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While networks have been the standard mathematical representation for detailedarrangements of relations in society, the simplicity of the representation limits whatinformation can be preserved in the abstraction, and subsequently, what can bemathematically analyzed. In this paper, we introduce a more rigorous and flexibleabstraction for representing arrangements of relations in society, the Messy Structure.After introducing the representational form and theoretically justifying it, we introducesome basic generative procedures for creating Messy Structures with “hierarchical”properties.

OBJECTIVE The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study compared the effects of once-monthly paliperidone palmitate with daily oral antipsychotics on treatment failure in adults with schizophrenia. METHOD The PRIDE study is a 15-month, randomized, multicenter study (May 5, 2010, to December 9, 2013) of adult subjects with a DSM-IV diagnosis of schizophrenia and a history of incarceration. Subjects were randomly assigned to once-monthly paliperidone palmitate injections or daily oral antipsychotics (randomly assigned from 7 acceptable, prespecified oral antipsychotics) for 15 months. The primary end point was time to first treatment failure, defined as arrest/incarceration; psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. Time to first treatment failure was determined by a blinded event-monitoring board and analyzed with the Kaplan-Meier method. RESULTS In this study, 450 patients were randomly assigned, and 444 were included in the intent-to-treat population. Paliperidone palmitate was associated with significant delay in time to first treatment failure versus oral antipsychotics (hazard ratio, 1.43; 95% CI, 1.09-1.88; log rank P = .011). Observed treatment failure rates over 15 months were 39.8% and 53.7%, respectively. Arrest/incarceration and psychiatric hospitalization were the most common reasons for treatment failure in the paliperidone palmitate and oral antipsychotic groups (21.2% vs 29.4% and 8.0% vs 11.9%, respectively). The 5 most common treatment-emergent adverse events for the paliperidone palmitate treatment group were injection site pain (18.6% of subjects), insomnia (16.8%), weight increased (11.9%), akathisia (11.1%), and anxiety (10.6%). CONCLUSIONS In a trial designed to reflect real-world management of schizophrenia, once-monthly paliperidone palmitate demonstrated superiority compared to oral antipsychotics in delaying time to treatment failure. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT01157351.

Patients with schizophrenia often suffer from comorbid hepatic disease. This multicenter, open-label, single-arm, crossover study evaluated the safety and efficacy of paliperidone extended-release (ER) in patients with schizophrenia or schizoaffective disorder and hepatic disease.The study comprised a screening period, followed by 9 weeks' open-label treatment, divided into 2 phases. Phase 1 (4 weeks) was a continuation of usual antipsychotic treatment (UAT); phase 2 (5 weeks) consisted of a 1-week cross-titration from UAT to flexibly dosed paliperidone ER (3-12 mg/d), followed by 4 weeks of paliperidone ER alone. Treatment-emergent adverse events (TEAEs), including those considered more relevant to antipsychotic treatment (prespecified adverse events [AEs]), were analyzed.Although more subjects reported TEAEs during the paliperidone ER alone period than during the UAT period, no significant differences occurred in prespecified AE rates. No new safety signals were detected, and minimal shifts in liver function test values were observed. Improvements in psychiatric symptoms and functioning were observed after 4 weeks' paliperidone ER treatment.This study suggests that paliperidone ER is well tolerated in patients with schizophrenia or schizoaffective disorder and hepatic disease. To the best of our knowledge, this is the largest prospective study to date in this population.

Background Public health considerations require that clinical trials address the complex "real-world" needs of patients with chronic illnesses. This is particularly true for persons with schizophrenia, whose management is frequently complicated by factors such as comorbid substance abuse, homelessness, and contact with the criminal justice system. In addition, barriers to obtaining health care in the United States often prevent successful community reentry and optimal patient management. Further, nonadherence to treatment is common, and this reinforces cycles of relapse and recidivism. Long-acting injectable antipsychotic therapy may facilitate continuity of treatment and support better outcomes, particularly in patients who face these challenges. Clinical trials with classical explanatory designs may not be the best approaches for evaluating these considerations. We describe the design and rationale of a novel trial that combines both explanatory and pragmatic design features and studies persons with schizophrenia who face these challenges. Design and rationale The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study is a prospective, open-label, randomized, 15-month study conducted between May 5, 2010, and December 9, 2013, comparing long-acting injectable paliperidone palmitate and oral antipsychotic medications in subjects with schizophrenia (according to DSM-IV criteria). Investigators and subjects had broad flexibility for treatment decision-making, thus making it a model that better reflects real-world practice. The primary end point was time to treatment failure, defined as arrest/incarceration psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. This end point was adjudicated by a blinded event monitoring board. Patients were followed to the 15-month end point, regardless of whether they were maintained on their initial randomized treatment. This article provides some of the reasoning behind the authors' choices when combining features from both explanatory and pragmatic approaches to this trial's design. Conclusions The PRIDE study incorporates real-world design features in a novel, prospective, comparative study of long-acting injectable and oral antipsychotics in persons with schizophrenia who have had recent contact with the criminal justice system. Insights provided should help the reader to better understand the need for more real-world approaches for clinical studies and how a broader approach can better aid clinical treatment and public health decision-making. Trial registration ClinicalTrials.gov identifier: NCT01157351.

