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      Augmentation Strategies for Partial or Non-responders to Clozapine in Patients with Schizophrenia: A Bayesian Network Meta-analysis of Randomized Controlled Trials

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      https://www.riss.kr/link?id=A109078127

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      다국어 초록 (Multilingual Abstract) kakao i 다국어 번역

      Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (−5.2 [95%CrI: −7.7, −2.7]) and memantine (−2.1 [95%CrI: −4.0, −0.19]) were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.
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      Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a ...

      Clozapine is the only approved drug for treatment-resistant schizophrenia, but the response to the drug is often inadequate. Augmentation with other antipsychotics, anticonvulsants, and antidepressants is recommended for such patients, but there is a lack of evidence regarding the most effective therapy. This network meta-analysis was conducted to evaluate the efficacy of pharmacological agents used in the augmentation strategies in patients who were partial/non-responders to clozapine. Relevant data were extracted from 30 randomized controlled trials through searches of electronic databases (MEDLINE/PubMed, Embase, Cochrane, clinical trial registries). PRISMA guidelines were followed for the extraction, management, analysis, and reporting of the data. The outcome measure in this study was a reduction in symptom severity according to total PANSS/BPRS and was reported as the standardized mean difference with a 95% credible interval. Bayesian network meta-analysis with random effects model and uninformative priors was conducted, and the ranking probability of each intervention was done. Meta-regression was done to assess the effect of duration on the reduction in symptom severity scores. Mirtazapine (−5.2 [95%CrI: −7.7, −2.7]) and memantine (−2.1 [95%CrI: −4.0, −0.19]) were more efficacious than placebo for augmentation of clozapine in partial/non-responders and were the most effective adjunctive agents as per SUCRA scores. Both drugs did not cause a significant increase in frequency of adverse events compared to placebo. There was a significant effect of duration on the reduction in symptom severity. There was no evident publication bias. Mirtazapine and memantine may prove beneficial for augmentation of clozapine in non/partial responders to monotherapy.

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      참고문헌 (Reference)

      1 Meltzer HY, "Treatment-resistant schizophrenia--the role of clozapine" 14 : 1-20, 1997

      2 Nucifora FC Jr, "Treatment resistant schizophrenia : clinical, biological, and therapeutic perspectives" 131 : 104257-, 2019

      3 Muscatello MR, "Topiramate augmentation of clozapine in schizophrenia : a double-blind, placebo-controlled study" 25 : 667-674, 2011

      4 Kane JM, "The role of clozapine in treatment-resistant schizophrenia" 73 : 187-188, 2016

      5 Tiihonen J, "The efficacy of lamotrigine in clozapine-resistant schizophrenia : a systematic review and meta-analysis" 109 : 10-14, 2009

      6 Zoccali R, "The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia : a double-blind, placebo-controlled study" 19 : 71-76, 2004

      7 Zoccali R, "The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients : a double-blind, placebo-controlled study" 93 : 109-116, 2007

      8 Hutton B, "The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions : checklist and explanations" 162 : 777-784, 2015

      9 Higgins JP, "The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials" 343 : d5928-, 2011

      10 Shiloh R, "Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A doubleblind, placebo-controlled study" 171 : 569-573, 1997

      1 Meltzer HY, "Treatment-resistant schizophrenia--the role of clozapine" 14 : 1-20, 1997

      2 Nucifora FC Jr, "Treatment resistant schizophrenia : clinical, biological, and therapeutic perspectives" 131 : 104257-, 2019

      3 Muscatello MR, "Topiramate augmentation of clozapine in schizophrenia : a double-blind, placebo-controlled study" 25 : 667-674, 2011

      4 Kane JM, "The role of clozapine in treatment-resistant schizophrenia" 73 : 187-188, 2016

      5 Tiihonen J, "The efficacy of lamotrigine in clozapine-resistant schizophrenia : a systematic review and meta-analysis" 109 : 10-14, 2009

      6 Zoccali R, "The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia : a double-blind, placebo-controlled study" 19 : 71-76, 2004

      7 Zoccali R, "The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients : a double-blind, placebo-controlled study" 93 : 109-116, 2007

      8 Hutton B, "The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions : checklist and explanations" 162 : 777-784, 2015

      9 Higgins JP, "The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials" 343 : d5928-, 2011

      10 Shiloh R, "Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A doubleblind, placebo-controlled study" 171 : 569-573, 1997

      11 Lin CH, "Sodium benzoate, a D-amino acid oxidase inhibitor, added to clozapine for the treatment of schizophrenia : a randomized, double-blind, placebo-controlled trial" 84 : 422-432, 2018

      12 Freudenreich O, "Risperidone augmentation for schizophrenia partially responsive to clozapine : a double-blind, placebo-controlled trial" 92 : 90-94, 2007

      13 Lao KSJ, "Prescribing trends and indications of antipsychotic medication in Hong Kong from 2004 to 2014 : general and vulnerable patient groups" 26 : 1387-1394, 2017

      14 Moher D, "Preferred reporting items for systematic review and meta-analysis protocols(PRISMA-P)2015 statement" 4 : 1-, 2015

      15 "PlotDigitizer" Porbital

      16 Evins AE, "Placebocontrolled trial of glycine added to clozapine in schizophrenia" 157 : 826-828, 2000

      17 Friedman JI, "Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy" 36 : 1289-1295, 2011

      18 Yeh TC, "Pharmacological and nonpharmacological augmentation treatments for clozapine-resistant schizophrenia : a systematic review and network meta-analysis with normalized entropy assessment" 79 : 103375-, 2023

      19 Davis J, "Neuroprogression in schizophrenia : pathways underpinning clinical staging and therapeutic corollaries" 48 : 512-529, 2014

