Valproate as prophylaxis for clozapine-induced seizures: survey of practice

AIMS AND METHOD

To evaluate the prescribing of valproate in clozapine-treatedindividuals who may be at risk of seizure. We collected point-prevalentclinical characteristics and demographics of all in-patientsprescribed clozapine in an acute mental health trust. Datawere collected from case notes, electronic records and drugcharts, and analysed against a set audit standard.

RESULTS

Data were collected for 81 in-patients. Of all deemed to beat risk of seizure (n=37) only 24% were prescribed valproateat a therapeutic plasma level.

CLINICAL IMPLICATIONS

The majority of patients prescribed clozapine at risk of seizureswere not adequately protected from this risk. Clear guidelinesare required.

Introduction

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Introduction

Clozapine is an atypical antipsychotic agent with an establishedand valuable role in treatment-refractory schizophrenia (National Institute for Health and Clinical Excellence, 2002).In this patient group, clozapine has been shown to be consistentlyeffective (Taylor & Duncan-McConnell, 2000) and is moreeffective than switching to another atypical antipsychoticwhen other atypical agents have failed (McEvoy et al, 2006). However, it has a serious adverse effect profile and attritionfrom treatment is high (Ciapparelli et al, 2003). Outcomehas been shown to be poor for individuals who discontinue clozapinefor any reason and it has been observed that preventable deathis a common occurrence in those stabilised on clozapine, includingdeath associated with seizure (Atkinson et al, 2007).

Much has been written on clozapine’s propensity for loweringthe seizure threshold (Devinsky & Pacia, 1994; Pacia & Devinsky, 1994;Sajatovic & Meltzer, 1996; Silvestri et al, 1998; Welch et al, 1994),including guidance for the management and prophylaxis of clozapine-relatedseizures (Devinsky & Pacia, 1994; Taner et al, 1998; Welch et al, 1994). Recommendations include dose reduction, electroencephalogram(EEG), plasma-level monitoring and prophylactic valproate treatment.

The risk of seizure during clozapine treatment has been estimatedat approximately 1% to 4.4% dependent on dose (Devinsky et al, 1991; Devinsky & Pacia, 1994). However, seizures have been observedat all stages of treatment (Sajatovic & Meltzer, 1996),at both high and low doses, and thus may not in fact be dose-dependent(Pacia & Devinsky, 1994). They are perhaps more likelyto be blood-level related (Greenwood-Smith et al, 2003) thandose-related and therefore more useful measures in assessingthe risk of seizure may include EEG and plasma blood-level monitoring.

Although stringent licensing requirements demand tight controland monitoring for signs of clozapine-induced blood dyscrasias,little is known of monitoring in respect to other potentialadverse effects of clozapine in clinical practice. Despiterecommendations in the literature, clinical guidelines forpreventing and managing seizures are not well established and practice may vary in the clinical setting (Welch et al, 1994). Management of such adverse effects is important and prophylactictreatment may enable the continued and valuable prescribingof clozapine in individuals who may be at risk of seizuresdespite therapeutic benefit (Taner et al, 1998).

An audit was carried out to evaluate the monitoring of clozapineplasma levels and the steps taken to reduce seizure risk ineveryday clinical practice in a large mental health trust.

Method

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Method

In June 2007 this study was approved by the Drugs and Therapeutics Committee in South London and Maudsley National Health Service(NHS) Trust. All in-patients with a current prescription forclozapine were identified and those with complete and accessiblemedical notes were included in the study sample. Medical notes(case notes, hospital computer records and drug charts) werelocated and the relevant information collected in relation toa set audit standard. Information recorded included patientdemographics, current clozapine dose, reason for prescribing,plasma blood level, all other prescribed medication includingdose and plasma level of valproate, and history of seizureor head injury.

The audit standard was set at: all in-patients prescribed clozapinewith a plasma blood level more than 0.6 mg/l or a dose at ormore than 600 mg/day and/or co-prescribed additional epileptogenicdrugs and/or with an existing seizure disorder, should be prescribedvalproate at a dose sufficient to afford a therapeutic plasmalevel of >50 mg/l.

There were 81 in-patients with a current clozapine prescriptionwho were included in the analysis. Their demographic and clinicalcharacteristics are shown in Table 1. Data analysis was performedusing SPSS 15.0 for Windows.

