The longitudinal interplay between negative and positive symptom trajectories in patients under antipsychotic treatment: a post hoc analysis of data from a randomized, 1-year pragmatic trial

BACKGROUND: Schizophrenia is a highly heterogeneous disorder with positive and negative symptoms being characteristic manifestations of the disease. While these two symptom domains are usually construed as distinct and orthogonal, little is known about the longitudinal pattern of negative symptoms and their linkage with the positive symptoms. This study assessed the temporal interplay between these two symptom domains and evaluated whether the improvements in these symptoms were inversely correlated or independent with each other. METHODS: This post hoc analysis used data from a multicenter, randomized, open-label, 1-year pragmatic trial of patients with schizophrenia spectrum disorder who were treated with first- and second-generation antipsychotics in the usual clinical settings. Data from all treatment groups were pooled resulting in 399 patients with complete data on both the negative and positive subscale scores from the Positive and Negative Syndrome Scale (PANSS). Individual-based growth mixture modeling combined with interplay matrix was used to identify the latent trajectory patterns in terms of both the negative and positive symptoms. Pearson correlation coefficients were calculated to examine the relationship between the changes of these two symptom domains within each combined trajectory pattern. RESULTS: We identified four distinct negative symptom trajectories and three positive symptom trajectories. The trajectory matrix formed 11 combined trajectory patterns, which evidenced that negative and positive symptom trajectories moved generally in parallel. Correlation coefficients for changes in negative and positive symptom subscale scores were positive and statistically significant (P < 0.05). Overall, the combined trajectories indicated three major distinct patterns: (1) dramatic and sustained early improvement in both negative and positive symptoms (n = 70, 18%), (2) mild and sustained improvement in negative and positive symptoms (n = 237, 59%), and (3) no improvement in either negative or positive symptoms (n = 82, 21%). CONCLUSIONS: This study of symptom trajectories over 1 year shows that changes in negative and positive symptoms were neither inversely nor independently related with each other. The positive association between these two symptom domains supports the notion that different symptom domains in schizophrenia may depend on each other through a unified upstream pathological disease process

Energy-consistent integration of mechanical systems based on Livens principle

In this work we make use of Livens principle (sometimes also referred to as Hamilton-Pontryagin principle) in order to obtain a novel structure-preserving integrator for mechanical systems. In contrast to the canonical Hamiltonian equations of motion, the Euler-Lagrange equations pertaining to Livens principle circumvent the need to invert the mass matrix. This is an essential advantage with respect to singular mass matrices, which can yield severe difficulties for the modelling and simulation of multibody systems. Moreover, Livens principle unifies both Lagrangian and Hamiltonian viewpoints on mechanics. Additionally, the present framework avoids the need to set up the system's Hamiltonian. The novel scheme algorithmically conserves a general energy function and aims at the preservation of momentum maps corresponding to symmetries of the system. We present an extension to mechanical systems subject to holonomic constraints. The performance of the newly devised method is studied in representative examples.Comment: 12 pages, 8 figures, Proceeding for the ECCOMAS Thematic Conference on Multibody Dynamics July 24 - 28, 2023, Lisbon, Portuga

Structure‐preserving integrators for constrained mechanical systems in the framework of the GGL principle

Simulating multi-body systems often requires an appropriate treatment of the differential-algebraic equations (DAEs). The recently proposed GGL principle considers constraints both on configuration and on velocity level and embodies an index-reduction technique in the spirit of the often-applied GGL stabilization. In sharp contrast to the original formulation, the Euler-Lagrange equations of the GGL principle, fit into the Hamiltonian framework of mechanics. Therefore, the GGL principle facilitates the design of structure-preserving integrators. Due to the close relationship of the GGL principle to optimal control, previously developed direct methods can be used to obtain variational integrators for constrained mechanical systems. Furthermore, slight modifications can be applied to obtain second-order energy-momentum consistent integrators emanating from the GGL principle, which represent another important class of structure-preserving time-stepping schemes. The newly devised schemes circumvent issues of standard methods and provide more realistic results by accounting for velocity level constraints

