TECHNISCHE UNIVERSITÄT MÜNCHEN Klinik und Poliklinik für Psychiatrie und Psychotherapie Klinikum rechts der Isar (Direktor: Prof. Dr. J. Förstl) Meta-analysis in schizophrenia trials: comparison of chlorpromazine versus every other antipsychotic drug for schizophrenia and assessment of an imputation technique for estimating response rates from means and standard deviations in schizophrenia. Myrto Samara Vollständiger Abdruck der von der Fakultät für Medizin der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Medizin genehmigten Dissertation. Vorsitzender: Prof. Dr. E. J. Rummeny Prüfer der Dissertation: 1. apl. Prof. Dr. St. M. Leucht 2. Prof. Dr. J. Förstl Die Dissertation wurde am 08.09.2015 bei der Technischen Universität München eingereicht und durch die Fakultät für Medizin am 16.11.2016 angenommen. 1 Publications included in the thesis ! I. Samara MT, Cao H, Helfer B, Davis JM, Leucht S. Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs. Eur Neuropsychopharmacol. 2014 Jul;24(7):1046-55. II. Samara MT, Spineli LM, Furukawa TA, Engel RR, Davis JM, Salanti G, Leucht S. Imputation of response rates from means and standard deviations in schizophrenia. Schizophr Res. 2013 Dec;151(1-3):209-14. 2 Table of contents ! A. List of symbols and abbreviations .................................................................................................. 5 B. Abstract ........................................................................................................................................... 7 C. Cumulative thesis ............................................................................................................................ 8 Introduction and motivation ................................................................................................................ 8 I. Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs ...................... 8 II. Imputation of response rate from means and standard deviations in schizophrenia ............. 10 Methods ............................................................................................................................................. 13 I. Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs .................... 13 a. Setting the research question and defining the study protocol .............................................. 13 b. Search and selection of trials ................................................................................................ 14 c. Data extraction ...................................................................................................................... 15 d. Risk of bias assessment ......................................................................................................... 16 e. Meta-analytical calculations ................................................................................................. 17 f. Assessment of publication bias ............................................................................................. 19 g. Presentation of results ........................................................................................................... 19 II. Imputation of response rate from means and standard deviations in schizophrenia ............. 20 a. Imputation strategy ............................................................................................................... 21 1. Based on mean endpoint scores ................................................................................................ 23 2. Based on mean change scores ................................................................................................... 24 b. Assessment of the imputation method .................................................................................. 25 1. The Concordance Correlation Coefficient (CCC) .................................................................... 25 2. Predictive accuracy ................................................................................................................... 25 3. The “limits of agreement” method ............................................................................................ 26 Results ............................................................................................................................................... 28 I. Chlorpromazine versus every other antipsychotic for schizophrenia: a systematic review and meta-analysis challenging the dogma of equal efficacy of antipsychotic drugs .................... 28 II. Imputation of response rate from means and standard deviations in schizophrenia ............. 29 1. The Concordance Correlation Coefficient (CCC) .................................................................... 29 2. Predictive accuracy ................................................................................................................... 29 3. The “limits of agreement” method ............................................................................................ 30 Discussion and conclusions .............................................................................................................. 32 3 Table of contents IEw Chlorpromazinewversusweverywotherwantipsychoticwforwschizophrenia:wawsystematicwrevieww andwmeta0analysiswchallengingwthewdogmawofwequalwefficacywofwantipsychoticwdrugswEEEEEEEEEEEEEEEEEEEEw32w IIE ImputationwofwresponsewratewfromwmeanswandwstandardwdeviationswinwschizophreniawEEEEEEEEEEEEEw35 ReferenceswEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw38w DEw PublicationswEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw55w FirstwpublicationwEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw55w AppendixwEwOnlinewsupplement EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE66w SecondwpublicationwEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw489w AppendixwEwOnlinewsupplement EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE4w EEw AcknowledgementswEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw494w FEw CopyrightwpermissionwEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEw495w 4 A. List of symbols and abbreviations ANOVA: Analysis of Variance BPRS: Brief Psychiatric Rating Scale CC: Completer Cases CCC: Concordance Correlation Coefficient CGI: Clinical Global Impression ECT: Electroconvulsive Therapy EU: European Union FGA: First Generation Antipsychotic FINER: Feasible, Interesting, Novel, Ethical, Relevant ICC: Intraclass Correlation Coefficient ITT: Intention-to-treat LOCF: Last Observation Carried Forward MD: Mean Difference MSE: Mean Squared Error NNT: Number Needed to Treat OR: Odds Ratio PANSS Positive and Negative Syndrome Scale PICOT: Population, Intervention, Comparison, Outcome, Time 5 A. List of symbols and abbreviations ! RCT: Randomized Controlled Trial RR: Risk Ratio SD: Standardized Difference SGA: Second Generation Antipsychotic SMD: Standardized Mean Difference WHO: World Health Organisation WFSBP: World Federation of Societies of Biological Psychiatry ! ! 6 B. Abstract Systematic reviews and meta-analyses can provide answers to long-standing dubious scientific statements. Thus, in my first project, I conducted a systematic review and meta-analysis in order to address one of the major psychiatric dogmas that all antipsychotic drugs are equally efficacious. Randomized controlled trials (RCTs) comparing the benchmark drug chlorpromazine to any other antipsychotic in the treatment of schizophrenia were assessed. Binary response to treatment, mean values in schizophrenia rating scales and drop-out rates were analyzed. 128, mostly small, RCTs with 10667 participants were included. Chlorpromazine was compared with 43 other antipsychotics and was shown more efficacious than five (butaperazine, mepazine, oxypertine, quetiapine and reserpine) and less efficacious than six antipsychotics (clomacran, clozapine, olanzapine, risperidone and zotepine). There were no statistically significant efficacy differences between chlorpromazine and the remaining 25 antipsychotics. Nevertheless, the main limitation of this meta-analysis was that most comparisons were underpowered; thus any conclusion that chlorpromazine is more or less efficacious than any other antipsychotic could not be driven. Apparently, limited power is one of meta-analysis major drawbacks. As one of its causes is missing data, in my second project I assessed the performance of an imputation method in schizophrenia trials that has been previously applied with success in anxiety and depression trials. This imputation method converts continuous to binary data using means and standard deviations. To assess its performance in