      20 Tiihonen J, "Lamotrigine in treatment-resistant schizophrenia : a randomized placebo-controlled crossover trial" 54 : 1241-1248, 2003

      21 Vayısoğlu S, "Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment" 143 : 207-214, 2013

      22 de Lucena D, "Improvement of negative and positive symptoms in treatment-refractory schizophrenia : a double-blind, randomized, placebo-controlled trial with memantine as add-on therapy to clozapine" 70 : 1416-1423, 2009

      23 Lane HY, "Glycine transporter I inhibitor, N-methylglycine(sarcosine), added to clozapine for the treatment of schizophrenia" 60 : 645-649, 2006

      24 van Valkenhoef G, "Gemtc: network meta-analysis using bayesian methods"

      25 Buchanan RW, "Fluoxetine augmentation of clozapine treatment in patients with schizophrenia" 153 : 1625-1627, 1996

      26 Gunduz-Bruce H, "Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia" 143 : 344-347, 2013

      27 Correll CU, "Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia : systematic overview and quality appraisal of the meta-analytic evidence" 74 : 675-684, 2017

      28 Zink M, "Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine : a randomised controlled clinical trial" 23 : 305-314, 2009

      29 Fleischhacker WW, "Effects of adjunctive treatment with aripiprazole on body weight and clinical efficacy in schizophrenia patients treated with clozapine : a randomized, double-blind, placebo-controlled trial" 13 : 1115-1125, 2010

      30 Lu ML, "Effects of adjunctive fluvoxamine on metabolic parameters and psychopathology in clozapine-treated patients with schizophrenia : a 12-week, randomized, double-blind, placebo-controlled study" 193 : 126-133, 2018

      31 Muscatello MR, "Effect of aripiprazole augmentation of clozapine in schizophrenia : a double-blind, placebo-controlled study" 127 : 93-99, 2011

      32 Mico’ U, "Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia : a randomized, placebo-controlled trial" 26 : 303-310, 2011

      33 Tsai GE, "D-serine added to clozapine for the treatment of schizophrenia" 156 : 1822-1825, 1999

      34 Genç Y, "Comparison of clozapineamisulpride and clozapine-quetiapine combinations for patients with schizophrenia who are partially responsive to clozapine : a single-blind randomized study" 24 : 1-13, 2007

      35 Gray L, "Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse : association with N-methyl-D-aspartic acid receptor up-regulation" 12 : 45-60, 2009

      36 Josiassen RC, "Clozapine augmented with risperidone in the treatment of schizophrenia : a randomized, double-blind, placebo-controlled trial" 162 : 130-136, 2005

      37 Honer WG, "Clozapine alone versus clozapine and risperidone with refractory schizophrenia" 354 : 472-482, 2006

      38 Sernyak MJ, "Clinicians’ reasons for antipsychotic coprescribing" 65 : 1597-1600, 2004

      39 Lieberman JA, "Clinical effects of clozapine in chronic schizophrenia : response to treatment and predictors of outcome" 151 : 1744-1752, 1994

      40 Kapur S, "Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia" 156 : 286-293, 1999

      41 Campana M, "Characteristics and definitions of ultra-treatment-resistant schizophrenia-A systematic review and meta-analysis" 228 : 218-226, 2021

      42 Adam Montgomery ; Marianna Rogowska ; Luiz Dratcu, "Cariprazine-an alternative treatment for clozapine-resistant schizophrenia?" 21 : 202-206, 2023

      43 Nielsen J, "Augmenting clozapine with sertindole : a doubleblind, randomized, placebo-controlled study" 32 : 173-178, 2012

      44 Siskind DJ, "Augmentation strategies for clozapine refractory schizophrenia : a systematic review and meta-analysis" 52 : 751-767, 2018

      45 Muscatello MR, "Augmentation of clozapine with ziprasidone in refractory schizophrenia : a double-blind, placebo-controlled study" 34 : 129-133, 2014

      46 Barbui C, "Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia in routine clinical care : A randomized, controlled trial" 31 : 266-273, 2011

      47 Chang JS, "Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia : an 8-week, randomized, doubleblind, placebo-controlled trial" 69 : 720-731, 2008

      48 Bighelli I, "Are randomized controlled trials on pharmacotherapy and psychotherapy for positive symptoms of schizophrenia comparable? A systematic review of patient and study characteristics" 46 : 496-504, 2020

      49 Galling B, "Antipsychotic augmentation vs. monotherapy in schizophrenia : systematic review, meta-analysis and meta-regression analysis" 16 : 77-89, 2017

      50 Zhu MH, "Amisulpride augmentation therapy improves cognitive performance and psychopathology in clozapine-resistant treatment-refractory schizophrenia : a 12-week randomized, double-blind, placebo-controlled trial" 9 : 59-, 2022

      51 Assion HJ, "Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial" 41 : 24-28, 2008

      52 Barnes TR, "Amisulpride augmentation in clozapine-unresponsive schizophrenia(AMICUS) : a double-blind, placebo-controlled, randomised trial of clinical effectiveness and costeffectiveness" 21 : 1-56, 2017

      53 Weiner E, "Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine" 35 : 2274-2283, 2010

      54 Kelly DL, "Adjunctive minocycline in clozapine-treated schizophrenia patients with persistent symptoms" 35 : 374-381, 2015

      55 Lieberman JA, "A randomized, placebo-controlled study of memantine as adjunctive treatment in patients with schizophrenia" 34 : 1322-1329, 2009

      56 Doruk A, "A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia" 23 : 223-227, 2008

      57 Goff DC, "A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia" 21 : 484-487, 2001

      58 Goff DC, "A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia" 45 : 512-514, 1999

      59 Anil Yağcioğlu AE, "A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine : efficacy and safety" 66 : 63-72, 2005

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