Background Because wide variations in mental health care utilization exist throughout the world, determining long-term effectiveness of psychotropic medications in a real-world setting would be beneficial to physicians and patients. The purpose of this analysis was to describe the effectiveness of injectable risperidone long-acting therapy (RLAT) for schizophrenia across countries. Methods This was a pragmatic analysis of data from two prospective observational studies conducted in the US (Schizophrenia Outcomes Utilization Relapse and Clinical Evaluation [SOURCE]; ClinicalTrials.gov registration number for the SOURCE study: NCT00246194) and Spain, Australia, and Belgium (electronic Schizophrenia Treatment Adherence Registry [eSTAR]). Two separate analyses were performed to assess clinical improvement during the study and estimate psychiatric hospitalization rates before and after RLAT initiation. Clinical improvement was evaluated using the Clinical Global Impressions-Severity (CGI-S) and Global Assessment of Functioning (GAF) scales, and change from baseline was evaluated using paired t tests. Psychiatric hospitalization rates were analyzed using incidence densities, and the bootstrap resampling method was used to examine differences between the pre-baseline and post-baseline periods. Results The initial sample comprised 3,069 patients (US, n = 532; Spain, n = 1,345; Australia, n = 784; and Belgium, n = 408). In all, 24 months of study participation, completed by 39.3% (n = 209), 62.7% (n = 843), 45.8% (n = 359), and 64.2% (n = 262) of patients from the US, Spain, Australia, and Belgium, respectively, were included in the clinical analysis. Improvements compared with baseline were observed on both clinical assessments across countries (P < 0.001 at all post-baseline visits). The mean improvement was approximately 1 point on the CGI-S and 15 points on the GAF. A total of 435 (81.8%), 1,339 (99.6%), 734 (93.6%), and 393 (96.3%) patients from the US, Spain, Australia, and Belgium, respectively, had ≥1 post-baseline visit and were included in the analysis of psychiatric hospitalization rates. Hospitalization rates decreased significantly in all countries regardless of hospitalization status at RLAT initiation (P < 0.0001) and decreased significantly in the US and Spain (P < 0.0001) when the analysis was limited to outpatients only. Conclusions RLAT in patients with schizophrenia was associated with improvements in clinical and functional outcomes and decreased hospitalization rates in the US, Spain, Australia, and Belgium, despite differences in health care delivery systems.

ObjectifsUn échec de traitement peut entraîner diverses conséquences à la fois pour le patient souffrant de schizophrénie mais aussi en terme de santé publique (arrêt du traitement, hospitalisation, addiction, arrestation/incarcération) [1–3]. Cette étude a comparé en vraie vie, les délais avant échec au traitement des patients souffrant de schizophrénie ayant des antécédents d’incarcération, traités soit par palmitate de paliperidone (PP) ou par des antipsychotiques oraux (APO).MéthodesPaliperidone Research In Demonstrating Effectiveness (PRIDE) est une étude en ouvert, prospective, randomisée, d’une durée de 15 mois, comparant le PP une fois par mois aux APO chez des sujets atteints de schizophrénie, avec des antécédents d’incarcération (NCT01157351). Les sujets ont été randomisés (1:1) en deux groupes :– PP à doses flexibles (78–234 mg) administrées une fois par mois ou à ;– l’un des 7 APO couramment prescrits par l’investigateur.Le critère de jugement principal était le délai avant échec du traitement (défini comme arrestation/incarcération, hospitalisation, suicide, arrêt du traitement ou supplémentation par manque d’efficacité ou mauvaise tolérance et/ou besoin d’intensifier les soins psychiatriques) évalué par la méthode de Kaplan-Meier.RésultatsUn total de 450 sujets ont été inclus (sexe masculin = 86,3 %). Le délai avant échec du traitement était significativement plus long avec le PP par rapport aux APO (médiane = 416 vs 226 jours avant arrêt du traitement ou supplémentation ; Rapport de risque [IC95 %] = 1,43 [1,09, 1,88] ; p = 0,011). Les taux d’échecs du traitement étaient de 39,8 % avec le PP et de 53,7 % avec les APO. Des résultats similaires ont été observés pour le délai avant hospitalisation ou arrestation/incarcération (médiane ≥ 450 vs 274 jours ; rapport de risque [IC95 %] = 1,43 [1,06, 1,93] ; p = 0,019). Les événements indésirables les plus fréquents (PP vs APO, ≥ 10 %) étaient : douleur au site d’injection (18,6 % vs 0 %) ; insomnie (16,8 % vs 11,5 %) ; prise de poids (11,9 % vs 6,0 %) ; akathisie (11,1 % vs 6,9 %) ; anxiété (10,6 % vs 7,3 %).ConclusionLe traitement mensuel par PP injectable retarde significativement le délai de survenue d’un large éventail de conséquences négatives de la schizophrénie en vie réelle.

