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  ["project_title"]=>
  string(201) "An evaluation of lack of early improvement and later non-response in early-onset schizophrenia: a systematic review and diagnostic test accuracy meta-analysis of data from randomized controlled trials."
  ["project_narrative_summary"]=>
  string(2199) "Although there is considerable interpersonal variability, schizophrenia is generally considered one of the most serious psychiatric disorders. Most often schizophrenia onsets in (early) adulthood. However, for about 8% of people who live with schizophrenia,  it onsets during childhood or adolescence (that is, before 18 years old). There is concern that early-onset schizophrenia (EOS) is a more severe form of this condition that arises at a critical developmental period, when individuals acquire their independence (for example, start living alone). In this context, it is important to ensure early and effective treatment for EOS. Unfortunately, to date we are not capable of predicting which individuals will benefit most from a specific medication, and clinical practice still involves iterating through medications that, on average, have been demonstrated efficacious for a given condition. Current clinical practice guidelines such as that from the UK NICE recommend that practitioners wait for 6 to 8 weeks with an antipsychotic at optimum dosage before switching to a different medication. However, there is evidence that individuals who do not show early improvement are likely not to respond at the end of the treatment trial. Nonetheless, this evidence is overwhelmingly based on adult data, although children and adolescents are not 'small adults' and need need evidence that is directly applicable to them. This proposal aims at addressing this issue through conducting meta-analysis of diagnostic test accuracy similarly to Samara et al., (2015) (AJP 172(7):617-629). We hope that this study will help inform clinical practice regarding antipsychotic use for EOS. For example, if lack of early improvement is a predictor of later nonresponse in children and adolescents with schizophrenia or schizophrenia spectrum disorders, then clinical practice guidelines (and practitioners) could consider revising the current recommendation to wait for 6-8 weeks before switching antipsychotic medication in the hopes of improving the risk-benefits trade-offs of treatment with antipsychotics (that is, if an individual is unlikely to benefit from a treatment, they could be switched before)."
  ["project_learn_source"]=>
  string(10) "web_search"
  ["principal_investigator"]=>
  array(7) {
    ["first_name"]=>
    string(4) "Luis"
    ["last_name"]=>
    string(6) "Farhat"
    ["degree"]=>
    string(7) "MD, PhD"
    ["primary_affiliation"]=>
    string(24) "University of São Paulo"
    ["email"]=>
    string(18) "luis.farhat@usp.br"
    ["state_or_province"]=>
    string(2) "SP"
    ["country"]=>
    string(6) "Brazil"
  }
  ["project_key_personnel"]=>
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    [0]=>
    array(6) {
      ["p_pers_f_name"]=>
      string(9) "Guilherme"
      ["p_pers_l_name"]=>
      string(9) "Polanczyk"
      ["p_pers_degree"]=>
      string(7) "MD, PhD"
      ["p_pers_pr_affil"]=>
      string(24) "University of São Paulo"
      ["p_pers_scop_id"]=>
      string(10) "6507552141"
      ["requires_data_access"]=>
      string(3) "yes"
    }
  }
  ["project_ext_grants"]=>
  array(2) {
    ["value"]=>
    string(2) "no"
    ["label"]=>
    string(68) "No external grants or funds are being used to support this research."
  }
  ["project_date_type"]=>
  string(18) "full_crs_supp_docs"
  ["property_scientific_abstract"]=>
  string(2649) "Background: Clinical practice guidelines recommend that antipsychotics should be trialed for 6-8 weeks at optimum dosage before determining non-response and switching to another antipsychotic medication for the treatment of an acute episode of schizophrenia in children and adolescents. However, currently available meta-analytical data (mostly based on adult studies) indicate that the lack of early improvement is a predictor of later non-response. Because children and adolescents are not 'small adults', we need evidence that is directly applicable to this population.



