Psychiatric Side Effects of Antiepileptic Drugs

Bettina Schmitz

Introduction

Central effects of antiepileptic drugs (AEDs) are not restricted to the modulation of cortical excitability. AEDs may also modify systems that regulate mood and behavior. Anticonvulsant and psychotropic effects are not independent. Effects on seizure control have indirect effects on the mental state. Patients who are seizure-free have no risk of developing seizure-related psychiatric complications. On the other hand, the sudden cessation of seizures may lead to an imbalance in the mental state, as in “forced normalization” (FN). Some AEDs have dose-related paradoxical proconvulsive properties that may cause behavioral disturbances through underlying nonconvulsive status epilepticus.

Psychotropic effects may be negative or beneficial in individual patients. These effects depend on the antiepileptic strength, the mode of action of the anticonvulsant, and the patient’s biologic and psychological predisposition. With the increasing variety of AEDs available, behavioral drug profiles have become very important for optimal treatment choices in epilepsy. Recent quality-of-life studies have shown that measurements of depression and the tolerability of AEDs are more important to patients than seizure reduction.¹⁶ Furthermore, the high psychiatric comorbidity in epilepsy often requires psychopharmacologic interventions, which may be avoided when those anticonvulsants used have positive psychotropic properties.

In clinical praxis, the adverse psychiatric effects of AEDs are often not recognized. Often patients don’t complain about behavior or mood changes unless they are specifically interviewed. Many neurologists are not competent in the exploration of a mental state, or they don’t have the additional time needed to evaluate a patient’s mental state. Many depressed patients are not primarily troubled by obvious depressive symptoms such as sadness or feelings of guilt. Depression in epilepsy often presents with sleep disorders or somatoform complaints and memory problems, which makes the diagnosis difficult unless the full psychopathologic status is explored. If delayed adverse psychiatric effects occur after months or years of exposure, the causal relationship with drug treatment is often not considered and is in fact difficult to prove, unless drug withdrawal is followed by the remission of psychiatric symptoms.

The exact prevalence of psychiatric AED events is difficult to estimate. In a consecutive series of patients with epilepsy and significant depression, about 30% were considered to have AED-related symptoms.²¹^,³⁹ With respect to psychoses, the percentage of episodes triggered by AEDs has been calculated to be 40% in one study.³⁰

Adverse Psychiatric Effects of Specific AEDs

Conventional Drugs

Barbiturates

Several studies suggested a link between depression and treatment with barbiturates, both in adults and in children.^5,36. Forty percent of school children treated with barbiturates were diagnosed with “major depression,” as compared with only 4% of children treated with carbamazepine.⁴ In children, a conduct disorder resembling attention deficit hyperactivity disorder may be provoked by many AEDs, the most frequently implicated drug being phenobarbitone. Irritability and aggressive behavior are side effects particularly often seen when barbiturates are used in mentally retarded patients. Withdrawal problems, which present with nervousness, dysphoria, and insomnia, may occur even when barbiturates are very slowly tapered down.

Phenytoin

Phenytoin may provoke schizophrenia-like psychoses at high serum levels.³² These psychoses are dose related—and are thus toxic syndromes—but they are not associated with the cerebellar signs that are the most common central nervous system side effects of phenytoin. In a study of 45 patients with drug-related psychoses, 25 (56%) cases were attributed to treatment with phenytoin.²⁰ A chronic encephalopathy has also been described with phenytoin use, and has been referred to as “Dilantin dementia.”⁴⁴

Ethosuccimide

Psychoses typically following cessation of seizures and associated with a normalization of the electroencephalogram (EEG) occur in 2% of children treated with ethosuccimide. The risk of FN is higher (8%) in adolescents and adults treated with ethosuccimide for persisting absence seizures.⁴⁵

Carbamazepine

Affective problems are rare complications of treatment with carbamazepine.⁸ These complications present as either depressive disorders or mania, the latter being explained as a paradoxical effect due to the antidepressant properties of carbamazepine, which is chemically related to tricyclic antidepressants.⁹

Valproate

Rarely, valproate is associated with acute or chronic encephalopathies.³⁷^,⁴⁰^,⁴⁷ These encephalopathies are related to dose and perhaps polytherapy, and they are reversible with dose reduction.

