Open Access | Case
This work is licensed under a Creative
Commons Attribution-ShareAlike 4.0 International License.
The case of a geriatric female experiencing frequent falls and epileptic seizures during long-term low-dose clozapine and extended-release bupropion treatment
* Corresponding author: Charisse Dzierba
Mailing address: Buffalo Psychiatric Center, 400 Forest Avenue,
Buffalo, NY 14213, USA.
Email: cbchehov@buffalo.edu
Received: 11 May 2023 / Revised: 05 June 2023 / Accepted: 19 June 2023 / Published: 28 June 2023
DOI: 10.31491/APT.2023.06.114
Abstract
There are few reports describing the incidence of seizures in patients prescribed a combination of clozapine and bupropion for the treatment of psychiatric disorders, despite the known drug-drug interaction associated with concomitant use. We report the case of a 67-year-old geriatric woman who experienced multiple falls and seizures while receiving a low daily dose of clozapine 200 mg and bupropion extended-release (XL) 150 mg. There was no recurrence of seizure activity after discontinuation of bupropion and initiation of an antiepileptic drug, divalproex. This case report suggests that bupropion in combination with low-dose clozapine may increase the risk of seizures in elderly patients.
Keywords
Epilepsy, drug-induced seizures, adverse drug reaction, bupropion, clozapine, geriatric, falls, falls risk
Introduction
Although the occurrence of a single seizure does not constitute a diagnosis of epilepsy, seizure episodes can have
serious consequences and should therefore be a constant
consideration when prescribing, and when risky combinations are clinically necessary, this pharmacologic monitoring should include reducing the additive risk whenever
possible. One such risk-reduction strategy is the addition
of an antiepileptic drug such as divalproex (Depakote),
which has mood-stabilizing benefits in addition to reducing seizure risk [1]. Other risk factors in the elderly include infection, head trauma/injury (which can occur as
a result of falls), and electrolyte imbalances [2]. Some of
these factors are more prevalent in the geriatric population. In addition, several medications have been associated
with the potential to cause seizures, including medications
used to treat psychiatric disorders, such as antipsychotics
and antidepressants [2, 3].
Two medications commonly associated with seizure risk
are the dopamine-modulating antidepressant bupropion
(Wellbutrin) and the second-generation antipsychotic
clozapine (Clozaril) [4, 5]. Concomitant use of both has
been reported to increase this risk. However, there is little
information on the absolute risk or rate of seizures associated with the combination of low-dose clozapine and bupropion, and there is no clear indication of whether these
medications, when used together, provide a synergistic
effect that results in improved psychiatric outcomes where
the benefit of the combination exceeds the risk of seizures
[6].
Clozapine is indicated for patients with treatment-resistant
schizophrenia or for patients with suicidal ideation in
schizophrenia and is associated with serious side effects,
including seizures [4, 7]. There are conflicting results in
the literature regarding the rate of seizures with clozapine
use. One report concluded that the incidence of seizures
was 6%, with the risk increasing with increasing daily
dose, with a risk of 3% in those receiving less than 300
mg, 8% in those receiving 325 mg to 500 mg, and 38%
in those receiving more than 500 mg daily [7]. Clozapine
may be continued in patients with seizures if their epilepsy is controlled, whereas bupropion is contraindicated in
patients with a seizure disorder [4, 7]. Bupropion is indicated for patients with major depressive disorder and has
been shown to be safe and effective in elderly patients [7].
As with clozapine, evidence suggests that the risk of seizures with bupropion use is dose-dependent, with higher
doses associated with greater risk.
Although epileptic seizures in adults are most common in
later life, with 25% of new seizures occurring in the elderly, seizures are difficult to identify in this population [8].
For this and likely other reasons, seizure-related falls are
underestimated and not well documented in older adults.
While generalized tonic-clonic seizures can lead to a fall
while standing, several types of seizures can lead to falls,
including focal parietal or frontal seizures and generalized
myoclonic seizures [8]. However, other types of seizures
may also lead to falls and cannot be excluded. It must be
considered that our patient may have had undiagnosed
seizures that were attributed to falls [8].
This case report discusses an elderly patient who experienced sixteen falls over a five-month period. Some of the
falls were documented as seizures or seizure-like activity.
However, due to the nature of seizures, which are difficult
to diagnose in this population, and because several falls
were unwitnessed, the patient may have experienced more
seizures than were documented. The patient had been receiving a combination of bupropion XL 150 mg daily and
clozapine 200 mg daily for several years to treat her depression and schizophrenia. While neither medication was
dosed at its maximum, there is little information to reflect
the potential synergistic effects these medications may
have on the seizure threshold. Their use together should
be approached with extreme caution. Because clozapine
is used in treatment-resistant schizophrenia, bupropion
should be substituted with another medication when appropriate, especially in geriatric patients who are prone to
falls.
