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Evaluation of Differences in Individual Treatment Response in Schizophrenia Spectrum Disorders: A Meta-analysis.

ABSTRACT: Importance:An assumption among clinicians and researchers is that patients with schizophrenia vary considerably in their response to antipsychotic drugs in randomized clinical trials (RCTs). Objective:To evaluate the overall variation in individual treatment response from random variation by comparing the variability between treatment and control groups. Data Sources:Cochrane Schizophrenia, MEDLINE/PubMed, Embase, PsycINFO, Cochrane CENTRAL, BIOSIS Previews, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform from January 1, 1955, to December 31, 2016. Study Selection:Double-blind, placebo-controlled, RCTs of adults with a diagnosis of schizophrenia spectrum disorders and prescription for licensed antipsychotic drugs. Data Extraction and Synthesis:Means and SDs of the Positive and Negative Syndrome Scale pretreatment and posttreatment outcome difference scores were extracted. Data quality and validity were ensured by following the PRISMA guidelines. Main Outcomes and Measures:The outcome measure was the overall variability ratio of treatment to control in a meta-analysis across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. A personal element of response was hypothesized to be reflected by a substantial overall increase in variability in the treatment group compared with the control group. Results:An RCT was simulated, comprising 30 patients with schizophrenia randomized to either the treatment or the control group. The different components of variation in RCTs were illustrated with simulated data. In addition, we assessed the variability ratio in 52 RCTs involving 15?360 patients with a schizophrenia or schizoaffective diagnosis. The variability was slightly lower in the treatment compared with the control group (variability ratio?=?0.97; 95% CI, 0.95-0.99; P?=?.01). Conclusions and Relevance:In this study, no evidence was found in RCTs that antipsychotic drugs increased the outcome variance, suggesting no personal element of response to treatment but instead indicating that the variance was slightly lower in the treatment group than in the control group; although the study cannot rule out that subsets of patients respond differently to treatment, it suggests that the average treatment effect is a reasonable assumption for the individual patient.

SUBMITTER: Winkelbeiner S

PROVIDER: S-EPMC6547253 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Evaluation of Differences in Individual Treatment Response in Schizophrenia Spectrum Disorders: A Meta-analysis.

Winkelbeiner Stephanie S Leucht Stefan S Kane John M JM Homan Philipp P Homan Philipp P

JAMA psychiatry 20191001 10

<h4>Importance</h4>An assumption among clinicians and researchers is that patients with schizophrenia vary considerably in their response to antipsychotic drugs in randomized clinical trials (RCTs).<h4>Objective</h4>To evaluate the overall variation in individual treatment response from random variation by comparing the variability between treatment and control groups.<h4>Data sources</h4>Cochrane Schizophrenia, MEDLINE/PubMed, Embase, PsycINFO, Cochrane CENTRAL, BIOSIS Previews, ClinicalTrials. ...[more]

PMID: 31158853

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Project description:Objectives: We investigated the time course of clinical response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study (TEOSS). Methods: TEOSS randomized 119 predominantly outpatient youth ages 8-19 years with schizophrenia or schizoaffective disorder to 8 weeks of treatment with molindone, risperidone, or olanzapine. We used proportional hazards regression to determine whether these three antipsychotics differed in the time until clinical response, defined as the time from treatment initiation to the point of achieving a Clinical Global Impressions-Improvement (CGI-I) scale score of 1 ("very much improved") or 2 ("much improved") that was maintained until week 8. Results: Of the 116 youth who initiated treatment, 56 (48%) achieved clinical response. Among clinical responders, the median (±interquartile range) time until clinical response was 4.0 (±4.0) weeks for olanzapine, 4.5 (±4.0) weeks for risperidone, and 6.0 (±4.0) weeks for molindone. There were no significant differences in time course for clinical response between medications (p = 0.84). Youth without symptom improvement (CGI-I ≥ 4) after 3 weeks were more likely to be clinical nonresponders at week 8 (relative risk ratio = 1.98, 95% confidence interval 1.29-3.05), compared with youth with at-least-minimal symptom improvement after 3 weeks when looking at all antipsychotics combined. Conclusion: To our knowledge, our study is the first to investigate medication differences in treatment response timing in early onset schizophrenia spectrum disorders. Clinical response times for molindone, risperidone, and olanzapine were not significantly different. Furthermore, while lack of early improvement predicted clinical nonresponse, whether or not to continue antipsychotic treatment after 3 or more weeks without symptom improvement should be based on clinical judgment after weighing potential risks, benefits, and alternatives. ClinicalTrials.gov Identifier: NCT00053703.

