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Systematic review

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Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis.

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Journal The Australian and New Zealand journal of psychiatry
Year 2018
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This article is included in 1 Broad synthesis 46 Broad syntheses (1 reference)

This article includes 46 Primary studies 46 Primary studies (46 references)

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BACKGROUND: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. METHODS: We systematically reviewed PubMed, PsycINFO, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness RESULTS: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: −0.89 to −0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: −0.97 to −0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: −3.96 to −0.75). Memantine was effective for negative symptoms (standardised mean difference: −0.56 95% confidence interval: −0.93 to −0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and <i>Ginkgo biloba</i> showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. CONCLUSIONS: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine.

Journal Expert opinion on pharmacotherapy
Year 2014
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This article is included in 1 Broad synthesis 58 Broad syntheses (1 reference)

This article includes 58 Primary studies 58 Primary studies (58 references)

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INTRODUCTION: Although clozapine (CLZ) is considered the best evidence-based therapeutic option for treatment of resistant schizophrenia patients, a significant proportion of CLZ-treated patients show a partial or inadequate response to treatment, leading to increased healthcare cost and poor quality of life for affected individuals. AREAS COVERED: This paper comprises a review of main research in CLZ augmentation strategies for treatment-refractory schizophrenia, with a focus on research conducted between 1990 and 2014. Databases that were searched include: PubMed, CINAHL, EMBASE PsychINFO, AgeLine and Cochrane Database of Systematic Reviews. Primary search terms were 'clozapine augmentation', 'clozapine and add-on' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. We reviewed the available evidence on CLZ augmentation with antipsychotics, antidepressants, mood stabilizers and other agents. EXPERT OPINION: Many drugs have been evaluated as CLZ add-on therapies without demonstrating convincing efficacy in treating refractory schizophrenia symptoms. More research is needed to better define outcomes in schizophrenia, the topic of treatment-resistance and more well-designed trials are required to establish true efficacy and safety of CLZ augmentation strategies.

Systematic review

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Non-glutamatergic clozapine augmentation strategies: A review and meta-analysis.

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Journal Pharmacopsychiatry
Year 2014
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This article is included in 2 Broad syntheses 22 Broad syntheses (2 references)

This article includes 22 Primary studies 22 Primary studies (22 references)

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Persistent negative symptoms and cognitive impairment are major clinical problems in the treatment of schizophrenia. There is no convincing evidence regarding the efficacy of augmentation of clozapine with a second antipsychotic, ethyl eicosapentaenoic acid (E-EPA), an antidepressant, a mood stabilizer or extract of <i>Ginkgo</i><i>biloba</i> in clozapine-resistant schizophrenia. We present an overview of studies in which the potential clinical utility of the addition of non-glutamatergic agents to clozapine is assessed. We performed a meta-analysis on the efficacy of both risperidone and aripiprazole compared to placebo. We compared the effects of the addition of a second antipsychotic or an antidepressant to clozapine on positive, negative, overall and affective symptoms of schizophrenia in double-blind placebo-controlled trials. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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[Augmentation strategies in patients with schizophrenia who show partial response to clozapine treatment].

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Journal Türk psikiyatri dergisi = Turkish journal of psychiatry
Year 2014
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This article is included in 1 Broad synthesis 17 Broad syntheses (1 reference)

This article includes 18 Primary studies 17 Primary studies (18 references)

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A significant proportion of patients with schizophrenia receiving clozapine remain with partial response. In this group of patients findings regarding addition of various psychotropics to ongoing clozapine treatment for augmentation are controversial. In this review, literature regarding the efficacy and safety of adjunctive agents in clozapine resistant schizophrenic patients is examined. Augmentation agents added to clozapine in treatment resistant schizophrenic patients consist of antipsychotics, antidepressants, mood stabilizers, other agents (eg. omega 3 fatty acids and glutamatergic agents) and electroconvulsive therapy (ECT) in this review. The number of controlled studies evaluating augmentation of clozapine in schizophrenia patients are highest for risperidone and lamotrigine add on treatments. However, the results of recent meta-analyses studies do not support any benefit of either agent as adjunct to clozapine treatment. Some evidence regarding the success of clozapine augmentation with amisulpride, aripiprazole, mirtazapine, omega 3 fatty acids and ECT have been obtained which needs further clinical investigation. Current findings from relevant clinical studies point that theses studies have limitations of small sample size, variable definitions of clozapine resistance, heterogenity of outcome measures and methodological designs and that sufficient evidence does not yet exist regarding the success of various adjunctive treatments for clozapine resistant patients.

