SAN FRANCISCO—When felbamate was approved as a treatment for seizures in patients with epilepsy in the mid-1990s, it became the first new antiepileptic drug on the market in 15 years. Since then, another seven agents have become available. Although these newer agents offer patients an improved side-effect profile compared to older drugs such as phenobarbital, little is known about the relative prevalence among newer antiepileptic drugs of such adverse effects as cognitive impairment or psychiatric/behavioral problems.

The results of several retrospective analyses drawn from a larger, ongoing database study suggest that many of the newer antiepileptic drugs have a distinct side-effect profile and that individual patients have different risks for specific side effects.

Such results have important implications for how neurologists and other clinicians should be treating —or altering their treatment of—patients with epilepsy, said Lawrence J. Hirsch, MD, principal investigator of the Columbia Antiepileptic Drug Database study. In his view, the data emphasize the need for clinicians to individualize treatment, including considering how well patients responded to prior antiepileptic drug treatment before prescribing a new regimen. Perhaps more importantly, the results can help guide clinicians to compare and choose agents depending on their expected side-effect profile for a given patient—an evidence-based approach that was not previously possible.

“Our data allow head-to-head comparisons of all the newer antiepileptic drugs with regard to overall effectiveness and tolerability or with regard to specific side effects,” Dr. Hirsch said. He is Associate Clinical Professor of Neurology at Columbia University in New York City.

DISTINCT SIDE-EFFECT PROFILES

In these latest analyses, Dr. Hirsch and colleagues at the Comprehensive Epilepsy Center and the Mailman School of Public Health at Columbia University examined predictors of psychiatric side effects in patients with epilepsy and compared psychiatric and cognitive side effects of the newer antiepileptic drugs. The results were presented at the 56th Annual Meeting of the American Academy of Neurology.

• In an analysis of the incidence of psychiatric side effects in 1,222 epileptic patients in the Columbia database, the investigators found that the leading nonpharmacologic predictors are a previous psychiatric condition, particularly treated depression, and myoclonic seizures, whereas such factors as age, static encephalopathy, and surgery for epilepsy were not predictors of psychiatric side effects. Three antiepileptic drugs—levetiracetam, topiramate, and zonisamide—were significantly associated with psychiatric side effects, and two drugs —lamotrigine and the older agent carbamazepine—demonstrated a trend toward a lower risk.

• In a subset of 1,170 patients on 7,468 different antiepileptic drug regimens that included at least one of the newer agents, 14% of patients experienced psychiatric side effects, resulting in a dosage or medication change in 9% of cases and in the discontinuation of a medication in 6%. Levetiracetam had the highest incidence of psychiatric side effects (16%) among the eight newer agents studied, and it was the only agent associated with a significantly increased incidence rate in monotherapy (18%) when compared to the overall monotherapy incidence (9%).

Gabapentin, lamotrigine, and oxcarbazepine were all associated with a decreased risk of psychiatric side effects when compared to the overall incidence—differences that held in patients newly started on a particular drug. Zonisamide and topiramate had intermediate rates of psychiatric side effects.

• In the same group of patients whose records were analyzed for psychiatric side effects, 13.4% experienced cognitive side effects, resulting in a dosage or medication change in 9% of cases and in discontinuation in 4%. Topiramate had the highest incidence of cognitive side effects (21.3%) among the eight newer agents analyzed, with a similar rate in monotherapy.

Gabapentin, levetiracetam, and lamotrigine were associated with a decreased risk of cognitive side effects when given in any regimen compared to the overall incidence, but only for the latter two agents did these differences remain in patients new to a particular drug. Similar results were seen in monotherapy, though these results only reached significance for lamotrigine due to the smaller number of patients on monotherapy for the other two antiepileptic drugs.

INDIVIDUAL RISK

For Dr. Hirsch, the fact that patients have different risks of certain adverse effects is among the most important findings of the database study. “A patient with no prior history of a drug-induced rash has a 4% risk of developing a rash if placed on lamotrigine,” he said, citing an example from a substudy on the incidence of rash. “However, a patient with a prior antiepileptic-drug–induced rash has a risk of a rash from lamotrigine of at least triple that, or about 14%.”

Another important finding is the distinct side-effect profile seen for several of the newer antiepileptic drugs. Dr. Hirsch cited the association of topiramate with an increased rate of cognitive side effects, and the association of levetiracetam with an increased rate of psychiatric side effects despite the fact that it is well tolerated overall. Conversely, some antiepileptic drugs are unlikely to cause certain side effects, Dr. Hirsch noted, citing the low incidence of psychiatric side effects associated with lamotrigine, gabapentin, and oxcarbazepine.

“In fact, these antiepileptic drugs may be preventing psychiatric symptoms,” he said. “As another example, there are several newer antiepileptic drugs that are almost never associated with an allergic rash—namely, levetiracetam, gabapentin, and topiramate.”

SIDE EFFECTS VERSUS SEIZURE FREEDOM

There is a reason why a clear understanding of side effects is so important in the management of epileptic seizures: Of all the new antiepileptic drugs introduced in the past decade, none have demonstrated significantly improved efficacy over the older drugs. Their main benefit is an improved side-effect profile, said David Weintraub, Research Coordinator for the Columbia Antiepileptic Drug Database Study and coinvestigator with Dr. Hirsch on three studies.

“It’s something that a lot of people don’t appreciate, because there are all these new drugs that are available, and people think, ‘Well, they must just be getting more and more people seizure-free,’” Mr. Weintraub said. “There’s a very small percentage of incremental benefit in terms of the number of patients seizure-free on an additional drug.” He pointed to a well-known, oft-cited study by Kwan and Brodie. “They showed that if patients failed two or more drugs, the chances of becoming seizure-free on a third or more drugs is only a few percent—a very low number.”

Seizure freedom is the “gold standard” of epilepsy treatment, according to Mr. Weintraub. He estimated that the overall rate of seizure freedom was somewhere in the range of 60% to 70% in patients with newly diagnosed epilepsy who are treated with one or more drugs. However, lack of significant antiepileptic drug side effects is equally important and now quite feasible, leading to the modern goal of “no seizures, no side effects.”

Because the newer antiepileptic drugs are in general better tolerated than established agents such as carbamazepine, phenobarbital, phenytoin, and valproic acid, knowing which newer drug is associated with which set of side effects has taken on a greater significance for clinicians and patients. “Given the essentially equivalent efficacy for partial seizures with all the existing drugs, but dramatically different side-effect profiles, the particular side-effect profile of each drug is increasingly important when choosing an antiepileptic drug; that’s really where [the newer agents] differentiate themselves,” Mr. Weintraub said. “It’s also what this particular database does very well; in other words, we have very good information on the side effects. We will have more head-to-head comparison data in the future, as data entry and analysis are continuing.”

NR

—Fred Balzac

Suggested Reading
Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med. 2000;342:314-319.
LaRoche SM, Helmers SL. The new antiepileptic drugs: clinical applications. JAMA. 2004;291:615-620.

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