US Pharm. 2013;38(11):HS15-HS20.
ABSTRACT: Most antiepileptic drugs (AEDs) cause some degree of
adverse drug reactions. Behavioral side effects (BSEs) associated with
AEDs are often overlooked, but are a significant consideration.
Agitation, aggression, psychosis, behavioral disorders, hyperactivity,
and restlessness are some AED-related BSEs. Contributing causes may
include pharmacologic activity, forced normalization, patient
characteristics, individual susceptibility, and medication parameters
such as dosage and drug interactions. The pharmacist must educate the
patient and caregivers about possible BSEs in order to minimize the
impact of behavioral changes and improve quality of life.
The goal of epilepsy treatment is to achieve a seizure-free state
with minimal medication side effects. Information about expected or
alarming side effects should always be communicated to patients.
Although behavioral side effects (BSEs) are fairly common with
antiepileptic drugs (AEDs), information in the pharmacy literature is
sparse. BSEs associated with AEDs frequently are overlooked, but are an
The first AED in clinical use—potassium bromide—was associated with psychiatric toxicities. Bromism, described as somnolence, psychosis, and delirium, has been extensively documented.1
Nearly all anticonvulsants cause some degree of cognitive, behavioral,
or psychiatric adverse reactions. One of the newest agents, perampanel,
has a black box warning regarding BSEs, including a 0.07% incidence of
homicidal ideation.2 A literature review, however, reveals
that this BSE may not be unique to perampanel. The purpose of this
article is to review the literature on available AEDs and categorize
their BSEs so that this information can be shared more effectively with
patients and caregivers. Specifically, this article will focus on
AED-related agitation, aggression, psychosis, behavioral disorders,
hyperactivity, and restlessness.
Pharmacology of AEDs
The AEDs have various major mechanisms of action, including blockade of voltage-gated sodium ion (Na+) and calcium ion (Ca2+)
channels; enhancement of gamma-aminobutyric acid (GABA)–ergic
neurotransmission; inhibition of glutamatergic neurotransmission; and
other mechanisms, such as modulation of synaptic vesicle proteins
(levetiracetam), potassium ion (K+) channels (ezogabine), or carbonic anhydrase (topiramate and zonisamide).3
Most AEDs have multiple pharmacologic targets; thus, a number of
activities contribute to their efficacy, as well as to their adverse
Many AEDs block voltage-gated Na+ channels. Most AEDs
delay the recovery of these channels from their fast-inactivated state,
limiting the burst firing of neurons underlying epileptic seizures. One
exception is lacosamide, which increases the number of Na+ channels in their slow-inactivated state, decreasing their availability for propagation of action potential.3 Drugs that act as Na+
channel blockers include carbamazepine, ethotoin, phenytoin, primidone,
lacosamide, lamotrigine, oxcarbazepine, rufinamide, topiramate,
zonisamide, valproic acid, and felbamate.3 Since a number of these drugs are associated with BSEs, it is likely that Na+
transport and homeostasis influence mood and behavior, and some
evidence for this exists. Studies indicate that patients with affective
disorders exhibit high plasma Na+ levels and that low Na+ diets have positive effects on mood.4,5 Furthermore, many other mood-stabilizing and antidepressant agents share the mechanism of Na+ channel blockade.6
Voltage-gated Ca2+ channels are another target for AEDs.
Ethosuximide, valproic acid, lamotrigine, and zonisamide inhibit low
voltage–activated T-type Ca2+ channels, which are implicated in absence seizures.3,7
Additionally, carbamazepine, phenobarbital, felbamate, gabapentin,
lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate,
zonisamide, and possibly phenytoin block high voltage–activated Ca2+ channels (L-, R-, P/Q-, and N-types), which are involved in neurotransmitter release.3,7 This mechanism may contribute to BSEs, since several studies indicate that Ca2+ homeostasis is important for mood and behavior. Notably, genetic variations in an L-type voltage-gated Ca2+ channel are associated with increased risk of bipolar disorder, depression, and schizophrenia.8 Furthermore, in some experimental models, Ca2+ channel blockers have antidepressant efficacy, and some antidepressants inhibit Ca2+ channel activity.9,10
Several AEDs enhance GABA-ergic neurotransmission by modulating GABAA
receptors or by increasing GABA levels in the synaptic cleft. This
mechanism is relevant for phenobarbital, clobazam, clonazepam,
tiagabine, vigabatrin, primidone (via its metabolite, phenobarbital),
valproic acid, felbamate, lamotrigine, topiramate, and zonisamide.3,7 GABA-ergic synapse dysfunction has been shown to contribute to aggressive behavior and schizophrenia.11,12
Inhibition of ionotropic glutamate receptors is another key mechanism
for AEDs. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid/kainate receptor antagonists include phenobarbital, lamotrigine,
perampanel, and topiramate.3,7,13 Additionally, carbamazepine, valproic acid, felbamate, lamotrigine, and oxcarbazepine inhibit N-methyl-D-aspartate receptors.3,7
Recent evidence suggests that aberrant regulation of glutamatergic
synapses may contribute to schizophrenia and, possibly, to mood
disorders.14 In one study, plasma glutamate levels in
patients with major depression and bipolar disorder were elevated
compared with control levels.15
While the pharmacologic activities discussed above may cause the BSEs seen with some AEDs, another factor—forced normalization—may
also contribute. In this phenomenon described in 1953 by Heinrich
Landolt, patients’ electroencephalograms paradoxically normalized and
seizure activity was inhibited during psychotic episodes.16
This idea is supported by epidemiologic studies that found lower seizure
frequency in epileptic patients with psychosis, and studies citing the
relatively few cases involving comorbid schizophrenia and epilepsy.17,18
In other words, AEDs may cause BSEs simply by suppressing seizure
activity. The symptom most commonly associated with forced normalization
is psychosis, but hypomania/mania, depression, and anxiety also have
All AEDs have the potential to affect behavior. While this article
focuses on medications as the likely cause of behavioral change, there
are other potential factors to consider. The occurrence of BSEs may be
related to seizure control (i.e., forced normalization).16
Patient characteristics and individual susceptibility also play a role
in BSE incidence. Age, epilepsy type, and presence of a learning
disability or other central nervous system or psychiatric disorder may
also influence BSEs. Specific medication parameters, including dosage,
titration rate, drug interactions, and effectiveness, also may be
related to BSEs.20
Role of the Pharmacist
Based on the available data, it can be difficult to determine the
true risk of psychiatric side effects with AEDs. The reported incidence
of these behavioral reactions varies significantly in the literature.
However, in general, AEDs with the highest incidence of aggressive-type
behavior are topiramate, tiagabine, clobazam, levetiracetam, vigabatrin,
and perampanel (TABLE 1). Psychosis, while reported much less commonly, is most frequently seen with zonisamide and topiramate (TABLE 2). Hyperactivity and restlessness have been reported most often with phenobarbital, clobazam, and vigabatrin (TABLE 3).
Finally, the more generalized term “behavioral disorder” has been
reported most frequently with topiramate, clobazam, and ethosuximide (TABLE 4).
Therefore, especially with these medications, the pharmacist must
effectively communicate possible BSEs to the patient and family or
caregivers. This dialogue is crucial, since behavioral changes can
result in a stressful environment, family instability, and other more
serious consequences. Knowledge of these behaviors can minimize the
impact of behavioral changes, lead to more rapid therapeutic adjustment,
and improve patients’ and caregivers’ quality of life.
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