Open Journal of Psychiatry, 2011, 1, 30-32 OJPsych
doi:10.4236/ojpsych.2011.12005 Published Online July 2011 (
Published Onl ine July 2011 in SciRes.
Withdrawal seizure associated with high dosage of
aripiprazole and fluoxetine: a case report
Jian-An Su1,2,3*, Shih-Yong Chou1,2,3, Ching-Shu Tsai1,2,3, Tai-Hsin Hung1,2,3
1Department of Psychiatry, Chang Gung Memorial Hospital, Chiayi, Ch inese Taipei;
2Graduate Institute of Clinical Medical Sciences at Chang Gung University, Taoyuan, Chinese T aipei;
3Department of Nursing, Chang Gung Institute of Technology, Taoyuan, Chinese Taipei.
E-mail: *
Received 13 May 2011; revised 22 June 2011; accepted 30 June 2011.
Aripiprazole, a third-generation antipsychotic, has
been considered to have a high safety profile and rare
withdrawal symptoms. We reported the case of a schi-
zophrenic patient with a significant obsession, who
was treated with a high dosage of aripiprazole and
fluoxetine. Generalized tonic-clonic seizure occurred
two days after abruptly stopping these two medica-
tions. Gradually tapering aripiprazole is suggested in
clinical practice, especially when using a high dosage.
Keywords: Aripiprazole; High Dosage; Withdrawal
Aripirazole is a so-called third-generation antipsychotic
with a unique pharmacological mechanism [1,2]. It has
indications for the treatment of schizophrenic and bipolar
patients [3,4] and is also effective in augmenting antide-
pressants in neurotic patients including major depressive
disorder and obsessive compulsive disorder [5-7]. Its
safety and efficacy are already well-established [3,8],
and few withdrawal symptoms have been reported in
clinical trials. Herein, we present the case of a patient
with schizophrenia, paranoid type, with significant ob-
session and delusion. High-dosage aripiprazole 30 mg
and fluoxetine 60 mg were prescribed concurrently for
three weeks for symptom relief. Generalized tonic-clonic
seizure occurred two days after abruptly stopping the two
This 40-year-old male patient had been diagnosed with
paranoid schizophrenia for about 10 years. He took ha-
loperidol 4 mg and zotepine 50 mg per day, but the re-
sponse was incomplete remission. The patient still had
residual psychotic symptoms including delusion of per-
secutory and reference under these regimens. In addition,
the gradual exacerbation of significant obsession, sexual
image intuition, was impacting his quality of life. Aripi-
prazole was prescribed and combined with fluoxetine to
help control of his delusions and obsession. The score of
clinical global impression-severity (CGI-S) was 5 at that
time. We arranged for aripiprazole 10 mg to be taken in
the first week, which was then titrated to aripiprazole 20
mg and we also added on fluoxetine 40 mg in the second
and third weeks. Because the patient’s psychotic symp-
toms and obsession still persisted, we escalated the do-
sage to aripiprazole to 30 mg and fluoxetine to 60 mg.
The symptoms showed little improvement after one week
on this high-dose regimen and his delusions even wor-
sened. In addition, the patient also complained of akathi-
sia. Therefore, we abruptly stopped the above two medi-
cations and set up olanzapine 10 mg specifically for his
exacerbated delusions. However, generalized ton-
ic-clonic seizure was noted the second day after stopping
aripiprazole and fluoxetine. Head injury with subarach-
noid hemorrhage occurred because the patient lost con-
sciousness and fell down during a seizure. He was ad-
mitted to the Neurosurgery Ward for observation and a
survey of the seizure etiologies, but no remarkable ab-
normality was detected, including the electroencephalo-
graphy (EEG) results. The family denied a past history or
family history of seizur e attack. After discharge, the me-
dication was maintained at olanzapine 10 mg, haloperi-
dol 5 mg and escitalopram 30 mg, concurrently, for his
obsession and psychotic symptoms. Under this regimen,
his condition gradually improved. An EEG was arranged
again four months after discharge, and still there was no
abnormality noted.
