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Objective Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. Method Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry ( VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms ( SANS) and Scale for the Assessment of Positive Symptoms ( SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. Results Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex ( DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. Conclusion Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC. [ABSTRACT FROM AUTHOR]

This study examines the static position sense from the ankle joint following a unilateral exhaustive stretch-shortening cycle (SSC)-type exercise involving mostly the triceps surae muscle group. Fatigue effects were quantified within the exercised and non-exercised leg through a maximal isometric voluntary plantarflexion test (MVC) performed immediately before (Pre) and after the SSC exercise, and repeated 2 (D2) and 8 (D8) days later. The static position sense test consisted in active reproductions with the non-exercised ankle of two target dorsiflexed positions (small and large) previously maintained with either the non-exercised ( control procedure) or the exercised ankle ( fatigue procedure). This test was carried out at Pre, D2, and D8. At D2, the MVC test revealed significant decreases in voluntary soleus muscle activity and peak plantarflexion force. The position sense test showed no error in reproduction accuracy in the control procedure. In contrast, the fatigue procedure revealed an overestimation of the large dorsiflexed position, only, with an associated increase of the agonist tibialis muscle activity. In agreement with the antagonist (stretched) muscle influence on the position sense, this overestimation is mostly attributed to potential SSC fatigue effects on ascending proprioceptive afferents issued from the exercised/inflamed antagonist muscles. [ABSTRACT FROM AUTHOR]

Adjustment Disorders With Anxiety (ADWA) account for almost 10% of psychologically motivated consultations in primary care. The aim of this double-blind randomised parallel group study was to compare (non-inferiority test) the efficacies of etifoxine, a non-benzodiazepine anxiolytic drug, and lorazepam, a benzodiazepine, for ADWA outpatients followed by general practitioners. 191 outpatients (mean age: 43, female: 66%) were assigned to receive etifoxine (50 mg tid) or lorazepam (0.5-0.5-1 mg /day) for 28 days. Efficacy was evaluated on days 7 and 28 of the treatment. The main efficacy assessment criterion was the Hamilton Rating Scale for Anxiety score (HAM-A) on Day 28 adjusted to Day 0. The anxiolytic effect of etifoxine was found not inferior to that of lorazepam (HAM-A score decrease: 54.6% vs 52.3%, respectively, p = 0.0006). The two drugs were equivalent on Day 28. However, more etifoxine recipients responded to the treatment (HAM-A score decreased by ≥50%, p = 0.03). Clinical improvement (based on Clinical Global Impression scale CGI, Social Adjustment Scale Self-Report SAS-SR, and Sheehan scores) was observed in both treatment arms, but more etifoxine patients improved markedly (p = 0.03) and had a marked therapeutic effect without side effects as assessed by CGI, p = 0.04. Moreover, 1 week after stopping treatment, fewer patients taking etifoxine experienced a rebound of anxiety, compared to lorazepam (1 and 8, respectively, p = 0.034). Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary Anti-psychotic medications are an important therapeutic option for many individuals with schizophrenia. Recently, a growing interest has been observed on weight gain, which is now a well-known adverse effect of many anti-psychotics. As obesity is frequently a comorbid condition with schizophrenia, patients with schizophrenia are inherently at increased risk of developing obesity-related conditions such as cardiovascular disease and type 2 diabetes. The consequences of excessive weight gain (obesity) associated with anti-psychotic drugs are likely to include adverse effects on health, social burden and poor compliance or even discontinuation of therapy by the patients. In this article, we focus on different aspects of weight gain induced by anti-psychotics. This review comprises the following sections: (i) the pharmacological basis of anti-psychotic-induced weight gain and metabolic effects with a review of all anti-psychotics that can be used in patients with schizophrenia; (ii) the clinical impact of the body weight gain (morbidity, psychatric consequences, mortality); (iii) the management of obesity (identification of risk factors including pharmacogenetics, diet, behavioural therapies, pharmacological approach). An understanding of these aspects is important for those who prescribe anti-psychotics in order to provide the patient the best therapeutic management. [ABSTRACT FROM AUTHOR]

This paper describes the psychomotor and amnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects. Forty-eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list). Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects. These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam. [ABSTRACT FROM AUTHOR]

Compares the pharmacokinetics of sabeluzole, a benzothiazole derivative in healthy volunteers and subjects with severe hepatic dysfunction. Impact of chronic liver disease on memory and learning activities; Correlation between CYP2D6 activity and hepatic dysfunction.

