502829

2013

APY22110.1177/1039856213502829Australasian PsychiatryCaetano

AP

Review article

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine

Australasian Psychiatry 2014, Vol 22(1) 78­–82 © The Royal Australian and New Zealand College of Psychiatrists 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1039856213502829 apy.sagepub.com

Dorgival Caetano  Conjoint Professor, University of Western Sydney, Blacktown, NSW, Australia

Abstract Objective: The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. Method: A systematic review of English-language MEDLINE articles was undertaken. Conclusions: Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug–drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician’s choice should consider drug–drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided. Keywords:  clozapine, clozapine-induced seizures, clozapine serum concentrations, drug-drug interactions, seizure prophylaxis

C

lozapine is the treatment of choice for patients with refractory schizophrenia because of its efficacy over both typical and atypical antipsychotics.1 Although good response may occur at any dose/serum concentration, for most patients the best clinical results appear to occur at 600 mg/day,2 or at clozapine serum concentrations >350 ng/ml.3–7

The purposes of this article are to: (i) critically review the rationale for recommendation of the concomitant use of anticonvulsant in patients on clozapine; (ii) discuss the relationship between clozapine dose, serum concentration and risk for seizures as well as other factors than dose that affect clozapine levels; and (iii) provide recommendations for the management of clozapine-induced seizures.

Amongst antipsychotics, clozapine has been associated with the highest incidence of seizures (1–5%) and the risk increases with high dose (≥ 600 mg/day)8–10 as well as with high serum concentration (≥ 1300 ng/ml).11–13

Method

In 1991 Devinsky et al.9 recommended as one (but not the only) strategy that patients taking > 600 mg/day of clozapine be commenced on anticonvulsant therapy as a primary prophylaxis for seizures. This recommendation has been taken at face value and incorporated in an influential textbook of psychiatry14 and also in two widely consulted drug directories.7,10 In some quarters this has been seen as the best clinical practice.15

78

The author reviewed English-language MEDLINE articles on clozapine dose/serum concentration and risk of seizures as well as recommendations for primary and secondary prevention for clozapine-induced seizures. Correspondence: Professor Dorgival Caetano, University of Western Sydney, 11/16-24 Oxford Street, Blacktown, NSW 2140, Australia. Email: [email protected]

Caetano

Literature search findings

Clozapine serum concentration and its relationship with dose and drug–drug interactions In vitro studies have shown that clozapine is mainly metabolised by 1A2, 2D6 and 3A4 genotypes16 and in humans CYP1A2 accounts for 70% of the variance in clozapine clearance.17 Hence, any drug that inhibits 1A2 to an important extent may raise clozapine serum concentration to toxicity. For instance, erythromycin can increase clozapine blood concentration by 100%11 and fluvoxamine (a powerful 1A2 inhibitor)16,18,19 by up to ninefold.18–23 On the other hand, other drugs can decrease clozapine concentration. For instance, tobacco decreases clozapine serum concentration by about 50%,24,25 and dose adjustment is required when patients change their smoking habits. Animal studies indicated that components of cigarette smoke bind to receptors to form a complex that binds to genes such as that encoding for CYP1A2, resulting in enhanced transcription of this enzyme.26 Although not as important as 1A2, CYP 2D6 and 3A4 enzymes are also routes for the metabolism of clozapine16,27 and any concomitant drug that affects both or either enzyme, for instance, paroxetine and fluoxetine (powerful 2D6 inhibitors) significantly increase clozapine and norclozapine serum concentrations.28 A positive linear relationship between oral dose of clozapine and its serum concentration has been shown over a dosing range of 25–800 mg/day.3,29 However, the latter is also significantly affected by other factors such as smoking, gender and age.4,30 There is a sharp decrease in clozapine metabolism in those 55 years old and over, and lower serum concentrations in males compared with females.30 Perry et al.’s dosing nomogram4 can be used to calculate the influence of gender and smoke. Hence, according to this nomogram, the same clozapine dose of 600 mg/day will yield serum concentrations (ng/ ml) of 423 and 534 in male smokers and non-smokers, respectively; and 805 and 916 in female smokers and non-smokers, respectively. Dose, gender and smoking habit together seem to account for only for 47% of the variance in clozapine serum concentrations.4 Phenotypic variation in the main CYP450 isoenzymes (1A2, 2D6 and 3A4) involved in the metabolism of clozapine also plays a significant role. In short, although dose (mg/day) is clinically important to predict serum concentration, dose alone cannot accurately predict the latter as it co-varies with age, gender, smoking habit as well as with clozapine–drug interactions and CYP450 genotypes.