Systematic review

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Clozapine resistance: Augmentation strategies

Journal European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
Year 2012
Links Pubmed DOI www.epistemonikos.org

This article is included in 2 Broad syntheses 59 Broad syntheses (2 references)

This article includes 60 Primary studies 59 Primary studies (60 references)

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Background: Clozapine (CLZ) is not effective in more than 50% of treatment-resistant schizophrenic patients. In these cases, several pharmacological strategies are used in clinical practice, with different levels of evidence for both safety and efficacy. Objectives: In the present paper we critically reviewed literature data regarding the efficacy and safety of adjunctive agents in CLZ-resistant schizophrenics. The following classes of agents were considered: 1) antipsychotics, 2) antidepressants, 3) mood stabilizers, 4) other agents (e.g. fatty acid supplement and glutamatergic agents), 5) electroconvulsive therapy (ECT). For lamotrigine and risperidone sufficient data were available to perform a meta-analysis. Methods: A Medline literature search covering a 20-year period was performed. For the meta-analysis, data were entered and analyzed with the Cochrane Collaboration Review Manager Software (RevMan version 5). Results: 62 pertinent studies were identified, including 1556 schizophrenic or schizoaffective patients. Among treatments investigated, there is evidence for CLZ augmentation with 1) amisulpride and aripiprazole, 2) mirtazapine and 3) ethyl eicosapentaenoic acid (E-EPA). Although promising, ECT augmentation needs further validation. The meta-analyses did not support either the use of risperidone or lamotrigine as CLZ adjunct. Conclusion: Overall, there is scarce evidence of efficacy and safety as regards adjunctive strategies for CLZ-resistant patients. However, several limitations do not allow to draw any definitive conclusion; among these we underline the small sample size of clinical trials, the variable definitions of CLZ resistance, the heterogeneity of outcome measures and methodological designs. © 2011 Elsevier B.V. and ECNP.

Systematic review

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Pharmacological augmentation strategies for schizophrenia patients with insufficient response to Clozapine: A quantitative literature review.

Journal Schizophrenia bulletin
Year 2012
Links Pubmed DOI PubMed Central

This article is included in 2 Broad syntheses 28 Broad syntheses (2 references)

This article includes 28 Primary studies 28 Primary studies (28 references)

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BACKGROUND: When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder. METHODS: Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges’s <i>g</i>). RESULTS: Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies. CONCLUSIONS: Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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Augmentation of clozapine with a second antipsychotic - a meta-analysis

Authors Taylor DM , Smith L , Gee SH , Nielsen J
Journal Acta psychiatrica Scandinavica
Year 2012
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This article is included in 2 Broad syntheses 14 Broad syntheses (2 references)

This article includes 14 Primary studies 14 Primary studies (14 references)

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Objective: To examine using meta-analysis the effect of adding a second antipsychotic to established clozapine monotherapy. Method: A literature search was conducted in April 2011, and randomised placebo-controlled double-blind studies were identified. We performed a meta-analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel-plot analysis. Results: Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size -0.239 (95% CI: -0.452, -0.026); P=0.028). Meta-regression of the effect of length of treatment on effect size showed no relationship (P=0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR=1.20, 95% CI 0.80-1.82). There was no evidence of publication bias. Conclusion: Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation. © 2011 John Wiley & Sons A/S.

Systematic review

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Sulpiride augmentation for schizophrenia.