1. Apomorphine (1 and 5 micrograms kg-1) and placebo were given to nine normal volunteers, using a Latin-square design and double-blind procedures. The visual perception of static and moving patterns (static and motion contrast sensitivity) was evaluated before and 15 min after the dose administration. 2. Apomorphine (1 and 5 micrograms kg-1), as compared with placebo, led to a significant overall reduction of the visual perception of movement. This effect was dose-related, and apomorphine (5 micrograms kg-1) induced a more pronounced decrease in the visual perception of movement than apomorphine (1 microgram kg-1). With apomorphine (5 micrograms kg-1), the reduction was more pronounced for low spatial frequencies, and was linearly inversely correlated to the spatial frequency for a temporal frequency of 3 Hz. Finally, no significant effect of apomorphine was observed for sensitivity to static patterns. 3. Several non exclusive hypotheses may be suggested: The effects of apomorphine may result from stimulation of retinal D1- and/or D2-dopaminergic receptors. Apomorphine may increase the surround inhibition of ganglion cells' receptive-fields. This modification of the centre-surround balance may explain the decrease in contrast sensitivity for low spatial frequencies. The specific effects of apomorphine on the visual perception of movement support the hypothesis that apomorphine preferentially affects the magnocellular pathway which mediates sensitivity to moving patterns. [ABSTRACT FROM AUTHOR]

Yawning and spontaneous blink rate (SBR) are two physiological reflexes which have been incompletely examined but one neurobiological step of these two behaviours seems, at least in part, dopamine-dependent. The reference dopaminergic agonist, apomorphine hydrochloride (0.5, 1, and 2 micrograms kg-1 s.c.), was compared with a placebo in a double-blind latin-square design, and was shown to induce yawning and increase SBR in a population of eight healthy volunteers. These two behavioral effects were not dose-related. The individual SBR differences were correlated with the individual number of yawns for all the four treatments at the 10-30 min interval. Thus, parallel yawning and SBR behaviour suggests a similar pharmacological mechanism. Apomorphine- induced yawning and blinking may be therefore of use in the evaluation of central dopaminergic pathways in man. [ABSTRACT FROM AUTHOR]

Human Psychopharmacology 2006. DOI: 10.1002/hup.757 It has come to the attention of the authors that this published article contained an error. On Page 146, right hand column, second paragraph, the equivalence margins should have appeared as [-2.5; + 2.5]. [ABSTRACT FROM AUTHOR]

For management of osteoarticular infections, rifampicin appears to be the key antibiotic. We aimed to evaluate the actual rifampicin dosing regimens using a population pharmacokinetic model of rifampicin in patients with osteoarticular infections. A Monte Carlo simulation study was performed to simulate steady-state plasma concentrations for 1000 randomly sampled subjects using a total daily dose between 600 and 1200 mg (600 and 900 mg once daily, 450 and 600 mg twice daily, or 300 mg 3 times daily). When rifampicin was administered with fusidic acid, the pharmacokinetic/pharmacodynamic (PK/PD) target (area under the curve/minimum inhibitory concentration ≥952) was achieved with all tested dosing regimen, except 600 mg once daily for Staphylococcus epidermidis infections. Without coadministration of fusidic acid, none of tested dosing regimens achieved this PK/PD target. Most recommended drug-dosing regimens allow attaining the fixed area under the curve/minimum inhibitory concentration target for Staphylococcus aureus and coagulase-negative staphylococcal osteoarticular infections. In future studies, PK/PD target for osteoarticular infections in human should also be confirmed., (© 2020 The British Pharmacological Society.)

Aims: Rifampicin represents the key antibiotic for the management of osteoarticular infections. An important pharmacokinetic variability has already been described, particularly for absorption and metabolism. All previous pharmacokinetic studies have been focused only on patients treated for tuberculosis. The objective of the present study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, which has not been investigated to date., Method: Rifampicin concentrations were collected retrospectively from 62 patients treated with oral rifampicin 300 mg three times daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters. Demographic data, infection characteristics and antibiotics taken in addition to rifampicin antibiotics were investigated as covariates., Results: A one-compartment model, coupled to a transit absorption model, best described the rifampicin data. Fusidic acid coadministration was identified as a covariate in rifampicin pharmacokinetic parameters. The apparent clearance and apparent central volume of distribution mean values [95% confidence interval (CI)] were 5.1 1 h -1 (1.2, 8.2 1 h -1 )/23.8 l (8.9, 38.7 l) and 13.7 1 h -1 (10.6, 18.0 1 h -1 )/61.1 1 (40.8, 129.0 1) for patients with and without administration of fusidic acid, respectively. Interindividual variability (95% CI) in the apparent clearance and apparent central volume of distribution were 72.9% (49.5, 86.0%) and 59.1% (5.5, 105.4%), respectively. Residual variability was 2.3 mg l -1 (1.6, 2.6 mg l -1 )., Conclusion: We developed the first population pharmacokinetic model of rifampicin in patients with osteoarticular infections. Our model demonstrated that fusidic acid affects rifampicin pharmacokinetics, leading to potential high drug exposure. This finding suggests that fusidic acid dosing regimens should be reconsidered., (© 2016 The British Pharmacological Society.)

