ORLANDO—Patients who have used tricyclic antidepressants may face an increased risk of developing unprovoked seizures, according to research presented at the 53rd Annual Meeting of the American Epilepsy Society. The case-control study, conducted by researchers from the United States and Iceland, also found that depression itself may predispose individuals to developing seizures—a finding consistent with other recent studies. However, the mechanism by which depression and tricyclic use might increase seizure risk remains unclear, researchers said, and it is not yet known whether selective serotonin reuptake inhibitors (SSRIs) also raise the risk of seizures.

Building on two prior epidemiologic studies that suggested an association between depression and epilepsy, W. Allen Hauser, MD, and colleagues reviewed all newly identified cases of unprovoked seizures in Iceland over a three-year period to see whether depression or antidepressant use correlated with new-onset epilepsy. They drew study subjects from a national seizure surveillance system that included health care facilities throughout the Icelandic community of 270,000 people. According to Dr. Hauser, who is Professor of Neurology and Public Health at Columbia University's College of Physicians and Surgeons, the data set comprised "every case of new-onset seizure" during the study period.

All adults who had at least one unprovoked seizure qualified for entry into the study. Using a computerized registry, the researchers then selected as controls the next two same-sex individuals born in Iceland. In order to identify participants with past or current depression, they administered a modified version of the Structured Clinical Interview for DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition) to cases and controls over the telephone. (In-person interviews were not practical because of limited access to subjects in rural areas, owing to the harsh Icelandic terrain.) Interviewers also inquired about subjects' tricyclic use and experience with electroconvulsive therapy. The mean age of the 271 cases and 542 controls was 45, and 49% were male.

A NEUROCHEMICAL MECHANISM?

The researchers analyzed the data separately for young adults (ages 16 to 55) and older adults (age 56 and older). In both young and older individuals, they found that a history of depression correlated with seizures; this mirrored findings from a recent study of patients in Rochester, Minn (in press, Annals of Neurology), which showed an increased risk of epilepsy in patients with depression. According to Dr. Hauser, it now appears that "depression is a risk factor for epilepsy," although "the mechanism is not clear." He speculated that there might be a "common antecedent neurochemical abnormality" in the brain that predisposes certain individuals to develop both depression and epilepsy; in children, he added, both depression and migraine appear to be risk factors for epilepsy, suggesting that an underlying brain abnormality may predispose them to these disorders.

In a multivariate analysis, the investigators found that, unlike in the Rochester study, tricyclic antidepressant use was independently associated with a threefold increased risk of unprovoked seizures in the overall sample. In young adults, a history of tricyclic use was more than five times as common among epilepsy patients (14.1%) as among controls (2.3%). However, tricyclic use among older adults was similar between the seizure (4.3%) and control (3.9%) groups.

According to Dr. Hauser, the findings raise the question of whether "the medication may be contributing in some way as a risk for epilepsy." The correlation between antidepressant use and epilepsy, he said, is a "complex finding that we cannot fully explain right now; whether or not the antidepressant is some sort of inducer is not clear." He emphasized, however, that the seizures were "not an acute effect of medication," as they were associated "with both current and past use" of antidepressants.

If tricyclics are a significant risk factor for the development of epilepsy, their use by certain patients may need to be limited, particularly if those patients have other risk factors for epilepsy. It is unknown whether other types of antidepressants, such as the SSRIs, pose a similar risk. It is also unknown why this effect was found only in the younger age-group. Dr. Hauser plans additional analyses on the Iceland data and promised that a "more complete paper will be published within the year." Also, he stated that it is "clear we need to do additional studies" to confirm these new findings and learn more about antidepressants as risk factors for epilepsy, including the potential effects of timing and dosage.

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