Case report
A 67-year-old Hispanic woman was admitted to an inpatient psychiatric facility with a diagnosis of schizophrenia,
treated with 200 mg oral clozapine and 5 mg oral fluphenazine daily, and depression, treated with 150 mg oral
bupropion XL daily. Her medical diagnoses included osteopenia treated with alendronate and calcium carbonate;
constipation treated with docusate, polyethylene glycol,
magnesium hydroxide, and phosphate enema; vitamin D
deficiency treated with ergocalciferol; and hypothyroidism treated with levothyroxine. The patient had no history
of seizures before and during her treatment with clozapine
and bupropion, which began in 2015 and 2017, respectively, and continued through 2019. In addition, her mother had a history of epileptic disorder, but no additional
information was available.
Beginning in March 2019, the patient experienced frequent falls, resulting in the initiation of hip pads and a helmet (Table 1). Her falls were attributed to behavioral and
environmental factors. The patient received nonpharmacologic interventions, including a haircut to ensure that her
bangs were out of her face, decluttering of her bedroom,
and education on the importance of standing and walking
slowly and safely. On June 24, 2019, staff reported that
she fell to the floor and appeared to be having a seizure. She experienced upper and lower extremity twitching, an
inability to follow commands or concentrate, and a scalp
laceration. She was also noted to have an increase in impaired neurological function and subsequent increase in
falls according to her psychologist’s reports. Following
the fall, she was transported to an acute care medical facility for further evaluation and returned to the inpatient psychiatric facility the following day. Her pharmacotherapy
was continued without change.
Table 1
History of frequent falls.
Fall date (2019) | Additional details |
---|---|
March 18 | Tripped on the way to lunch |
April 7 | Patient found on floor, required stitches |
May 9 | Unwitnessed, laceration to right forehead |
May 14 | Reopened previous wound with two new lacerations requiring Steri-Strips |
June 10 | Occurred while walking, skin tear to forehead |
June 16 | Contusion to forehead |
June 24 | Seizure with head laceration requiring sutures |
June 26 | Occurred while walking and resulted in no injuries |
July 4 | Myoclonic jerks, repetitive hand motion, and limited response to verbal cues |
July 11 | Tripped over feet |
July 12 | Unwitnessed, found lying in hall |
July 20 | Lost balance running down hallway |
July 23 | Walking fast, bruised knees and palm |
July 28 | Tripped over her feet standing from chair |
August 9 | Found sitting on floor in hallway |
August 11 | 3-minute seizure with convulsions, mouth frothing and unconsciousness |
July 23 | Walking fast, bruised knees and palm |
July 28 | Tripped over her feet standing from chair |
August 9 | Found sitting on floor in hallway |
August 11 | 3-minute seizure with convulsions, mouth frothing and unconsciousness |
On July 4, 2019, the patient experienced a fall that was
described as myoclonic jerking with repetitive hand move ments and limited response to verbal cues. On August 11,
2019, she experienced another seizure. This seizure was
longer, lasting three minutes. The seizure was described as
having started while the patient was walking. The patient
was transported to an acute care facility for follow-up,
where she was diagnosed with acute post-ictal encephalopathy. Bupropion was withheld due to its potential contribution to seizure activity, and divalproex was added as
an antiepileptic agent. Although clozapine has a side effect
of seizures, it was continued because of the risk of withdrawal symptoms with abrupt discontinuation. A head CT
without IV contrast on August 16 showed mild age-related
brain changes and chronic small vessel ischemic disease.
There was no evidence of acute abnormality, intracranial
mass, hemorrhage, fracture, or significant interval change.
The patient’s psychiatrist was uncertain whether the seizure was due to a recent fall in which the patient hit her
right forehead.
Upon return to our inpatient facility five days later, bupropion was not reinitiated and divalproex was titrated and switched to valproic acid. Lithium was also discontinued.
On August 22, the patient’s valproic acid level was within
the therapeutic range for the treatment of epilepsy at 61
µg/mL. Sertraline was started on September 14 and titrated to 100 mg daily. The patient did not have another
fall or seizure during the remainder of her treatment at our
institution. She was discharged in January 2020.
Discussion
Medications, alcohol withdrawal, metabolic disorders,
stroke, and traumatic brain injury are some causes of
seizures [9]. Medications considered to have a moderate risk of seizures include chlorpromazine, meperidine,
clozapine, and bupropion. Of the medications prescribed
to this patient, bupropion and clozapine are two medications that may have precipitated the two seizure events as
an adverse drug reaction (ADR). A drug safety committee
reviewing this event as a potential ADR accepted the prescriber’s suggestion that other factors were responsible for
these events because the patient had been taking the two
medications concurrently for an extended period of time
without seizures.