Maintenance treatment regimens for patients with schizophrenia are often suboptimal. Partial adherence and outright noncompliance are associated with symptom recurrence and increased likelihood of rehospitalization. Long-acting conventional neuroleptics have limited efficacy and are associated with treatment-limiting adverse events, while oral atypical antipsychotics have not improved adherence substantially. A long-acting formulation of risperidone, an atypical antipsychotic with proven efficacy, has been developed. Introduction of long-acting injectable treatment may be appropriate during inpatient hospitalization, when consequences of relapse are most evident. To support this intervention, a subanalysis of patients who were inpatients at study initiation was conducted from a 12-week, double-blind, placebo-controlled long-acting risperidone study (N = 214). Long-acting risperidone was associated with a significant reduction in total Positive and Negative Syndrome Scale (PANSS) score (mean change +/- standard error [S.E.] at endpoint: long-acting risperidone, -9.27 +/- 1.44, n = 133; placebo, 0.72 +/- 2.59, n = 41; P0.001), and a significantly higher rate of treatment response, defined asor = 20% reduction in total PANSS score (50% vs. 27%, P0.05). Significantly more long-acting risperidone patients had endpoint Clinical Global Impressions (CGI) assessments of not ill, very mild or mild (32% vs. 5%; P0.01). Long-acting risperidone was well tolerated. Long-acting risperidone initiated during inpatient treatment may be an important strategy in improving long-term outcomes among patients with schizophrenia.

2-methylresorcinol (2-MR) was administered to groups of 40 male and 35 female Sprague-Dawley rats by admixture with diets at levels of 0.1, 0.4, and 1.5% for periods up to 6 months. Methemoglobin levels were determined after 6 weeks. After 90 days 10 animals/sex/group were killed for clinical pathological and histopathologic determinations. The 25 remaining females and 20 males per group were utilized in teratology and dominant lethal studies presented in Part II (T.A. Re, R.F. Loehr, S.C. Rodriguez, D. E. Rodwell, C.M. Burnett, 1986, Fundam. Appl. Toxicol. 7, 293-298). Ten additional males were killed after 6 months of exposure for additional clinical pathologic determinations and gross pathologic observations. The 20 males/group used in the dominant lethal study (Part II) were also killed after 6 months to serve as a comparison recovery group (gross examination of organs). Feeding 2-MR at a level of 1.5% in the diet was associated with a significant reduction in body weight gains. Females fed at a level of 0.4% also weighed significantly less than the control. No pathological effects were noted after either 90 or 180 days of feeding.

2-Methylresorcinol (2-MR) was administered to groups of 40 male and 35 female Sprague-Dawley rats by admixture with the diets at levels of 0.1, 0.4, and 1.5% (see Part I; T.H. Re, R.F. Loehr, S.C. Rodriguez, C.E. Gilmore, and C.M. Burnett, 1986, Fundam. Appl. Toxicol. 7, 287-292). Following 90 days of exposure, 25 randomly selected females in each group were mated to untreated males in a teratology study in which exposure to 2-MR continued throughout the gestation period. After 20 weeks of exposure to 2-MR, 20 males per group were removed from the test diets containing 2-MR and were mated to untreated females in a dominant lethal study. Feeding 2-MR at levels of 0.4 and 1.5% in the diet was associated with a significant reduction in body weight gain. 2-MR was not teratogenic nor did it induce a dominant lethal effect under the conditions of this study.

Background To evaluate effectiveness outcomes in a real-world setting in patients with schizophrenia initiating risperidone long-acting therapy (RLAT). Methods This was a 24-month, multicenter, prospective, longitudinal, observational study in patients with schizophrenia who were initiated on RLAT. Physicians could change treatment during the study as clinically warranted. Data were collected at baseline and subsequently every 3 months up to 24 months. Effectiveness outcomes included changes in illness severity as measured by Clinical Global Impression-Severity (CGI-S) scale; functional scores as measured by Personal and Social Performance (PSP) scale, Global Assessment of Functioning (GAF), and Strauss-Carpenter Levels of Functioning (LOF); and health status (Medical Outcomes Survey Short Form-36 [SF-36]). Life-table methodology was used to estimate the cumulative probability of relapse over time. Adverse events were evaluated for safety. Results 532 patients were enrolled in the study; 209 (39.3%) completed the 24-month study and 305 (57.3%) had at least 12 months of follow-up data. The mean (SD) age of patients was 42.3 (12.8) years. Most patients were male (66.4%) and either Caucasian (60.3%) or African American (23.7%). All changes in CGI-S from baseline at each subsequent 3-month follow-up visit were statistically significant (p < .0001), indicating improvement in disease severity. Improvements were also noted for the PSP, GAF, and total LOF, indicating improvement in daily functioning and health outcome. Conclusions Patients with schizophrenia who were initiated on RLAT demonstrated improvements in measures of effectiveness within 3 months, which persisted over 24 months. Trial Registration ClinicalTrials.gov: NCT00246194