CASE REPORT
Clozapine Safety and Efficacy for Interictal Psychotic
Disorder in Pharmacoresistant Epilepsy
Vincent Jette´ Pomerleau, MSc,* Franc¸ois Dubeau, MD, FRCP(C),w
and Simon Ducharme, MD, MSc, FRCP(C)wz
Abstract: Since the middle of the 19th century, both neurologists
and psychiatrists have linked psychosis and epilepsy. Clozapine, the
most effective antipsychotic drug, alters electroencephalographic
activity and carries a significant risk of causing seizures. Un-
fortunately, this risk limits the drug’s potential use in treating
pharmacoresistant psychosis in patients with epilepsy. We present a
unique case in which we used clozapine successfully as a last resort
treatment for chronic interictal psychosis in a 43-year-old woman
with severe pharmacoresistant epilepsy and recurrent status epi-
lepticus. Her psychotic symptoms improved markedly without an
increase in the frequency of seizures despite gradual titration of the
clozapine dose up to 300 mg daily. Her response demonstrates that,
properly monitored, clozapine can be an effective treatment for
psychosis even in patients with daily seizures.
Key Words: epilepsy, psychosis, clozapine, interictal, pharma-
coresistant
(Cogn Behav Neurol 2017;30:73–76)
EEG = electroencephalographic.
S ince the middle of the 19th century, both neurologists
and psychiatrists have linked psychosis and epilepsy.
Epilepsy leads to chronic interictal psychotic disorders in
about 5% of people who have a prolonged history of
uncontrolled seizures (Nadkarni et al, 2007; Toone, 2000).
Classically, these patients show predominantly positive
psychotic symptoms, although the extent of negative
symptoms may be underestimated (Nadkarni et al, 2007).
Interictal psychosis responds to antipsychotic drugs. Once
a drug regimen is established, patients’ response is mini-
mally influenced by their seizures (Toone, 2000).
Received for publication November 30, 2016; accepted April 5, 2017.
From the *Department of Medicine, University of Montreal; Departments
of wNeurology & Neurosurgery and zPsychiatry, McGill University
Health Centre and Montreal Neurological Hospital and Institute,
McGill University; Montreal, Quebec, Canada.
S.D. receives salary support from the Fonds de Recherche du Québec—Santé.
The authors declare no conflicts of interest.
Reprints: Simon Ducharme, MD, MSc, FRCP(C), 3801 University
Street, Montreal, Quebec, Canada H3A 2B4
(e-mail: simon.ducharme@mcgill.ca).
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Cogn Behav Neurol  Volume 30, Number 2, June 2017
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Treating patients who have both epilepsy and psy-
chosis is complex because a number of antipsychotic
medications alter electroencephalographic (EEG) activity
and lower the seizure threshold (Devinsky et al, 1991).
Patients treated with second-generation antipsychotic
drugs are likely to have slightly more EEG alterations and
seizures than those given first-generation antipsychotics
(Centorrino et al, 2002; Kumlien and Lundberg, 2010).
Clozapine, in particular, carries a strong seizure
risk, especially at higher doses (Devinsky et al, 1991).
Consequently, clozapine is usually considered contra-
indicated in patients with epilepsy. A few cases have been
reported of patients with epilepsy and psychosis being
treated safely with clozapine, but none until now in which
the patient had daily seizures (Antony et al, 2008; Langosch
and Trimble, 2002).
Here we describe a woman with pharmacoresistant
epilepsy, daily seizures, and a history of recurrent status
epilepticus whom we treated successfully with clozapine
for secondary psychosis.
CASE REPORT
A 43-year-old woman who had been followed at the
epilepsy clinic of the Montreal Neurological Institute
since age 20 was admitted to the Institute with a severe
psychotic episode.
History of Present Illness
At age 7 the patient had suffered a severe traumatic
brain injury (Menon et al, 2010) that caused bilateral
anterior frontal lobe damage and some cognitive deficits.
At age 13 she developed severe epilepsy. Despite these
challenges, she was able to finish school and attend uni-
versity until age 23, when she suffered recurrent status
epilepticus, leading to a significant functional decline.
Then she had to live under her family’s supervision. Later
she moved into an assisted-living facility for patients who
have experienced traumatic brain injury.
The epilepsy proved to be resistant to the anti-
epileptic drugs carbamazepine, topiramate, valproate,
lamotrigine, vigabatrin, and clobazam.