Conserving integration of multibody systems with singular and non-constant mass matrix including quaternion-based rigid body dynamics

Mechanical systems with singular and/or configuration-dependent mass matrix can pose difficulties to Hamiltonian formulations, which are the standard choice for the design of energy-momentum conserving time integrators. In this work, we derive a structure- preserving time integrator for constrained mechanical systems based on a mixed variational approach. Livens’ principle (or sometimes called Hamilton–Pontryagin principle) features independent velocity and momentum quantities and circumvents the need to invert the mass matrix. In particular, we take up the description of rigid body rotations using unit quater- nions. Using Livens’ principle, a new and comparatively easy approach to the simulation of these problems is presented. The equations of motion are approximated by using (par- titioned) midpoint discrete gradients, thus generating a new energy-momentum conserving integration scheme for mechanical systems with singular and/or configuration-dependent mass matrix. The derived method is second-order accurate and algorithmically preserves a generalized energy function as well as the holonomic constraints and momentum maps cor- responding to symmetries of the system. We study the numerical performance of the newly devised scheme in representative examples for multibody and rigid body dynamics

Time course of improvement with antipsychotic medication in treatment-resistant schizophrenia

Background Improvements are greatest in the earlier weeks of antipsychotic treatment of patients with non-resistant schizophrenia. Aims To address the early time-line for improvement with antipsychotics in treatment-resistant schizophrenia. Method Randomised double-blind trials of antipsychotic medication in adult patients with treatment-resistant schizophrenia were investigated (last search June 2010). A series of meta-regression analyses were carried out to examine the effect of time on the average item scores in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) at three or more distinct time points within the first 6 weeks of treatment. Results Study duration varied from 4 weeks to 1 year and the definitions of treatment resistance as well as of treatment response were not necessarily consistent across 19 identified studies, resulting in highly variable rates of response (0–76%). The mean standardised baseline item score in the PANSS or BPRS was 3.4 (s.e. = 0.06) in the five studies included in the meta-regression analysis, with the average baseline Clinical Global Impression – Severity score being 5.2 (marked illness). For the pooled population treated with a range of antipsychotics (n = 1019), significant reductions in the mean item scores occurred during the first 4 weeks; improvements observed in later weeks were smaller and non-significant. In contrast, weekly improvement with clozapine was significant throughout (n = 356). Conclusions Our findings provide preliminary evidence that the majority of improvement with antipsychotics may occur relatively early. More consistent improvements with clozapine may be associated with a gradual titration. To further elucidate response patterns, future studies are needed to provide data over regular intervals during earlier stages of treatment.peer-reviewe

Structure-preserving integrators based on a new variational principle for constrained mechanical systems

A new variational principle for mechanical systems subject to holonomic constraints is presented. The newly proposed GGL principle is closely related to the often used Gear-Gupta-Leimkuhler (GGL) stabilization of the differential–algebraic equations governing the motion of constrained mechanical systems. The GGL variational principle relies on an extension of the Livens principle (sometimes also referred to as Hamilton–Pontryagin principle) to mechanical systems subject to holonomic constraints. In contrast to the original GGL stabilization, the new approach facilitates the design of structure-preserving integrators. In particular, new variational integrators are presented, which result from the direct discretization of the GGL variational principle. These variational integrators are symplectic and conserve momentum maps in the case of systems with symmetry. In addition to that, a new energy–momentum scheme is developed, which results from the discretization of the Euler–Lagrange equations pertaining to the GGL variational principle. The numerical properties of the newly devised schemes are investigated in representative examples of constrained mechanical systems

