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Time to Clinical Response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study.

ABSTRACT: 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.

SUBMITTER: Taylor JH

PROVIDER: S-EPMC7891207 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:BackgroundAntipsychotic-related weight gain is a common clinically relevant side effect when treating psychotic disorders in pediatric populations, yet few predictors and no moderators of antipsychotic-related weight gain are known.MethodsThe Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study randomized 119 youths (age 8-19 years) with schizophrenia or schizoaffective disorder to 8 weeks of antipsychotic treatment with molindone, risperidone, or olanzapine and assessed treatment response and side effects. In this secondary analysis, we used multivariable linear regression and receiver operating characteristic analysis to investigate predictors and moderators of weight change and percent weight change from baseline to week 8.ResultsTreatment assignment was the most discriminant predictor of weight change [F(2, 66) = 17.00, p < 0.001] and percent weight change [F(2, 66) = 16.85, p < 0.001]. Mean weight gain was 0.74 (standard deviation ±3.51) kg for molindone, 4.13 ± 3.79 kg for risperidone, and 7.29 ± 3.44 kg for olanzapine. After adjusting for treatment assignment, lower pretreatment hemoglobin A1C (HgbA1C) predicted more weight gain [F(1, 55) = 4.71, p = 0.03]. Diagnosis (schizoaffective vs. schizophrenia) moderated weight change [F(2, 63) = 6.02, p = 0.004] and percent weight change [F(2, 63) = 5.26, p = 0.008] such that schizoaffective diagnosis predicted larger weight gain for youths in the risperidone treatment arm. Age, sex, family income, baseline weight, and symptoms neither predicted nor moderated weight change or percent weight change.ConclusionWe identified prognostic subgroups and novel risk factors for antipsychotic-related weight gain. We confirmed that antipsychotic choice is extremely important for predicting future weight gain. We also found that younger age did not predict greater weight gain, in contrast to prior studies. Our findings require replication in an independent sample because we did not adjust for multiple comparisons to minimize false negatives. ClinicalTrials.gov Identifier: NCT00053703.

Project description:ImportanceAn assumption among clinicians and researchers is that patients with schizophrenia vary considerably in their response to antipsychotic drugs in randomized clinical trials (RCTs).ObjectiveTo evaluate the overall variation in individual treatment response from random variation by comparing the variability between treatment and control groups.Data sourcesCochrane 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 selectionDouble-blind, placebo-controlled, RCTs of adults with a diagnosis of schizophrenia spectrum disorders and prescription for licensed antipsychotic drugs.Data extraction and synthesisMeans 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 measuresThe 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.ResultsAn 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 relevanceIn 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.

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Time to Clinical Response in the Treatment of Early Onset Schizophrenia Spectrum Disorders Study.

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