Clozapine and the risk of seizures Seizures may occur in patients on antipsychotics other than clozapine as well on antidepressants,31 or even be

unrelated to antipsychotic medication. Devinsky and colleagues9 estimated a frequency of epilepsy in schizophrenic patients between 1–18% in the prephenothiazines era. Logothetis32 found an average prevalence of spontaneous seizure of 1.2% amongst 859 patients taking phenothiazine against 0% in 669 patients not taking phenothiazines. Moreover, the seizure frequency rose sharply from 0.7% in those taking a moderate dose of phenothiazines to 9.0% in the high-dosage group. Amongst the antipsychotics, clozapine has the highest prevalence of seizures and this seems to be dose related. Hence, the prevalence of seizures was 5% for those patients treated with 600–900 mg/day; 3–4% for patients on 300–599 mg/day; and 1–2% for those on less than 300 mg/day.8 In 1990, Haller and Bindr33 reported ictal activity in three patients taking clozapine ≥ 600 mg/day. One of the patients was concomitantly treated with a very high dose of haloperidol (60 mg/day), which decreases seizure threshold as well as increases clozapine level by inhibition of 2D6 and 3A4.10 In this case, the ictal activity resolved when clozapine was reduced. In the other two cases, phenytoin was added on and the dose of clozapine decreased. It is worth noting that phenytoin, through induction of 1A2, decreases clozapine serum concentration by 65–85%.34 Devinsky et al.,9 in a large sample of 1418 clozapine patients, found that 2.8% had generalised tonic–clonic seizures and it seemed that neither age nor sex significantly influenced seizure risk. Seizures, however, appeared to be dose related. High-dose therapy (≥ 600 mg/day) was associated with a greater seizure risk of 4.4%, medium dose (300–599 mg/day) with a moderate risk of 2.7%, and low dose (< 300 mg/day) with a low risk of 1.0%. About 76% of the patients who had seizures were successfully continued on clozapine either through reduction of dose or administration of anticonvulsants: phenytoin, phenobarbital or carbamazepine (these drugs decrease clozapine concentrations), and phenytoin and phenobarbital through activation of 1A2 hepatic enzymes34 and carbamazepine through activation of 3A4.18 Devinsky et al. acknowledged that six out of 41 patients who had seizures were taking other drugs that lowered the seizure threshold, two had a prior history of seizures and one was undergoing a course of electroconvulsive therapy. About 60% of all seizure cases occurred in patients receiving clozapine ≥ 600 mg/day. In a subsequent study in 5629 patients treated with clozapine, Parcia and Devensky35 found a frequency of tonic–clonic seizures of 1.3%, and seizures tended to occur at low doses (< 300 mg/day) during the titration phase and at high doses (> 600 mg/day) during the maintenance phase. Wong and Delva36 in a recent review of the literature showed that patients had seizure-like symptoms at a clozapine daily dose varying from 275–600 mg/day. Unfortunately, clozapine blood concentrations were not

79

Australasian Psychiatry 22(1)

available, nor was information on factors known to raise clozapine blood concentration or decrease seizure threshold. Although clinically important, dose alone may be misleading and does not, on its own merit, support the statement that an anticonvulsant should be added on to prevent seizures when patients are taking more than 600 mg daily.