Her typical seizures were brief losses of contact,
with facial redness, grimacing, urinary incontinence, and
occasional vocalizations. Longer seizures caused con-
fusion and sometimes secondary generalization.
www.cogbehavneurol.com | 73
Jette´ Pomerleau et al
When she was 38, a brain magnetic resonance
imaging scan showed bilateral encephalomalacia in both
frontal polar regions. An intracranial EEG recorded eight
to 10 electrographic and clinical seizures a day, but with
no single epileptic focus; seizures arose simultaneously
from both frontal lobes. Because she had no clear epi-
leptic focus, surgery was not tried.
As to the patient’s behavior changes: When she was
27, her family and treating neurologist noticed that she
had started to develop compulsions, fluctuating paranoid
ideation, and mood swings. Her symptoms were at first
mild and inconsistent, and therefore did not require on-
going treatment. At age 43, however, she developed her
first severe episode of psychotic decompensation. Over
the next few months, she made several visits to the
emergency room at her community hospital. Un-
fortunately, neither the neurology nor the psychiatry
service was willing to admit her, each claiming that the
other should do it. Each time she was sent home. Thus,
months passed without her receiving adequate treatment
for her psychotic episode. Finally, she was sent to our
emergency room and was admitted.
Hospital Admission
On admission she showed disorganized behavior,
emotional lability, florid visual hallucinations (eg, people
flying in her room), and bizarre delusions in the form of
reduplicative paramnesia for place (eg, stating that she
was simultaneously in her own bedroom, in the hospital,
and traveling to a foreign country).
When she was admitted, she was taking these daily
oral medications: topiramate 100 mg in the morning and
150 mg at bedtime, oxcarbazepine 900 mg in the morning
and at bedtime, and phenytoin 350 mg at bedtime.
We transferred her to the EEG telemonitoring unit.
Author S.D. conducted the neuropsychiatric assessment.
On the first evaluation, she was alert, but a mental status
examination showed disinhibition, psychomotor re-
tardation, restricted elated affect, impoverished thought
content, visual hallucinations, response to internal stim-
uli, and poor insight. Her Montreal Cognitive Assessment
score was 18/30 (z-score =  2.24) (Rossetti et al, 2011).
Her EEG was unchanged from baseline, recording eight
to 10 brief electrographic seizures daily and suggesting
that her new psychotic symptoms were unrelated to the
timing of her seizures.
The only other admission finding was a urinary
tract infection.
Our initial diagnostic hypotheses included delirium
and adverse effects from the patient’s antiepileptic drugs.
We treated her for the urinary tract infection, without
improvement in her psychotic symptoms. We reduced her
phenytoin dose from 350 to 300 mg based on her blood
level of 92 mmol/L. In an attempt to lessen her confusion,
we stopped her topiramate and started her on lacosamide,
which did not alter her seizure frequency. Despite these
changes, her psychotic symptoms worsened.
Because she did not respond to the medication
changes, we diagnosed a chronic interictal psychotic disorder
74 | www.cogbehavneurol.com
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Cogn Behav Neurol  Volume 30, Number 2, June 2017
superimposed over a slowly progressive cognitive decline
secondary to pharmacoresistant epilepsy (ie, the failure of
her antiepileptic drugs to prevent her seizures). Practically,
for epilepsy to be classified as pharmacoresistant, the patient
must be taking two or three antiepileptic drugs without
adequate response (Alexopoulos, 2013).
Inpatient Trials of Second-Generation
Antipsychotic Drugs
We started the patient on the antipsychotic drug
aripiprazole at 5 mg, below the therapeutic dose, to try to
ensure her safety. Over the next 2 weeks we increased to
the therapeutic dose of 10 mg, and then, when she did not
respond, to 20 mg. Because she still did not improve, we
gradually cross-tapered her from aripiprazole to risper-
idone at a starting dose of 2 mg. Once she was off the
aripiprazole, we gradually raised the risperidone over
about 2 weeks to a maximum dose of 7 mg: 3 mg in the
morning and 4 mg at bedtime. On this regimen her dis-
inhibition improved but her psychotic symptoms con-
tinued without significant change. Further, her prolactin
level became elevated.
A note about our choice of antipsychotic drugs:
First-generation antipsychotics such as haloperidol tend
to cause slightly fewer EEG abnormalities than second-
generation drugs, but we favored the second generation in
light of our patient’s age and the potential risks of
extrapyramidal side effects. We chose to try her first on
aripiprazole to minimize weight gain in an already over-
weight woman.
