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CNS Drugs
Published in: CNS Drugs 2/2015

01-02-2015 | Therapy in Practice

Seizure Associated with Clozapine: Incidence, Etiology, and Management

Authors: Andrew M. Williams, Susie H. Park

Published in: CNS Drugs | Issue 2/2015

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Abstract

Seizures are a known adverse effect of clozapine therapy. The literature varies on incidence rates of seizures, secondary to varying time frames in which each seizure occurred. Tonic-clonic seizures comprise the majority of seizures experienced secondary to clozapine use, but it is imperative to recognize the potential variety of seizure presentation. The exact etiology of clozapine-induced seizure is unknown. Conflicting reports regarding total oral dose, serum concentration, dose titration, and concomitant medications make it difficult to identify a single cause contributing to seizure risk. Following seizure occurrence, it may be in the best interests of the patient to continue clozapine treatment. In this clinical situation, the use of an antiepileptic drug (AED) for seizure prophylaxis may be required. The AED of choice appears to be valproate, but several successful case reports also support the use of lamotrigine, gabapentin and topiramate. Well-designed clinical trials regarding clozapine seizure prophylaxis are lacking. Given clozapine’s strong evidence for efficacy in the treatment of schizophrenia and schizoaffective disorder, every attempt to manage side effects, including seizure, should be implemented to allow for therapeutic continuation.
Literature
1.
2.
3.
Haddad PM, Dursun SM. Neurological complications of psychiatric drugs: clinical features and management. Hum Psychopharmacol. 2008;23(Suppl 1):15–26.PubMedCrossRef
4.
Iqbal MM, Rahman A, Husain Z, Mahmud SZ, Ryan WG, Feldman JM. Clozapine: a clinical review of adverse effects and management. Ann Clin Psychiatry. 2003;15(1):33–48.PubMedCrossRef
5.
6.
7.
Conca A, Beraus W, Konig P, Waschgler R. A case of pharmacokinetic interference in comedication of clozapine and valproic acid. Pharmacopsychiatry. 2000;33(6):234–5.PubMedCrossRef
8.
Welch J, Manschreck T, Redmond D. Clozapine-induced seizures and EEG changes. J Neuropsychiatry Clin Neurosci. 1994;6(3):250–6.PubMedCrossRef
9.
Kohlrausch FB, Severino-Gama C, Lobato MI, Belmonte-de-Abreu P, Carracedo A, Hutz MH. The CYP1A2-163C>A polymorphism is associated with clozapine-induced generalized tonic-clonic seizures in Brazilian schizophrenia patients. Psychiatry Res. 2013;209(2):242–5. doi:10.​1016/​j.​psychres.​2013.​02.​030.PubMedCrossRef
10.
Devinsky O, Pacia SV. Seizures during clozapine therapy. J Clin Psychiatry. 1994;55(Suppl B):153–6.PubMed
11.
Freudenreich O, Weiner RD, McEvoy JP. Clozapine induced electroencephalogram changes as a function of clozapine serum levels. Biol Psychiatry. 1997;42(2):132–7.PubMedCrossRef
12.
Liukkonen J, Koponen HJ, Nousiainen U. Clinical picture and long-term course of epileptic seizures that occur during clozapine treatment. Psychiatry Res. 1992;44(2):107–12.PubMedCrossRef
13.
Malow BA, Reese KB, Sato S, Bogard PJ, Malhotra AK, Su TP, Pickar D. Spectrum of EEG abnormalities during clozapine treatment. Electroencephalogr Clin Neurophysiol. 1994;91(3):205–11.PubMedCrossRef
14.
Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52(7):457–63.PubMed
15.
Pacia SV, Devinsky O. Clozapine-related seizures: experience with 5,629 patients. Neurology. 1994;44(12):2247–9.PubMedCrossRef
16.
Bak Th, Bauer M, Schaub RT, Hellweg R, Reischies FM. Myoclonus in patients treated with clozapine: a case series. J Clin Psychiatry. 1995;56(9):418–22.PubMed
17.
Lieberman JA, Safferman AZ. Clinical profile of clozapine: adverse reactions and agranulocytosis. Psychiatr Q. 1992;63(1):51–70.PubMedCrossRef