The risk of seizure and its prophylaxis Devinsky et al.9 reported a risk for seizures in patients taking > 600 mg/day of clozapine at 4%. If one takes into account a 1% risk for spontaneous seizures in untreated patients with schizophrenia and another 1% for the risk of seizures for antipsychotics other than clozapine, then the overall risk for clozapine-induced seizures will be closer to that for neutropenia/agranulocytosis. The latter is usually managed by close clinical monitoring and white cell counts instead of adding on granulocyte colony-stimulating factors as a primary prophylaxis. Likewise, the risk of seizures would be better managed by close clinical monitoring and measures of clozapine serum concentration rather than adding an anticonvulsant drug. Furthermore, 600 mg/day will yield serum levels ranging from 423–916 ng/ml (according to gender and smoking habit), and the upper level is still below the concentration (≥ 1300 ng/ml) at which there is a higher risk of seizure. The mechanism by which clozapine causes seizures has not yet been totally elicited, but studies in animals have linked these seizures with kindling, that is, progressive brain excitability following repeated administration of a fixed dose of clozapine.37 The use of anticonvulsants as a primary prophylaxis for seizures in patients on higher clozapine doses (≥ 600 mg/ day) has been largely proposed.7,9,10,14,15 This proposal, however, has some pitfalls. First, the risk of seizure seems to be more accurately predicted by clozapine serum concentration,25 and this cannot be accurately predicted from dose alone. Second, even if the 4% risk9 is taken at face value, clinicians would be over medicating at least 96% of those patients on a higher dose. Third, ≥ 600 mg/day is often already highly sedating, and this side effect will likely worsen by adding on an anticonvulsant with sedative effects, which can lead to non-compliance. Fourth, there is an additional risk of agranulocytosis with some anticonvulsants. Fifth, the risk of drug–drug interactions must be considered. Phenytoin and phenobarbital (through induction of 1A2) and carbamazepine (through induction of 3A4) can significantly decrease clozapine serum concentration,10,34,38 thus compromising clinical efficacy, as in most cases a serum concentration of at least 350 ng/ml is usually required for an optimal clinical response.3–7 On the other hand, anticonvulsants such as lamotrigine may increase clozapine plasma level by threefold,15,39 which may lead to toxic effects.

80

Primary and secondary prophylaxis for clozapine-induced seizures Taking into account previous recommendations,9,10,14,33 the author would like to emphasise that the risk management for primary prophylaxis for clozapine-induced seizures should rely on close clinical and serum concentration monitoring, and entails: (i) Awareness of those patients at a higher risk (previous history of seizures, febrile seizures and head injury); (ii) Use of gradual dose titration; (iii)  Avoidance or discontinuation of concomitant drugs that directly lower seizure threshold; (iv)  Enlisting the patient’s cooperation in reporting drop attacks, myoclonic jerks or any other partialseizure symptoms which may precede generalised tonic–clonic seizures. Should they be present, decrease the dose and monitor serum concentration; (v) Awareness of clozapine plasma level (≥ 1300 ng/ml) at which most cases of tonic–clonic seizures have been reported; (vi)  Avoidance or gradual discontinuation of drugs that inhibit the major isoenzymes involved in the metabolism of clozapine, which in turns raises the risk of seizures. For example: fluvoxamine, erythromycin and smoking cessation (through 1A2); paroxetine, fluoxetine, high dose of sertraline, and risperidone (through 2D6); norfluoxetine (through 3A4); and lamotrigine (unknown mechanism), all increase clozapine blood concentration. If refractory patients benefiting from clozapine have seizures, clozapine treatment should not be necessarily discontinued, as most patients will not probably respond to other antipsychotics and the following should be initiated. Secondary prophylaxis should entail: (i) Ruling out other causes of seizures; (ii) Monitoring clozapine serum levels; (iii)  Looking for drugs (including smoking cessation) that increase clozapine levels, or lower seizure threshold (e.g. phenothiazines, haloperidol) and decrease or discontinue them; (iv) Decreasing clozapine dose; (v)  If a patient has a second seizure, consider adding an anticonvulsant before discontinuation of treatment. The choice of anticonvulsants The choice of anticonvulsant should take into consideration the risk of neutropenia/agranulocytosis and sedation

Caetano

as well as relevant drug–drug interactions. Carbamazepine has been unanimously not recommended9,10,13,14,33,40 because of the risk of bone marrow suppression. Interestingly enough, none of these authors mentioned that carbamazepine, via activation of 3A4,19 can significantly decrease clozapine concentration and compromise therapeutic response. Some authors9,10,14,33,40,41 recommend sodium valproate; others10,14,42–45 recommend sodium valproate, gabapentin, topiramate or lamotrigine. Should an anticonvulsant be deemed necessary for secondary prophylaxis, sodium valproate seems to be the choice given its low, non-clinically important interference with clozapine metabolism as well as small risk of bone marrow suppression.46 Phenobarbital, phenytoin and carbamazepine are to be avoided because they can, additionally to side effects, compromise therapeutic response by decreasing clozapine concentration. Carbamazepine may put patients at a higher risk for blood dyscrasias, including neutropenia/ agranulocytosis. This risk is considerably lower for sodium valproate, lamotrigine and gabapentin.46 Lamotrigine, however, may increase clozapine concentration threefold,10,39 thus increasing the risk of toxicity, including seizures.

