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 important consideration.

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 effects.

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 been described.19

Other Considerations

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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