Evidence-Based Reviews

Antipsychotics and seizures: What are the risks?

Current Psychiatry. 2019 March;18(3):21-22,24,26-33

References

1. Bruijnzeel D, Suryadevara U, Tandon R. Antipsychotic treatment of schizophrenia: an update. Asian J Psychiatr. 2014;11:3-7.
2. Hrdlicka M, Dudova I. Atypical antipsychotics in the treatment of early-onset schizophrenia. Neuropsychiatr Dis Treat. 2015;11:907-913.
3. Koch-Stoecker S. Antipsychotic drugs and epilepsy: indications and treatment guidelines. Epilepsia. 2002;43(suppl 2):19-24.
4. Alper K, Schwartz KA, Kolts RL, et al. Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biol Psychiatry. 2007;62(4):345-354.
5. Torta R, Keller R. Behavioral, psychotic, and anxiety disorders in epilepsy: etiology, clinical features, and therapeutic implications. Epilepsia. 1999;40(suppl 10):S2-S20.
6. Kumlien E, Lundberg PO. Seizure risk associated with neuroactive drugs: data from the WHO adverse drug reactions database. Seizure. 2010;19(2):69-73.
7. Lertxundi U, Hernandez R, Medrano J, et al. Antipsychotics and seizures: higher risk with atypicals? Seizure. 2013;22(2):141-143.
8. Bloechliger M, Rüegg S, Jick SS, et al. Antipsychotic drug use and the risk of seizures: follow-up study with a nested case-control analysis. CNS Drugs. 2015;29(7):591-603.
9. Wu CS, Wang SC, Yeh IJ, et al. Comparative risk of seizure with use of first- and second-generation antipsychotics in patients with schizophrenia and mood disorders. J Clin Psychiatry. 2016;77(5):e573-e579.
10. Cold JA, Wells BG, Froemming JH. Seizure activity associated with antipsychotic therapy. [Erratum in DICP. 1990;24(10):1012.] DICP. 1990;24(6):601-606.
11. Hedges DW, Jeppson KG. New-onset seizure associated with quetiapine and olanzapine. Ann Pharmacother. 2002;36(3):437-439.
12. Dogu O, Sevim S, Kaleagasi HS. Seizures associated with quetiapine treatment. Ann Pharmacother. 2003;37(9):1224-1227.
13. Young AC, Kleinschmidt KC, Wax PM. Late-onset seizures associated with quetiapine poisoning. J Med Toxicol. 2009;5(1):24-26.
14. US Food and Drug Administration. Recommendation of approvable action for quetiapine fumarate extended release (Seroquel® XR) for the treatment of schizophrenia. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022047Orig1s000MedR.pdf. April 24, 2007. Accessed January 28, 2019.
15. Malik AR, Ravasia S. Aripiprazole-induced seizure. Can J Psychiatry. 2005;50(3):186.
16. Tsai JF. Aripiprazole-associated seizure. J Clin Psychiatry. 2006;67(6):995-996.
17. Arora M, Arndorfer L. EEG abnormalities in a patient taking aripiprazole. Psychiatry (Edgmont). 2007;4(7):18-19.
18. Yueh CL, Yu SL, Chen HM, et al. Aripiprazole-induced seizure: a second case report. BMJ case reports. 2009;2009:bcr03.2009.1693. doi: 10.1136/bcr.03.2009.1693.
19. Thabet FI, Sweis RT, Joseph SA. Aripiprazole-induced seizure in a 3-year-old child: a case report and literature review. Clin Neuropharmacol. 2013;36(1):29-30.
20. US Food and Drug Administration. Abilify (Aripiprazole) tablets. Medical Review Part 2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-436_Abilify_medr_P2.pdf. Published March 07, 2003. Accessed January 28, 2019.
21. US Food and Drug Administration. Drugs@FDA: FDA approved drug products. Risperdal tablets, Risperdal oral solution & Risperdal M-tab orally disintegrating tablets. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2003/021444_S004_RISPERDAL_TABLETS.pdf. Published September 10, 2003. Accessed January 28, 2019.
22. Gonzalez-Heydrich J, Pandina GJ, Fleisher CA, et al. No seizure exacerbation from risperidone in youth with comorbid epilepsy and psychiatric disorders: a case series. J Child Adolesc Psychopharmacol. 2004;14(2):295-310.
23. Holzhausen SPF, Guerreiro MM, Baccin CE, et al. Use of risperidone in children with epilepsy. Epilepsy Behav. 2007;10(3):412-416.