This case involved a seizure that occurred after abruptly
discontinuing a high dosage of aripiprazole and fluoxe-
J. A. Su et al. / Open Journal of Psychiatry 1 (2011) 30-32
Copyright © 2011 SciRes. OJPsych
tine. This is the first reported case of a withdrawal sei-
zure related to the abrupt discontinuation of both aripi-
prazole and fluoxetine in combination. There are some
possible explanations for the emergence of a seizure at-
tack in this patient, including aripiprazole withdrawal,
fluoxetine withdrawal, or induction by olanzapine. Ari-
piprazole is supposed to be at low-risk for seizure attack
and the reported risk is 0.1% [9]. Only two cases of sei-
zure during treatment with aripiprazole have been re-
ported in the related literature and the daily dosage was
10mg and 15mg respectively [10,11]. Aripiprazole has
the unique effect of dopamine stabilization, and also has
a partial 5-HT1 agonist effect and antagonist activity at
5-HT2A receptors [1]. The mechanism of partial agonist
effect in 5-HT1 provides efficacy, not only in treating
psychotic symptoms, but also in augmenting antidepres-
sants in the treatment of depression and obses-
sion-compulsion [5-7]. The combination of aripiprazole
and fluoxetine seemed appropriate for this case. However,
fluoxetine is a cytochrome P450 (CYP) 2D6 inhibitor
and aripiprazole is metabolized mainly by CYP2D6 [12].
This patient had taken the maximum recommended daily
dosage of aripiprazole; however, the serum concentration
may have been higher than we expected because of the
inhibition of CYP2D6 by fluoxetine. Withdrawal seizure
may occur when abruptly stopping such a high-level
concentration of aripiprazole.
Fluoxetine has been marketed much longer than aripi-
prazole. The possibility of fluoxetine-induced seizure
attack was around 0.1% in randomized controlled trials,
and is classified as low-risk among antidepressants [13].
It has been a report of a seizure protective effect in an
ani mal model [14]. Fluoxetine has a long half-life for 24
to 48 hours [12]. Withdrawal symptoms are fewer, com-
pared to other antidepressants [15], and no fluoxetine
withdrawal seizure has been reported so far. Thus, the
seizure attack in this case more likely resulted from ari-
piprazole withdrawal than fluoxetine withdrawal, espe-
cially with the high concentration of aripiprazole. In
most drug trials with aripiprazole, the dosage usually f ell
between 15 and 30 mg, and the patients seemed to tole-
rate this dosage well [16]. No severe withdrawal symp-
toms have been reported. Some adult patients have taken
high-dosage aripiprazole, 45 to 75 mg per day, and all of
them seemed to tolerate it well [17-19]. However, an
adolescent who took 60 mg aripiprazole and 60 mg flu-
oxetine concurrently per day for at least three weeks re-
vealed a blunted affect, sluggishness, and cognitive
slowing [20]. These reports described the patients' cond i-
tion under a high dosage of aripiprazole, so we had no
idea if any withdrawal symptoms would occur when
stoppin g s uch a high dos age abru ptly.
This patients seizure attack occurred on the second
day after switching to olanzapine. Olanzapine probably
lowered the seizure threshold [21]; the pre-marketing
seizure incidence for olanzapine was about 0.9% [22].
However, this patient continued olanzapine for three
months after the seizure, and no other attacks occurred.
An olanzapine-induced seizure attack was therefore less
likely in this case.
Aripiprazole is very frequently combined with antide-
pressants in clinical practice such as augmentation for
refractory major depressive disorder or obsessive com-
pulsive disorder. The potential 2D6 suppression by the
antidepressants might increase the serum level of aripi-
prazole. Withdrawal seizure might occur when abruptly
discontinuing treatment, if the patient has taken high
doses of aripiprazole with an antidepressant. Thus, gra-
dual tapering is quite important to avoid possible with-
drawal symptoms including seizure attack.
[1] Burris K.D., Molski, T.F., Xu, C., Ryan, E, Tottori, K.,
Kikuchi, T., Yocca, F.D. and Molinoff, P.B. (2002) Aripi-
prazole, a novel antipsychotic, is a high-affinity partial
agonist at human dopamine D2 receptors. The Journal of
Pharmacology and Experimental Therapeutics, 302,
381-389. doi:10.1124/jpet.102.033175
[2] Naber, D. and Lambert, M. (2004) Aripiprazole: A new
atypical antipsychotic with a different pharmacological
mechanism. Progress in Neuropsychopharmacology &
Biological Psychiatry, 28, 1213-1219.
[3] Potkin, S.G., Saha, A.R., Kujawa, M.J., Carson, W.H., Ali,
M., Stock, E., Stringfellow, J., Ingenito, G. and Marder,
S.R. (2003) Aripiprazole, an antipsychotic with a novel
mechanism of action, and risperidone vs. placebo in pa-
tients with schizophrenia and schizoaffective disorder.
Archives of General Psychiatry, 60, 681-690.
