Pseudo-potentials and loading surfaces for an endochronic plasticity theory with isotropic damage

The endochronic theory, developed in the early 70s, allows the plastic behavior of materials to be represented by introducing the notion of intrinsic time. With different viewpoints, several authors discussed the relationship between this theory and the classical theory of plasticity. Two major differences are the presence of plastic strains during unloading phases and the absence of an elastic domain. Later, the endochronic plasticity theory was modified in order to introduce the effect of damage. In the present paper, a basic endochronic model with isotropic damage is formulated starting from the postulate of strain equivalence. Unlike the previous similar analyses, in this presentation the formal tools chosen to formulate the model are those of convex analysis, often used in classical plasticity: namely pseudopotentials, indicator functions, subdifferentials, etc. As a result, the notion of loading surface for an endochronic model of plasticity with damage is investigated and an insightful comparison with classical models is made possible. A damage pseudopotential definition allowing a very general damage evolution is given

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

<p>Abstract</p> <p>Background</p> <p>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study.</p> <p>Methods/Design</p> <p>The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome.</p> <p>Discussion</p> <p>The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.</p> <p>Trial Registration</p> <p><b>Clincaltrials.gov Identifier</b>: NCT00395915</p

Costi ed efficacia della cura della schizofrenia con antipsicotici tipici e atipici

Cost-effectiveness of treatment of schizophrenia with typical and atypical antipsychotics Introduction: Schizophrenia is a ravaging and costly mental illness. Treatment of schizophrenia is long term and involves different kinds of care (drugs, outpatient, hospital, and residential care). Antipsychotic drugs contribute substantially to control patients positive and negative symptoms. In the late 90's, new \u201catypical\u201d antipsychotics have been introduced, which are supposed to be more effective, but also are more expensive. However evidence on cost-effectiveness of atypical drugs is yet limited. Objective: First, to compare effectiveness and costs of 12 month treatment of schizophrenia, using typical and atypical antipsychotics, associated with psychiatric services. Second, to compare the three most prescribed atypical drugs (olanzapine, clozapine, and risperidone) to the drug of choice, haloperidol. Patients and methods: This study originates from a large scale survey carried out in Lombardy (Italy) in the year 2000, where 9,817 psychiatric patients were assessed using the HoNOS scale. Out of 1,537 schizophrenic patients with an initial (January) and final (December) assessment, 365 patients meeting eligibility criteria were elected for the study on cost-effectiveness (NHS perspective). The study is based on the observation of real clinical behaviours; therefore patients are not randomised to different treatments. Results: The group treated with typical antipsychotics (n = 117) reported a light increase in severity index (10.0 vs 10.2; n.s.), whereas in the atypical group (n = 248) there was a significant decrease (11.5 vs 10.0; p = 0.03). Haloperidol (\u20130.16; n.s.) and risperidone (\u20130.57; n.s.) subgroups showed no significant reduction of clinical severity, while olanzapine (\u20132.5; p = 0.05) and clozapine (\u20131.6; p = 0.02) subgroups proved a significant lowering. Therefore, the average annual total treatment cost per point of reduction on the HoNOS scale was \u20ac 6,754 for the atypical drugs and impossible to evaluate for the typical drugs. The same was \u20ac 4,554 for olanzapine, \u20ac 7,546 for clozapine, \u20ac 10,897 for risperidone, and \u20ac 22,394 for haloperidol. Assuming that typical neuroleptics are the first choice treatment for schizophrenia, the incremental costs for one point reduction on the severity scale is \u20ac 3,136 for atypical drugs; or is \u20ac 3,342 for olanzapine vs haloperidol (comparator), \u20ac 5,895 for clozapine, and \u20ac 6,591 for risperidone. Conclusions: Although the pure cost for the atypical drugs is 16 times higher than for the typical ones (\u20ac 1,563 vs \u20ac 96), the total treatment costs prove to be the most cost-effective and, among atypical drugs, olanzapine appears to be the best option

Reduced coronary flow reserve and parasympathetic dysfunction in patients with cardiovascular syndrome X