24. Lane HY, Chang WH, Chou JC. Seizure during risperidone treatment in an elderly woman treated with concomitant medications. J Clinl Psychiatry. 1998;59(2):81-82.
25. Komossa K, Rummel-Kluge C, Schwarz S, et al. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2011;(1):19:CD006626.
26. Paliperidone [package insert]. Mountainville, CA: Janssen Pharmaceuticals, Inc.; 2007.
27. Brugge, MD; US Food and Drug Administration. Paliperidone OROS oral formulation. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/021999s000_MedR_Part4.pdf. Accessed January 28, 2019.
28. Schneider RA, Lizer MH. Apparent seizure and atrial fibrillation associated with paliperidone. Am J Health System Pharm. 2008;65(22):2122-2125.
29. Liang CS, Yang FW, Chiang KT. Paliperidone-associated seizure after discontinuation of sodium valproate: a case report. J Clin Psychopharmacol. 2011;31(2):246-247.
30. Fulton B, Goa KL. Olanzapine. A review of its pharmacological properties and therapeutic efficacy in the management of schizophrenia and related psychoses. Drugs. 1997;53(2):281-298.
31. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: Zyprexa (olanzapine). ORIG-1. http://www.accessdata.fda.gov/drugsatfda_docs/nda/96/020592_Original_Approval_Pkg%20.pdf. Published September 30, 1996. Accessed January 28, 2019.
32. Anzellotti F, Capasso M, Frazzini V, et al. Olanzapine-related repetitive focal seizures with lingual dystonia. Epileptic Disord. 2016;18(1):83-86.
33. Lee JW, Crismon ML, Dorson PG. Seizure associated with olanzapine. Ann Pharmac. 1999;33(5):554-556.
34. Woolley J, Smith S. Lowered seizure threshold on olanzapine. Br J Psychiatry. 2001;178(1):85-86.
35. Behere RV, Anjith D, Rao NP, et al. Olanzapine-induced clinical seizure: a case report. Clin Neuropharmacol. 2009;32(5):297-298.
36. Camacho A, García-Navarro M, Martínez B, et al. Olanzapine-induced myoclonic status. Clin Neuropharmacol. 2005;28(3):145-147.
37. Rosen JB, Milstein MJ, Haut SR. Olanzapine-associated myoclonus. Epilepsy Res. 2012;98(2-3):247-250.
38. Wyderski RJ, Starrett WG, Abou-Saif A. Fatal status epilepticus associated with olanzapine therapy. Ann Pharmacother. 1999;33(7-8):787-789.
39. Spyridi S, Sokolaki S, Nimatoudis J, et al. Status epilepticus in a patient treated with olanzapine and mirtazapine. Int J Clin Pharmacol Ther. 2009;47(2):120-123.
40. Schatzberg AF, Nemeroff CB. Essentials of clinical psychopharmacology. 2nd ed. Arlington, Virginia: American Psychiatric Publishing; 2006.
41. US Food and Drug Administration. Drug approval package: Geodon (Ziprasidone HCI) Capsules. Medical Review Part 2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2001/20-825_Geodan_medr_P2.pdf. Published February 5, 2001. Accessed January 29, 2019.
42. Clozaril [package insert]. East Hanover, NJ: Novartis; 2008.
43. Devinsky O, Pacia SV. Seizures during clozapine therapy. J Clin Psychiatry. 1994;55(suppl B):153-156.
44. Williams AM, Park SH. Seizure associated with clozapine: incidence, etiology, and management. CNS Drugs. 2015;29(2):101-111.
45. Wong J, Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry. 2007;52(7):457-463.
46. Berman I, Zalma A, DuRand CJ, et al. Clozapine-induced myoclonic jerks and drop attacks. J Clin Psychiatry. 1992;53(9):329-330.
47. Gouzoulis E, Ozdaglar A, Kasper J. Myoclonic seizures followed by grand mal seizures during clozapine treatment. Am J Psychiatry. 1993;150(7):1128.
48. Sajatovic M, Meltzer HY. Clozapine-induced myoclonus and generalized seizures. Biol Psychiatry. 1996;39(5):367-370.
49. Grover S, Hazari N, Chakrabarti S, et al. Association of clozapine with seizures: a brief report involving 222 patients prescribed clozapine. East Asian Arch Psychiatry. 2015;25(2):73-78.
50. Byerly MJ, DeVane CL. Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol. 1996;16(2):177-187.
51. Caetano D. Use of anticonvulsants as prophylaxis for seizures in patients on clozapine. Australas Psychiatry. 2014;22(1):78-83.
