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Broad synthesis / Overview of systematic reviews

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Clozapine augmentation strategies - a systematic meta-review of available evidence. Treatment options for clozapine resistance.

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Journal Journal of psychopharmacology (Oxford, England)
Year 2019
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This article includes 19 Systematic reviews Systematic reviews (19 references)

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BACKGROUND:: Treatment options for clozapine resistance are diverse whereas, in contrast, the evidence for augmentation or combination strategies is sparse. AIMS:: We aimed to extract levels of evidence from available data and extrapolate recommendations for clinical practice. METHODS:: We conducted a systematic literature search in the PubMed/MEDLINE database and in the Cochrane database. Included meta-analyses were assessed using Scottish Intercollegiate Guidelines Network criteria, with symptom improvement as the endpoint, in order to develop a recommendation grade for each clinical strategy identified. RESULTS:: Our search identified 21 meta-analyses of clozapine combination or augmentation strategies. No strategies met Grade A criteria. Strategies meeting Grade B included combinations with first- or second-generation antipsychotics, augmentation with electroconvulsive therapy for persistent positive symptoms, and combination with certain antidepressants (fluoxetine, duloxetine, citalopram) for persistent negative symptoms. Augmentation strategies with mood-stabilisers, anticonvulsants, glutamatergics, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or cognitive behavioural therapy met Grades C-D criteria only. CONCLUSION:: More high-quality clinical trials are needed to evaluate the efficacy of add-on treatments for symptom improvement in patients with clozapine resistance. Applying definitions of clozapine resistance would improve the reporting of future clinical trials. Augmentation with second-generation antipsychotics and first-generation antipsychotics can be beneficial, but the supporting evidence is from low-quality studies. Electroconvulsive therapy may be effective for clozapine-resistant positive symptoms.

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Is electroconvulsive therapy effective as augmentation in clozapine-resistant schizophrenia?

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Journal Medwave
Year 2016
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This article includes 6 Systematic reviews Systematic reviews (6 references) 55 Primary studies Primary studies (55 references)

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Clozapine is considered to be the most effective antipsychotic drug for patients with treatment resistant schizophrenia, but up to a third of the patients do not respond to this treatment. Various strategies have been tried to augment the effect of clozapine in non-responders, one of these strategies being electroconvulsive therapy. However, its efficacy and safety are not yet clear. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 55 studies, among them six randomized controlled trials addressing clozapine-resistant schizophrenia. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded electroconvulsive therapy probably augments response to clozapine in patients with treatment resistant schizophrenia, but it is not possible to determine if it leads to cognitive adverse effects because the certainty of the evidence is very low.

Broad synthesis / Living FRISBEE

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Does adding a second antipsychotic to clozapine improve clinical response in resistant schizophrenia?

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Journal Medwave
Year 2016
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This article includes 17 Systematic reviews Systematic reviews (17 references) 63 Primary studies Primary studies (63 references)

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Clozapine constitutes the treatment of choice in patients with schizophrenia with persisting symptoms despite antipsychotics at adequate dose and treatment duration. However, an important proportion does not respond to optimal doses of clozapine, so the addition of a second antipsychotic might increase clinical response. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 17 systematic reviews comprising 62 studies addressing the question of this article, including 26 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding a second antipsychotic to clozapine in patients with refractory schizophrenia probably leads to little or no difference in clinical response, and increases adverse effects.

Broad synthesis

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Optimisation of prescription in patients with long-term treatment-resistant schizophrenia.

Authors Maiocchi L , Bernardi E
Journal Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists
Year 2013
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This article includes 1 Systematic review Systematic reviews (1 reference)

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OBJECTIVE: The aim of this clinical review was to investigate the effectiveness and safety of the practice of antipsychotic poly-pharmacy (AP) in the long-term management of hospitalised patients with insufficient response to antipsychotic monotherapy. METHOD: The databases Medline, PsycINFO, Embase and Scopus were searched. Studies were required to include inpatients with long-term, treatment-resistant schizophrenia on maintenance AP. The search was restricted to systematic review studies. RESULTS: The review yielded four studies of interest that showed no categorical advantage for maintenance AP for the population of interest. However, clozapine combination faired marginally well. Particular weaknesses of the present literature are low number of participants, and inadequate monitoring of potential adverse effects. The evidence on the risks and benefits of maintenance AP is not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. CONCLUSIONS: This review provides a synthesis of the evidence on the maintenance use of AP for hospitalised patients with long-term, treatment-resistant schizophrenia. The results show both no support for AP with some marginal benefit for clozapine combination therapy, and methodological weaknesses of the included studies. These findings have clinical implications for treatment decisions and suggest that sufficiently powered studies are needed.

Broad synthesis / Overview of systematic reviews

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A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia.

Authors Citrome L
Journal Expert opinion on pharmacotherapy
Year 2012
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This article includes 70 Systematic reviews Systematic reviews (70 references) 10 Primary studies Primary studies (10 references)

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INTRODUCTION: Meta-analyses are a convenient way for clinicians and researchers to review data regarding different interventions. Meta-analyses can overcome many of the limitations of individual studies, namely the power to detect differences, and help resolve the results of inconsistent studies. AREAS COVERED: This paper is a review of meta-analyses of oral atypical antipsychotics for the treatment of schizophrenia, located through PubMed and the Cochrane Database of Systematic Reviews. A total of 91 meta-analyses were identified that included efficacy outcome data for the 10 atypical antipsychotics available in the USA (11 focused on clozapine, 17 for risperidone, 8 for olanzapine, 5 for quetiapine, 3 for ziprasidone, 10 for aripiprazole, 5 for paliperidone, 1 for iloperidone, 0 for asenapine or lurasidone, and 31 others that were classified more broadly). These include Cochrane Reviews and other similarly executed reports, as well as pooled analyses meta-tagged in PubMed as a meta-analysis. EXPERT OPINION: In general, there is heterogeneity among the atypical antipsychotics in terms of efficacy, with clozapine evidencing consistent superiority over typical antipsychotics, trailed behind by olanzapine and risperidone. Meta-analyses generally do not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. Although this review is focused on efficacy, other considerations are also important, including the large tolerability differences among all the agents and the need to individualize medication choice based on past history of therapeutic response, past history of tolerability issues and the individual's personal values and preferences.