Clozapine-Induced Seizuresand EEG Chanses

A Case Report and DIscussionof Clinical Management

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

Abstract

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

C lozapine (C lozaril) is a unique ant ipsychotic whi ch has been shown to beeffec t ive in th e treatment of refract ory schizo phe nia ( 1,2). Com pa red with standardneuroleptics clozapine has minimal ext ra pyra midal side effects a nd poses a low riskfor tardive dysk inesia (1,3,4,5,6).

Develop ed in 1960, clozapine was delayed from earl ie r wid esp read use by it s sideeffec t profile. The most dangerous of th e com mo n side effects is agranu locytosis ,which has been re po rted in I% to 2% of cas es (7). Other adverse effects includehypotension, fatigu e, drug fever, pharmacogenic delirium, tachycardia, a nd seizu res .Associat ed se izu re s have be en found in 4% of U.S . cases (7) com pa red to I% to 2% instandard neurolept ics (8) . Data from th e manufacturer, Sandoz, indicat es tha t theseseizures are dos e dependent with patients treated with 600 to 900 mg/day having ase izu re fr equency of 5%; those treated with 300 to 599 mg/day, 3-4%; a nd thosepatients treated with less than 300 mg/day having a se izu re frequency of 1- 2% (9). Asim ilar dos e depen den t frequ ency was found by Devinsky et aI, who also sugges t thatrapid upward titrat ion of cloz apine may incr ease se izu re risk ( 10) .

EEG abnorma liti es have been not ed in 72% of patient s on clozapine (II) . T heEEG typicall y shows slow waves a nd paroxysmal d isch a rg es whi ch may ap pear to beepilep tifor m. As clozapine use incr eases, th e issue of how to man age clozapine­induced seizures and EEG changes becomes a n important clinica l pro blem .

In this report we present th e case of a pat ient who had a se izu re while on a lowdo se of clozapine and an abnormal EEG wh ich persisted for weeks a fter her lastseizure. 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 con t ribu te to it s incr eased seizure fr equen cy, it s effect on EEG's, and a review ofcurre n t guide lines in th e clinical man agement of clozapine-induced seizures .

CASE REPORT

Ms. B. is a 64 year old whit e femal e, gro up home residen t , with no medi calpr obl ems who has a 40 year hist ory of chro nic undi fferent iat ed sch izophreni a. Herpsych osis and disorganized beh avior had been re fractory to electroconvu lsive th erapya nd trials of multiple neuroleptics. The patient was most recently on haloperidol andlithium when she develop ed a seve re dyst oni c reacti on. These medicat ions weredi scontinued and treatment with cloza pine was initiated as a n outpa tient. An initialdose of 25 mg/day was incr eased 25 mg eve ry two days. O n day 14 of clozapinetreatment, a t a dos e of 175 mg/day, the patient had a witnessed gen eralizedtonic-clonic se izu re. At this time she fell to th e floor , had clo nic move ments of allex t re mit ies lasting approximately two minutes th en became flaccid an d unresponsivefor a nothe r two minutes. Upon regaining consc ious ness she ex pe rie nced a one hourperiod of confusion and di sorientation . The patient had no histo ry of seizures , headtrauma , or subst a nce abuse . She had no kn own me dical condi tio ns or recentmed ication cha nges other th en sta r t ing cloza pine which put her a t increased risk fora se izure. TO additional ge neralized se izures were noted. The group hom e treatmenttea m did not seek immedi at e medi cal cons ultatio n a nd cont in ued cloz apine treat ­ment a t a dose of 175 mg/day. Her beh avior remained d isorganized for seven daysafte r th e se izu re and she was admi tted to the psychi atric hospital for evalua t ion ofhe r prolon ged change in ment al status.

Ne uro log ic ex a m reveal ed psych omotor re tarda t ion and confusion without focalse 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 scree ns as well as ahead CT we re unremarkabl e. Ini tial EEG obtaine d nine days after th e witnessedse izu re, with th e patient st ill on clozapine, showed bet a rhythms in the ba ckgroundsecondary to treatment with benzodiazepines a nd bri ef runs of diffuse high voltageslow a nd sharp wave paroxysm al di sch arges as shown in Figure I.

Du e to conce rn abou t her prolon ged ence pha lopa thy clozapine was discontinuedand th e patient was sta r te d on ca rba mazepine. The a u thors were called in forneurological consulta tion a t this tim e. Follow-up EEG 15 days a fter sto pping th eclozapine showed resolution of epile pt ifor m activity.