Project description:INTRODUCTION:Antipsychotic treatment in early-onset schizophrenia (EOS) lacks a rich evidence base, and efforts to rank different drugs concerning their efficacy have not proven any particular drug superior. In contrast to the literature regarding adult-onset schizophrenia (AOS), comparative effectiveness studies in children and adolescents are limited in number and size, and only a few meta-analyses based on conventional methodologies have been conducted. METHODS AND ANALYSES:We will conduct a network meta-analysis of all randomised controlled trials (RCTs) that evaluate antipsychotic therapies for EOS to determine which compounds are efficacious, and to determine the relative efficacy and safety of these treatments when compared in a network meta-analysis. Unlike a contrast-based (standard) meta-analysis approach, an arm-based network meta-analysis enables statistical inference from combining both direct and indirect comparisons within an empirical Bayes framework. We will acquire eligible studies through a systematic search of MEDLINE, the Cochrane Central Registry of Controlled Trials, Clinicaltrials.gov and Centre for Reviews and Dissemination databases. Eligible studies should randomly allocate children and adolescents presenting with schizophrenia or a related non-affective psychotic condition to an intervention group or to a control group. Two reviewers will-independently and in duplicate-screen titles and abstracts, complete full text reviews to determine eligibility, and subsequently perform data abstraction and assess risk of bias of eligible trials. We will conduct meta-analyses to establish the effect of all reported therapies on patient-relevant efficacy and safety outcomes when possible. ETHICS AND DISSEMINATION:No formal ethical procedures regarding informed consent are required as no primary data collection is undertaken. The review will help facilitate evidence-based management, identify key areas for future research, and provide a framework for conducting large systematic reviews combining direct and indirect comparisons. The study will be disseminated by peer-reviewed publication and conference presentation. TRIAL REGISTRATION NUMBER:PROSPERO CRD42013006676.

Project description:Abstract Background We sought to characterize the trajectory of symptom change in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study (TEOSS), the largest randomized control trial in early-onset schizophrenia. Methods TEOSS randomized 119 youths ages 8–19 years old to 8 weeks of treatment with molindone, risperidone, or olanzapine (First Randomization). TEOSS defined treatment response as: completion of 8 weeks of treatment with the randomized antipsychotic, a Clinical Global Impression-Improvement (CGI-I) Scale score of 1(“very much improved”) or 2 (“much improved”), and a 20% reduction in symptoms on the Positive and Negative Syndrome Scale (PANSS). If participants did not respond to the initial randomized antipsychotic, participants were re-randomized to one of the two remaining antipsychotics (Second Randomization, n=50). If participants did not respond to the second antipsychotic, participants received the remaining antipsychotic (Third Randomization, n=23). Prior work found there was no statistically significant difference in response rates in the First Randomization when comparing molindone (50%), risperidone (46%), and olanzapine (34%) [Sikich et al. 2008]. Our study extends prior work by reporting the response rates for the Second and Third Randomizations, and also by reporting how long it took for youths to improve clinically with each antipsychotic. Results When combining all three Randomizations, response rates were: molindone 36.8% (25/68), risperidone 48.4% (31/64), and olanzapine 33.3% (20/60) (p=0.19). Response rates for the Second and Third Randomizations were: molindone 14.8% (4/27), risperidone 40.9% (9/22), and olanzapine 33.3% (8/24) (p=0.28). For youths who responded in the First Randomization (n=55), those randomized to molindone took 5.4 weeks (SD=2.4), risperidone 4.4 weeks (SD=2.3), and olanzapine 4.1 weeks (SD=2.4) to achieve and sustain a CGI-I of 1 (“very much improved”) or 2 (“much improved”) (p=0.24). When we combined the Second and Third Randomizations, it took youths randomized to molindone (n=4) 5.3 weeks (SD=2.8), risperidone (n=13) 4.8 weeks (SD=2.4), and olanzapine (n=4) 6.0 weeks (SD=2.2) to achieve and sustain a CGI-I of 1 or 2 (p=0.71).When we combined all three Randomizations, it took youths randomized to molindone (n=25) 5.4 weeks (SD=2.4), risperidone (n=33) 4.6 weeks (SD=2.3), and olanzapine (n=18) 4.6 weeks (SD=2.4) to achieve and sustain a CGI-I of 1 or 2 (p=0.39). Discussion This is the largest study in early-onset schizophrenia to look at response rates after failing randomized antipsychotic treatment. Furthermore, our study reports the average time it takes to achieve clinically-significant improvement in early-onset schizophrenia. ClinicalTrials.Gov Identifier: NCT00053703.