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Table 1. Demographic and clinical characteristics of patients in the study¹

Results

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Results

Medication
Reason for clozapine prescription and dose and plasma levelsof clozapine are shown in Table 2. Four in-patients were alsoprescribed venlafaxine, a significantly epileptogenic drug,and 32.1% of those prescribed clozapine were also prescribedan additional antipsychotic agent. The majority of co-prescriptionwas augmentation with amisulpride (n=19). Others included quetiapine, risperidone, aripiprazole and sulpiride. No other notable epileptogenicagents were prescribed in our sample. The only two anticonvulsantdrugs prescribed in our sample were valproate (n=33) at a meandose of 1358 mg/day and lamotrigine (n=4). Most commonly individualswere prescribed valproate as a mood stabiliser (48.5%) ratherthan for seizure prophylaxis (9.1%). Alternative indicationsincluded clozapine augmentation and pre-existing epilepsy.

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Table 2. Clozapine prescription¹

‘High-risk’ individuals
Of the 24 individuals with a clozapine level >0.6 mg/dayor a dose of >600 mg/day (‘high-clozapine group’)11 were also prescribed valproate (45.8% of the high-clozapinegroup).

Of the four individuals prescribed an additional epileptogenicdrug, one also had a ‘high’ clozapine level ordose but none had a history of seizure disorder. Eleven ofthe total patients sample had a history of seizure or significanthead injury recorded in the case notes. Of these, one patientalso had a ‘high’ clozapine level. There were no individuals in this group also prescribed other epileptogenicdrugs.

Audit standard
In-patients meeting any of the criteria as set by the auditstandard (n=37, 46%) were deemed to be at risk of seizure (Table 3).Of these, 20 were prescribed valproate, but only 9 had an adequatevalproate level. None of those who were not prescribed valproatewere prescribed an alternative anticonvulsant. Thus only 24%of the relevant patients met the audit standard and 76% ofthose at highest risk of seizure were not adequately protectedfrom it.

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Table 3. Valproate prescription ‘high-risk’ group¹

Discussion

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Discussion

Our findings present some concern as to the number of individualswho might be vulnerable to the risks associated with clozapineprescription within our sample, which may be reflective ofother large mental health trusts. The prevalence of seizuresduring clozapine treatment has been estimated at as high as8% (Welch et al, 1994) and seizures have been shown to be aleading cause of death in those receiving clozapine (Atkinson et al, 2007).Even when not resulting in death, seizures occurring duringclozapine treatment may result in its withdrawal with a notoriouslypoor outcome - increased bed stay, polypharmacy and a declinein global functioning have all been observed in the first yearafter cessation of clozapine prescription (Atkinson et al, 2007).

Despite the known risks, our results show that many cliniciansinvolved in the care of those prescribed clozapine do not takesteps to prevent seizure or to adequately measure or monitorits risk. More disturbing still was the observation that themost common reason for prescribing valproate in the ‘atrisk’ sample was mood stabilisation and not seizure prophylaxis.

When considering the adverse effect profile of clozapine, muchemphasis is placed on the drug’s ability to cause blooddyscrasias and little on the risk of seizure. This may be attributedto the controls over regular blood monitoring which makes cliniciansvery aware of this possible adverse effect and often makesit their utmost concern when prescribing clozapine. It may alsobe that they are simply not aware of the risk of seizure orunderestimate its magnitude. Alternatively, the risk may bewell known but when considered against the likelihood of additionaland enhanced adverse effects caused by a co-prescription ofvalproate, clinicians and patients may choose to avoid prophylacticmedication in the light of a comparably smaller risk of seizures. It is also possible that clinicians, while aware of the risk,have little clear guidance on how best to manage it and thereforedo not make appropriate treatment plans. Such guidance canbe found in the Maudsley Prescribing Guidelines (Taylor et al, 2007)and, as the most widely used prescribing reference within theTrust and nationally, it raises the possibility that cliniciansmay be aware of the guidance in the literature but decide notto prescribe prophylactic valproate, perhaps based on the lackof good evidence that valproate actually prevents clozapine-inducedseizures.

This study analysed all in-patients prescribed clozapine ina large urban mental health trust thus providing a completesample of patients in a naturalistic setting. Despite the study’sstrengths, the sample size is small and the results reflecta point prevalence study of prescribing rather than a prospectivestudy of outcome. The results are also representative of justone trust, and may not actually reflect practice elsewhere wherelocal guidelines and experience may have a greater impact onprescribing. To our knowledge, there are currently no publisheddata with which we can compare our results. Larger studiesover different trusts would be useful in establishing currentpractice and to aid the development of much needed guidancein this critical area of clozapine management, in order toprevent harm and ultimately death in those prescribed clozapine.

References

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