Objective: To evaluate whether lack of early improvement predicts later non-response in children and adolescents with schizophrenia or schizophrenia spectrum disorders.



Study design: Meta-analysis of double-blinded randomized controlled studies.



Participants: Children and adolescents (17 years or younger) with a primary diagnosis of schizophrenia or schizophrenia spectrum disorders (for instance, schizoaffective disorder or schizophreniform disorder) according to any operationalized criteria (including Diagnostic and Statistical Manual of Mental Disorders, International Classification of Diseases, among others) that were randomized to at least one treatment arm of antipsychotic (as defined in the World Health Organization ATC code) monotherapy.



Primary outcome: Nonresponse at the study endpoint. We will define nonresponse as less than 50% reduction of the total Positive And Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) score from baseline to endpoint. 



Secondary outcome: Nonremission at the study endpoint. We will define nonremission following the international consensus criteria sans the time requirement (that is, 6 month sustainment) considering the PANSS or BPRS required items.



Statistical analysis: We will follow the procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Meta-Analyses. We will use individual participant data to calculate, for each study,  counts of true positives, true negatives, false positives, and false negatives. Then, we will calculate sensitivity and specificity for each study and plot their estimates in summary receiver-operating characteristic (SROC) plot and forest plots. Because we are interested in estimating summary sensitivity and specificity, we will fit generalized linear mixed models (GLMM) to conduct bivariate random-effects meta-analysis to aggregate data across studies. We will explore heterogeneity through adding candidate study-level variables as covariates.

"
  ["project_brief_bg"]=>
  string(3906) "Schizophrenia is a serious psychiatric condition (Kahn et al., 2015). While there is considerable interpersonal variability, individuals who live with this condition generally experience psychosocial impairments (for example, difficulties to maintain relationships, employment, and independent living) and, on average, have a reduced life expectancy by 13-15 years (Bowie et al., 2006; Hjorthoj et al., 2017). Epidemiologic studies indicate that between 2 and 10 per 1,000 persons live with schizophrenia, and around 8% are estimated to have an onset in childhood or adolescence (that is, by 18 years) (GBD 2019 Mental Disorders Collaborators 2022; McGrath et al., 2008; Solmi et al., 2022). Schizophrenia in children or adolescents (also known as 'early-onset schizophrenia', EOS) may be associated with worse symptomatic and functional recovery in comparison to adult-onset schizophrenia (Ballageer et al., 2005). Hence, EOS may represent a more severe form of the disorder, which manifests at a critical stage of development and may dramatically disrupt age-related milestones, such as independent living, vocational training, and social integration. In this context, proper treatment of EOS is paramount. 



Clinical practice guidelines such as those from the UK National Institute for Health and Care Excellence (NICE) recommend that antipsychotics should be adopted in the treatment of acute episodes of schizophrenia in children and adolescents. Because clinicians are unable to predict treatment outcomes in schizophrenia - even through sophisticated models (Chekroud et al., 2024) - routine clinical practice involves iterating through the available antipsychotics until a patient shows benefit with a specific medication. NICE recommends that practitioners should trial antipsychotics at optimum dosages for 6 to 8 weeks before switching to another agent. However, the evidence base that justifies this specific duration of treatment is unclear. Because there are important safety concerns around antipsychotics in children and adolescents (Solmi et al., 2020), minimizing unnecessary exposure to such medications (for example in patients who are unlikely to benefit from them) may be a sensible strategy to maximize risk-benefits trade-offs of antipsychotics in EOS.



In adults, a meta-analysis by Samara et al., (2015) demonstrated that lack of early improvement predicted later non-response at the study endpoint with a specificity of 86% and a positive predictive value of 90%. However, the overwhelming majority of the 34 included studies were conducted in adults. Children and adolescents are not 'small adults' and need corresponding evidence that is directly applicable to them. In children and adolescents, three previous randomized controlled trials (RCTs) have examined whether lack of early improvement predicts later non-response (Correll et al., 2013; Pagsberg et al., 2022; Taylor et al., 2021). Overall, their findings indicate that most benefits occur early in the treatment (during the first 2 weeks) and lack of early improvement may predict later non-response. However, clinical practice guidelines and recommendations should be based on all available evidence, following the intention-to-treat principle. In that way, a systematic review and meta-analysis of those studies is highly relevant and currently needed.