Project description:ImportanceSchizophrenia spectrum disorders (SSDs) and autism spectrum disorder (ASD) both feature social cognitive deficits; however, these disorders historically have been examined separately using a range of tests and subdomain focus and at different time points in the life span. Moving beyond diagnostic categories and characterizing social cognitive deficits can enhance understanding of shared pathways across these disorders.ObjectiveTo investigate how deficits in social cognitive domains diverge or overlap between SSDs and ASD based on the extant literature.Data sourcesLiterature searches were conducted in MEDLINE, PsycInfo, Embase, and Web of Science from database inception until July 26, 2020.Study selectionOriginal research articles were selected that reported performance-based measures of social cognition in both SSDs and ASD samples. Selected articles also had to be published in English and use International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, DSM-IV, or more recent diagnostic criteria.Data extraction and synthesisThis systematic review and meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines, including data extraction and quality assessment using a modified version of the Newcastle-Ottawa Scale. Data were pooled using a random-effects model.Main outcomes and measuresEffect sizes were calculated as Hedges g (SSDs vs ASD). The primary outcomes were performance on emotion processing tasks, theory of mind (ToM) tasks, and the Reading the Mind in the Eyes Test (RMET) in SSDs compared with ASD. Meta-regressions were performed for age difference, publication year, quality assessment scores, and antipsychotic medication use.ResultsOf the 4175 screened articles, 36 studies directly comparing social cognitive performance in individuals with SSDs vs ASD were included in the qualitative analysis (n = 1212 for SSDs groups and n = 1109 for ASD groups), and 33 studies were included in the quantitative analyses (n = 1113 for SSDs groups and n = 1015 for ASD groups). Most study participants were male (number of studies [k] = 36, 72% [878 of 1212] in SSDs groups and 82% [907 of 1109] in ASD groups), and age (k = 35) was older in SSDs groups (mean [SD], 28.4 [9.5] years) than in ASD groups (mean [SD], 23.3 [7.6] years). Included studies highlighted the prevalence of small, male-predominant samples and a paucity of cross-disorder clinical measures. The meta-analyses revealed no statistically significant differences between SSDs and ASD on emotion processing measures (k = 15; g = 0.12 [95% CI, -0.07 to 0.30]; P = .21; I2 = 51.0%; 1 outlier excluded), ToM measures (k = 17; g = -0.01 [95% CI, -0.21 to 0.19]; P = .92; I2 = 56.5%; 1 outlier excluded), or the RMET (k = 13; g = 0.25 [95% CI, -0.04 to 0.53]; P = .10; I2 = 75.3%). However, SSDs vs ASD performance differences between studies were statistically significantly heterogeneous, which was only minimally explained by potential moderators.Conclusions and relevanceIn this analysis, similar levels of social cognitive impairment were present, on average, in individuals with SSDs and ASD. Cross-disorder studies of social cognition, including larger samples, consensus batteries, and consistent reporting of measures, as well as data across multiple levels of analysis, are needed to help identify subgroups within and across disorders that may be more homogeneous in etiology and treatment response.