Conclusions In the classical paper by Devinsky and colleagues,9 it was reported that patients on a clozapine dose > 600 mg/day had a 4% risk for developing seizures and that addition of an anticonvulsant would be one of the strategies for a primary prophylaxis of clozapine-induced seizures. Despite the lack of other information about other factors that have a bearing upon clozapine serum concentration and consequently on the risk of seizures, these authors’ reported risk and recommendation have been taken at face value and repeated by other authors. This has had an impact on clinical practice and needs review. Overall, the risk of seizures is related to dose and, more specifically, to serum concentration. The latter, however, cannot be accurately predicted from dose alone as age, gender, smoking habit and concomitant use of drugs play significant roles. The concentration (> 350 ng/ml) usually required for optimal clinical response is well below that (≥ 1300 ng/ml) which poses a high risk for seizures. Anticonvulsants are not recommended as a primary prophylaxis for seizures, and when deemed necessary as secondary prophylaxis clinicians should consider drug–drug interactions that may increase the risk of side effects, including neutropenia/agranulocytosis and seizures, or decrease clinical efficacy. Thus, primary and secondary prophylaxis of clozapine related-seizures should rely more on clinical and blood concentration monitoring than on the use of anticonvulsants.

Disclosure The author reports no conflict of interest. The author alone is responsible for the content and writing of the paper.

References 1. Davis JM, Chen N and Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003; 60: 553–564. 2. Simpson GM, Josiassen RC, Stanilla JK, et al. Double-blind study of clozapine dose response in chronic schizophrenia. Am J Psychiatry 1999; 156: 1744–1750. 3. Byerly MJ and DeVane CL. Pharmacokinetics of clozapine and risperidone: A review of recent literature. J Clin Psychopharmacol 1996; 16: 177–187. 4. Perry PJ, Bever KA, Arndt S, et al. Relationship between patient variables and plasma clozapine concentrations: A dosing nomogram. Biol Psychiatry 1998; 44: 733–738. 5. Kronig MH, Munne RA, Szymanski S, et al. Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995; 152: 179–182. 6. Hasegawa M, Guttierez-Esteinou R, Way L, et al. Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: Effect of smoking. J Clin Psychopharmacol 1993; 13: 383–390. 7. Taylor D, Paton C and Kapur S. The Maudsley prescribing guidelines (10th edition). UK: Informa Health Care, 2010, p.62–65. 8. Iqbal MM et al. Therapeutic options in the treatment of clozapine-induced adverse effects. J Pharm Technol 2004; 20: 155–64 9. Devinsky O, Honigfeld G and Patin J. Clozapine-related seizures. Neurology 1991; 41: 369–731. 10. Bazire S. Psychotropic drug directory 2010: The professionals’ pocket handbook and memoire. UK: HealthCommon Ltd, 2010. 11. Funderburg LG, Vertrees JE, True JE, et al. Seizure following addition of erythromycin to clozapine therapy (letter). Am J Psychiatry 1994; 151: 1840–1841. 12. Dumortier G, Mahé V, Pons D, et al. Clonic seizure associated with high clozapine plasma level. J Neuropsychiatry Clin Neurosci 2001; 13:302–303. 13. Simpson GM and Cooper TA. Clozapine plasma concentrations and convulsions. Am J Psychiatry 1978; 135: 99–100. 14. Kammen DP and Marder SR. Serotonin-dopamine antagonist (atypical or secondary generation antipsychotics). In: Sadock BJ, Sadoc VA (eds) Comprehensive textbook of psychiatry. Philadelphia: Lippincott Williams & Wilkins, 2005, p.2922–2923. 15. Sparshatt A, Wiskey E and Taylor D. Valproate as prophylaxis for clozapine-induced seizures: Survey of practice. Psychiatr Bull 2008; 32: 262–265. 16. Linnet K and Olesen OV. Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos 1997; 25:1379–1382. 17. Berttilsson L, Carrillo JA, Dahl ML, et al. Clozapine disposition covaries with CYP1A2 activity determined by caffeine test. Br J Clin Pharmacol 1994; 38: 471–473. 18. Jerling M, Lindstrom L, Bondeson U, et al. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: Evidence from a therapeutic drug monitoring service. Ther Drug Monit 1994; 16: 368–374. 19. Bronsen K, Skjelbo E, Rasmussen BB, et al. Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 1993; 35: 1211–1214. 20. Dequardo JR and Roberts M. Elevated clozapine levels after fluvoxamine initiation (letter). Am J Psychiatry 1996; 153: 840–841. 21. Dumortier G, Lochu A, Melo PC, et al. Elevated clozapine plasma concentrations after fluvoxamine initiation (letter). Am J Psychiatry 1996; 153: 738–739. 22. Armstrong SC and Stephans JR. Blood clozapine levels elevated by fluvoxamine: Potential for side effects and lower clozapine dosage (letter). J Clin Psychopharmacol 1997; 58: 499.

