title: Clozapine-related EEG changes and seizures: dose and plasma-level relationships.
abstract: Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Seizures are more common during the initiation phase of clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the clozapine plasma level exceeds 500 μg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of clozapine-induced seizures are valproate (particularly where there is mood disturbance) and lamotrigine (where there is resistance to clozapine).
authors: Pharmacy Department, Maudsley Hospital, London SE5 8AZ, UK.
authors: Seema
authors: S
authors: Varma
authors: Delia
authors: D
authors: Bishara
authors: Frank M C
authors: FM
authors: Besag
authors: David
authors: D
authors: Taylor
keywords: antiepileptic; clozapine; seizure; valproate
references: J Clin Psychiatry. 1994 Sep;55 Suppl B:153-6
references: 7961562
references: Neurology. 2004 Aug 10;63(3):571-3
references: 15304599
references: Aust N Z J Psychiatry. 2005 Mar;39(3):202
references: 15701074
references: J Clin Psychiatry. 1994 May;55(5):184-8
references: 8071267
references: Aust N Z J Psychiatry. 2001 Aug;35(4):544-5
references: 11531743
references: Ther Drug Monit. 1999 Jun;21(3):341-5
references: 10365650
references: Am J Psychiatry. 2001 Jun;158(6):968-9
references: 11384919
references: Arch Gen Psychiatry. 2003 Apr;60(4):392-400
references: 12695317
references: Neurology. 1994 Dec;44(12):2247-9
references: 7991106
references: Am J Psychiatry. 1994 Jan;151(1):123-5
references: 8267110
references: Ann Pharmacother. 1998 Nov;32(11):1147-51
references: 9825078
references: Neurology. 2008 May 27;70(22 Pt 2):2152-8
references: 18448870
references: J Clin Psychiatry. 1999 Jun;60(6):408-9
references: 10401922
references: Schizophr Res. 2009 Apr;109(1-3):10-4
references: 19186030
references: Can J Psychiatry. 2007 Jul;52(7):457-63
references: 17688010
references: J Psychosoc Nurs Ment Health Serv. 1995 Feb;33(2):42-3
references: 7769576
references: Can J Psychiatry. 1994 May;39(4):236-8
references: 8044732
references: Br J Psychiatry. 2009 Feb;194(2):165-7
references: 19182180
references: Am J Psychiatry. 1994 Jul;151(7):1096
references: 8010372
references: J Emerg Med. 2008 Nov;35(4):407-9
references: 17961958
references: Pharmacopsychiatry. 1993 May;26(3):69-74
references: 8415896
references: Am J Psychiatry. 1990 Aug;147(8):1069-71
references: 2375443
references: Pharmacopsychiatry. 2000 Nov;33(6):234-5
references: 11147932
references: Psychopharmacology (Berl). 1994 Feb;114(1):97-100
references: 7846212
references: Am J Psychiatry. 1991 Oct;148(10):1406
references: 1897630
references: Neurology. 2005 Mar 22;64(6):955-60
references: 15781807
references: Am J Psychiatry. 1994 Aug;151(8):1246-7
references: 8080553
references: Hosp Community Psychiatry. 1992 Jul;43(7):700-3
references: 1516900
references: J Neuropsychiatry Clin Neurosci. 1995 Fall;7(4):466-70
references: 8555749
references: Neurology. 1991 Mar;41(3):369-71
references: 2006003
references: J Neuropsychiatry Clin Neurosci. 2001 Spring;13(2):302-3
references: 11449038
references: Am J Psychiatry. 1978 Jan;135(1):99-100
references: 412427
references: J Neuropsychiatry Clin Neurosci. 1992 Fall;4(4):454-7
references: 1422175
references: Am J Psychiatry. 2000 Mar;157(3):482-3
references: 10698845
references: Am J Psychiatry. 1991 Sep;148(9):1265-6
references: 1883011
references: Psychopharmacol Bull. 1988;24(1):62-7
references: 3290950
references: Am J Psychiatry. 1993 Jul;150(7):1128
references: 8317593
references: Arch Gen Psychiatry. 1999 Oct;56(10):950
references: 10530638
references: J Psychopharmacol. 2003 Jun;17(2):234-8
references: 12870573
references: Hum Psychopharmacol. 2002 Mar;17(2):115-9