18.
Berman I, Zalma A, DuRand CJ, Green AI. Clozapine-induced myoclonic jerks and drop attacks. J Clin Psychiatry. 1992;53(9):329–30.PubMed
19.
Fitzsimons J, Berk M, Lambert T, Bourin M, Dodd S. A review of clozapine safety. Expert Opin Drug Saf. 2005;4(4):731–44.PubMedCrossRef
20.
Gouzoulis E, Ozdaglar A, Kasper J. Myoclonic seizures followed by grand mal seizures during clozapine treatment. Am J Psychiatry. 1993;150(7):1128.PubMed
21.
Usiskin SI, Nicolson R, Lenane M, Rapoport JL. Gabapentin prophylaxis of clozapine-induced seizures. Am J Psychiatry. 2000;157(3):482–3.PubMedCrossRef
22.
Taner E, Cosar B, Isik E. Clozapine-induced myoclonic seizures and valproic acid. Int J Psychiatry Clin Pract. 1998;2:53–5.PubMedCrossRef
23.
Geaney D. Clozapine can cause hallucinations by inducing complex partial seizures of temporal lobe origin (temporal lobe epilepsy). A potentially serious complication in the management of schizophrenia with clozapine. J Psychopharmacol. 1995;9(1):64–6. doi:10.​1177/​0269881195009001​10.PubMedCrossRef
24.
Khan AY, Preskorn SH. Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring. J Psychiatr Pract. 2005;11(5):289–301.PubMedCrossRef
25.
Nielsen J, Correll CU, Manu P, Kane JM. Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided? J Clin Psychiatry. 2013;74(6):603–13. doi:10.​4088/​JCP.​12r08064 (quiz 613).PubMedCrossRef
26.
Freedman JE, Wirshing WC, Russell AT, Bray MP, Unutzer J. Absence status seizures during successful long term clozapine treatment of an adolescent with schizophrenia. J Child Adolesc Psychopharmacol. 1994;4(1):53–62.CrossRef
27.
Jarbin H, Johansson BA, Lundgren J. Clozapine and therapy-refractory epileptic seizures. Eur Child Adolesc Psychiatry. 2001;10(3):209–10.PubMedCrossRef
28.
Langosch JM, Trimble MR. Epilepsy, psychosis and clozapine. Hum Psychopharmacol. 2002;17(2):115–9.PubMedCrossRef
29.
Centorrino F, Price BH, Tuttle M, Bahk WM, Hennen J, Albert MJ, Baldessarini RJ. EEG abnormalities during treatment with typical and atypical antipsychotics. Am J Psychiatry. 2002;159(1):109–15.PubMedCrossRef
30.
Chung SJ, Jeong SH, Ahn YM, Kang UG, Koo YJ, HA JH, Lee SG, Kim YS. A retrospective study of clozapine and electroencephalographic abnormalities in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26(1):139–44.PubMedCrossRef
31.
32.
Naber D. Optimizing clozapine treatment. J Clin Psychiatry. 1999;60(Suppl 12):35–8.PubMed
33.
Sajatovic M, Meltzer HY. Clozapine-induced myoclonus and generalized seizures. Biol Psychiatry. 1996;39(5):367–70.PubMedCrossRef
34.
Freeman DJ, Oyewumi LK. Will routine therapeutic drug monitoring have a place in clozapine therapy? Clin Pharmacokinet. 1997;32(2):93–100.PubMedCrossRef
35.
Simpson GM, Cooper TA. Clozapine plasma concentrations and convulsions. Am J Psychiatry. 1978;135:99–100.PubMedCrossRef
36.
Funderburg LG, Vertrees JE, True JE, Miller AL. Seizure following addition of erythromycin to clozapine treatment. Am J Psychiatry. 1994;151(12):1840–1.PubMed
37.
38.
Hiemke C, Baumann P, Bergemann N, Conca A, Dietmaier O, Egberts K, Fric M, Gerlach M, Greiner C, Grunder G, Haen E, Havemann-Reinecke U, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44(6):195–235. doi:10.​1055/​s-0031-1286287.CrossRef
39.
Greenwood-Smith C, Lubman DI, Castle DJ. Serum clozapine levels: a review of their clinical utility. J Psychopharmacol. 2003;17(2):234–8.PubMedCrossRef
40.
Remington G, Agid O, Foussias G, Ferguson L, McDonald K, Powell V. Clozapine and therapeutic drug monitoring: is there sufficient evidence for an upper threshold. Psychopharmacology (Berl). 2013;225(3):505–18. doi:10.​1007/​s00213-012-2922-7.PubMedCrossRef
41.
Haring C, Neudorfer C, Schwitzer J, Hummer M, Saria A, Hinterhuber H, Fleischhacker WW. EEG alterations in patients treated with clozapine in relation to plasma levels. Psychopharmacology (Berl). 1994;114(1):97–100.PubMedCrossRef