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Authors Wang J , Omori IM , Fenton M , Soares B
Journal Cochrane database of systematic reviews (Online)
Year 2010
Links Pubmed DOI

This article is included in 1 Broad synthesis 4 Broad syntheses (1 reference)

This article includes 4 Primary studies 4 Primary studies (4 references)

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BACKGROUND: Sulpiride may be used in combination with other antipsychotic drugs in the hope of augmenting effectiveness - especially for those whose schizophrenia has proved resistant to treatment. OBJECTIVES: To evaluate the effects of sulpiride augmentation versus monotherapy for people with schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (July 2009) which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA: All relevant randomised clinical trials (RCTs). DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) based on a fixed-effect model. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. MAIN RESULTS: We included three short-term and one long-term trial (total N=221). All participants had schizophrenia that was either treatment-resistant or with prominent negative symptoms. All studies compared sulpiride plus clozapine with clozapine (+/- placebo), were small and at considerable risk of bias.Short-term data of 'no clinically significant response' in global state tended to favour sulpiride augmentation of clozapine compared with clozapine alone (n=193, 3 RCTs, RR 0.58 CI 0.3 to 1.09).People allocated to sulpiride plus clozapine had more movement disorders (n=70, 1 RCT, RR 48.24 CI 3.05 to 762.56) and an increase in serum prolactin (skewed data, 1 RCT), but less incidence of hypersalivation (n=162, 3 RCTs, RR 0.49 CI 0.29 to 0.83) and less weight gain (n=64, 1 RCT, RR 0.30 CI 0.09 to 0.99). The augmentation of clozapine by sulpiride also caused less appetite loss (n=70, 1 RCT, RR 0.09 CI 0.01 to 0.70, NNT 4 CI 4 to 12, Z=2.31, P=0.02) and less abdominal distension (n=70, 1 RCT, RR 0.10 CI 0.01 to 0.78, NNT 5 CI 4 to 19, Z=2.20, P=0.03).Long-term data showed no significant difference in global state (n=70, 1 RCT, RR 0.67 CI 0.42 to 1.08) and relapse (n=70, 1 RCT, RR 0.85 CI 0.5 to 1.3). AUTHORS' CONCLUSIONS: Sulpiride plus clozapine is probably more effective than clozapine alone in producing clinical improvement in some people whose illness has been resistant to other antipsychotic drugs including clozapine. However, much more robust data are needed.

Systematic review

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Augmentation of clozapine with a second antipsychotic — A meta-analysis of randomized, placebo-controlled studies.

Authors Taylor DM , Smith L
Journal Acta psychiatrica Scandinavica
Year 2009
Links Pubmed DOI

This article is included in 1 Structured summary of systematic reviews 10 Structured summaries of systematic reviews (1 reference) 3 Broad syntheses 10 Broad syntheses (3 references)

This article includes 10 Primary studies 10 Primary studies (10 references)

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OBJECTIVE: Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment. METHOD: Meta-analysis of randomized, placebo-controlled studies of antipsychotic augmentation of clozapine treatment. RESULTS: Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) -0.180, 95% CI-0.356 to -0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679–2.345) or on CGI scores (effect size -0.661, 95% CI -1.475 to 0.151). Duration of study was not associated with outcome (<i>P</i> = 0.95). There was no evidence of publication bias. CONCLUSION: In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co-therapy with clozapine. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Systematic review

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[Risperidone as adjunctive therapy in clozapine treatment of refractory schizophrenia: a meta-analysis of randomized, placebo-controlled trials]

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Journal Postêpy Psychiatrii i Neurologii
Year 2009

This article is included in 1 Broad synthesis 4 Broad syntheses (1 reference)

This article includes 4 Primary studies 4 Primary studies (4 references)

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OBJECTIVE: To establish whether augmentation of ongoing clozapine treatment with risperidone is efficacious in patients unresponsive or partially responsive to clozapine alone. METHOD: A meta-analysis of randomized, placebo-controlled clinical trials. RESULTS: In the presented meta-analysis of randomized, placebo-controlled trials risperidone augmentation of ongoing clozapine treatment in patients with refractory schizophrenia was not not found to be an effective method as assessed either by the odds ratio of patients showing an at least 20% improvement on clinical scales, or by the effect size calculated from continuous measures of psychopathology. The treatment outcome seems to be independent of the trial duration. Further independent clinical trials are needed to confirm the suggestion that the best response can possibly be obtained using moderate (44.5 mg/day) doses of risperidone. CONCLUSIONS: Risperidone augmentation of clozapine in the treatment of patients unresponsive or partially responsive to clozapine alone cannot be recommended as a standard clinical procedure.