We hope that the evidence that we will generate through the project will help inform practitioners about the duration of antipsychotic treatment in EOS in their routine practice. If individuals with EOS who do not improve early are demonstrated to be likely non-responders at the end of the antipsychotic trial, practitioners could consider switching the patient to a different antipsychotic earlier instead of waiting for 6-8 weeks as currently indicated in practice guidelines such as that from NICE. 



"
  ["project_specific_aims"]=>
  string(789) "We aim to build upon the previous meta-analysis conducted with data from mostly adult studies (Samara et al., 2015) and individual RCTs that examined this question in EOS (Correll et al., 2013; Pagsberg et al., 2022; Taylor et al., 2021). 



Specifically, this study aims to conduct a meta-analysis of RCTs examining antipsychotics (against each other or placebo) for the treatment of schizophrenia and schizophrenia spectrum disorders according to any operationalized criteria in children and adolescents (17 years or younger) to evaluate whether lack of early improvement predicts later non-response or non-remission.



We hypothesize that lack of early improvement will predict both later non-response and non-remission.









"
  ["project_study_design"]=>
  array(2) {
    ["value"]=>
    string(7) "meta_an"
    ["label"]=>
    string(52) "Meta-analysis (analysis of multiple trials together)"
  }
  ["project_purposes"]=>
  array(4) {
    [0]=>
    array(2) {
      ["value"]=>
      string(76) "confirm_or_validate previously_conducted_research_on_treatment_effectiveness"
      ["label"]=>
      string(76) "Confirm or validate previously conducted research on treatment effectiveness"
    }
    [1]=>
    array(2) {
      ["value"]=>
      string(22) "participant_level_data"
      ["label"]=>
      string(36) "Participant-level data meta-analysis"
    }
    [2]=>
    array(2) {
      ["value"]=>
      string(56) "participant_level_data_meta_analysis_from_yoda_and_other"
      ["label"]=>
      string(69) "Meta-analysis using data from the YODA Project and other data sources"
    }
    [3]=>
    array(2) {
      ["value"]=>
      string(34) "research_on_clinical_trial_methods"
      ["label"]=>
      string(34) "Research on clinical trial methods"
    }
  }
  ["project_software_used"]=>
  array(2) {
    ["value"]=>
    string(1) "r"
    ["label"]=>
    string(1) "R"
  }
  ["project_research_methods"]=>
  string(2746) "This study is a systematic review and meta-analysis of randomized controlled trials (RCTs) examining antipsychotics for the treatment of early-onset schizophrenia.



We searched PubMed, CENTRAL and Embase to identify eligible studies.



In terms of the eligibility criteria, we are interested in double-blinded RCTs that recruited children or adolescents (17 years or younger) with a primary diagnosis of schizophrenia or schizophrenia spectrum disorders (for instance, schizoaffective disorder or schizophreniform disorder) according to any operationalized criteria (including Diagnostic and Statistical Manual of Mental Disorders, International Classification of Diseases, among others) and randomized them to at least one treatment arm of antipsychotic monotherapy. We will consider antipsychotics as eligible considering the World Health Organization Anatomical Therapeutic Chemical Classification. We will consider monotherapy in terms of co-occurring antipsychotics, which will not be allowed, but we will not restrict eligibility according to concomitant psychotherapeutic/psychosocial/familial interventions. We expect that in some studies participants will be allowed to start medications for adverse events (for example, biperiden).



