Elevated clozapine levels associated with infection: A systematic review

Abstract

Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.

Introduction

Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia (Siskind et al., 2016). The use of clozapine is however limited to third line due to an increased incidence of agranulocytosis and neutropenia (Nielsen et al., 2013). Clozapine also has a range of other serious side effects including myocarditis, seizures, gastrointestinal hypomotility and diabetic ketoacidosis (Cohen et al., 2012, Williams and Park, 2015, Young et al., 1998). Only some of these side effects are thought to be related to the clozapine serum level, including sedation, delirium, seizures, arrhythmias, hypotension, aspiration, and respiratory depression (Stark and Scott, 2012). The concept of ‘clozapine toxicity’ is widely used despite difficulty in clearly defining the clinical presentation of toxicity and the clozapine level at which this occurs (Stark and Scott, 2012, VanderZwaag et al., 1996). The risk of seizures increases from 600 mcg/L, with 1000 mcg/L often quoted as the threshold beyond which risk of seizures, sedation and delirium outweighs treatment benefit (Bell et al., 1998, Stark and Scott, 2012, Williams and Park, 2015). In saying this, there is a significant inter-personal variability in clozapine levels, response and adverse events. This variability may be explained by pharmacogenomic variation as well as alteration to its metabolism through effect on Cytochrome P450 (CYP450) enzymes by drug interactions, smoking cessation, excessive caffeine and the more recently identified risk of infection and inflammation (Stark and Scott, 2012, Williams and Park, 2015).

A growing number of case reports have linked infection and its treatment to elevated clozapine levels (Leung et al., 2014, Nielsen et al., 2016). Patients with chronic psychosis are known to be more at risk of infection though factors such as elevated smoking rates, metabolic disorders, dental caries and poorer relationships to community health providers (Kisely et al., 2015). Clozapine treatment has been shown to be associated with increased rates of single incidence and recurrent pneumonia (Abdelmawla and Ahmed, 2009, Hung et al., 2016, Kuo et al., 2013). Systemic infection and inflammation may also inhibit CYP450 enzymes, potentially leading to risk of raised clozapine levels in people hospitalised for severe infections (Leung et al., 2014).

There are no relevant cross-sectional, cases - control or cohort studies in the literature dealing with this potentially high risk phenomenon, with only single case reports or small series currently published. We thus aimed to consolidate and expand upon currently published literature by performing a systematic review including eight new cases of elevated clozapine level associated with infection identified in patients treated in Australian public psychiatry services in two states.