Bupropion has a long history of known seizure risk and
was removed from the market by the FDA in 1985 due to
the high incidence of seizures and was implicated in 23
percent of drug-induced seizures reported to the California
Poison Control System in 2003, nearly three times the rate
of any other drug, according to a retrospective review [10,
11]. However, the risk of seizures with bupropion XL has
not been formally reviewed [11]. With bupropion in particular, older adults may be at greater risk of accumulation
with chronic dosing [6]. As our patient was over 65 years
of age, serum bupropion levels may have been useful in
determining the cause of her seizures, but these levels
were never obtained.
Antipsychotics share a class-related risk of lowering the
seizure threshold. The antipsychotic most commonly associated with seizures is clozapine, the most effective
antipsychotic for treatment-resistant schizophrenia [3, 6].
Clozapine lowers the seizure threshold in both epileptic
and non-epileptic patients, and a seizure can occur at any
stage of treatment [12]. The estimated cumulative risk of
seizure is 10 percent in patients treated with clozapine for
3.8 years [6]. Seizures may be avoided or the risk minimized if the daily dose does not exceed 450 mg, as was
the case in our patient who was on a daily dose of 200 mg
[3].
Interestingly, an evidence-based review found that there is
little convincing evidence to support a strict relationship
between clozapine serum levels and seizure risk [13]. Seizures can occur at doses as low as 37.5 mg daily. Plasma
clozapine levels as low as 144 nmol/L have been associated with seizure activity. Therefore, serum clozapine
concentrations may be used as a guide but are not a definitive predictor of therapeutic efficacy or seizures [12]. A
seizure is not an adverse reaction that generally warrants
discontinuation of clozapine, and its onset usually occurs
between two and four weeks after initiation, but may occur at any stage of treatment. If discontinuation of clozapine is not appropriate, as was the case in our patient, an
antiepileptic drug such as divalproex can be started and
the patient monitored for adverse effects [3].
Seizure risk may be increased in patients with a history
of seizures, head trauma, anorexia/bulimia, CNS tumor,
severe liver cirrhosis, abrupt discontinuation of a sedative
hypnotic or alcohol, and medications that lower seizure
threshold [14]. In our patient’s case, she had a history of
one seizure in June 2019, experienced head trauma from
her many frequent falls, some of which required stitches
and hospitalization, and was prescribed clozapine and
bupropion. Another factor to consider is the patient’s age,
which at the time was 67 years old. Older patients differ
from younger patients in their response to pharmacologic
treatment, which can be unpredictable and variable. In
comparison, the average therapeutic dose of clozapine for
non-geriatric adults is 300-600 mg/day.
Both clozapine and bupropion are recognized as medications with a tendency to lower seizure thresholds individually, but there is currently little information on the
risk of using these two medications in combination. It is
unclear whether these agents have an additive seizure risk
or possible synergistic effects when used in combination.
However, bupropion should be used with caution in patients treated with clozapine. Agents that do not lower the
seizure threshold should be used as a safer option when
possible [6]. In the case of two patients without a history
of seizures who experienced epileptic events while treated
with clozapine and bupropion, the seizures resolved after
bupropion was discontinued and divalproex was initiated
for seizure prophylaxis, as was observed in our patient [6].
The patient had two seizures within two months of each
other. The factors that caused the falls cannot be definitively determined. In two cases of elderly patients with
falls secondary to seizures, the falls were not recognized
as seizures because of the many other comorbidities [8].
Clozapine and bupropion have a long history of lowering
the seizure threshold. The risk of seizures increases with
dose escalations of each of these medications, but the risk
of seizures when these two medications are used together
is unknown. The patient also had a history of frequent
falls that may have resulted in neurologic injury, a factor
that was considered by her care team. The patient’s history of tolerating the combination of low-dose clozapine
and bupropion is known. Her psychiatrist ensured that the
patient was on the lowest effective dose of each medication. However, with age, some medications can become
less well tolerated. In addition, the patient’s recent history
of falls leading to neurological changes and possible brain
injury are exactly the conditions that could have led to
seizures.
The patient’s history of multiple falls, many of which resulted in injury even while wearing protective equipment,
placed her at even greater risk for seizures. The patient’s
care team quickly changed her therapy to remove bupropion and continue an antiepileptic drug, divalproex, added
by the acute care facility where she was being treated.
