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 patient’s 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.
4. CONCLUSIONS
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.
REFERENCES
[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.
doi:10.1016/j.pnpbp.2004.06.020
[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.
doi:10.1001/archpsyc.60.7.681
[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.
doi:10.1016/j.pnpbp.2007.10.009
[7] Sarkar, R., Klein, J. and Kruger, S. (2008) Aripiprazole
augmentation in treatment-refractory obssive-compulsive
disorder. Psychopharmacology, 197, 687-688.