Project description:ContextImpaired social cognition is a cardinal feature of Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the functional neuroanatomy of social cognition in either disorder remains unclear due to variability in primary literature. Additionally, it is not known whether deficits in ASD and SZ arise from similar or disease-specific disruption of the social cognition network.ObjectiveTo identify regions most robustly implicated in social cognition processing in SZ and ASD.Data sourcesSystematic review of English language articles using MEDLINE (1995-2010) and reference lists.Study selectionStudies were required to use fMRI to compare ASD or SZ subjects to a matched healthy control group, provide coordinates in standard stereotactic space, and employ standardized facial emotion recognition (FER) or theory of mind (TOM) paradigms.Data extractionActivation foci from studies meeting inclusion criteria (n = 33) were subjected to a quantitative voxel-based meta-analysis using activation likelihood estimation, and encompassed 146 subjects with ASD, 336 SZ patients and 492 healthy controls.ResultsBoth SZ and ASD showed medial prefrontal hypoactivation, which was more pronounced in ASD, while ventrolateral prefrontal dysfunction was associated mostly with SZ. Amygdala hypoactivation was observed in SZ patients during FER and in ASD during more complex ToM tasks. Both disorders were associated with hypoactivation within the Superior Temporal Sulcus (STS) during ToM tasks, but activation in these regions was increased in ASD during affect processing. Disease-specific differences were noted in somatosensory engagement, which was increased in SZ and decreased in ASD. Reduced thalamic activation was uniquely seen in SZ.ConclusionsReduced frontolimbic and STS engagement emerged as a shared feature of social cognition deficits in SZ and ASD. However, there were disease- and stimulus-specific differences. These findings may aid future studies on SZ and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.

Project description:BACKGROUND:Schizophrenia is a heterogeneous disorder that is characterized by varying levels of hallucinations, delusions, negative symptoms, and disorganized features. The presence and severity of neurodevelopmental precursors and premorbid psychopathology also vary among individuals. To fully understand individual patients and to sort out phenotypic heterogeneity for genetic research studies, instruments designed to collect developmental history relevant to schizophrenia may be helpful. OBJECTIVE:The goal was to describe a pair of self-report and parent-report instruments developed for the purpose of collecting the developmental history of patients with known or suspected schizophrenia spectrum disorders. METHOD:Two developmental history instruments were designed for use in studies of brain morphology and cognition in schizophrenia probands and their unaffected siblings. The instruments focus mainly on motor abnormalities and other features that have been described as schizophrenia precursors. RESULTS:The Motor Skills History Form is a brief self-report form that asks about patients' childhood and adolescent motor abilities as well as their current motor functioning. The Developmental & Motor History Form is a more detailed parent-rated form that covers aspects of patients' early (infant/preschool) development; their childhood and adolescent motor abilities; any childhood behaviors that may be related to later psychosis risk; and their history of any neurological, emotional, or cognitive disorders diagnosed during childhood or adolescence. The instruments can be used either for interviews or as self-administered questionnaires. The parent-rated form has been used for research and for the clinical assessment of children and adolescents with complex neurodevelopmental presentations with or without strong evidence of schizophrenia risk. CONCLUSIONS:The collection of developmental history information is important when evaluating individuals with schizophrenia and related disorders. The Motor Skills History Form and the Developmental & Motor History Form can be used to collect this information for clinical evaluation or research purposes.

Dataset Information

Evaluation of Differences in Individual Treatment Response in Schizophrenia Spectrum Disorders: A Meta-analysis.

Publications

Evaluation of Differences in Individual Treatment Response in Schizophrenia Spectrum Disorders: A Meta-analysis.

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