Elevated clozapine levels associated with infection: A systematic review
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.
Section snippets
Methods
This study was registered with PROSPERO, (registration number: CRD42016037536), an international database of prospectively registered systematic reviews (Booth et al., 2012). Articles were located through a search of PubMed (1964 to April 2016) and Embase (1974 to April 2016), with search terms: clozapine, toxicity, infection. All languages were included and translated into English. Identified records and abstracts were screened independently by authors (NW, SC, GK). References were checked to
Results
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines were followed (Fig. 1) (Moher et al., 2009). There were 412 non-duplicate studies identified in the databases, with a further seven identified through hand searching of references. Following screening of the title and the abstracts, a further 39 studies were excluded at full text as they did not contain adequate information to indicate a diagnosis of infection or the elevated clozapine levels were
Discussion
We identified 40 cases where elevated clozapine levels have been associated with infection. When documented prior to infection, baseline clozapine level was under 600 mcg/L, with no reported symptoms of dose dependent clozapine side effects. With the onset of infection a significantly elevated clozapine level was recorded as well a clinical deterioration. The most commonly documented adverse events were prominent sedation or delirium; however other gross neurological signs such as speech and
Conclusion
Clozapine treatment places patients at an increased risk of developing an infection and potentially a delay or missed diagnosis of that infection due to a lack of classic symptoms and altered mental status. Infection is associated with significantly increased clozapine levels due to inhibition of CYP450 metabolism. Adaptive mechanisms, such as increased production of AGP that binds clozapine in plasma, may limit the rate of serious adverse events. However, some clozapine level related adverse
Conflicts of interest
The authors do not have any conflicts of interest.
Contributors
Clark and Warren were involved in new case identification and reporting, case review, writing and editing. Jankowiak and Forrester were also involved in new case identification. Kim performed review of the cases. Schubert, Kisely and Baune were involved in editing. Siskind was involved in writing and editing. All authors have contributed and have approved the final manuscript.
Funding body agreements and policies
Dr. Clark is the recipient of an investigator initiated grant from the Lundbeck Institute. Dr. Siskind is partially supported through a grant from NHMRC (ECF APP1111136).
Acknowledgement
The authors would like to thank Dr. Tjeerd Tijhof (Metro South Addiction and Mental Health Service, Brisbane, Australia) for assisting with translation of articles in Dutch.
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