Because this analysis considers data from individual arms instead of comparative effects, RCTs that randomized participants to at least one eligible arm (as defined above) will be eligible for inclusion. Nevertheless, we are going to restrict eligibility to RCTs and will not consider other experimental studies (for example, uncontrolled trials) because in those studies individuals that participate get treatment, while in RCTs they know that chance will decide whether they get a treatment or not. This means that the population in uncontrolled trials and RCTs can differ considerably and it cannot be assumed that they are comparable enough to be combined in meta-analyses (Cuijpers et al., 2017). Besides, open label or single-blind RCTs will not be eligible anyway since the outcomes (response and remission) are subjective and knowledge of the intervention could influence outcomes.



A list of eligible studies was appended as a supplementary material. Please note that this list may be expanded if we identify additional eligible studies. We are currently pursuing individual participant data from sponsors through Vivli and other company-specific channels (for those which do not have an agreement with Vivli) as well as study authors. A concomitant Vivli request has been submitted to this proposal. We plan to conduct all analyses in the Vivli environment and will 'bring our own' data for studies that are not currently in the platform."
  ["project_main_outcome_measure"]=>
  string(1450) "Our primary outcome is nonresponse at the study endpoint (6 or 8 weeks for studies requested in YODA). Nonresponse will be defined as less than 50% reduction of the total Positive And Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) score from baseline to endpoint. We are considering both the PANSS and BPRS as eligible because the two scales are highly correlated (Leucht et al., 2013). We will subtract the minimum score of 30/18 to calculate the PANSS/BPRS percentage reductions as recommended by Leucht et al., (2007).



This definition of non-response is in accordance with the one from the previous meta-analysis in adults (Samara et al., 2015) as well as individual RCTs in children and adolescents (Pagsberg et al., 2022).



Our secondary outcome is nonremission at the study endpoint. Nonremission will be defined following the international consensus criteria outlined by Andreasen et al., (2005) sans the time requirement (that is, 6 month sustainment). Specifically, we will determine remission (and nonremitters will be those who do not achieve remission) as simultaneous ratings of mild or less on all the required items from the PANSS or BPRS. For studies that adopted the BPRS, we will also use items from the Scale for the Assessment of Negative Symptoms (SANS) to evaluate overall remission (if available); otherwise, we will just score remission based on the available BPRS items."
  ["project_main_predictor_indep"]=>
  string(1015) "The primary predictor is lack of early improvement, defined as less than 20% reduction of the total PANSS or BPRS score from baseline to 2 weeks. This definition of lack of early improvement is in accordance with the one from the previous meta-analysis in adults (Samara et al., 2015) as well as the individual RCTs in children and adolescents (Correll et al., 2013; Pagsberg et al., 2022).



In secondary analyses, we will examine the following predictors:

1) Other cutoff thresholds to determine lack of early improvement (0% or less than 5%, 10%, 15%, 20%, 25%, 30%, 40%, and 50%)

2) Positive symptom scores (PANSS items 1 to 7; BPRS items 4, 11, 12, and 15), instead of total scores, to determine lack of early improvement following the rationale that the degree of improvement in positive symptoms alone could better predict nonresponse at the endpoint.



These secondary analyses are in line with the procedures adopted in the adult meta-analysis (Samara et al., 2015)."
  ["project_other_variables_interest"]=>
  string(858) "We are interested in assessing the effects of covariates on the summary estimates of sensitivity and specificity of the primary analysis.



We will consider the following covariates:



1) sex (dichotmous: male versus female);

2) age (continuous: mean age; dichotomous: 16-18 versus ≤ 15 years);

3) diagnosis (for exclusion of primary diagnoses other than schizophrenia in sensitivity analysis);

4) baseline severity (continuous);

5) duration of illness (continuous);

6) medication administered (nominal; note: we will consider risperidone and paliperidone since the latter is the primary metabolite of the former);

7) week of response assessment (nominal);

8) dosing design (dichotomous: fixed or flexible doses)

9) sponsorship (dichotomous: sponsored versus not sponsored)."
  ["project_stat_analysis_plan"]=>
  string(2510) "We will follow the procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Meta-Analyses. All procedures are described in detail below.



