Barriers to using clozapine in treatment-resistant schizophrenia: systematic review

Farooq, Saeed; Choudry, Abid; Cohen, Dan; Naeem, Farooq; Ayub, Muhammad

doi:10.1192/bjb.2018.67

Cited by 120 publications

(143 citation statements)

References 30 publications

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“…Clozapine (CLZ) is considered the double-edged sword antipsychotic drug, since CLZ is one of the most effective but toxic antipsychotics against antipsychotics-resistant schizophrenia [17]. In fact, despite causing myocarditis, cardiomyopathy, agranulocytosis, and seizures [18][19][20][21][22], CLZ remains the gold-standard antipsychotic for treatment-refractory schizophrenia and is the only approved medication licensed for this indication [17,23]. The mechanisms of clinical actions of CLZ against antipsychotics-resistant schizophrenia have been considered to be modulated by multimodal targets actions, including NMDAR and dopamine D2 receptor.…”

Section: Introductionmentioning

confidence: 99%

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

Fukuyama

Okubo

Murata

et al. 2020

Cells

110

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Clozapine (CLZ) is a gold-standard antipsychotic against treatment-refractory schizophrenia, but is one of the most toxic antipsychotic agents. Pharmacological mechanisms of the double-edged sword clinical action of CLZ remain to be clarified. To explore the mechanisms of CLZ, the present study determined the astroglial transmission associated with connexin43 (Cx43), which is the most principal expression in astrocytes and myocardial cells, and expression of Cx43 in primary cultured astrocytes. Both acute and subchronic administrations of CLZ concentration-dependently increased Cx43-associated astroglial release of l-glutamate and d-serine, whereas therapeutic-relevant concentration of CLZ acutely did not affect but subchronically increased astroglial release. In contrast, after the subchronic administration of therapeutic-relevant concentration of valproate (VPA), acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43-associated astroglial releases. VPA increased Cx43 expression in cytosol fraction without affecting plasma membrane fraction, whereas CLZ increased Cx43 expression in both fractions. Acute administration of therapeutic-relevant concentration of CLZ drastically increased Cx43 expression in the plasma membrane fraction of astrocytes subchronically treated with VPA. The present findings suggest that CLZ-induced the activation of Cx43-associated channel activity and transported Cx43 to plasma membrane, probably contribute to the double-edged sword clinical action of CLZ, such as improvement of cognitive dysfunction and CLZ-induced myocarditis.

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Section: Introductionmentioning

confidence: 99%

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

Fukuyama

Okubo

Murata

et al. 2020

Cells

110

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“…This underutilization responds to barriers related to the perceived burden of treatment, as well as clinicians' lack of familiarity with the use of clozapine . While there is a large body of literature on safety and efficacy of clozapine , to date there are few recommendations to clinicians on how to apply this research in clinical practice, particularly in the face of the prescription barriers . In this narrative review, we consider data from randomized controlled trials, prescription registries, and patient and prescriber surveys to generate practical and actionable recommendations for clinicians.…”

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confidence: 99%

“…This mismatch between evidence‐based recommendations and practice in the real world results in suboptimal treatment for individuals with severe mental illness, with important implications for societal burden, and individual morbidity and mortality. This underutilization responds to barriers related to the perceived burden of treatment, as well as clinicians' lack of familiarity with the use of clozapine . While there is a large body of literature on safety and efficacy of clozapine , to date there are few recommendations to clinicians on how to apply this research in clinical practice, particularly in the face of the prescription barriers .…”

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confidence: 99%

How and when to use clozapine

Rubio

Kane

2019

Acta Psychiatr Scand

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Objective Clozapine is the only approved strategy for treatment‐resistant schizophrenia, although it is highly underutilized. We aim to generate practical and actionable evidence‐based recommendations for the use of this drug considering prescription barriers. Method Narrative review. Results A consistent body of evidence supports the efficacy of clozapine reducing morbidity and mortality in schizophrenia. The main obstacles to its use are the lack of experience by prescribers and perceived treatment burden. Systematic screening of eligibility, utilization of available resources for consultation, developing a professional network with other stakeholders, as well as optimizing how clozapine is presented to patients is discussed. Furthermore, specific evidence‐based recommendations for initiation, maintenance, and safety monitoring with clozapine are provided. Conclusion Clozapine prescription is one of the areas in psychiatry with the greatest mismatch between efficacy and utilization in clinical practice. Although multiple barriers to the use of clozapine exist, some of these may be overcome by updates of routine clinical practice.

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“…It has also been shown that in first episode schizophrenia the response rate to a second antipsychotic drops dramatically then increases again with clozapine, suggesting that second-line use of clozapine may well be more appropriate than third line [16]. There are many reported barriers to clozapine prescribing, including concerns over need for blood testing and potential for side-effects but also clinician and patient attitudes to clozapine [89][90][91]. Recent authors have highlighted the need to review stringent blood monitoring requirements for clozapine, which can lead to unnecessary treatment discontinuation [92].…”

Section: Discussionmentioning

confidence: 99%

Effect of age on the relative efficacy of clozapine in schizophrenia

Jones

MacCabe

Price

et al. 2020

Acta Psychiatr Scand

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Objective: Early treatment of schizophrenia improves outcomes. Clozapine appears to have unique benefit when other antipsychotic medication has failed. This systematic review and meta-analysis aims to assess clozapine's superiority over alternative antipsychotic medication and examine whether earlier use is associated with additional benefit. Method: Systematic retrieval of blinded, randomized controlled trials comparing clozapine with alternative antipsychotics in adults with schizophrenia. The effect of mean age on relative clozapine response was examined using random effects meta-regression, and multiple linear regression on available patient data. Results: A total of 276 studies were retrieved. Thirty-four studies were included in the meta-analysis. Clozapine was significantly more effective than alternative antipsychotics in reducing psychotic symptoms and increasing response. However, meta-regression failed to show a more significant effect in younger patients (age on effect size (total psychotic symptoms) 0.00, P = 0.79 CI À0.03 to 0.03). Individual patient data were available for two studies, the larger of which showed a significant interaction between younger age and superiority of clozapine. Conclusion: The results support clozapine's superiority over other antipsychotics. A convincing effect of age on this effect was not demonstrated, although this was suggested in one study. In view of the age of many of the included studies, and changes in reporting practice over time, new clozapine RCTs, which include age of illness onset as well as age at trial time, would be welcome in order to provide metaanalysable data for future use.

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Barriers to using clozapine in treatment-resistant schizophrenia: systematic review

Cited by 120 publications

References 30 publications

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

Activation of Astroglial Connexin Is Involved in Concentration-Dependent Double-Edged Sword Clinical Action of Clozapine

How and when to use clozapine

Effect of age on the relative efficacy of clozapine in schizophrenia

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