Jefferson Journal of Psychiatry

Volume 11 Issue 1 Article 8

January 1993

Clozapine-Induced Seizures and EEG Changes: A Case Report and Discussion of Clinical Management

Jeffrey Daly, M.D. Butler Hospital, Rhode Island, Providence

Stephen Salloway, M.D., M.S. Butler Hospital, Rhode Island, Providence

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Recommended Citation Daly, M.D., Jeffrey and Salloway, M.D., M.S., Stephen (1993) "Clozapine-Induced Seizures and EEG Changes: A Case Report and Discussion of Clinical Management," Jefferson Journal of Psychiatry: Vol. 11 : Iss. 1 , Article 8. DOI: https://doi.org/10.29046/JJP.011.1.011 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol11/iss1/8

This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Jefferson Journal of Psychiatry by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Clozapine-Induced Seizures and EEG Chanses A Case Report and DIscussion ofClinical Management

Jeffrey Daly M.D. Stephen Salloway M.D., M.S.

Abstract

Clorapine is an atypical antipsychotic agent associated with a higherfrequency ofseizures than standard neuroleptics. In addition, clozapinecauses epileptiform abnormalities in the EEG in up to 72% qfpatients. A patient who developed a generalized seizure shortly after beginning clozapine treatment and the patient's EEG fi ndings are presented. The neuropharmacology qf dozapine and the management ofcioeapine-induced seizures and EEG abnormalities are discussed.

C lozapine (C lozaril) is a unique antipsychotic whi ch has been shown to be effec tive in th e treatment of refract ory schizo phe nia ( 1,2). Compa red with standard neuroleptics clozapine has minimal ext ra pyra midal side effects a nd poses a low risk for tardive dyskinesia (1,3,4,5,6). Develop ed in 1960, clozapine was delayed from earl ier wid esp read use by its side effec t profile. The most dangerous of th e com mo n side effects is agranulocytosis , which has been re po rted in I% to 2% of cas es (7). Other adverse effects include hypotension, fatigue, drug fever, pharmacogenic delirium, tachycardia, a nd seizures . Associated seizu re s have be en found in 4% of U.S . cases (7) compa red to I% to 2% in standard neuroleptics (8) . Data from th e manufacturer, Sandoz, indicat es tha t these seizures are dos e dependent with patients treated with 600 to 900 mg/day having a seizu re fr equency of 5%; those treated with 300 to 599 mg/day, 3-4%; a nd those patients treated with less than 300 mg/day having a se izu re frequency of 1- 2% (9). A similar dos e depen den t frequ ency was found by Devinsky et aI, who also suggest that rapid upward titration ofcloz apine may incr ease se izu re risk ( 10). EEG abnormaliti es have been not ed in 72% of patients on clozapine (II). T he EEG typicall y shows slow waves a nd paroxysmal disch a rg es whi ch may ap pear to be epileptifor m. As clozapine use incr eases, th e issue of how to man age clozapine­ induced seizures and EEG changes becomes a n important clinical pro blem . In this report we present th e case of a patient who had a seizu re while on a low do se of clozapine and an abnormal EEG wh ich persisted for weeks after her last seizure. This is follow ed by a discu ssion of th e unique pr op erties of clozapine which

36 CLOZAPINE-INDUCE D SEIZURES AND EEG CHANGES 37

may cont ribute to it s incr eased seizure fr equen cy, it s effect on EEG's, and a review of curre nt guide lines in th e clinical man agement ofclozapine-induced seizures.

CASE REPORT

Ms. B. is a 64 year old white femal e, gro up home resident, with no medi cal pr obl ems who has a 40 year hist ory of chro nic undifferentiat ed sch izophreni a. Her psych osis and disorganized beh avior had been re fractory to electroconvu lsive th erapy a nd trials of multiple neuroleptics. The patient was most recently on haloperidol and lithium when she develop ed a seve re dyst oni c reacti on. These medications were discontinued and treatment with cloza pine was initiated as a n outpatient. An initial dose of 25 mg/day was incr eased 25 mg eve ry two days. O n day 14 of clozapine treatment, a t a dos e of 175 mg/day, the patient had a witnessed gen eralized tonic-clonic seizu re. At this time she fell to th e floor , had clonic move ments of all extre mities lasting approximately two minutes th en became flaccid an d unresponsive for a nothe r two minutes. Upon regaining consc ious ness she ex pe rie nced a one hour period of confusion and disorientation . The patient had no histo ry of seizures, head trauma , or subst a nce abuse . She had no known me dical condi tio ns or recent med ication cha nges other th en starting cloza pine which put her a t increased risk for a se izure. TO additional ge neralized se izures were noted. The group home treatment tea m did not seek immedi at e medi cal cons ultatio n a nd contin ued cloz apine treat ­ ment a t a dose of 175 mg/day. Her beh avior remained disorganized for seven days after th e seizu re and she was admitted to the psychi atric hospital for evalua tion of he r prolon ged change in mental status. Ne uro logic ex a m revealed psych omotor re tardation and confusion without focal se nso ry or mot or findings a nd th e remai nd er of the ph ysical exam was unremarkabl e. Met abolic, toxicology, endoc rine, infecti ou s a nd hema tological screens as well as a head CT we re unremarkabl e. Ini tial EEG obtaine d nine days after th e witnessed se izure, with th e patient still on clozapine, showed bet a rhythms in the background secondary to treatment with benzodiazepines a nd bri ef runs of diffuse high voltage slow a nd sharp wave paroxysm al disch arges as shown in Figure I. Du e to conce rn about her prolon ged ence pha lopa thy clozapine was discontinued and th e patient was sta r te d on ca rba mazepine. The a uthors were called in for neurological consultation a t this time. Follow-up EEG 15 days after sto pping th e clozapine showed resolution of epile ptifor m activity.