Although this analysis is based on single-arm data and not comparative effects, we still plan to follow intention-to-treat (ITT) principles and consider, in our analyses, all participants that were randomized. 



We expect that some participants discontinued during the studies, and therefore there will be some missing data at the studies endpoint. 



To minimize the impact of missing data, we will include all individuals who had one post-treatment PANSS/BPRS assessment at 4 weeks or later considering recent evidence from Taylor et al., (2021) that found a median time until clinical response of 4 weeks for risperidone/ olanzapine. However, we will exclude participants who discontinued the study before 4 weeks due to missing data, in accordance with the modified ITT. For participants with time points after 4 weeks (for example, 4 and 5 weeks), we will consider the one closest to the study endpoint.



We will calculate sensitivity and specificity for each study and plot their estimates in summary receiver-operating characteristic (SROC) plot and forest plots. Because we are interested in estimating summary sensitivity and specificity, we will fit generalized linear mixed models (GLMM) with R-package "lme4" to conduct bivariate meta-analysis. The bivariate model allows for correlation between sensitivity and specificity, and therefore is considered appropriate for diagnostic test accuracy meta-analyses.



While our strict eligibility criteria justifies pooling studies together, heterogeneity is to be expected (Samara et al., 2015). To address between-study variability, we will adopt a random-effects model by adding study-level random effects. We will also assume heterogeneity and proceed to investigate the effects of covariates by introducing them one by one as covariates in the bivariate model.



In terms of sensitivity analyses, we will re-run our analyses after excluding participants who had a primary diagnosis other than schizophrenia (for example, schizoaffective disorder). For studies with endpoint later than 6 weeks, we will also run a sensitivity analysis considering the assessment at 6 weeks instead of the endpoint to increase homogeneity of measurement.



All analyses will be conducted in the Vivli Environment with R."
  ["project_timeline"]=>
  string(485) "We will be capable of starting the project after approval in the data sharing platforms (e.g., Vivli, YODA). We are also contacting individual authors and sponsors to enquiry about other studies that are not available through Vivli or YODA. We are hopeful to start analyses 1st August 2024. We expect to be able to run analyses in an additional 6 months (by 1st February 2025) and then draft the manuscript and submit it for publication within an additional 3 months (by 1st May 2025)."
  ["project_dissemination_plan"]=>
  string(358) "We plan to publish an article in a leading journal in psychiatry or child and adolescent psychiatry to describe this study and its results.