42.
43.
44.
45.
Haberfellner EM. Myoclonic and generalized tonic-clonic seizures during combined treatment with low doses of clozapine and haloperidol. Eur Psychiatry. 2002;17(1):55–6.PubMedCrossRef
46.
Garcia G, Crismon ML, Dorson PG. Seizures in two patients after the addition of lithium to a clozapine regimen. J Clin Psychopharmacol. 1994;14(6):426–8.PubMed
47.
Raaska K, Neuvonen PJ. Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia. Eur J Clin Pharmacol. 2000;56(8):585–9.PubMedCrossRef
48.
DuMortier G, Lochu A, Colen de Melo P, Ghribi O, Roche-Rabreau D, DeGrassat K, Desce JM. Elevated clozapine plasma concentrations after fluvoxamine initiation. Am J Psychiatry. 1996;153(5):738–9.PubMed
49.
50.
de Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr Res. 2005;76(2–3):135–57.PubMedCrossRef
51.
Meyer JM. Individual changes in clozapine levels after smoking cessation: results and a predictive model. J Clin Psychopharmacol. 2001;21(6):569–74.PubMedCrossRef
52.
McCarthy RH. Seizures following smoking cessation in a clozapine responder. Pharmacopsychiatry. 1994;27(5):210–1.PubMedCrossRef
53.
Kando JC, Tohen M, Castillo J, Centorrino F. Concurrent use of clozapine and valproate in affective and psychotic disorders. J Clin Psychiatry. 1994;55(6):255–7.PubMed
54.
Almeida J, Serrão EM, Almeida AT, Afonso JG. Effective treatment with clozapine and valproate for refractory schizophrenia-like psychosis after cerebellar hemorrhage. Clin Neuropharmacol. 2011;34(3):131–2.PubMedCrossRef
55.
Meltzer HY, Ranjan R. Valproic acid treatment of clozapine-induced myoclonus. Am J Psychiatry. 1994;151(8):1246–7.PubMed
56.
Guha P, Nizamie HS. Refractory schizophrenia, clozapine and epilepsy: management strategies. Indian J Psychiatry. 1998;40(1):84–6.PubMedCentralPubMed
57.
Foster R, Olajide D. A case of clozapine-induced tonic-clonic seizures managed with valproate: implications for clinical care. J Psychopharmacol. 2005;19(1):93–6.PubMedCrossRef
58.
59.
Wirshing WC, Ames D, Bisheff S, Pierre JM, Mendoza A, Sun A. Hepatic encephalopathy associated with combined clozapine and divalproex sodium treatment. J Clin Psychopharmacol. 1997;17(2):120–1.PubMedCrossRef
60.
Madeb R, Hirschmann S, Kurs R, Turkie A, Modai I. Combined clozapine and valproic acid treatment-induced agranulocytosis. Eur Psychiatry. 2002;17(4):238–9.PubMedCrossRef
61.
Muzyk A, Gala G, Kahn DA. Use of lamotrigine in a patient with a clozapine-related seizure. J Psychiatr Pract. 2010;16(2):125–8.PubMedCrossRef
62.
Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res. 2012;141(2–3):173–8.PubMedCrossRef
63.
64.
Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry. 2000;45(2):198.PubMed
65.
Navarro V, Pons A, Romero A, Bernardo M. Topiramate for clozapine-induced seizures. Am J Psychiatry. 2001;158(6):968–9.PubMedCrossRef
66.
Jerling M, Lindström L, Bondesson U, Bertilsson L. Fluvoxamine inhibition and carbamazepine induction of the metabolism of clozapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit. 1994;16(4):368–74.PubMedCrossRef
67.
Logothetis J. Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine therapy. Neurology. 1967;17(9):869–77.PubMedCrossRef
68.
Pisani F, Oteri G, Costa C, Di Raimondo G, Di Perri R. Effects of psychotropic drugs on seizure threshold. Drug Saf. 2002;25(2):91–110.PubMedCrossRef
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
Metadata
Title
Seizure Associated with Clozapine: Incidence, Etiology, and Management
Authors
Andrew M. Williams
Susie H. Park
Publication date
01-02-2015
Publisher
Springer International Publishing
Published in
CNS Drugs / Issue 2/2015
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI
https://doi.org/10.1007/s40263-014-0222-y

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