52. Perry PJ, Bever KA, Arndt S, et al. Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram. Biol Psychiatry.1998;44(8):733-738.
53. Dumortier G, Mahé V, Pons D, et al. Clonic seizure associated with high clozapine plasma level. J Neuropsychiatry Clin Neurosci. 2001;13(2):302-303.
54. Funderburg LG, Vertrees JE, True JE, et al. Seizure following addition of erythromycin to clozapine treatment. Am J Psychiatry. 1994;151(12):1840-1841.
55. Varma S, Bishara D, Besag FMC, et al. Clozapine-related EEG changes and seizures: dose and plasma-level relationships. Ther Adv Psychopharmacol. 2011;1(2):47-66.
56. Amann BL, Pogarell O, Mergl R, et al. EEG abnormalities associated with antipsychotics: a comparison of quetiapine, olanzapine, haloperidol and healthy subjects. Hum Psychopharmacol. 2003;18(8):641-646.
57. Pisani F, Oteri G, Costa C, et al. Effects of psychotropic drugs on seizure threshold. Drug Saf. 2002;25(2):91-110.
58. Maurice T, Phan VL, Urani A, et al. Neuroactive neurosteroids as endogenous effectors for the sigma1 (sigma1) receptor: pharmacological evidence and therapeutic opportunities. Jpn J Pharmacol. 1999;81(2):125-155.
59. Haller E, Binder RL. Clozapine and seizures. Am J Psychiatry. 1990;147(8):1069-1071.
60. Torta R, Monaco F. Atypical antipsychotics and serotoninergic antidepressants in patients with epilepsy: pharmacodynamic considerations. Epilepsia. 2002;43(suppl 2):8-13.
61. Spina E. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr, eds. The treatment of epilepsy. 3rd ed. Oxford, UK: Blackwell Publishing; 2009:361-377.
62. Spina E, Perucca E. Clinical significance of pharmacokinetic interactions between antiepileptic and psychotropic drugs. Epilepsia. 2002;43(suppl 2):37-44.
63. de Leon J, Santoro V, D’Arrigo C, et al. Interactions between antiepileptics and second-generation antipsychotics. Expert Opin Drug Metab Toxicol. 2012;8(3):311-334.
64. Finley P, Warner D. Potential impact of valproic acid therapy on clozapine disposition. Biol Psychiatry. 1994;36(7):487-488.
65. Longo LP, Salzman C. Valproic acid effects on serum concentrations of clozapine and norclozapine. Am J Psychiatry. 1995;152(4):650.
66. Centorrino F, Baldessarini RJ, Kando J, et al. Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. Am J Psychiatry. 1994;151(1):123-125.
67. Facciolà G, Avenoso A, Scordo MG, et al. Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. Ther Drug Monit. 1999;21(3):341-345.
68. Hyde TM, Weinberger DR. Seizures and schizophrenia. Schizophr Bull. 1997;23(4):611-622.
69. Muzyk A, Gala G, Kahn DA. Use of lamotrigine in a patient with a clozapine-related seizure. J Psychiatr Pract. 2010;16(2):125-128.
70. Kikuchi YS, Sato W, Ataka K, et al. Clozapine-induced seizures, electroencephalography abnormalities, and clinical responses in Japanese patients with schizophrenia. Neuropsychiatr Dis Treat. 2014;10:1973-1978.
71. Taner E, Coşar B, Işik E. Clozapine-induced myoclonic seizures and valproic acid. Int J Psychiatry Clin Pract. 1998;2(1):53-55.
72. 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):107-112.
73. Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neurology. 1991;41(3):369-371.
74. Foster R, Olajide D. A case of clozapine-induced tonic-clonic seizures managed with valproate: implications for clinical care. J Psychopharmacol. 2005;19(1):93-96.
75. Gandelman-Marton R, Theitler J, Klein C, et al. Phenytoin intoxication in a clozapine-related prolonged seizure. J Emerg Med. 2008;35(4):407-409.
76. Primavera A, Giberti L, Scotto P, et al. Nonconvulsive status epilepticus as a cause of confusion in later life: a report of 5 cases. Neuropsychobiology. 1994;30(2-3):148-152.
77. Boutros NN, Arfken C, Galderisi S, et al. The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Schizophrenia Res. 2008;99(1-3):225-237.
78. Takahashi T, Cho RY, Mizuno T, et al. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: a multiscale entropy analysis. Neuroimage. 2010;51(1):173-182.