DISCUSSION

Dopamine Receptors and ClozapineAction

A great deal of information abo u t dop amine receptor subtypes has recent lybecome ava ilable whi ch sho uld she d light on clozapine 's a n tipsychotic and proconvul­sa n t effec ts. Dop amine rece p to rs are glycopro te in molecul es, locat ed on pr e-synaptica nd post-synaptic membra nes a nd found primarily in th e st r ia tum , cortex and limbic

38 JEFFERSON JOURNAL OF PSYCHIATRY

FIGURE 1. reveals beta rhythms in the background and f r equen t pa roxysmal bursts ofslow and s h a r 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 abundan t dopaminergic rece ptors in the humanbrain. They are found in both striatal and cor t ico-lim bic a reas, and they activat eade nyla te cyclase and cyclic AMP. D2 recep to rs are found in greates t concen trat ion inth e st r ia tum and were t ho ug h t to inhibit cyclic AMP. Ne uro lep tic potency has beenrated 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 of genes for 2 typ es of D, a nd D2receptors ( 12,13) andth e dis covery of D3 , D4 and D, re ceptors (14 ,15) . The D3_S receptor s a ppear to belocalized primarily outside th e striatum in cor t ica l and limbic region s.

The me chanism of clozapine's clinical antipsychotic efficacy has prompted agreat deal of investigation. The neuropharmacology of clozapine was rec ently re­viewed by Baldessarini and Frankenberg (16) and Meltzer (17). C loza pine is a weakantagonist a t th e dopamine D 1 and D2 rec eptors and moderat e an tagonist of 5HT2,5H T3, alpha I, alpha 2 and bet a-adren ergic receptors and exhibits a n tic ho linergicand antihistiminic properties . Recent work ha s pointed to D4 and D3 a n tagonism asth e possible medi ator of th e antipsychotic ac t ivity of clozapine (14,15). Ne urophysio­logi c studies of clozapine indicate a pr eferential effec t on th e A I0 neu ron s pr oj ect ingto limbic areas and minimal affect on th e A9 neurons pr ojecting in to th e bas alganglia (18). The D4 receptor appears to be loca ted primarily outside the striatumwhich could explain clozapine 's lack of significant ex t ra pyramida l effec ts .

Dopamine and Seiz ures

H ow dopamine antagonists induce seizures is not well underst ood . Som e eVI­dence points to dopamine as a regulator of se izu re acti vit y (19). The specifi c ro lewhi ch each dopamine receptor plays has ye t to be fully resolved. Loscher andC zuczwar and Turski e t al found that D2 agonist s su ch as L-D op a and th e mixed D bD2 agonist apomorphine had an anticonvulsant effec t whil e D2 an tagonists, likeclozapine, tend to lower th e seizure threshold (19 ,20 ,21 ,22). These da ta suggest thatclozapine's blockade of D2 receptors is responsibl e for its associa te d se izu res but th isdo es not explain th e incr eased preval en ce of clozapine relat ed se izures compared tost andard neuroleptics. Burke e t al demonstrated th e opposite effec t with D, receptorcom pounds (19) . In his study in mi ce, D, agonist s lower th e se izu re threshold topilocarpine and picrotoxin and D 1 antagonists ex erted a protecti ve effect againstseizures. An additional mechanism is suggest ed by Giardino et al who repor ted ade cr ease in benzodiazepine re ceptor density in rat cor te x a fte r chro nic clozapineadministration (23), raising th e possibility that clozapine could alt er t he seizurethreshold 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 EEGfollowing administration of clozapine. Re cent studies su ggest th at most patientsreceiving clozapine have abnormal EEGs (11 ,24,2 5) . These changes have be enreported to be dos e related (26) but cha nges have been noted a fte r a sin gle dose (27) .Tiihonen et al found that 16 of 16 subjects studied had profound disturban ces ofbackground activity and also paroxysms consist ing of delt a a nd th et a waves, sevenpatients had paroxysms which were classified as epilept iform, cons ist ing of sp ikes,polyspikes , or spikes and slow wave com plexe s (24) . These findin gs corre la te with anea rlie r study by Isermann and Haupt who found 26 of 36 subjects st udi ed had

40 JEFFERSON JOURNAL OF PSYCHIATRY

abnormal EEGs after beginning clozapine (II) . Fifteen had paroxysm al episodes ofgeneralized slowing and 8 had epilep t iform dis charges . Koukkou also suggest ed tha tclozapine-induced EEG cha nges a re associat ed with a better respon se to clozapinethan 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 ou t anumber of important points concerning clozapine-induced seizu res . The g roup hometreatment team was unfamiliar with th e management of cloz apine-indu ced seizu resas evide nced by th e continuation of the clozapine a t th e sam e do se a fte r the seizureand the seven day delay in obtaining a medical eva lua tion.

Several recent papers comment on the management of cloza pine-r elat ed se i­zures (7, 10,16 ,28,29,30) . Prevention of seizures ca n be enha nced by: I) no t exceedingdos es of 600 mg/day; 2) slowly increasing daily dos es; and 3) avoidi ng concomitan tuse of other medications whi ch also lower th e seizure threshold . For exa m ple,lithium, neuroleptics and tricyclic antidepressants ca n lower th e seizure th reshold .