Altogether, we allowed 51 days for the aripiprazole
and then the risperidone to take effect. After those two
unsuccessful trials of antipsychotics at therapeutic doses,
we deemed the patient’s psychosis to be pharmaco-
resistant (using the definition of pharmacoresistance in
schizophrenia: a failure to respond to two different anti-
psychotic drugs at therapeutic doses [Conley and Buchanan,
1997]). Faced with the prospect of the patient’s being placed
in long-term care, we elected to try one last resort: treating
her with clozapine despite the risk of destabilizing her
seizure disorder.
We kept her on her current risperidone regimen of
3 mg in the morning+4 mg at bedtime, and started her on
clozapine 12.5 mg at bedtime. If she tolerated the cloza-
pine, we planned to try raising the dose to an initial target
level of 25 to 75 mg. To ensure her safety, we kept her in
the hospital’s EEG telemonitoring unit while titrating her
dose.
Because the combined treatment did not disrupt her
seizure frequency or produce an adequate response, we
modified our plan. We transferred her to the psychiatric
ward and began gradually tapering her risperidone while
increasing her clozapine. We kept her antiepileptic drugs
at their previously optimized doses.
Over the course of 45 days, we lowered the risper-
idone to 3 mg daily and raised the clozapine to 300 mg at
bedtime. We monitored her through a pre-treatment
electrocardiogram, daily vital signs, and a weekly blood
cell count.
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Cogn Behav Neurol  Volume 30, Number 2, June 2017
Throughout the titration, she continued to have
clinical seizures with impaired awareness at their usual
frequency of one every 1 to 2 days. However, after the
first few weeks of the titration, she had a marked reduc-
tion in visual hallucinations and her occasional episodes
did not affect her behavior. The intensity of her bizarre
delusions was also greatly reduced. Her behavior became
less oppositional, evidencing only brief periods of irrita-
bility in postictal states.
This remarkable improvement allowed her to be
discharged back to her previous semi-autonomous su-
pervised housing.
It is noteworthy that she did not show any ex-
trapyramidal symptoms, cytopenia, dyslipidemia, glucose
abnormality, or gait instability throughout the titration
or at any time after her discharge.
Follow-Up After Discharge
In the first months after discharge, the patient had a
brief increase in seizure frequency, but not intensity. Then
the rate of seizures quickly returned to baseline.
Over the first 8 months after discharge, we were able
to taper the risperidone down to 1 mg at bedtime. Because
complete cessation caused a transient increase in her
psychotic symptoms, we reinstated the minimal dose. We
kept her clozapine dose at 300 mg at bedtime.
We were able to monitor her seizure frequency
clinically rather than with video-EEG, given her well-
documented almost constantly abnormal EEG and the
stability of the video-EEG monitoring during the titra-
tion.
At her last follow-up visit, 18 months after dis-
charge, the patient exhibited little psychotic disturbance,
making only fleeting odd comments. The clozapine and
risperidone had caused her a moderate weight gain of
20 pounds as well as mild orthostatic hypotension and
a slight, tolerable sedation.
DISCUSSION
Giving antipsychotic drugs to patients with epilepsy
carries an inherent risk of lowering the seizure threshold
(Kumlien and Lundberg, 2010). In a blind study com-
paring the EEGs of patients receiving typical or atypical
antipsychotics, Centorrino et al (2002) found abnormal-
ities in 1.9% and 5.1% of recordings, respectively.
Among the atypical antipsychotics, clozapine causes
the most EEG alterations and seizures (Centorrino et al,
2002; Kumlien and Lundberg, 2010). The physiological
mechanism behind this phenomenon remains unclear, but
might be related to a higher selectivity for mesolimbic
dopamine receptors, which would induce a proconvulsive
effect (Kumlien and Lundberg, 2010). Despite this risk,
control of psychotic symptoms is crucial both to patients’
well-being and to the control of their epilepsy, and most
patients’ symptoms can be controlled without increasing
seizure frequency (Hamed, 2011; Okazaki et al, 2014).
Clozapine has been shown to induce EEG abnor-
malities in up to 47.1% of recipients (Centorrino et al,
2002) and to induce seizures in 1.3% to 4.4% (Devinsky
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Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.
