Paliperidone ER and oral risperidone in patients with schizophrenia: a comparative database analysis

<p>Abstract</p> <p>Background</p> <p>To compare the efficacy and tolerability of paliperidone extended-release (ER) with risperidone immediate-release using propensity score methodology.</p> <p>Methods</p> <p>Six double-blind, randomized, placebo-controlled, short-term clinical trials for acute schizophrenia with availability of individual patient-level data were identified (3 per compound). Propensity score pairwise matching was used to balance observed covariates between the paliperidone ER and risperidone patient populations. Scores were generated using logistic regression models, with age, body mass index, race, sex, baseline Positive and Negative Syndrome Scale (PANSS) total score and baseline Clinical Global Impressions–Severity (CGI-S) score as factors. The dosage range of paliperidone ER (6-12 mg/day) was compared with 2 risperidone dosage ranges: 2-4 and 4-6 mg/day. The primary efficacy measure was change in PANSS total score at week 6 end point. Tolerability end points included adverse event (AE) reports and weight. AEs with rates ≥5% and with a ≥2% difference between paliperidone ER and risperidone were identified.</p> <p>Results</p> <p>Completion rates for placebo-treated subjects in paliperidone ER trials (n = 95) and risperidone trials (n = 122) groups were 36.8% and 51.6%, respectively; end point changes on PANSS total scores were similar (p = 0.768). Completion rates for subjects receiving paliperidone ER 6-12 mg/day (n = 179), risperidone 2-4 mg/day (n = 113) or risperidone 4-6 mg/day (n = 129) were 64.8%, 54.0% and 66.7%, respectively (placebo-adjusted rates: paliperidone ER vs risperidone 2-4 mg/day, p = 0.005; paliperidone ER vs risperidone 4-6 mg/day, p = 0.159). PANSS total score improvement with paliperidone ER was greater than with risperidone 2-4 mg/day (difference in mean change score, -6.7; p < 0.05) and similar to risperidone 4-6 mg/day (0.2; p = 0.927). Placebo-adjusted AEs more common with paliperidone ER were insomnia, sinus tachycardia and tachycardia; more common with risperidone were somnolence, restlessness, nausea, anxiety, salivary hypersecretion, akathisia, dizziness and nasal congestion. Weight changes with paliperidone ER and risperidone were similar (paliperidone ER vs risperidone 2-4 mg/day, p = 0.489; paliperidone ER vs risperidone 4-6 mg/day, p = 0.236).</p> <p>Conclusions</p> <p>This indirect database analysis suggested that paliperidone ER 6-12 mg/day may be more efficacious than risperidone 2-4 mg/day and as efficacious as risperidone 4-6 mg/day. The AE-adjusted incidence rates suggest differences between treatments that may be relevant for individual patients. Additional randomized, direct, head-to-head clinical trials are needed to confirm these findings.</p

Doping-induced carrier profiles in organic semiconductors determined from capacitive extraction-current transients

A method to determine the doping induced charge carrier profiles in lightly and moderately doped organic semiconductor thin films is presented. The theory of the method of Charge Extraction by a Linearly Increasing Voltage technique in the doping-induced capacitive regime (doping-CELIV) is extended to the case with non-uniform doping profiles and the analytical description is verified with drift-diffusion simulations. The method is demonstrated experimentally on evaporated organic small- molecule thin films with a controlled doping profile, and solution-processed thin films where the non- uniform doping profile is unintentional, probably induced during the deposition process, and a priori unknown. Furthermore, the method offers a possibility of directly probing charge-density distributions at interfaces between highly doped and lightly doped or undoped layers

Item response analysis of the Positive and Negative Syndrome Scale

<p>Abstract</p> <p>Background</p> <p>Statistical models based on item response theory were used to examine (a) the performance of individual Positive and Negative Syndrome Scale (PANSS) items and their options, (b) the effectiveness of various subscales to discriminate among individual differences in symptom severity, and (c) the appropriateness of cutoff scores recently recommended by Andreasen and her colleagues (2005) to establish symptom remission.</p> <p>Methods</p> <p>Option characteristic curves were estimated using a nonparametric item response model to examine the probability of endorsing each of 7 options within each of 30 PANSS items as a function of standardized, overall symptom severity. Our data were baseline PANSS scores from 9205 patients with schizophrenia or schizoaffective disorder who were enrolled between 1995 and 2003 in either a large, naturalistic, observational study or else in 1 of 12 randomized, double-blind, clinical trials comparing olanzapine to other antipsychotic drugs.</p> <p>Results</p> <p>Our analyses show that the majority of items forming the Positive and Negative subscales of the PANSS perform very well. We also identified key areas for improvement or revision in items and options within the General Psychopathology subscale. The Positive and Negative subscale scores are not only more discriminating of individual differences in symptom severity than the General Psychopathology subscale score, but are also more efficient on average than the 30-item total score. Of the 8 items recently recommended to establish symptom remission, 1 performed markedly different from the 7 others and should either be deleted or rescored requiring that patients achieve a lower score of 2 (rather than 3) to signal remission.</p> <p>Conclusion</p> <p>This first item response analysis of the PANSS supports its sound psychometric properties; most PANSS items were either very good or good at assessing overall severity of illness. These analyses did identify some items which might be further improved for measuring individual severity differences or for defining remission thresholds. Findings also suggest that the Positive and Negative subscales are more sensitive to change than the PANSS total score and, thus, may constitute a "mini PANSS" that may be more reliable, require shorter administration and training time, and possibly reduce sample sizes needed for future research.</p

