The Value of Desmethylclozapine and Serum CRP in Clozapine Toxicity: A Case Report

Abstract

Clozapine, an atypical antipsychotic, has proved to be superior to other antipsychotics in treating patients with refractory schizophrenia. An increased plasma clozapine level above the therapeutic window may be associated with serious adverse events including paralytic ileus. Clozapine toxicity may occur in association with infection or after drug overdose. In a medical emergency situation, differentiating between a toxic clozapine ingestion and an infection-induced toxicity might be hindered by associated CNS changes and by the clozapine modulation of the inflammatory process. This may delay prompt initiation of a tailored treatment strategy. Here, we report a case of paralytic ileus developed within the context of clozapine toxicity. Although the underlying cause of toxicity was not clinically obvious, giving antimicrobial therapy resulted in an improvement in the patient's clinical condition. This report indicates the value of serum levels of C-reactive protein and desmethylclozapine, major metabolite of clozapine, in the treatment of aetiologically unclear clozapine toxicity.

Retrospective Pilot Study for Analysis of Antidepressant Serum Concentrations of Citalopram and Venlafaxine during Inflammation

“…The strength of this study was the intraindividual comparison of drug serum levels under normal and elevated CRP serum concentrations. Our findings thus indicate no major effect of inflammation on metabolism of VEN and CIT as it was observed for clozapine [8,9,13,14]. From a toxicological point of view, the efficacy and tolerability of most psychotropic drugs depend on drug serum concentrations [7,15].…”

Infection and Inflammation Leading to Clozapine Toxicity and Intensive Care

“…Authors also suggest that elevated CRP may be the only clinical sign of infection as clozapine may blunt immune mediated increases of WBC or development of fever. 5 Elevated CRP may also be associated with myocarditis and benign clozapine-induced fever. 18 Unfortunately, during suspected toxicity, AGP and CRP laboratory values were not available in our cases.…”

“…Activity of 1A2 may be reduced by up to 90% because of increases of interleukin-6, interferon, and tumor necrosis factor-α during acute infectious and/or inflammatory processes. 2,5 Strengthening this hypothesis is the fact that patients receiving theophylline, another medication significantly metabolized by 1A2, are more likely to develop toxicity after the development of respiratory infections. 19 The degree to which a clozapine dose should be adjusted in the setting of an acute infectious and/or inflammatory process is unknown but it has been suggested that at least a 50% reduction may be necessary to avoid toxicity.…”

“…There is also evidence that clozapine toxicity may occur in the setting of an acute infectious and/or inflammatory process as a result of reduced 1A2 activity (Table 1). [2][3][4][5][6][7][8][9] Prior cases describing clozapine toxicity as a result of infectious and/or inflammatory processes have mostly involved respiratory infections; however, involvement of gastrointestinal and urinary infections have also been described. Symptoms of toxicity in the reported cases have been generally mild to moderate and included sedation, dizziness, and confusion.…”

Pathological Concentration of C-reactive Protein is Correlated to Increased Concentrations of Quetiapine, But Not of Risperidone, Olanzapine and Aripiprazole in a Naturalistic Setting

“…However, inflammation can decrease metabolic clearance of CYP substrates by 20-70 % [10]. Case studies reported higher concentrations of clozapine [11][12][13][14] and higher concentrations of risperidone during inflammation [15] and an association between elevated CRP concentrations and increased clozapine serum concentrations were reported repeatedly [16,17]. Among clozapine, a 3-to 5-fold increase in serum levels occurred in most patients during inflammation but also a 10-fold increase compared with the basal levels of clozapine was observed [18].…”