Table 1. Incidence rates of psychoses and depression in controlled trials (Besag,² Janssen-Cilag,¹⁸ and Levinson and Devinsky²⁸)

	Psychoses (%)	Depression (%)
Vigabatrin	2.5	12.1
Lamotrigine	0.2	–
Felbamate	0.02	–
Gabapentin	0.5	–
Topiramate	0.8	9–18
Tiagabine	0.8–2	5
Levetiracetam	0.3–0.7	0.5–2

Newer AEDs

Table 1 summarizes data from premarketing controlled trials suggesting a relatively high frequency of depressive reactions in vigabatrin, tiagabine, and topiramate, and relative low rates for lamotrigine, gabapentin, and levetiracetam. Obviously psychiatric risks of the newer AEDs are not the same for all compounds. Some of the drugs seem to have neutral effects, some have a relevant risk for negative effects, and some may have predominantely beneficial psychotropic effects. A general comment is that the overall psychiatric risks of newer AEDs are not lower than those of older AEDs.

Vigabatrin

The risk of psychiatric complications caused by vigabatrin has been analyzed in two meta-analyses. The overall incidence of psychoses and severe behavioral reactions leading to drug discontinuation in seven placebo-controlled European studies was 3.4% in the vigabatrin group and 0.6% in the placebo group.¹³ Another meta-analysis on the psychiatric risks of vigabatrin²⁸ translated psychopathologic symptoms described in the investigator forms into standardized psychiatric terminology, which was then summarized into a syndromatic diagnosis. This analysis of U. S. and non-U. S. double-blind studies demonstrated a significantly increased risk for psychosis and particularly for depression. Psychoses occurred in 2.5% of patients treated with vigabatrin compared to an incidence of 0.3% in the placebo group (p < 0.05), and depression occurred in 12.1% of patients treated with vigabatrin in contrast to only 3.5% in the placebo group (p < 0.001).

Lamotrigine

Severe psychiatric complications are rare with lamotrigine, and psychosis and depression occurred only in very few cases in trials.¹⁴ Insomnia, which may be associated with irritability, anxiety, or even hypomania, is the only significant psychiatric side effect, occurring in 6% of patients treated in monotherapy, compared with 2% in patients treated with carbamazepine and 3% in patients treated with phenytoin.⁶

When first reports surfaced of caregivers complaining that handicapped patients had become more alert and demanding, it was interpreted as reflecting inadequate rehabilitation facilities, rather than a negative side effect.³ Besag refers to this as a “release phenomenon.”² There are, however, a number of reports that children with learning difficulties and adults with mental handicaps develop behavioral problems such as aggression.¹^,¹² Reports have also noted the induction of a reversible Tourette syndrome, which in some cases was accompanied by obsessive compulsive symptoms.²⁹

Felbamate

Felbamate is at present only used in a minority of patients, particularly those with Lennox-Gastaut syndrome, due to its hematologic and hepatic toxicity. Felbamate may lead to increased alertness, thus inducing sleep problems and behavioral problems related to agitation in some patients, particularly in children with learning disabilities.³¹

Gabapentin

Beyond somnolence, negative psychotropic effects have not been demonstrated in controlled studies of gabapentin. However, a number of studies suggest that gabapentin may induce behavioral problems such as aggression in children with learning disabilities and adults with mental handicap,²⁶^,⁴²^,⁴⁶ possibly related to rapid titration. In elderly people with reduced creatinine clearance, gabapentin may cause various neurotoxic symptoms due to its renal elimination.

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