Predicting hospital admission and discharge with symptom or function scores in patients with schizophrenia: pooled analysis of a clinical trial extension

<p>Abstract</p> <p>Background</p> <p>The purpose of this analysis was to evaluate relationships between hospital admission or discharge and scores for symptom or functioning in patients with schizophrenia.</p> <p>Methods</p> <p>Data were from three 52-week open-label extensions of the double-blind pivotal trials of paliperidone extended-release (ER). Symptoms and patient function were measured every 4 weeks using the Personal and Social Performance (PSP) scale and the Positive and Negative Syndrome Scale (PANSS). The intent-to-treat analysis set was defined as open-label patients who had at least one post-baseline PSP and PANSS measurement. Time until first hospitalization was evaluated using the Cox proportional hazard model with categorical time-dependent measures for the PSP (1 to 30, 31 to 70, 71 to 100) or PANSS (< 75, ≥ 75 to < 95, ≥ 95), as well as age, gender, schizophrenia duration, and country. Similar analyses were performed for time to discharge.</p> <p>Results</p> <p>Of the 1,077 enrolled patients, 1,028 (95.5%) met study criteria; of these, 382 (37.2%) were hospitalized at open-label baseline. Compared with patients with PSP ≥ 71 group, the hazard for new hospitalization was 8.351 times greater (<it>P </it>= 0.0001) for patients with the poorest functioning (PSP 1 to 30) and 1.977 times greater (<it>P </it>= 0.0295) for patients with PSP of 31-70 compared to the ≥ 71 group. The hazard for new hospitalization was 5.457 times greater (<it>P </it>< 0.0001) for patients PANSS ≥ 95 and 2.316 times greater (<it>P </it>= 0.0027) for the ≥ 75 to < 95 group compared with the < 75 group. For patients hospitalized at baseline, the PANSS ≥ 95 patients had a discharge hazard that was 0.456 times lower than for the < 75 patients (<it>P </it>< 0.0001). The hazard for discharge was 0.646 times lower (<it>P = </it>0.0012) for the PANSS ≥ 75 to < 95 group compared with the < 75 group. A patient's country was a significant predictor variable, with US patients being admitted and discharged faster.</p> <p>Conclusions</p> <p>Better functioning or being less symptomatic is associated with reduced risk for hospitalization and greater chance for early discharge. Treatments or programs that reduce symptoms or improve function decrease the risk of hospitalization in community patients or increase the chance of discharge for hospitalized patients.</p

Publication Bias in Antipsychotic Trials: An Analysis of Efficacy Comparing the Published Literature to the US Food and Drug Administration Database

A comparison of data held by the U.S. Food and Drug Administration (FDA) against data from journal reports of clinical trials enables estimation of the extent of publication bias for antipsychotics

Global burden of human brucellosis : a systematic review of disease frequency

BACKGROUND: This report presents a systematic review of scientific literature published between 1990-2010 relating to the frequency of human brucellosis, commissioned by WHO. The objectives were to identify high quality disease incidence data to complement existing knowledge of the global disease burden and, ultimately, to contribute towards the calculation of a Disability-Adjusted Life Years (DALY) estimate for brucellosis.METHODS/PRINCIPAL FINDINGS: Thirty three databases were searched, identifying 2,385 articles relating to human brucellosis. Based on strict screening criteria, 60 studies were selected for quality assessment, of which only 29 were of sufficient quality for data analysis. Data were only available from 15 countries in the regions of Northern Africa and Middle East, Western Europe, Central and South America, Sub-Saharan Africa, and Central Asia. Half of the studies presented incidence data, six of which were longitudinal prospective studies, and half presented seroprevalence data which were converted to incidence rates. Brucellosis incidence varied widely between, and within, countries. Although study biases cannot be ruled out, demographic, occupational, and socioeconomic factors likely play a role. Aggregated data at national or regional levels do not capture these complexities of disease dynamics and, consequently, at-risk populations or areas may be overlooked. In many brucellosis-endemic countries, health systems are weak and passively-acquired official data underestimate the true disease burden.CONCLUSIONS: High quality research is essential for an accurate assessment of disease burden, particularly in Eastern Europe, the Asia-Pacific, Central and South America and Africa where data are lacking. Providing formal epidemiological and statistical training to researchers is essential for improving study quality. An integrated approach to disease surveillance involving both human health and veterinary services would allow a better understand of disease dynamics at the animal-human interface, as well as a more cost-effective utilisation of resources