references: 12404701
references: Psychiatry Res. 1992 Nov;44(2):107-12
references: 1480676
references: J Clin Psychiatry. 2003 Oct;64(10):1267-8
references: 14658980
references: Pharmacopsychiatry. 1994 Sep;27(5):210-1
references: 7838893
references: Psychiatr Q. 1992 Spring;63(1):51-70
references: 1438605
references: Ir J Psychol Med. 2007 Sep;24(3):121
references: 30290494
references: Br J Psychiatry. 2009 Jan;194(1):4-9
references: 19118318
references: Am J Electroneurodiagnostic Technol. 2007 Sep;47(3):190-7
references: 17982847
references: J Clin Psychiatry. 2007 Jul;68(7):1027-30
references: 17685738
references: Am J Psychiatry. 2002 Feb;159(2):315
references: 11823281
references: Am J Psychiatry. 1999 Oct;156(10):1663-4
references: 10518185
references: Pharmacopsychiatry. 2000 May;33(3):109-11
references: 10855462
references: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jan;26(1):139-44
references: 11853104
references: J Clin Psychiatry. 2000;61 Suppl 8:14-7; discussion 18-9
references: 10811238
references: Electroencephalogr Clin Neurophysiol. 1994 Sep;91(3):205-11
references: 7522149
references: Ther Drug Monit. 1994 Aug;16(4):368-74
references: 7974626
references: Am J Psychiatry. 2002 Apr;159(4):675
references: 11925318
references: J Clin Psychopharmacol. 2010 Aug;30(4):437-40
references: 20531222
references: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Apr;26(3):473-80
references: 11999897
references: Eur Arch Psychiatry Clin Neurosci. 1991;240(6):370-2
references: 1831670
references: J Clin Psychiatry. 1994 Jun;55(6):255-7
references: 8071281
references: Psychopharmacology (Berl). 1995 Feb;117(3):371-8
references: 7770613
references: Neurology. 2006 Dec 26;67(12 Suppl 4):S39-44
references: 17190921
references: Psychopharmacol Bull. 1996;32(2):253-7
references: 8783895
references: Am J Psychiatry. 1995 Apr;152(4):650
references: 7694927
references: J Clin Psychiatry. 1989 Mar;50 Suppl:23-9
references: 2494155
references: Int Clin Psychopharmacol. 1998 May;13(3):141-5
references: 9690983
references: Biol Psychiatry. 1997 Jul 15;42(2):132-7
references: 9209730
references: CNS Drugs. 2007;21(11):911-36
references: 17927296
references: J Psychopharmacol. 2005 Jan;19(1):93-6
references: 15671134
references: Eur Neuropsychopharmacol. 1996 May;6(2):93-4
references: 8791033
references: Am J Psychiatry. 1994 Dec;151(12):1840-1
references: 7977898
references: Can J Psychiatry. 1998 May;43(4):420
references: 9598281
references: Int J Psychiatry Clin Pract. 1998;2(1):53-5
references: 24946248
references: Clin Neuropharmacol. 1996 Feb;19(1):81-6
references: 8867521
references: J Psychiatr Pract. 2010 Mar;16(2):125-8
references: 20511737
references: Eur Psychiatry. 2002 Mar;17(1):55-6
references: 11918994
references: Int Clin Psychopharmacol. 2005 May;20(3):163-8
references: 15812267
references: Biol Psychiatry. 1994 Dec 1;36(11):759-62
references: 7858072
references: Can J Psychiatry. 2000 Mar;45(2):198
references: 10742883
references: Am J Psychiatry. 2001 Nov;158(11):1930-1
references: 11691708
references: Can J Psychiatry. 2002 Dec;47(10):975-6
references: 12553139
references: Am J Psychiatry. 1999 Jul;156(7):990-9
references: 10401441
references: Int J Psychiatry Clin Pract. 1999;3(4):249-51
references: 24921227
references: Biol Psychiatry. 1996 Mar 1;39(5):367-70
references: 8704069
references: J Clin Psychiatry. 1992 Sep;53(9):329-30
references: 1517198
references: Clin Neuropharmacol. 2006 Jan-Feb;29(1):34-44
references: 16518133
references: J Clin Psychiatry. 1991 Jan;52(1):23-5
references: 1988414
references: Ann Clin Psychiatry. 2003 Mar;15(1):33-48
references: 12839431
references: J Neuropsychiatry Clin Neurosci. 1994 Summer;6(3):250-6
references: 7950347