Sodium valproate and clozapine induced neutropenia: A case control study using register data
Introduction
Treatment resistant schizophrenia (TRS) affects approximately 1/3 of patients with schizophrenia, with 70% of TR cases not responding to antipsychotics from illness onset (Lally et al. 2016a). Clozapine is the only evidence based medication in treatment resistant schizophrenia (TRS) (Essali et al. 2009) with 60–70% of those treated with clozapine showing a response (Chakos et al., 2001, McEvoy et al., 2006, Meltzer, 1992). Clozapine is not only an effective treatment in TRS (Siskind et al. 2016) but is associated with long term reductions in mortality (Hayes et al., 2015, Tiihonen et al., 2009).
However, despite this, clozapine is underutilised (Manuel et al., 2012, Nielsen et al., 2016, Stroup et al., 2014), with delays of up to four years in its use in clinical practice (Howes et al., 2012, Nielsen et al., 2016, Taylor et al., 2003). Despite its beneficial effects, approximately 25% of clozapine users discontinue treatment due to adverse effects (Legge et al. 2016). Although the more common clozapine adverse events can generally be symptomatically managed, one of the primary reasons for clozapine underprescribing and delays in its use, is patient and clinician fears about the emergence of life threatening adverse events, and in particular agranulocytosis (Nielsen et al. 2010).
Clozapine induced agranulocytosis (CIA) occurs with a period prevalence of 0.8% in the first year of clozapine treatment (Alvir et al. 1993), with peak incidence at 6–18 weeks after commencing clozapine (Atkin et al. 1996). The one year prevalence of clozapine-induced neutropenia is 2.7% in the first year, with the peak incidence occurring at 6–18 weeks (Munro et al. 1999). In the UK, stringent and mandatory full blood count (FBC) monitoring is a requirement for continuing clozapine therapy so that the emergence of neutropenia can be detected early and clozapine treatment can be promptly discontinued if indicated (Atkin et al., 1996, Patel et al., 2005).
The occurrence of clozapine associated neutropenia and agranulocytosis necessitates discontinuation of clozapine. However, if the risk neutropenia could be reduced, this would have the additional effect of denying fewer patients the potential long term benefits of clozapine treatment. Recent evidence suggests that psychotropic medications and other drugs when, administered with clozapine may contribute to the development of neutropenia. Olanzapine, chlorpromazine, benzodiazepines, and anticonvulsants have been shown to be independently associated with increased incidence of neutropenia (Andres et al., 2008, Andres and Maloisel, 2008, Garbe, 2007, Meyer et al., 2015).
There is little research into clinical factors that may impact on the risk of clozapine associated neutropenia. The aim of the study was to identify concurrent medication use that increases the risk of clozapine associated neutropenia. We analysed factors related to clinical management (i.e. concomitant medication) and demographic characteristics (gender, age, ethnicity) which may predispose to the development of neutropenia in individuals treated with clozapine.
Section snippets
Data source and ethical approval
A case control study was performed using de-identified clinical records at South London and Maudsley NHS Foundation Trust (SLaM). This anonymised data was accessed using the Clinical Record Interactive Search (CRIS) facility. This was developed by the National Institute for Health Research, Biomedical Research Centre at SLaM and full details of this data resource have been provided elsewhere (Stewart et al. 2009). Governance for all CRIS projects is provided by a patient-led oversight committee
Results
136 cases met the case definition for clozapine associated neutropenia and were matched to 136 controls. A similar number of males were found in cases (n = 89) and controls (n = 91). Cases were significantly younger (mean age 35.7 ± 12.5 years, range 21–77 years) than controls (mean age 44.2 ± 11.4 years, range 17–74 years; t = 5.86, df = 267, p < 0.001).
Thirty nine percent (n = 53) developed neutropenia within the first 6 months of clozapine treatment, 17.6% (n = 24) between 6 and 12 months of treatment, and 43.4% (n =
Discussion
This study found that sodium valproate is a significant risk factor for the development of clozapine associated neutropenia. This supports the findings of previous case series and reports suggesting an association between neutropenia and concordant clozapine and valproate use (Imbarlina et al., 2004, Madeb et al., 2002, Meyer et al., 2015, Pantelis and Adesanya, 2001).
The first cases of sodium valproate associated neutropenia were reported in paediatric populations in the 1970s (Jaeken et al.
Limitations
Limited data on plasma clozapine concentrations prevented us from further exploring the inverse association between clozapine dose and risk of developing neutropenia, though previous research has found no difference in plasma clozapine and norclozapine concentrations in patients who either do or do not develop neutropenia (Hasegawa et al. 1994). Further, a lack of data on smoking habits of patients limited us in evaluating the effects of smoking on the relationship between sodium valproate and
Conclusion
Our findings indicate a strong association between clozapine and sodium valproate use and neutropenia risk. These findings have clinical implications, both when investigating possible causes of severe neutropenia on clozapine, and on the choice of anticonvulsant used for seizure prophylaxis.
Conflict of interest
Only 1 author (FG) has a potential conflict of interest, although not in relation to this work.
FG has received support or honoraria for CME, advisory work and lectures from Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Roche, and Sunovion, has research funded by an NHS Innovations/Janssen-Cilag award and has a family member with professional links to Lilly and GSK, including shares.
All other authors (SM, JL, OA, MP, AK, HS, RJF, and JHM) declare no conflict of interest.
The other authors have
Contributors
We affirm that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. SM, JL and JHM made substantial contributions to the conception and design of the work. SM, JL, MP, HS were involved in the acquisition of the data and SM, JL and OA in the analysis of the data. SM, JL, AK, FG, RJF, and JHM also contributed towards data interpretation for this study. SM and JL created the first draft of the work
Role of the funding source
This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Acknowledgements
None.
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