OBJECTIVE: Although cardiovascular syndrome X was described many years ago, its causes are still unclear. Many studies have addressed the autonomic function, whereas others have investigated the coronary reserve. The purpose of this study was to investigate the correlations between parasympathetic dysfunction and coronary flow reserve deficiency. BASIC METHODS: Eleven consecutive women suffering from cardiovascular syndrome X were enrolled in the study. All the patients underwent the analysis of heart rate and blood pressure variability, the cold face test and noninvasive evaluation of the coronary flow reserve by transthoracic echocardiography. Comparison was made with healthy volunteers. RESULTS: Seven patients (64%) showed vagal impairment in the analysis of heart rate and blood pressure variability and a pathological response to the cold face test, whereas four patients (36%) did not show significant differences from the control group. In these three groups, patients with and without vagal impairment and controls, there was a difference in the mean diastolic coronary velocity reserve (1.94+/-0.48; 3.73+/-0.95, 2.88+/-0.55, P=0.0005) and in maximal diastolic velocity reserve (2.00+/-0.48, 3.26+/-0.64, 2.65+/-0.57, P=0.0047). Post-hoc analysis demonstrated that the mean and maximal diastolic velocity reserves of the patients with vagal impairment seemed to be reduced compared with those of the other groups (P<0.05), which were similar. CONCLUSIONS: This study confirmed that syndrome X patients represent a heterogeneous group. More than half of the patients exhibited vagal dysfunction. In these patients, coronary flow reserve was abnormal compared with controls and other syndrome X patients without vagal impairment

Patterns of referral in first-episode schizophrenia and ultra high-risk individuals: results from an early intervention program in Italy

PURPOSE: This study set out to investigate the patterns of referral in a sample (n = 206) of patients having first-time access to an Italian comprehensive program that targets the early detection of and early intervention on subjects at the onset of psychosis. The primary goal of the study was to investigate the duration of untreated illness (DUI) and/or the duration of untreated psychosis (DUP) in the sample since the implementation of the program. METHOD: Data on pathways of referrals prospectively collected over a 11-year period, from 1999 to 2010; data referred to patients from a defined catchment area, and who met ICD-10 criteria for a first episode of a psychotic disorder (FEP) or were classified to be at ultra-high risk of psychosis (UHR) according to the criteria developed by the Personal Assessment and Crisis Evaluation (PACE) Clinic in Melbourne. Changes over time in the DUI and DUP were investigated in the sample. RESULTS: Referrals increased over time, with 20 subjects enrolled per year in the latter years of the study. A large majority of patients contacted a public or private mental health care professional along their pathway to treatment, occurring more often in FEP than in UHR patients. FEP patients who had contact with a non-psychiatric health care professional had a longer DUP. Over time, DUP and DUI did not change in FEP patients, but DUI increased, on average, in UHR patients. CONCLUSIONS: The establishment of an EIP in a large metropolitan area led to an increase of referrals from people and agencies that are not directly involved in the mental health care system; over time, there was an increase in the number of patients with longer DUI and DUP than those who normally apply for psychiatric services

Psychotropic drug use in an Italian psychiatric hospital: a two-year-long follow-up study

OBJECTIVE: Following the introduction of guidelines of rational drug use, the pharmacoepidemiology of psychotropic drugs was investigated in a sample of long-stay patients living in a Italian psychiatric hospital. DESIGN: A prospective, longitudinal two-year follow-up study was carried out. Information about sociodemographic and clinical characteristics of the inpatient population, and about medications prescribed, was collected at baseline and after one and two years of follow-up. SETTING: Three wards of the psychiatric hospital of Milan. MAIN OUTCOME MEASURES: Number of patients taking psychotropic drugs, number of patients taking more than one neuroleptic or benzodiazepine, mean neuroleptic dose, psychopathological status according to the Brief Psychiatric Rating Scale (BPRS). RESULTS: 70 patients were recruited and followed for two years. At follow-up a reduction in the number of patients taking neuroleptic drugs was recorded, together with a 50% decrease in the number of patients taking more than one neuroleptic. A reduction in the use of depot formulations was in addition shown. Patients taking benzodiazepines decreased of 50%. According to the BPRS, no psychopatological changes were observed during the study. CONCLUSIONS: These data suggest that education in psychopharmacology may guide towards a more rational use of drugs; longitudinal clinical audits should be implemented to monitor everyday practice