It is not known if pre-existing subclinical EEG abnor malit ies incr ease a patien t 'srisk for seizures while on clozapine but at pr esent , we do not recommend a n EEG forall patients prior to beginning cloz apine treatm ent. Patients with a hist ory of seizu resand /or confusional sta tes should have a ba seline EEG before star t ing clozapine. AnEEG should also be performed on patients who have a cha nge in ment al status orseizure while on cloz apine. In th e case described this ste p should have been takenimm ediately after th e patient had the seizure.

Subclinical EEG changes in the abse nce of associated clin ical findi ngs do notnecessarily require a n alteration in clozapine treatment. Cl ozapine-relat ed se izuresare not a n absolute indication for discontinuation of th erapy bu t cer tain ste ps, whichwere not follow ed in th e cas e described , should be taken immediat ely a fter suc h aneve nt. Other possible causes of seizure should be investigated . This work-up sho uldinclude EEG, head CT, laboratory evalua tion and possibl y a neurological consulta­tion. Following a seizure, clozapine should be held until th e patient 's mental sta tereturns to baseline and th en th e daily dos e of cloz apine should be reduced . Lieber­man et al suggest a 50% reduction in th e daily dos e (7). The manufactu rer sta te s t ha t31 of th e 41 cases in whi ch seizures developed remained on cloz apine despit e se izures .Less than 5% have had a second seizure with simultaneou s treatm ent with valpro icacid (data on file, Sandoz Pharmaceuticals, 1991) . In th e case pr esented clozapinehad not yet demonstrated an antipsychotic effec t and th e t reatment team decided todis continue her cloz apine and use ca rba maze pine tempor arily to stabilize her mentalstate .

A lack of consensus exists conce r ning th e concomita n t use of an t iconvu lsa ntsafter a clozapine-induced seizure. If a clinician decid es to use a n a nt iconvulsan t ,valproic acid is th e drug of choice as ph en ytoin may ca use a decr ease in clozapineplasma levels (31) and ca rba mazepine should be avoide d du e to th e possib ility ofdepress ed granulocyte production. One death has been rep ort ed in a pa tien t on

CLOZAPINE-INDUCE D SEIZURES AND EEG CHANGES 4\

combine d treatment of clozapine a nd carba maze pine (data on file, Sa nd oz Ph ar ma­ce utica ls, 1991) .

Kane suggests th at th ere may be as many as 100,000 to 200,000 schizophrenicsresist ant to sta ndard neuroleptics in th e U.S. ( I) . C urren t ly there a re a pproximately23,000 individuals in th e U.S. being t rea ted with clozapine. The use of clozapine willcer tainly incr ease in th e 1990 's. We believe thi s pap er addresses th e import ant needfor clinicians to cont inue to further th eir underst a nding of clozap ine a nd th emanagement of its side effects such as seizu res a nd EEG cha nges.

RE FER ENC ES

I. Ka neJ, Hon igfeld G, Singer J , e t al: C lozapine for th e t reat men t resis ta n t sch izophreni c.Arch Gen Psych 1988; 45:789-796

2. Melt zer H, Bast a ni B, Young Kown K, et al: A pro spect ive study of clozapine intr eatment-r esist ant schizophrenic patient s. Psych opharmacology 1989; 99 suppl:68-72

3. G lenenbe rg A, Ooller J : C loza pine versus chlorpromazine for the t rea tmen t of schizophre­nia: Pr elimina ry result s double-bl ind stud y.J C lin Psych iat ry 1979; 40:238- 240

4. Pan teleeva G, Lovskaya M, Belyaev B, et a l: C lozapine in the t rea tment of sch izoph reni cpa tien ts: An internat ion al mul ticentered tri al. C lin Therapy 1987; 10( 1):57-68

5. Lind st ro m L: T he effect of lon g-term t rea tmen t with clozap ine in sch izophrenia: Aret ros pect ive s tudy in 96 pa t ien ts treat ed with cloz apine for up to 13 yea rs. Acta Psychia t rSca nd 1988; 77:524-529

6. Cas ey 0 : C loza pine: Neurolept ic-ind uced EPS a nd ta rdive dyskinesia . Psychopha rmacol­ogy 1989; 99 suppl:47- 53

7. Lieberma n J , Ka ne J , Ce les te J : C loza pine guide lines for clini cal ma nagement. J C linPsychiat ry 1989; 50 :329- 338

8. Logoth et is J : Spontan eous epilept ic se izures and elec troe nce pha log ra phic changes in th ecour se of ph enot hiazine resista n t schizophre nic. Arch Gen Psych 1988; 45:789-796

9. Sando z, Inc. C lozari l (clozapine) : The at ypical a nt ipsycho tic. East Hanover , N] . Sa ndozPharmaceutical s Co rp. , 1990

10. Devinsky 0 , Honi gfeld G, PatinJ : C loza pine-r ela ted se izu res. Neurology 1991 ; 4 1:369- 371II. Iserm an H , Haupt R: Au ffalli ge EEG-veranderungen un ter clozapin-beh andlun g be i

par an oid- ha lluzinatorischen psycho sen . Oer Ne rve na rz t 1979; 47:26812. T iberi ~I,Jarvi e KR, Silvia C , et a l: C lon ing , molecu lar characte riza t ion a nd chromosomal

ass ignme n t of a gene cod ing a seco nd 0 I dopamine recep to r subtype: di fferen tialexpre ssion patt ern in ra t br ain com pare d with the 0 IA receptor. Proc Na tl Acad Sci 199 1;88:749 1-7495

13. Grandy OK, Mar chionni MA, Makam H , et a l: C loning of th e cDna a nd ge ne for a hum an0 2 receptor. Proc Na t l Acad Sci 1989; 86 :9762-9766

14. Sokoloff P, Giros B, Martres M, e t al: Molecul ar cloning and cha rac te riza tio n of a noveldop amine receptor (03) as a target for neurolept ics. Na tu re 1990; 347:146-1 5 1

15. Va n Tol H, Bou nzow J , Guan H , et al: C lon ing of the ge ne for a human dop amine D4receptor with high affini ty for th e antipsycho tic clozapine. Na ture 1991; 350:6 10-6 14

16. Bald essarin i R, Frankenburg F: C loza pine: A novel a n tipsycho t ic agen t. NEJ M 1991;324( 11):746-754

17. Meltzer H: The mech anism of act ion of novel a n tipsycho t ic drugs. Schizophreni a Bull1991; 17(2):263-287

42 JEFFERSON JO URNAL OF PSYCHIATRY

18. Hand T, Hu X, Wang R: Differential effects of acu te clozapine a nd haloper idol on th eact ivity of ventral tegmental (AIO) and nigrostriatal (A9) dop amine neurons. Brain Res1987 ; 4 14:257- 269

19. Burke K, Chandler C , St arr B, et a l: Se izure prom ot ion a nd pro tection by D , and D2

dop aminergic drugs in th e mouse. Ph a rm Bioch e m a nd Beh avior 1990; 36:729-73320. Tursk i L, Cavalhe iro E, Bortolotto Z, et a l: Dopa mine-sensit ive anti-convu lsant site in th e

ra t st ria tum.J of Ne urosc ience 1988; 8( II ):4027-40372 1. Losch er W, Czuczwar S: Studies on th e involvem ent of dop a mine D I and D2 receptors in

th e a nt iconvulsan t effects of dopamine ago nists in various rodent mod els of epilepsy. EurJof Ph armacol 1986; 128:55-6

22. Al-Tajir G , St arr M, C ha ndler e t a l: Opposin g effe cts of dop a mi ne D , and D2 receptorst im ula t ion on th e pr op agati on of mot or seiz ures in mice and rats. Br J ofPharmacol 1990;99:26 1P

23. Gi ardi no L, Calza L, Piazza PV, Am a to G: Multiple neu roch e mical action of clozapine: aqu antit ative a uto ra diogra phic study of DA2, opia te a nd be nzo diazcp ine receptor s in th erat br ain a nd afte r long-term tr eatment.J of Ne ural Tran smi ssion 199 1; 83: 189-203

24. Tiihonen J , Nou siainen U, Hak ola P, et al: EEG abno rma lities associated with clozapinctreatmen t. AmJ Psychi atry 1991; 148(10):1406

25. Koukkou M, Angst J , Zimmer D: Pa rox ysm al EEG act ivity a nd psychopathology duringtreat men t wit h clozapine . Ph a rm acopsych iatry 1979; 12: 173- 183

26. Leppig M, Bosch B, abe r D: C loza pine in the treatme nt of 12 1 out-patient s. Psych oph ar­macology 1989; 99 suppl:77-79

27. RoubicekJ , Major I: EEG profile and beh avior al cha nges after a sing le dose ofclozepine innormals a nd schizophren ics. Bio Psychiatry 1977; 12:613-633

28. Haller E, Binder R: Cl ozapine and se izu res . AmJ Psychi atry 1990; 147(8): 1069- 107129. Bak er R, Co nley R: Seizures d urin g clozapine th era py. Am J Psychi a t ry 199 1; 148(9):

1265-6630. Sa fferma n A, LiebermanJ, Kan eJ, et a l: U pdate on the clini ca l efficacy and sid e effects of

clozapine. Schi zoph renia Bull 1991 ; 17(2) :248-2633 1. Mill er D: Effect s of ph en ytoin on th e plasm a clozapine levels in two patients . J Clin

Psychiatry 1991; 52:23- 25