DISCUSSION

Dopamine Receptors and ClozapineAction

A great deal of information abo ut dop amine receptor subtypes has recently become ava ilable whi ch sho uld she d light on clozapine's a ntipsychotic and proconvul­ sa nt effec ts. Dop amine recepto rs are glycopro te in molecul es, locat ed on pr e-synaptic a nd post-synaptic membra nes a nd found primarily in th e st ria tum, cortex and limbic 38 JEFFERSON J OURNAL OF PSYCHIATRY

FIGURE 1. reveals beta rhythms in the background and fr equen t pa roxysmal bursts of slow and sh ar p wave discharges. syste m . Until recently, dopamine receptors have been ca tegorize d int o D 1 and D2 subtypes. D 1 receptors are the most abundant dopaminergic receptors in the human brain. They are found in both striatal and cortico-limbic a reas, and they activat e ade nyla te cyclase and cyclic AMP. D2 recepto rs are found in greatest concen tration in th e stria tum and were t ho ug ht to inhibit cyclic AMP. Ne uro leptic potency has been rated by th e dose required to antagonize th e D2 receptor. Advances in molecular CLOZAPINE-INDUCED SEIZURES AND EEG CHANGES 39 biology have led to the cloning ofgenes for 2 types of D, a nd D2receptors ( 12,13) and th e dis covery of D3 , D4 and D, re ceptors (14 ,15) . The D3_S receptor s a ppear to be localized primarily outside th e striatum in cor tica l and limbic region s. The me chanism of clozapine's clinical antipsychotic efficacy has prompted a great deal of investigation. The neuropharmacology of clozapine was rec ently re­ viewed by Baldessarini and Frankenberg (16) and Meltzer (17). C loza pine is a weak antagonist a t th e dopamine D 1 and D2 rec eptors and moderat e an tagonist of 5HT2, 5HT3, alpha I, alpha 2 and bet a-adren ergic receptors and exhibits a ntic ho linergic and antihistiminic properties. Recent work ha s pointed to D4 and D3 a ntagonism as th e possible medi ator of th e antipsychotic ac tivity ofclozapine (14,15). Ne urophysio­ logi c studies ofclozapine indicate a pr eferential effec t on th e A I0 neu ron s pr ojecting to limbic areas and minimal affect on th e A9 neurons pr ojecting in to th e bas al ganglia (18). The D4 receptor appears to be loca ted primarily outside the striatum which could explain clozapine's lack ofsignificant extra pyramida l effects .

Dopamine and Seiz ures

H ow dopamine antagonists induce seizures is not well underst ood . Some eVI­ dence points to dopamine as a regulator of seizu re acti vit y (19). The specifi c ro le whi ch each dopamine receptor plays has ye t to be fully resolved. Loscher and C zuczwar and Turski et al found that D2 agonist s su ch as L-D op a and th e mixed D b D2 agonist apomorphine had an anticonvulsant effec t whil e D2 antagonists, like clozapine, tend to lower th e seizure threshold (19 ,20,21,22). These da ta suggest that clozapine's blockade of D2 receptors is responsibl e for its associa te d se izu res but th is do es not explain th e incr eased preval en ce of clozapine relat ed seizures compared to st andard neuroleptics. Burke e t al demonstrated th e opposite effect with D, receptor com pounds (19) . In his study in mi ce, D, agonists lower th e seizu re threshold to pilocarpine and picrotoxin and D 1 antagonists ex erted a protecti ve effect against seizures. An additional mechanism is suggest ed by Giardino et al who reported a de cr ease in benzodiazepine re ceptor density in rat corte x afte r chro nic clozapine administration (23), raising th e possibility that clozapine could alter t he seizure threshold throughits effec ts on GABA- ergic syst ems.

