Preliminary effects of pagoclone, a partial GABAA agonist, on neuropsychological performance

Pagoclone is a novel cyclopyrrolone that acts as a partial GABAA receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals’ performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use

The Sensitivity and Psychometric Properties of a Brief Computer-Based Cognitive Screening Battery in a Depression Clinic

At present, there is poor accuracy in assessing cognitive and vegetative symptoms in depression using clinician or self-rated measures, suggesting the need for development of standardized tasks to assess these functions. The current study assessed the psychometric properties and diagnostic specificity of a brief neuropsychological screening battery designed to assess core signs of depression; psychomotor retardation, attention and executive functioning difficulties, and impaired emotion perception within an outpatient psychiatry setting. Three hundred eighty-four patients with mood disorders and 77 healthy volunteers participated. A large percentage of patients met diagnostic criteria for Major Depressive Disorder alone (49%) or with another comorbid psychiatric disorder (24%). A brief, 25-min battery of computer-based tests was administered to control participants and patients measuring the constructs of inhibitory control, attention, visual perception, and both executive and visual processing speed. The patient groups performed significantly worse than the control group regardless of diagnosis on visual perception and attention accuracy and processing speed factors. Surprisingly, the anxiety disorder group performed better than several other psychiatric disorder groups in inhibitory control accuracy. Developing valid and reliable measures of cognitive signs in mood disorders creates excellent opportunities for tracking cognitive status prior to initiation of treatment, and allows for reliable retest following treatment

Lack of association between hyperglycaemia at arrival and clinical outcomes in acute stroke patients treated with tissue plasminogen activator

Hyperglycaemia is associated with adverse outcomes in some studies of acute ischaemic stroke.We hypothesised that in thrombolytic-treated stroke patients, hyperglycaemia would be independently associated with haemorrhagic transformation and unfavourable outcome.Consecutive rt-PA-treated acute ischaemic stroke patients presenting to four emergency departments were analysed. Associations of initial blood glucose and survival to hospital discharge, symptomatic intracerebral haemorrhage, any form of intracerebral haemorrhage, and disability at hospital discharge were determined. Potentially confounding factors of age, National Institutes of Health Stroke Scale, and smoking were analysed by univariate logistic regression and those with P <0·3 included in the multivariate model.In 268 patients, initial glucose values ranged from 62 to 507 mg/dl (mean 131). Elevated glucose at arrival was not significantly associated with any adverse clinical outcomes. A trend towards higher mortality in hyperglycaemic patients (odds ratio 1·71 per 100 mg/dl increase in glucose, 95% confidence interval 0·92–3·13, P =0·08) was seen, but is of unclear significance, and was not corroborated by effects on discharge disability, symptomatic intracerebral haemorrhage or intracerebral haemorrhage.Thrombolytic-treated stroke patients with hyperglycaemia at presentation did not have significantly worse outcomes than others in this cohort. These data fail to confirm previously described associations seen in similarly sized studies. Further study of these associations and their magnitude are necessary to better define the relationship between serum glucose and outcome in thrombolytic-treated acute ischaemic stroke.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79242/1/j.1747-4949.2010.00425.x.pd

Resource utilization and outcome at a university versus a community teaching hospital in tPA treated stroke patients: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Comparing patterns of resource utilization between hospitals is often complicated by biases in community and patient populations. Stroke patients treated with tissue plasminogen activator (tPA) provide a particularly homogenous population for comparison because of strict eligibility criteria for treatment. We tested whether resource utilization would be similar in this homogenous population between two hospitals located in a single Midwestern US community by comparing use of diagnostic testing and associated outcomes following treatment with t-PA.</p> <p>Methods</p> <p>Medical records from 206 consecutive intravenous t-PA-treated stroke patients from two teaching hospitals (one university, one community-based) were reviewed. Patient demographics, clinical characteristics and outcome were analyzed, as were the frequency of use of CT, MRI, MRA, echocardiography, angiography, and EEG.</p> <p>Results</p> <p>Seventy-nine and 127 stroke patients received t-PA at the university and community hospitals, respectively. The two patient populations were demographically similar. There were no differences in stroke severity. All outcomes were similar at both hospitals. Utilization of CT scans, and non-invasive carotid and cardiac imaging studies were similar at both hospitals; however, brain MR, TEE, and catheter angiography were used more frequently at the university hospital. EEG was obtained more often at the community hospital.</p> <p>Conclusions</p> <p>Utilization of advanced brain imaging and invasive diagnostic testing was greater at the university hospital, but was not associated with improved clinical outcomes. This could not be explained on the basis of stroke severity or patient characteristics. This variation of practice suggests substantial opportunities exist to reduce costs and improve efficiency of diagnostic resource use as well as reduce patient exposure to risk from diagnostic procedures.</p

A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam

The effects of any drug treatment on cognitive function are typically studied in groups of subjects. Observations made about the behavior of the drug, in the study sample, are then generalized to the population from which the sample was drawn. However, the magnitude and pharmacodynamic qualities of the response to many central nervous system-active drugs are known to vary in the population. Therefore, it is useful to consider statistical models for the detection of cognitive change in response to a drug treatment in individual subjects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46374/1/213_2006_Article_331.pd

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P = 0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.

Very early administration of progesterone for acute traumatic brain injury.

BackgroundTraumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI.MethodsWe conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score.ResultsA total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes.ConclusionsThis clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.)