Acknowledgment

23. Lu ML, Lane HY, Jann MW, et al. Dosing strategies of clozapine-fluvoxamine cotreatment. J Clin Psychopharmacol 2002; 22: 626–628.

The author would like to thank Prof. Roger Bartrop, University of Western Sydney, for his review of this paper and suggestions.

24. Skogh E, Bengtsson F and Nordin C. Could discontinuing smoking be hazardous for patients administered clozapine medication? A case report. Ther Drug Monit 1999; 21: 580–583.

81

Australasian Psychiatry 22(1) 25. Meyer J. Individual changes in clozapine after smoking cessation: Results and predictive model. J Clin Psychopharmacol 2001; 21: 569–574.

36. Wong J and Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry 2007; 52: 457–463.

26. Quattrochi LC and Tukey RH. The human CYP1A2 gene contains regulatory elements responsive to 3-methylcholanthrene. Mol Pharmacol 1989; 36: 66–71.

37. Stevens JR, Denney D and Szot P. Kindling with clozapine: Behavioral and molecular consequences. Epilepsy Res 1996; 26: 295–304.

27. Fischer V, Vogels B, Maurer G, et al. The antipsychotic clozapine is metabolised by the polymorphic human microsomal and recombined cytochrome p450 2D6. J Phamacol Exp Ther 1992; 260: 1355–1360.

38. Raitasuo V, Lehtovaara R and Huttunnen MO. Carbamazepine and plasma levels of clozapine (letter). Am J Psychiatry 1993; 150: 169.

28. Centorrino F, Baldessarini R, Frankenburg F, et al. Serum levels of clozapine and norclozapine in patients treated with selective serotonin reuptake inhibitors. Am J Psychiatry 1996; 153: 820–822. 29. Bondesson U and Lindstrom L. Determination of clozapine and its N-desmethylated metabolite in plasma by use of gas chromatography-mass spectroscopy with single ion detection. Psychopharmacology 1988; 95: 472–475. 30. Touw DJ. Clinical implications of genetic polymorphisms and drug interactions mediated by cytochrome P-450 enzymes. Drug Metab Drug Interact 1977; 14: 55–82. 31. Pisani F, Oteri G, Costa C, et al. Effects of psychotropic drugs on seizure threshold. Drug Saf 2002; 25: 91–110. 32. Logothetis J. Spontaneous epileptic seizures and electroencephalographic changes in the course of phenotiazine therapy. Neurology 1967; 17: 869–877. 33. Haller E and Bindr RL. Clozapine and seizures. Am J Psychiatry 1990; 147: 1069–1071.

39. Kosen M, Selten JP and Kahn RS. Elevated clozapine plasma level with lamotrigine (letter). Am J Psychiatry 2001; 15: 1930–1931. 40. Ghaznavi S, Nakic M, Rao P, et al. Rechallenging with clozapine following neutropenia: Treatment options for refractory schizophrenia. Am J Psychiatry 2008; 165: 813–818. 41. Foster R and Olaide D. A case of clozapine-induced tonic-clonic seizures managed with valproate: Implications for clinical care. J Psychopharmacol 2005; 19: 93–96. 42. Taner E, Cosar B and Isik E. Clozapine-induced myoclonic seizures and valproic acid. Int J Psychiatry Clin Pract 1998; 2: 53–55. 43. Usiskin SL, Nicolson R, Lenane M, et al. Gabapentine prophylaxis of clozapine-induced seizures (letter). Am J Psychiatry 2000; 157: 482–483. 44. Navarro V, Pons A, Romero A, et al. Topiramate for clozapine-induced seizures (letter). Am J Psychiatry 2001; 158: 968–969.

34. Miller DD. Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry 1991; 52: 23–25.

45. Landry P. Gabapentin for clozapine-related seizures (letter). Am J Psychiatry 2001; 158: 1930.

35. Parcia SV and Devinsky O. Clozapine-related seizures: Experience with 5,629 patients. Neurology 1944; 44: 2247–2249.

46. Oyesanmi O, Kunkel EJS, Monti DA, et al. Hematologic side effects of psychotropics. Psychosomatics 1999; 40: 414–421.

82