EEG Changes Du ring Cloeapine Treatment

The patient described in this report had epil eptiform disch arges on her EEG following administration of clozapine. Re cent studies su ggest th at most patients receiving clozapine have abnormal EEGs (11 ,24,2 5) . These changes have been reported to be dos e related (26) but cha nges have been noted afte r a sin gle dose (27) . Tiihonen et al found that 16 of 16 subjects studied had profound disturban ces of background activity and also paroxysms consisting of delt a a nd th et a waves, seven patients had paroxysms which were classified as epileptiform, consisting of spikes, polyspikes , or spikes and slow wave complexes (24) . These findings corre la te with an ea rlie r study by Isermann and Haupt who found 26 of 36 subjects st udied had 40 JEFFERSON JOURNAL OF PSYCHIATRY abnormal EEGs after beginning clozapine (II). Fifteen had paroxysm al episodes of generalized slowing and 8 had epileptiform dis charges. Koukkou also suggest ed tha t clozapine-induced EEG cha nges a re associated with a better respon se to clozapine than those patients whose EEGs remain normal (25).

Management ofClozapine-Induced S eizures

We present this case since th e management of this patient bro ught out a number of important points concerning clozapine-induced seizures. The group home treatment team was unfamiliar with th e management of cloz apine-indu ced seizures as evide nced by th e continuation of the clozapine a t th e sam e do se afte r the seizure and the seven day delay in obtaining a medical evalua tion. Several recent papers comment on the management of cloza pine-r elat ed sei­ zures (7, 10,16,28,29,30) . Prevention ofseizures ca n be enha nced by: I) no t exceeding dos es of 600 mg/day; 2) slowly increasing daily dos es; and 3) avoidi ng concomitant use of other medications whi ch also lower th e seizure threshold. For exa mple, lithium, neuroleptics and tricyclic antidepressants ca n lower th e seizure th reshold. It is not known if pre-existing subclinical EEG abnor malities incr ease a patient's risk for seizures while on clozapine but at pr esent, we do not recommend a n EEG for all patients prior to beginning cloz apine treatment. Patients with a hist ory ofseizu res and/or confusional sta tes should have a ba seline EEG before starting clozapine. An EEG should also be performed on patients who have a cha nge in ment al status or seizure while on cloz apine. In th e case described this ste p should have been taken immediately after th e patient had the seizure. Subclinical EEG changes in the abse nce of associated clinical findi ngs do not necessarily require a n alteration in clozapine treatment. Cl ozapine-relat ed se izures are not a n absolute indication for discontinuation of th erapy bu t cer tain ste ps, which were not follow ed in th e cas e described , should be taken immediat ely after suc h an eve nt. Other possible causes of seizure should be investigated . This work-up sho uld include EEG, head CT, laboratory evalua tion and possibl y a neurological consulta­ tion. Following a seizure, clozapine should be held until th e patient's mental state returns to baseline and th en th e daily dos e of cloz apine should be reduced . Lieber­ man et al suggest a 50% reduction in th e daily dos e (7). The manufacturer sta te s t ha t 31 of th e 41 cases in whi ch seizures developed remained on cloz apine despite seizures. Less than 5% have had a second seizure with simultaneou s treatment with valpro ic acid (data on file, Sandoz Pharmaceuticals, 1991) . In th e case pr esented clozapine had not yet demonstrated an antipsychotic effect and th e treatment team decided to dis continue her cloz apine and use ca rba maze pine tempor arily to stabilize her mental state. A lack of consensus exists conce r ning th e concomita nt use of anticonvulsa nts after a clozapine-induced seizure. If a clinician decid es to use a n a nticonvulsant, valproic acid is th e drug of choice as ph en ytoin may ca use a decr ease in clozapine plasma levels (31) and ca rba mazepine should be avoide d du e to th e possibility of depress ed granulocyte production. One death has been rep orted in a pa tien t on CLOZAPINE-INDUCE D SEIZURES AND EEG CHANGES 4\ combine d treatment of clozapine and carba maze pine (data on file, Sand oz Ph arma­ ce utica ls, 1991) . Kane suggests th at th ere may be as many as 100,000 to 200,000 schizophrenics resist ant to sta ndard neuroleptics in th e U.S. ( I) . C urrently there are approximately 23,000 individuals in th e U.S. being trea ted with clozapine. The use of clozapine will certainly incr ease in th e 1990's. We believe thi s pap er addresses th e important need for clinicians to continue to further th eir underst anding of clozap ine and th e management of its side effects such as seizu res and EEG changes.

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