We expect that this study will be included in local and international treatment guidelines and should contribute to inform decision making regarding antipsychotic treatment for early-onset schizophrenia."
  ["project_bibliography"]=>
  string(5023) "
Andreasen, N. C., Carpenter, W. T., Kane, J. M., Lasser, R. A., Marder, S. R. & Weinberger, D. R. (2005). Remission in Schizophrenia: Proposed Criteria and Rationale Consensus. The American Journal of Psychiatry.162(3):441-449.
Ballageer, T., Malla, A., Manchada, R., Takhar, J. & Haricharan, R. (2005). Is adolescent-onset first-episode psychosis different from adult onset. Journal of the American Academy of Child & Adolescent Psychiatry. 44(8):782-789.
Bowie, C. R., Reichenberg, A., Patterson, T. L., Heaton, R. K. & Harvey, P. D. (2006). Determinants of real world functional performance in schizophrenia: correlations with cognition, functional capacity, and symptoms. The American Journal of Psychiatry. 163:418-425.
Chekroud, A. M., Hawrilenko, M., Loho, H., Bondar, J., Gueorguieva, R., Hasan, A., Kambeitz, J., Corlett, P. R., Koutsouleris, N., Krumholz, H. M., Krystal, J. H. & Paulus, M. (2024). Illusory generalizability of clinical prediction models. Science. 383(6679):164-167.
Correll, C. U., Zhao, J., Carson, W., Marcus, R., McQuade, R., Forbes, R. A. & Mankoski, R. (2013). Early antipsychotic response to aripiprazole in adolescents with schizophrenia: predictive value for clinical outcomes. Journal of the American Academy of Child & Adolescent Psychiatry. 52(7):689-698.
Cuijpers, P., Weitz, E., Cristea, I. A. & Twisk, J. (2017). Pre-post effect sizes should be avoided in meta-analyses. Epidemiology and Psychiatric Sciences. 26(4):364-368.
GBD 2019 Mental Disorders Collaborators. (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Psychiatry. 9(2):137-150.
Hjorthoj, C., Sturup, A. E., McGrath, J. J. & Nordentof, M. (2017). Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 4(4):295-301.
Kahn, R. S., Sommer, I. E., Murray, R. M., Meyer-Lindenberg, A., Weinberger, D. R., Cannon, T. D., O’Donovan, M., Correll, C. U., Kane, J. M., van Os, J. & Insel, T. R. (2015). Schizophrenia. Nature Reviews Disease Primers. 1: 15067.
Leucht, S., Davis, J. M., Engel, R. R., Kane, J. M. & Wagenpfeil, S. (2007). Defining response in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacology. 32:1903-1910.
Leucht, S., Rothe, P., Davis, J. M. & Engel, R. R. (2013). Equipercentile linking of the BPRS and the PANSS. European Neuropsychopharmacology. 23(8):956-959.
McGrath, J., Saha, S., Chant, D., & Welham, J. (2008). Schizophrenia: A Concise Overview of Incidence, Prevalence, and Mortality. Epidemiologic Reviews. 30: 67-76.
Pagsberg, A. K., Krogmann, A., Jeppesen, P. von Hardenberg, L., Klauber, D. G., Jensen, K. G., Rudå, D., Decara, M. S., Jepsen, J. R. M., Fagerlund, B., Fink-Jensen, A., Correll, C. U. & Galling, B. (2022). Early antipsychotic nonresponse as a predictor of nonresponse and nonremission in adolescents with psychosis treated with aripiprazole or quetiapine: results from the TEA trial. Journal of the American Academy of Child & Adolescent Psychiatry. 61(8):997-1009.
Samara, M. T., Leucht, C., Leeflang, M. M., Anghelescu, I. G., Chung, Y. C., Crespo-Facorro, B., Elkis, H., Hatta, K., Giegling, I., Kane, J. M., Kayo, M., Lambert, M., Lin, C. H., Möller, H. J., Pelayo-Terán, J. M., Riedel, M., Rujescu, D., Schimmelmann, B. G., Serreti, A., … & Leucht, S. (2015). Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review. The American Journal of Psychiatry. 172(7):617-629.
Solmi, M., Fornaro, M., Ostinelli, E. G., Zangani, C., Croatto, G., Monaco, F., Krinistki, D., Fusar-Poli, P. & Correll, C. U. (2020). Safety of 80 antidepressants, antipsychotics, anti-attention-deficit/hyperactivity medications and mood stabilizers in children and adolescents with psychiatric disorders: a large scale systematic meta-review of 78 adverse effects. World Psychiatry. 19(2):214-232.
Solmi, M., Radua, J., Olivola, M., Croce, E., Soardo, L., Salazar de Pablo, G., II Shin, J., Kirkbride, J. B., Jones, P., Kim, J. H., Kim, J. Y., Carvalho, A. F., Seeman, M. V., Correll, C. U., Fusar-Poli, P. (2022). Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies. Molecular Psychiatry. 27(1):281-295.
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NICE Guideline: Psychosis and schizophrenia in children and young people: recognition and management. NICE guideline CG155 Last updated: 26 October 2016
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