Although evidence suggests antipsychotics can induce different types of epileptic seizures, the quality of this evidence is low. Randomized controlled trials are needed to determine which antipsychotics increase seizure risk and whether there is a dose-effect relationship.

Bottom Line

Among second-generation antipsychotics, clozapine appears to increase the risk of clinical seizure the most. Correlations with dosage and/or plasma levels have not been proven. Psychiatrists should be vigilant for pharmacokinetic interactions between antipsychotics and antiepileptics, notably via CYP1A2 and CYP3A4.

Related Resources

Druschky K, Bleich S, Grohmann R, et al. Seizure rates under treatment with antipsychotic drugs: Data from the AMSP project. World J Biol Psychiatry. 2018;15:1-10.
Epilepsy Foundation. For professionals: Antipsychotics. https://www.epilepsy.com/learn/professionals/diagnosistreatment/psychotropic-drugs-developmental-disabilities/comorbid-5.

Drug Brand Names

Aripiprazole • Abilify
Benztropine • Cogentin
Bethanechol • Duvoid
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Cimetidine • Tagamet
Ciprofloxacin • Cipro
Citalopram • Celexa
Clonazepam • Klonopin
Clozapine • Clozaril
Donepezil • Aricept
Enalapril • Vasotec
Erythromycin • Erythrocin
Escitalopram • Lexapro
Flunitrazepam • Rohypnol
Fluvoxamine • Luvox
Gabapentin • Neurontin
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Eskalith, Lithobid
Metformin • Fortamet, Glucophage
Mirtazapine • Remeron
Nitrofurantoin • Furadantin
Olanzapine • Zyprexa
Paliperidone • Invega
Phenobarbital • Luminal
Phenytoin • Dilantin
Prochlorperazine • Compazine
Procyclidine • Kemadrin
Propranolol • Inderal
Quetiapine • Seroquel
Risperidone • Risperdal
Sertraline • Zoloft
Simvastatin • Zocor
Sulfamethoxazole/trimethoprim • Bactrim, Sulfatrim
Topiramate • Topamax
Trifluoperazine • Stelazine
Valproic acid • Depakene, Depakote
Ziprasidone • Geodon

References

Antidepressants may be best add-on to antipsychotics in schizophrenia

Antipsychotics and seizures: What are the risks?

References

Bottom Line

Related Resources

Drug Brand Names

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