MIAMI BEACH— In addition to the regulation of seizures, antiepileptic drugs have a variety of psychotropic effects that make these agents as intriguing to psychiatrists as they are to neurologists. Both the positive and negative effects should be considered when prescribing antiepileptic drugs to patients—especially elderly patients—with epilepsy or other nonepileptic disorders. Alan B. Ettinger, MD, summarized the mood- and behavior-altering effects frequently associated with antiepileptic drug therapy at the 13th Annual Meeting of the American Association for Geriatric Psychiatry.

PHENYTOIN

Dr. Ettinger warned of the potential risk of chronic encephalopathy associated with phenytoin—an effect that may partially reverse when therapy is reduced or discontinued. "Some of these patients may be ataxic, staggering to some extent," he noted. "Phenytoin is a concern when used in the elderly," continued Dr. Ettinger. He is Director of the Comprehensive Epilepsy Center at Long Island Jewish Hospital in New Hyde Park, New York, and Director of the Huntington Hospital Epilepsy Monitoring Program in Huntington, New York. "Many elderly patients may be on other drugs that compete with [phenytoin] for protein-binding sites, leading to higher free fractions of phenytoin and potential toxicity with this drug." Also, a reduced protein binding capacity in elderly patients may contribute to higher free fractions of phenytoin, resulting in toxicity.

CARBAMAZEPINE AND VALPROATE

Mood stabilization is a common positive psychotropic effect of carbamazepine and valproate, and both drugs are effective in the treatment of mania and aggression. Carbamazepine has also been used for bipolar and impulse control disorders, while valproate has been shown to reduce irritability, rage attacks, self-injurious behavior, and post-traumatic stress disorder.

It has been suggested, however, that elderly patients are sensitive to the central nervous system side effects of valproic acid. "These patients may feel duller or have some cognitive impairment on this drug," Dr. Ettinger warned.

Carbamazepine and valproate co-therapy can produce an interaction resembling carbamazepine toxicity, he noted. Patients may report double vision, poor coordination, and dizziness. Valproate monotherapy has been linked with drowsiness, decreased concentration, stupor in some cases, and encephalopathy in rare cases.

NEWER AGENTS

Many of the newer antiepileptic drugs are associated with positive and negative psychotropic effects. Gabapentin, for example, appears to have an anxiolytic property thought to result from sedation. It may also be useful as a heroic treatment in patients with severe behavioral disturbances, reported an audience member, particularly for symptoms such as sleep difficulty or disinhibitions that develop after sundown. In these cases, evening or bedtime dosing is appropriate.

There have also been anecdotal reports of improved mood, cognition, and sense of well-being in epilepsy patients treated with gabapentin, noted Dr. Ettinger, although he expressed skepticism about these reports. "How much of a role did reduction in seizures play in patients feeling better?" he questioned.

Anecdotal reports have suggested that gabapentin may cause agitation in children, especially those with intellectual disability. These children may exhibit sudden tantrums, aggression, hyperactivity, and defiant behavior, all of which tend to resolve when gabapentin is discontinued. Elderly dementia patients who are taking gabapentin may be at similar risk, Dr. Ettinger suggested.

Lamotrigine, which is effective for partial and generalized seizures, appears to stabilize mood and increase alertness. "Some of my patients actually feel quite bright, and it does appear to be independent of seizure reduction," observed Dr. Ettinger. Adverse psychotropic effects of lamotrigine may include irritability and hyperactivity, particularly in the elderly.

Though well-known for its potent antiepileptic effect, topiramate may cause psychomotor slowing. Characterized by clouded thinking and a reduced ability to express thoughts, this slowing can lead to frustration and possibly depression. Topiramate-induced psychomotor slowing is most likely in patients receiving epilepsy polytherapy, although it can be minimized by slow initiation of topiramate.

Tiagabine, which is most effective for partial seizures, has been linked with improved mood, as has the new nonpharmacologic epilepsy treatment, vagal nerve stimulation. Some studies suggest vagal nerve stimulation also enhances memory, and current studies are evaluating it as a treatment for primary depression.

A LAST RESORT

Despite the advent of newer antiepileptic treatments, phenobarbital and other barbiturates are still frequently prescribed for epilepsy. Barbiturates should be a last resort because of their potential adverse effects, Dr. Ettinger suggested.

Depression is common in patients taking barbiturates. In a study of pediatric epilepsy patients admitted to the emergency department, 40% of those taking phenobarbital had symptoms of major depressive disorder as compared with only 4% of carbamazepine recipients. The rate of suicidal ideation was also markedly greater among those treated with phenobarbital (47% versus 4% for carbamazepine).

"We also know that barbiturates may cause paradoxical effects such as hyperactivity, aggression, impulsiveness, sedation, and mood shifts," added Dr. Ettinger. Withdrawal seizures may occur when reducing or stopping chronic barbiturate therapy, necessitating dosage reductions in small, gradual increments.

Paradoxical effects tend to occur very quickly and acutely. They most often appear in younger patients with developmental disabilities and elderly patients with dementia and cognitive impairment. They are expected to reverse upon stopping barbiturate therapy, Dr. Ettinger said.

—Timothy Begany

Suggested Reading
Brent DA, Crumrine PK, Varma RR, et al. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics. 1987;80:909-917.
Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(suppl 2):S53-S67.
Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia. 1999;40 (suppl 10):S65-S70.

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