[4] Keck, P.E., Orsulak, P.J., Cutler, A.J., Sanchez, R., Tor-
beyns, A., Marcus, R.N., McQuade, R.D. and Carson,
W.H. (2009) Aripiprazole monotherapy in the treatment
of acute bipolar I mania: A randomized, double-blind,
placebo- and lithium-controlled study. Journal of Affe c-
tive Disorders, 112, 36-49. doi:10.4088/JCP.v66n1002
[5] Simon, J.S. and Nemeroff, C.B. (2005) Aripiprazole
augmentation of antidepressants for the treatment of par-
tially responding and nonresponding patients with major
depressive disorder. The Journal of Clinical Psychiatry,
66, 1216-1220. doi:10.4088/JCP.v66n1002
[6] Yang , K.C., Su, T.P. and Chou, Y.H. (2008) Effectiveness
of aripiprazole in treating obsessive compulsive symp-
toms. Progress in Neuropsychopharmacology & Biologi-
cal Psychiatry, 32, 585-586.
[7] Sarkar, R., Klein, J. and Kruger, S. (2008) Aripiprazole
augmentation in treatment-refractory obssive-compulsive
disorder. Psychopharmacology, 197, 687-688.
J. A. Su et al. / Open Journal of Psychiatry 1 (2011) 30-32
Copyright © 2011 SciRes. OJPsych
[8] DeLeon, A., Patel , N.C. a nd Crismon, M.L. (2004) Aripi-
prazole: A comprehensive review of its pharmacology,
clinical efficacy, and tolerability. Clinical Therapeutics,
26, 649-666. doi:10.1016/S0149-2918(04)90066-5
[9] Abilfy/aripiprazole (2004) Bristol-Meyers Squibb Com-
pany/Otsuka American Pharmaceutical Inc., New York.
[10] Tsai, J.F. (2006) Aripiprazole-associated seizure. The
Journal of Clinical Psychiatry, 67, 995-996.
[11] Malik, A.R. and Ravasia, S. (2005) Aripiprazole-induced
seizure. Canadian Journal of Psychiatry, 50, 186.
[12] Stahl, M.S. (2008) Stahl’s essential psychopharmacology:
Neuroscientific basis and practical applications, 3rd edi-
tion, Cambridge University Press, Cambridge.
[13] Alldredge, B.K. (1999) Seizure risk associated with psy-
chotropic drugs: Clinical and pharmacokinetic considera-
tions. Neurology, 53, S68-75.
[14] Dailey, J.W., Yan, Q.S., Mishra, P.K., Burger, R.L. and
Jobe, P.C. (1992) Effects of fluoxetine on convulsions
and on brain serotonin as detected by microdialysis in
genetically epilepsy-prone rats. The Journal of Pharma-
cology and Experimental Therapeutics, 260, 533-540.
[15] Stahl, M.M., Lindquist, M, Pettersson, M., Edwards, I.R.,
Sanderson, J.H., Taylor, N.F., Fletcher, A.P. and Schou,
J.S. (1997) Withdrawal reactions with selective serotonin
re-uptake inhibitors as reported to the WHO system. Eu-
ropean Journal of Clinical Pharmacology, 53,
163-169. doi:10.1007/s002280050357
[16] Cassano, G.B., Fagiolini, A., Lattanzi, L., Monteleone, P.,
Niolu, C., Sacchetti, E., Siracusano, A. and Vita, A. (2007)
Aripiprazole in the treatment of schizophrenia: A con-
sensus report produced by schizophrenia experts in Italy.
Clinical Drug Investigation, 27, 1-13.
[17] Duggal, H.S. and Mendhekar, D.N. (2006) High-dose
aripiprazole in treatment-resistant schizophrenia. The
Journal of Clinical Psychiatry, 67, 674-675.
[18] Gupta, S., Chohan, M. and Madhusoodanan, S. (2004)
Treatment of acute mania with aripiprazole in an older
adult with noted improvement in coexisting parkinson’s
disease. Primary Care Companion to the Journal of
Clinical Psychiatry, 6, 50-51. doi:10.1345/aph.1H240
[19] Chavez, B. and Poveda, R.A. (2006) Efficacy with
high-dose aripiprazole after olanzapine-related metabolic
disturbances. The Annals of Pharmacotherapy, 40, 2265-
2268. doi:10.1345/aph.1H240
[20] Preskorn, S.H. (2003) Relating clinical trials to psychia-
tric practice: Part I: The case of a 13-year old on aripi-
prazole and fluoxetine. Journal of Psychiatric Practice, 9,
307-313. doi:10.1097/00131746-200307000-00006
[21] Woolley, J. and Smith, S. (2001) Lowered seizure thre-
shold on olanzapine. The British Journal of Psychiatry,
178, 85-86. doi:10.1192/bjp.178.1.85-a
[22] Beasley, C.M.Jr., Tollefson, G., Tran, P., Satterlee, W.,
Sanger, T. and Hamilton S. (1996) Olanzapine versus
placebo and haloperidol: Acute phase results of the North
American double-blind olanzapine trial. Neuropsycho-
pharmacology, 14, 111-123.