Aims: To assess the sleepiness induced by pramipexole, a D2/D3-dopamine receptor agonist commonly used in Parkinson's disease and restless legs syndrome, without the problem of the confounding factors related to the disease., Methods: Placebo, bromocriptine (2.5 mg), L-dopa (100 mg) and pramipexole (0.5 mg) were administered in a single oral dose on four separate days, with at least a 2-week wash-out period in a randomized cross-over design. Induced somnolence was assessed using Multiple Sleep Latency Test (MSLT) and subjective scaling of vigilance. Twelve male subjects (26.3 +/- 5.5 years old) without anxiety, mood, sleep or sedation disorders were enrolled., Results: Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [-6.1 min (-9.8, -2.4), P = 0.002] and 5 h 30 min [-5.6 min (-7.7, -3.5), P = 0.003] after administration. In addition, the total duration of sleep during the tests was higher with pramipexole than with placebo [+6.0 min (2.3, 9.7), P < 0.001]. These differences were not observed with L-dopa and bromocriptine in comparison with placebo. The induced sleepiness was not associated with an increase in subjective somnolence scaling, indicating that this adverse event may occur without prior warning., Conclusions: These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects, independent of disease-related sleep dysfunction.

Aim: To test T1 intensity variations induced by levodopa administration in the regional fixation area in the human brain., Method: Using non-invasive magnetic resonance imaging (MRI) technique [T1-weighted sequence MPRAGE; TE/TR/TI = 5/25/800 ms; impulsion angle = 15 degrees; field of view = 256 x 230 x 180 mm3; acquisition matrix = 256 x 192 x 104; reconstruction matrix = 256 x 256 x 128), we tested changes in the T1 MRI signal intensity resulting in changes in the grey matter automatic classification after administration of a single dose of 100 mg of levodopa by a voxel-based morphometry method (VBM) in 12 healthy subjects., Results: The VBM analysis demonstrated an increased number of voxels attributed to grey matter after levodopa administration in an anatomical cluster which included substantia nigra, tegmental ventral area and subthalamic nucleus bilaterally, the principal origin and first relay nuclei of projections in brain dopaminergic systems (t = 8.61; corrected for all grey matter volume P < 0.001)., Conclusion: Our results suggest that levodopa administration could induce an MRI T1 signal intensity variation that is not evident to the naked eye, but is detectable by measuring local signal intensities. Possible clinical applications are discussed.

Objective: Bupropion sustained release is considered to be a weak inhibitor of dopamine and serotonin reuptake., Method: We report the case of an amphetamine-abusing patient who self-administered bupropion., Results: Since 30 years, a 52-year-old women used amphetamine derivates. She explained her need for amphetamine use in order to perform daily activities. Recently, she decided to experiment with bupropion. She abruptly stopped taking clobenzorex and simultaneously started taking bupropion (150 mg/day). The seventh day she reported a concomitant intake of clobenzorex; this induced adverse effects. Whilst taking bupropion, she described experiencing an euthymic state without any compulsion to take amphetamine drugs and was able to perform daily activities. After stopping it, no symptoms of withdrawal were reported by the patient., Conclusion: This observation supports an another report suggesting that bupropion may be of help in weaning from amphetamine users and should be confirmed by clinical trials.

Aims: To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers., Methods: This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures., Results: The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks., Conclusions: The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.

1. We studied the effects of midazolam (MDZ), a benzodiazepine, on spatio-temporal contrast sensitivity, choice reaction time, and mood visual analogue scales in healthy volunteers. 2. Eight extensively trained, healthy volunteers were included in a placebo-controlled cross-over double-blind trial of MDZ (0.15 mg kg-1). Treatments were injected intramuscularly and evaluations were performed before and 0.5, 1, 2, 3 and 4 h after drug administration. Spatio-temporal contrast sensitivity was measured using a micro-computer with appropriate software. Stimuli were vertical gratings with adjustable contrast, with spatial frequencies of 0.25, 1 and 4 cpd. Four conditions of temporal modulation were used: the grating was either static or drifting laterally with temporal frequencies of 1, 3 and 9 Hz. 3. An analysis of variance was performed on the data. As compared with placebo, MDZ induced an increase in choice reaction time and sedation (as assessed on visual analogue scales). From 0.5-4 h after the injection, MDZ produced an overall decrease in visual sensitivity, as compared with placebo. More specifically, MDZ preferentially affected medium to high spatial frequencies and low temporal frequencies. Several non-exclusive hypotheses may account for the results: 1) an increase in the size of the receptive fields, 2) a preferential effect on the visual parvocellular pathways which mediate the sensitivity to high spatial and low temporal frequencies.