Clozapine was continued, as it is typically used for treatment-resistant schizophrenia, and the patient has remained stable on this therapy. Seizures are not a contraindication to clozapine therapy; however, seizure disorders are
a contraindication to bupropion therapy. Therefore, the
decision to discontinue bupropion rather than clozapine
to reduce the risk of seizures is the most appropriate option from a patient care perspective. The patient was also
ordered a geriatric chair to reduce her risk of falls. With
these changes, the patient had no further epileptic events.
Bupropion and clozapine likely contributed to an adverse
drug reaction of seizures in this patient, and for this reason, bupropion should be used cautiously in patients treated with clozapine, especially those with a history of head
trauma, including those with a history of frequent falls.
In addition, this case provokes consideration of how a
prescriber’s perception or definition of an ADR can influence and alter the course of both clinical and academic
investigation of the actual event [15]. There are numerous
definitions of adverse drug reactions; however, most in the
medication safety community would agree that a previously reported adverse effect of a known drug-drug interaction, regardless of the timeline in which it occurred, is
an undesirable but preventable adverse drug reaction. The
benefit and value of identifying, investigating, and reporting ADRs not only to the institution’s clinical leadership,
but also to the FDA through MedWatch, is that these rates
can be more realistically measured and new, previously
unrecognized ADRs can be evaluated for possible inclusion in updated package labeling information [16].
Declarations
Authors’ contributions
Dzierba C, Lee C, and Demler TL contributed equally to the preparation of this case report. All listed authors concur in the submission and are responsible for its content; they have consented to its publication and have authorized the corresponding author to act on their behalf in all matters relating to publication.
Financial support and sponsorship
None.
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
Written informed consent for publication of clinical data and/or clinical images was not obtained from the patient, as the patient was not available for consent due to discharge. All information that would reveal the identity of the patient was removed. No patient-sourced tissue or material was involved in this paper.
References
1. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord, 2018, 20(2): 97-170. [Crossref]
2. Liu S, Yu W, & Lü Y. The causes of new-onset epilepsy and seizures in the elderly. Neuropsychiatr Dis Treat, 2016, 12: 1425-1434. [Crossref]
3. Oh CY, & Bainbridge J. Lowering the seizure threshold associated with antidepressants, stimulants, antipsychotics, and others. Ment Health Clin, 2012, 2(5): 127- 128. [Crossref]
4. Clozaril (clozapine)®. Rosemont, PA. Novartis Pharmaceuticals Corporation, February 2017.
5. Wellbutrin (bupropion)®. Greenville, NC. GlaxoSmithKline, June 2009.
6. Schmitz A, Botner B, & Hund M. Bupropion With Clozapine: Case Reports of Seizure After Coadministration. J Pharm Pract, 2021, 34(3): 497-502. [Crossref]
7. Grover S, Hazari N, Chakrabarti S, & Avasthi A. Association of Clozapine with Seizures: A Brief Report Involving 222 Patients Prescribed Clozapine. East Asian Arch Psychiatry, 2015, 25(2): 73-78.
8. Nguyen-Michel VH, Bornand A, Balathazar AM, Kinugawa K, Lâm XY, Piette F, et al. Fall related to epileptic seizures in the elderly. Epileptic Disord, 2015, 17(3): 287-291. [Crossref]
9. Beleza P. Acute symptomatic seizures: a clinically oriented review. Neurologist, 2012, 18(3): 109-119. [Crossref]
10. Thundiyil JG, Kearney TE, & Olson KR. Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System. J Med Toxicol, 2007, 3(1): 15-19. [Crossref]
11. Rissmiller DJ, & Campo T. Extended-release bupropion induced grand mal seizures. J Am Osteopath Assoc, 2007, 107(10): 441-442.
12. Wong J, & Delva N. Clozapine-induced seizures: recognition and treatment. Can J Psychiatry, 2007, 52(7): 457- 463. [Crossref]
13. Khoury R, & Ghossoub E. Antipsychotics and seizures: What are the risks? Current psychiatry, 2019, 18: 21-33.
14. Semla TP, Beizer JL, & Higbee MD. Geriatric dosage handbook: including monitoring, clinical recommendations, and OBRA guidelines. Hudson, Ohio: Lexi-Comp, 2009, 14th ed.
15. O’Donnell C, Demler TL, & Dzierba C. Perceptions and barriers of adverse drug reaction reporting within inpatient state psychiatric facilities. Ment Health Clin, 2022, 12(4): 247-253. [Crossref]
16. Demler TL, & Chehovich C. Trends of Adverse Drug Reaction Reports in a Hospitalized Psychiatric Population: Exploring Prescriber Discontinuations as Potential Unreported Adverse Drug Events. Innov Clin Neurosci, 2021, 18(7-9): 29-38.