Prevention of coronary heart disease in people with severe mental illnesses: a qualitative study of patient and professionals' preferences for care

BACKGROUND: People with severe mental illness (SMI) are at increased risk of developing coronary heart disease (CHD) and there is growing emphasis on the need to monitor their physical health. However, there is little consensus on how services for the primary prevention of CHD should be organised for this patient group. We explored the views of people with SMI and health professionals from primary care and community mental health teams (CMHTs) on how best to provide these services. METHODS: In-depth interviews were conducted with a purposive sample of patients with SMI (n = 31) and staff from primary care (n = 10) and community mental health teams (n = 25) in North Central London. Transcripts of the qualitative interviews were analysed using a 'framework' approach to identify the main themes in opinions regarding various service models. RESULTS: Cardiovascular risk factors in people with SMI were of concern to participants. However, there was some disagreement about the best way to deliver appropriate care. Although staff felt that primary care should take responsibility for risk factor screening and management, patients favoured CHD screening in their CMHT. Problems with both approaches were identified. These included a lack of familiarity in general practice with SMI and antipsychotic side effects and poor communication of physical health issues to the CMHT. Lack of knowledge regarding CHD risk factor screening and difficulties in interpreting screening results and implementing appropriate interventions exist in secondary care. CONCLUSION: Management of physical health care for people with SMI requires complex solutions that cross the primary-secondary care interface. The views expressed by our participants suggest that neither primary nor secondary care services on their own can provide a comprehensive service for all patients. The increased risk of CHD associated with SMI and antipsychotic medications requires flexible solutions with clear lines of responsibility for assessing, communicating and managing CHD risks

Dose-associated changes in safety and efficacy parameters observed in a 24-week maintenance trial of olanzapine long-acting injection in patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>In a recently published 24-week maintenance study of olanzapine long-acting injection (LAI) in schizophrenia (Kane et al., 2010), apparent dose-associated changes were noted in both efficacy and safety parameters. To help clinicians balance safety and efficacy when choosing a dose of olanzapine LAI, we further studied these changes.</p> <p>Methods</p> <p>Outpatients with schizophrenia who had maintained stability on open-label oral olanzapine for 4 to 8 weeks were randomly assigned to "low" (150 mg/2 weeks; N = 140), "medium" (405 mg/4 weeks; N = 318), or "high" (300 mg/2 weeks; N = 141) dosages of olanzapine LAI for 24 weeks. Potential relationships between dose and several safety or efficacy measures were examined via regression analysis, the Jonckheere-Terpstra test (continuous data), or the Cochran-Armitage test (categorical data).</p> <p>Results</p> <p>Safety parameters statistically significantly related to dose were mean weight change (low: +0.67 [SD = 4.38], medium: +0.89 [SD = 3.87], high: +1.70 [SD = 4.14] kg, p = .024; effect size [ES] = 0.264 high vs. low dose), mean change in prolactin (low: -5.61 [SD = 12.49], medium: -2.76 [SD = 19.02]), high: +3.58 [SD = 33.78] μg/L, p = .001; ES = 0.410 high vs. low dose), fasting triglycerides change from normal at baseline to high (low: 3.2%, medium: 6.0%, high: 18.9%, p = .001; NNT = 7 high vs. low dose) and fasting high-density lipoprotein cholesterol change from normal at baseline to low (low: 13.8%, medium: 19.6%, high: 30.7%, p = .019; NNT = 6 high vs. low dose). Efficacy measures significantly related to dose included Positive and Negative Syndrome Scale total score mean change (low: +2.66 [SD = 14.95], medium: -0.09 [SD = 13.47], high: -2.19 [SD = 13.11], p <.01; ES = 0.356 high vs. low dose), relapse rate (low: 16%, medium: 10%, high: 5%, p = .003; NNT = 9 high vs. low dose), all-cause discontinuation rate (low: 36%, medium: 30%, high: 24%, p = .037; NNT = 9 high vs. low dose), and rate of discontinuation due to efficacy-related reasons (low: 20%, medium: 14%, high: 6%, p <.001). Time to all-cause discontinuation (p = .035) and time to relapse (p = .005) were also significantly related to dose.</p> <p>Conclusions</p> <p>Analyses of several safety and efficacy parameters revealed significant associations with dose of olanzapine LAI, with the highest dose generally showing greater efficacy as well as greater adverse changes in metabolic safety measures. When considering olanzapine LAI, as with all antipsychotics, it is important to carefully consider the potential benefits and risks for an individual patient.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00088491">NCT00088491</a></p

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation