Arq Neuropsiquiat r 2002;60(2-A):285-287
ACUTE PSYCHOTIC DISORDERS
INDUCED BY TOPIRAMATE
Report of t w o cases
Florindo Stella
1, Dorgival Caetano
2, Fernando Cendes
3, Carlos A.M. Guerreiro
3ABSTRACT - We report on t w o epilept ic pat ient s w ho developed acut e psychosis aft er t he use of t opiramat e (TPM ). One pat ient exhibit ed severe psychom ot or agit at ion, het eroaggressiveness, audit ory and visual hallucinations as w ell as severe paranoid and mystic delusions. The other patient had psychomotor agitation, depersonalizat ion, derealizat ion, severe anxiet y and deluded t hat he w as losing his memory. Bot h pat ient s had to be taken to the casualty room. After interruption of TPM in one patient and reduction of dose in the ot her, a f ull rem ission of t he psychot ic sym pt om s w as obt ained w it hout t he need of ant ipsychot ic drugs. Clinicians should be aw are of the possibility of development of acute psychotic symptoms in patients undergoing TPM t reat m ent .
KEY WORDS: psychiat ric disorders, hallucinat ion, delusion, t opiramat e.
Episódio psicótico agudo induzido por topiramato: relato de dois casos
RESUM O - Relat am os dois pacient es epilépt icos que m anif est aram quadro psicót ico agudo induzido por t opiram at o (TPM ). Um pacient e apresent ou agit ação psicom ot ora grave, het eroagressividade, alucinações audit ivas e visuais, e delírios de cont eúdo paranóide e míst ico. O out ro pacient e apresent ou agit ação psico-motora, despersonalização, desrealização, ansiedade intensa e delírio de que estava perdendo a memória. Ambos os pacientes foram conduzidos ao serviço de emergência e, após a interrupção do TPM em um deles e redução da droga em outro, houve remissão total dos sintomas psicóticos sem necessidade de medicação antipsicótica. Alertamos os clínicos para o risco de surgimento de sintomas psicóticos em pacientes em uso do TPM .
PALAVRAS-CHAVE: t ranst ornos psiquiát ricos, alucinações, delírios, t opiramat o.
1Inst it ut o de Biociências, Universidade Est adual Paulist a (UNESP), Rio Claro SP, Brasil; 2Depart ament o de Psicologia M édica e Psiquiat ria,
Faculdade de Ciências M édicas (FCM ), Universidade Est adual de Campinas SP, Brasil (UNICAM P); 3Depart ament o de Neurologia, FCM ,
UNICAM P.
Received 29 M ay 2001, received in final form 5 Oct ober 2001. Accept ed 18 Oct ober 2001.
Dr. Florindo Stella - Instituto de Biociências / Psicologia, UNESP - Caixa Postal 199 - 13506-900 Rio Claro SP - Brasil.
Topiram at e (TPM ) is an ant iepilept ic drug (AED)
used as add-on t herapy f or generalized and part ial
seizures t hat are resist ant t o ot her ant iepilept ic
drugs
1- 6. It has also been proposed as a m ood st
abi-lizer f or pat ient s w it h bipolar disorders w ho have
not responded t o t he t radit ional t reat ment s
7- 9.
Neu-ropsychiat ric sym pt om s m ay em erge af t er t he use
of TPM , t he m ost com m on com plaint s are: som
no-lence, dizziness, t iredness, at axia, headache,
depres-sion, and cognit ive im pairm ent such as m ent al
con-fusion, slow reasoning, speech difficult y, and dist
ur-bance of memory
10-18. These sympt oms ranged from
m oderat e t o severe, how ever, t hey progressively
im proved as t reat m ent w ent on.
There are f ew report s in t he lit erat ure regarding
t he associat ion of TPM w it h psychot ic disorders
19, 20.
The majorit y of t he psychot ic sympt oms report ed in
scient ific meet ings lack in det ails
11, 21, 22. Patients w ith
hist ory of prior psychot ic or depressive sym pt om s
had a t endency t o develop t he sam e t ype of m ood
disorder w hen put on TPM
23.
The purpose of t his paper is t o report on t w o
pat ient s w it h epilepsy w ho present ed psychot ic out
-burst s af t er t he use of TPM .
CASES
Patient A - A 42-year old male, engineer, married w it h
generali-286 Arq Neuropsiquiat r 2002;60(2-A)
zat ion, once a w eek. He had no f am ily or personal hist ory of psychiat ric disorders. Bet w een 1997 and 2000 he had t en elect roencephalogram s perf orm ed: f ive show ed epi-lept iform act ivit y in right front o-t emporal region; one sho-w ed epilept if orm act ivit y in lef t f ront o-t em poral region; t w o int erm it t ent slow w aves in right t em poral region; one int erm it t ent slow w aves in lef t t em poral region; and one w as norm al. Int erict al brain SPECT (1997) suggest ed hy-poperf usion in t he right t em poral region. M agnet ic resonance im aging (M RI) displayed bilat eral hippocam pal at -rophy w it h lef t -sided predom inance and a sm all lesion in t he corpus callosum .
He w as t reat ed w it h several AEDs in m onot herapy and polyt herapy, but w as never seizure free. As he had been on carbam azepine CR 1600 m g/day over a year w it hout m uch im provem ent , he w as put on TPM 50 m g/day. This dose w as gradually increased t o 300 mg daily. There w ere no signif icant side ef f ect s but a m ild dif f icult y in recollect -ing recent f act s. As t he seizures did not im prove, t he TPM dosage w as increased from 300 mg t o 350 mg/day. Only one day aft er being on 350 mg/day, he present ed a full-blow n psychot ic episode: he w oke up about 3 a.m . w it h severe psychom ot or agit at ion, verbal and physical het ero-aggressiveness, disorient at ion in t im e and space as w ell as regarding him self , saying t hat a serious bus accident w it h a great num ber of f at al vict im s w as bound t o hap-pen and t hat he had received a m ission f rom God t o save people. He also had visual and audit ory hallucinat ions: vision of Our Lady t elling him t hat his epilept ic seizures had been cured; and severe paranoid ideas of being haun-t ed by haun-t he police and ohaun-t her persecuhaun-t ory audihaun-t ory halluci-nat ions. He w as t aken t o a psychiat ric out pat ient f acilit y w here he becam e m ore agit at ed, broke object s and dam -aged t he cars parked in t he vicinit y. He had t o be st opped by t he police and t aken t o a psychiat ric hospit al, w here he w as put on diazepam . Carbam azepine w as m aint ained and TPM w as w it hdraw n. He w as t hen t ransf erred t o t he Psychiat ric Unit of t he General Hospit al of t he St at e Uni-versit y of Cam pinas, w here he st ayed f or 11 days. Tot al rem ission of t he psychot ic sym pt om s t ook place w it hin 48 hours af t er TPM w as com plet ely t aken of f . This epi-sode w as unrelat ed t o epilept ic seizures. He w as kept on diazepam f or several days because of his high anxiet y and carbam azepine CR 1600 m g/day w as m aint ained. There w as no need f or ant ipsychot ic m edicat ion and st opping TPM did not af f ect t he f requency or t he clinical f eat ures of t he epilept ic seizures.
Patient B - A 41-year old f em ale, divorced w it h t w o
children, w ho w orked as a nanny. She w as being t reat ed for t emporal lobe epilepsy. She has had complex part ial seizures w it h secondary generalizat ion since t he age of 12. From 1997 t o 2000 five elect roencephalograms w ere carried out : one displayed bilat eral epilept iform act ivit y in f ront al regions; t w o show ed epilept if orm act ivit y in right t em poral region; and t w o w ere norm al. The CAT scan rev-eled mild cerebellar at rophy and M RI show ed mild diffuse
cerebellar at rophy, w it hout abnormalit ies in brain st ruc-t ures.
She underw ent m onot herapy as w ell as polyt herapy w it h several AEDs w hich f ailed t o bring t he seizures under cont rol. Over a period of 2 years she w as t reat ed w it h valproic acid t w ice daily in a t ot al of 1000 mg/day. Then TPM 50m g/day w as int roduced and gradually increased t o 100 m g/day t aken t w ice. As t he seizures w ere not con-t rolled, con-t he dosage of TPM w as increased con-t o 150 m g per day and on t his very sam e day, t he pat ient report ed a “ st rong st range f eeling” in relat ion t o her environm ent , depersonalizat ion, derealizat ion, severe anxiet y, fear, rest -lessness, and psychomot or agit at ion. She shout ed phrases like “ I’m going m ad” , “ I’m losing m y m em ory” and “ no-body believes in m e“ . She w as t aken t o t he casualt y room and m edicat ed w it h diazepam . TPM w as reduced f rom 150 m g t o 50 m g/day w hich alleviat e psychom ot or agit a-t ion and a-t he oa-t her sym pa-t om s. There w as no need f or an-t ipsychoan-t ic m edicaan-t ion. Again an-t his psychoan-t ic episode w as unrelat ed t o t he pat ient ’s epilept ic seizures and she had no previous hist ory of psychiat ric disorders.
DISCUSSION
Alt hough t opiram at e has been report ed t o be
associat ed w it h various adverse effect s like dizziness,
giddiness, t iredness, psychom ot or slow ness, dif f
i-culty in attention and concentration, memory
impair-m ent , loss of w eight and nephrolit hiasis, it is
con-sidered a saf e drug w it h good t olerance and f
avor-able pharm acokinet ics
24, 25. Despit e t he fact t hat it s
plasm at ic level is low ered by drugs t hat induce
he-pat ic m et abolism
4, it has relat ively f ew adverse
re-act ions and very lit t le int erre-act ion w it h ot her m
edi-cat ions
26. When adm inist ered w it h carbam azepine,
a pot ent enzym at ic Cyt ochrom e P450 inducer
27,28,
TPM undergoes 40% reduct ion of it s plasm at ic
lev-els and clearance
28. On t he ot her hand, plasm a
lev-els of carbamazepine or it s epoxide met abolit e does
not change signif icant ly w hen TPM is added
29. The
simult aneous use of TPM and valproat e increases t he
plasma levels of t he first by 15%. This has t o be t aken
int o account if valproat e is event ually w it hdraw n.
TPM , on t he ot her hand, increases valproat e
clear-ance, t hus reducing it s plasm a levels
29.
Alt hough Aldenkam p et al.
17claim t hat t he risk
of TPM im pairing cognit ive f unct ions is relat ively
small in comparison w it h valproat e, t hey report t hat
pat ient s on TPM did w orse on short -t erm verbal
mem ory t est . In t he samem e vein, TPM w as show n t o imem
-pair cognit ive funct ioning, especially as regards
me-mory
18. TPM m ay int erf ere w it h m nem onic process,
how ever, it is hard t o judge t he ext ent of it .
Accord-ing t o ICD-10 crit eria
30t he t w o report ed cases w ere
Arq Neuropsiquiat r 2002;60(2-A) 287
f eat ures appeared suddenly and w it hin a f ew days
af t er increasing t he TPM dosage. How ever, t hey
quickly remit t ed aft er TPM w as t aken off or reduced.
The f requency of psychot ic episodes relat ed t o
TPM is low and t he m ost com m on sym pt om s w ere
delusions, visual and audit ory hallucinat ions. Dat a
on t he adverse ef f ect s of TPM report only f ew cases
of psychot ic sympt oms such visual and audit ory
hal-lucinat ions and paranoid delusions
15,18, and t hese
pat ient s event ually w arrant ed hospit alizat ion
18.
The risk of psychot ic sym pt om s due t o t he int
er-act ion of t herapeut ic doses of TPM and carbam
a-zepine needs furt her invest igat ion. How ever, t his
in-t eracin-t ion upon reducing in-t he serum level of TPM , is
likely “ t o prot ect ” t he pat ient f rom t he risk of TPM
int oxicat ion provided t hat bot h drugs are in t he
t herapeut ic range. Theref ore, t he concom it ant use
of TPM and carbam azepine cannot be t aken as
re-sponsible f or t he psychot ic sym pt om s present ed
by t he pat ient s. These acut e psychot ic episodes seem
t o be have been ent irely due t o t he use of TPM .
An-ot her f inding t hat lends support t o t his hypAn-ot hesis
is t he complet e remission of t he psychot ic sympt oms
upon t he w it hdraw al of TPM , alt hough carbam
aze-pine w as m aint ained. M oreover, t hese pat ient s did
not need any ant ipsychot ic m edicat ion. Only
diaz-epam w as added t o reduce t he pat ient s’ anxiet y. .
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