Infection and Inflammation Leading to Clozapine Toxicity and Intensive Care

Leung, Jonathan G.; Nelson, Sarah; Takala, Christopher R.; Gören, Jessica L.

doi:10.1177/1060028014526701

Cited by 47 publications

(46 citation statements)

References 19 publications

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“…Introductorily, it should be noted that reports indicate that inflammation may precipitate clozapine toxicity, possibly due to a cytokine-mediated inhibition of cytochrome P450 1A2 [27]. Consequently, even moderate doses of clozapine could produce significant increase in serum levels in the presence of inflammation.…”

Section: Discussionmentioning

confidence: 99%

Probable clozapine-induced parenchymal lung disease and perimyocarditis: a case report

2016

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BackgroundClozapine is the archetypical atypical antipsychotic, its primary indication being treatment resistant schizophrenia. Severe side effects caused by clozapine, including leukopenia, agranulocytosis, and myocarditis, are well known. A rarely described side effect is concurrent perimyocarditis and parenchymal lung disease.Case presentationA previously physically healthy 23-year-old male Caucasian that suffered from schizophrenia presented with flu-like symptoms 1 week after starting clozapine treatment. Treatment with clozapine was discontinued. He developed respiratory distress. Investigations showed significant parenchymal infiltration in both of the lungs, pericardial fluid, and heart failure. He initially received treatment for suspected malignant neuroleptic syndrome and later for suspected infection, but these tentative diagnoses were not confirmed. The patient’s condition gradually improved. In retrospect, clozapine-induced parenchymal lung disease and perimyocarditis were deemed the most probable causes.ConclusionsConcurrent perimyocarditis and parenchymal lung disease are rare side effects of clozapine. Clozapine-induced disease in general is considered an exclusion diagnosis. Lacking a verifiable diagnosis when suspecting a side effect of clozapine, clinicians might treat the most likely and serious condition presenting and consider discontinuing clozapine until the diagnostic uncertainty is reasonably resolved.

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Section: Discussionmentioning

confidence: 99%

Probable clozapine-induced parenchymal lung disease and perimyocarditis: a case report

2016

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“…Our evidence indicates that neither is the problem. Rather, we believe the problem in extending analysis from buffer to serum is the large and possibly variable binding of clozapine to serum proteins (90–95% of clozapine is bound to serum proteins (Espnes et al, 2012; Flanagan et al, 2003; Leung et al, 2014; Schaber et al, 1998; Wu et al, 2011). Presumably, the unbound clozapine is measured electrochemically which may explain the diminished sensitivities when buffered solutions are compared against clozapine-spiked serum samples (Kim et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine

Kang

Kim

Winkler

et al. 2017

Biosensors and Bioelectronics

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Clozapine is one of the most promising medications for managing schizophrenia but it is under-utilized because of the challenges of maintaining serum levels in a safe therapeutic range (1–3 μM). Timely measurement of serum clozapine levels has been identified as a barrier to the broader use of clozapine, which is however challenging due to the complexity of serum samples. We demonstrate a robust and reusable electrochemical sensor with graphene-chitosan composite for rapidly measuring serum levels of clozapine. Our electrochemical measurements in clinical serum from clozapine-treated and clozapine-untreated schizophrenia groups are well correlated to centralized laboratory analysis for the readily detected uric acid and for the clozapine which is present at 100-fold lower concentration. The benefits of our electrochemical measurement approach for serum clozapine monitoring are: (i) rapid measurement (≈ 20 min) without serum pretreatment; (ii) appropriate selectivity and sensitivity (limit of detection 0.7 μM); (iii) reusability of an electrode over several weeks; and (iv) rapid reliability testing to detect common error-causing problems. This simple and rapid electrochemical approach for serum clozapine measurements should provide clinicians with the timely point-of-care information required to adjust dosages and personalize the management of schizophrenia.

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“…There have been a number of reports of toxic plasma concentrations of clozapine, a CYP1A2 substrate, during inflammation due to infection in patients who were on chronic medication and normally had stable plasma clozapine levels (Haack et al, 2003;van Gool et al, 2010;Darling and Huthwaite, 2011;Espnes et al, 2012;Leung et al, 2014). Decreased CYP1A2 activity in these patients is suggested by increased serum clozapine levels and lowered norclozapine-to-clozapine ratios (Raaska et al, 2002) and increased concentration-to-dose ratios (de Leon and Diaz, 2003) during the infection.…”

Section: Evidence For Potential Phenoconversion Of Dmes In Other Inflmentioning

confidence: 99%

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

Shah¹,

2014

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Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infectioninduced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

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Infection and Inflammation Leading to Clozapine Toxicity and Intensive Care

Abstract: Clozapine toxicity developed in 3 patients admitted to a medical setting suspected to be related to infection and/or inflammation. Clinicians should be aware of this potential adverse drug event with clozapine.

Cited by 47 publications

References 19 publications

Probable clozapine-induced parenchymal lung disease and perimyocarditis: a case report

Probable clozapine-induced parenchymal lung disease and perimyocarditis: a case report

Reliable clinical serum analysis with reusable electrochemical sensor: Toward point-of-care measurement of the antipsychotic medication clozapine

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

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