difference of latency between overlap and gap). CONCLUSIONS: This result can be interpreted as an impaired disengagement of attention after TSD. As the peak velocity, which is an indicator of alertness, was not altered by TSD, the impairment in the disengagement of spatial attention does not result from a decrease in alertness. SIGNIFICANCE: This study shows that saccadic eye movements enable studying alertness and disengagement of spatial attention simultaneously. The idea that specific brain areas are affected by TSD is confirmed by our results.

The saccadic component of ocular pursuit is influenced by the predictability of the target motion in humans.

Predictive control is an important aspect of the smooth pursuit eye movements: it has been shown that when the target motion is composed of a mixture of sinusoids of different frequencies it becomes unpredictable and there is a decline in gain for the lowest frequencies but not for the highest one. Using such a pseudo-random paradigm we studied the effect of predictability of the target motion on the saccadic component of pursuit. For both the saccadic and the smooth components of pursuit, we observed that the gains for the lowest frequencies were significantly lower than the gain for the highest frequency. Thus, predictability of the motion of a visual target seems to influence both the smooth pursuit component and the saccadic component of ocular pursuit in the same way.