Clozapine in Pharmacoresistant Epilepsy
et al, 1991; Pacia and Devinsky, 1994; Toth and Frank-
enburg, 1994; Trimble and Schmitz, 2011). Seizures are
more common in patients with documented EEG
abnormalities or epilepsy, patients who are taking other
epileptogenic drugs, and patients who recently quit
smoking (Devinsky et al, 1991; Williams and Park, 2015).
Seizures induced by clozapine are mostly of the tonic-
clonic type (Williams and Park, 2015).
Clozapine is a strong CYP1A2 enzyme inhibitor, a
moderate CYP2D6 inhibitor, and a strong CYP3A4 in-
ducer (Lexicomp Onlines, 2017). Notably, patients who
are poor CYP2D6 metabolizers may need lower doses of
clozapine, although recommendations remain contra-
dictory (Prior and Baker, 2003). Patients who have two
highly active copies of the CYP1A2 gene may also be
particularly susceptible to clozapine-induced seizures
(Kohlrausch et al, 2013). To avoid drug interactions when
starting clozapine, physicians need to consider carefully
the antiepileptic drugs and other medications that their
patient is taking.
Seizure frequency with clozapine is dose related
(Toth and Frankenburg, 1994). High doses (>600 mg
daily) have been linked to seizure rates of 4.4%, medium
doses (300 to 600 mg daily) to rates of 2.7%, and low
doses (<300 mg daily) to rates <1% (Devinsky et al,
1991). Seizures are more common during the
titration phase for the 300 mg dose and during the
maintenance phase for the 600 mg dose (Pacia and De-
vinsky, 1994).
The clozapine serum concentration has been re-
ported as potentially a better seizure predictor than dose,
with a serum concentration >1000 ng/mL (3 mmol/L)
being related to higher seizure rates (Greenwood-Smith
et al, 2003; Remington et al, 2013; Williams and Park,
2015). There also seems to be a minimum clozapine serum
level of somewhere between 350 and 420 ng/mL, below
which <25% of patients will respond to the drug.
We do not recommend adjusting a clozapine dose
based on serum concentration alone. It is a poor predictor
of seizures, as inter-individual and even intra-individual
serum levels vary widely (Greenwood-Smith et al,
2003; Remington et al, 2013; Williams and Park, 2015).
Further, patients whose dose has been changed based just
on serum level have been shown to have worse control of
their psychotic symptoms (Greenwood-Smith et al, 2003).
We recommend measuring serum levels only for
these reasons: poor clinical response, signs of toxicity, use
of a concomitant medication that interacts with the
CYP450 enzyme system, a change in caffeine or tobacco
consumption, liver disease, and concerns about com-
pliance (Greenwood-Smith et al, 2003).
Before our patient, eight others had been reported
who were treated with clozapine for psychosis, and none
showed an increase in seizures (Antony et al, 2008; Langosch
and Trimble, 2002). The novelty of our case report lies in
the successful use of clozapine in a patient with severe
pharmacoresistant epilepsy. We found that clozapine can be
used safely and effectively for pharmacoresistant psychosis,
even in a patient with daily seizures.
www.cogbehavneurol.com | 75
Jette´ Pomerleau et al
We advise starting the medication at a low dose under
inpatient EEG monitoring, and slowly increasing to a
theoretical maximum of 300 mg daily under close neuro-
psychiatric monitoring. Antiepileptic drugs should be
optimized before and during titration, as needed. A routine
outpatient EEG is not mandatory for monitoring once the
therapeutic dose has been established, but an EEG is
needed if the patient’s seizure profile or frequency changes.
There are conflicting data on the target serum level
for clozapine. The therapeutic range varies from 0.75 to
1.26 mmol/L or 250 to 420 ng/mL (Greenwood-Smith
et al, 2003; Remington et al, 2013; Williams and Park,
2015). To maximize safety, we recommend a target at the
lower end of the therapeutic range.
We do not recommend measuring all patients’ initial
clozapine serum concentrations, but we do recommend
getting serum levels for patients with adverse reactions
such as signs of toxicity or an increase in seizure
frequency (Greenwood-Smith et al, 2003; Williams and
Park, 2015). Above all, clinicians should be attentive to
any change in seizure frequency and/or psychotic symp-
toms and should base their decisions on these factors
rather than serum concentration alone.
ACKNOWLEDGMENTS
The authors thank the patient and her family for sharing
her medical information.
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