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Evaluating Monitoring Guidelines of Clozapine-Induced Adverse Effects: a Systematic Review

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Abstract

Background and Objectives

Despite the evidence that no other antipsychotic is effective as clozapine for the treatment of resistant schizophrenia, it is associated with various metabolic, neuroendocrine, cardiovascular, and gastrointestinal adverse effects. Guidelines aiming to address the monitoring of clozapine’s (serious) adverse effects can be helpful to prevent and treat these effects. However, many of these guidelines seem to lack one or more important monitoring recommendations. We aimed to systematically review the content and quality of existing monitoring guidelines/recommendations for clozapine-induced adverse effects.

Methods

A comprehensive and systematic literature search, using the MEDLINE, Embase, Web of Science, and Cochrane databases, was conducted for guidelines/recommendations on the monitoring of clozapine-induced adverse events, published between January 2004 and April 2023 (last search 16 April 2023). Only peer-reviewed published guidelines reporting on the comprehensive monitoring of all major clozapine-induced adverse effects and including evidence-based recommendations, developed after the year 2004, were included. Studies reporting on the monitoring of adverse effects of clozapine without being a formal guideline, guidelines reporting on the monitoring of one or a limited number of adverse effects of clozapine, guidelines that were not peer reviewed or published, expert opinion papers without formal consensus guideline development, or guidelines developed before the year 2004, were excluded. The Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool was used to evaluate the guidelines/recommendations’ quality.

Results

Only one guideline met the inclusion criteria. This consensus statement made recommendations for hematological monitoring, and the monitoring of metabolic, cardiac, and three other adverse effects. Highest scores for the qualitative assessment were found for the domains “scope and purpose” (66.7%), “clarity of presentation” (44.4%), and “editorial independence” (66.7%). Lowest scores were found for “rigor of development” (14.6%) and “applicability” (0%).

Conclusions

Future guidelines should develop more comprehensive recommendations about specific clozapine-induced adverse effects, including constipation, myocarditis, tachycardia, and seizures, as well as include a rechallenge policy. There is an urgent need for well-developed, methodologically stringent, guidelines.

Registration

PROSPERO registration number, CRD42023402480.

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Authors and Affiliations

  1. University Psychiatric Center Katholieke Universiteit Leuven, Leuvensesteenweg 517, 3070, Kortenberg, Belgium

    Sarah Smessaert, Franciska Desplenter & Marc De Hert

  2. Department of Biomedical Sciences, Research Group Psychiatry, University Psychiatric Center KU Leuven, Leuvensesteenweg 517, 3070, Kortenberg, Belgium

    Johan Detraux

  3. Clinical Pharmacology and Pharmacotherapy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium

    Franciska Desplenter

  4. Department of Neurosciences, Centre for Clinical Psychiatry, Katholieke Universiteit Leuven, Leuven, Belgium

    Marc De Hert

  5. Leuven Brain Institute, Katholieke Universiteit Leuven, Leuven, Belgium

    Marc De Hert

  6. Antwerp Health Law and Ethics Chair, University of Antwerp, Antwerp, Belgium

    Marc De Hert

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Smessaert, S., Detraux, J., Desplenter, F. et al. Evaluating Monitoring Guidelines of Clozapine-Induced Adverse Effects: a Systematic Review. CNS Drugs 38, 105–123 (2024). https://doi.org/10.1007/s40263-023-01054-z

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