Fluphenazine decanoate (depot) and enanthate for schizophrenia

Background: Intramuscular injections (depot preparations) offer an advantage over oral medication for treating schizophrenia by reducing poor compliance. The benefits gained by long-acting preparations, however, may be offset by a higher incidence of adverse effects. Objectives: To assess the effects of fluphenazine decanoate and enanthate versus oral anti-psychotics and other depot neuroleptic preparations for individuals with schizophrenia in terms of clinical, social and economic outcomes. Search methods: We searched the Cochrane Schizophrenia Group's Trials Register (February 2011 and October 16, 2013), which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. Selection criteria: We considered all relevant randomised controlled trials (RCTs) focusing on people with schizophrenia comparing fluphenazine decanoate or enanthate with placebo or oral anti-psychotics or other depot preparations. Data collection and analysis: We reliably selected, assessed the quality, and extracted data of the included studies. For dichotomous data, we estimated risk ratio (RR) with 95% confidence intervals (CI). Analysis was by intention-to-treat. We used the mean difference (MD) for normal continuous data. We excluded continuous data if loss to follow-up was greater than 50%. Tests of heterogeneity and for publication bias were undertaken. We used a fixed-effect model for all analyses unless there was high heterogeneity. For this update. we assessed risk of bias of included studies and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to create a 'Summary of findings' table. Main results: This review now includes 73 randomised studies, with 4870 participants. Overall, the quality of the evidence is low to very low.Compared with placebo, use of fluphenazine decanoate does not result in any significant differences in death, nor does it reduce relapse over six months to one year, but one longer-term study found that relapse was significantly reduced in the fluphenazine arm (n = 54, 1 RCT, RR 0.35, CI 0.19 to 0.64, very low quality evidence). A very similar number of people left the medium-term studies (six months to one year) early in the fluphenazine decanoate (24%) and placebo (19%) groups, however, a two-year study significantly favoured fluphenazine decanoate (n = 54, 1 RCT, RR 0.47, CI 0.23 to 0.96, very low quality evidence). No significant differences were found in mental state measured on the Brief Psychiatric Rating Scale (BPRS) or in extrapyramidal adverse effects, although these outcomes were only reported in one small study each. No study comparing fluphenazine decanoate with placebo reported clinically significant changes in global state or hospital admissions.Fluphenazine decanoate does not reduce relapse more than oral neuroleptics in the medium term (n = 419, 6 RCTs, RR 1.46 CI 0.75 to 2.83, very low quality evidence). A small study found no difference in clinically significant changes in global state. No difference in the number of participants leaving the study early was found between fluphenazine decanoate (17%) and oral neuroleptics (18%), and no significant differences were found in mental state measured on the BPRS. Extrapyramidal adverse effects were significantly less for people receiving fluphenazine decanoate compared with oral neuroleptics (n = 259, 3 RCTs, RR 0.47 CI 0.24 to 0.91, very low quality evidence). No study comparing fluphenazine decanoate with oral neuroleptics reported death or hospital admissions.No significant difference in relapse rates in the medium term between fluphenazine decanoate and fluphenazine enanthate was found (n = 49, 1 RCT, RR 2.43, CI 0.71 to 8.32, very low quality evidence), immediate- and short-term studies were also equivocal. One small study reported the number of participants leaving the study early (29% versus 12%) and mental state measured on the BPRS and found no significant difference for either outcome. No significant difference was found in extrapyramidal adverse effects between fluphenazine decanoate and fluphenazine enanthate. No study comparing fluphenazine decanoate with fluphenazine enanthate reported death, clinically significant changes in global state or hospital admissions. Authors' conclusions: There are more data for fluphenazine decanoate than for the enanthate ester. Both are effective antipsychotic preparations. Fluphenazine decanoate produced fewer movement disorder effects than other oral antipsychotics but data were of low quality, and overall, adverse effect data were equivocal. In the context of trials, there is little advantage of these depots over oral medications in terms of compliance but this is unlikely to be applicable to everyday clinical practice.Full Tex

Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia.</p> <p>Methods</p> <p>Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a ≥30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders.</p> <p>Results</p> <p>A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non-responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials.</p> <p>Conclusions</p> <p>Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions.</p> <p>Trial Registration</p> <p>This is a retrospective, non-intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required.</p