Severity of Depression May Affect Epilepsy Risk and Outcomes

Severity of depression may be associated with epilepsy risk and outcomes, according to a study published in the May issue of JAMA Neurology. “Treated depression is associated with worse epilepsy outcomes, suggesting that this [factor] may be a surrogate for more severe depression and that severity of depression is associated with severity of epilepsy,” said Colin B. Josephson, MD, Assistant Professor of Neurology at the University of Calgary in Alberta, and colleagues.

Colin B. Josephson, MD

“If one assumes that depression treatment is a surrogate marker for depression severity, then there … appears to be a biological gradient,” the investigators said. “This assertion is corroborated by the incremental hazard of epilepsy among those receiving counseling alone (lowest hazard), antidepressants alone (intermediate hazard), and a combination of counseling and antidepressants (highest hazard).”

Prior research has found that the incidence and prevalence of depression are significantly elevated before and after an epilepsy diagnosis. Studies have not assessed, however, the risk of epilepsy after an incident diagnosis of depression or whether depression severity affects the level of risk or seizure outcomes, the authors said.

Two Data Sources

Dr. Josephson and colleagues examined two independent sources of data to explore the relationship between depression and epilepsy further. First, they conducted an observational study using The Health Improvement Network (THIN) database, a population-based primary care cohort. The THIN database contains prospective data that are broadly representative of the general population of the United Kingdom. All patients included in the study were free of prevalent depression and epilepsy and between the ages of 18 and 90. Separately, they analyzed prospective data from the Calgary Comprehensive Epilepsy Programme, a registry of adult outpatient encounters.

Of the more than 10.5 million eligible patients in the THIN database, 229,164 (2.2%) developed depression and 97,177 (0.9%) developed epilepsy. The median age was 44 among patients with depression and 56 among patients with epilepsy. Sixty-three percent of the patients with depression and 56% of the patients with epilepsy were women.

Incident epilepsy was associated with an increased hazard of developing depression (hazard ratio [HR], 2.04), and incident depression was associated with an increased hazard of developing epilepsy (HR, 2.55). “The association with incident epilepsy was even stronger for those with treated depression (HR, 3.42), compared with a combination of those who did not develop depression and those who developed depression not requiring therapy.”

In a sensitivity analysis controlling for age, sex, socioeconomic status, and Charlson Comorbidity Index, “there was an incremental hazard according to depression treatment type, with lowest risk for those receiving counselling alone (HR, 1.84), an intermediate risk for those receiving antidepressants alone (HR, 3.43), and the highest risk for those receiving both (HR, 9.85).”

Likelihood of Seizure Freedom

To assess the effect of depression on seizure outcomes, the researchers analyzed data from 2,573 patients in the Calgary Comprehensive Epilepsy Programme cohort. Data were derived from patients’ first-visit evaluation forms. A total of 504 (20%) of the patients had achieved one-year seizure freedom during the year prior to their first clinic visit. Patients with past or current depression had higher odds of failing to achieve seizure freedom during the previous year, compared with patients without depression (odds ratio, 1.41). When considering only patients with current or past depression (n = 738), current depression treatment (ie, antidepressants, counseling, or both) was associated with significantly higher odds of failing to achieve one-year seizure freedom (odds ratio, 1.75) after controlling for age at onset of epilepsy, sex, lesional epilepsy detected by MRI, history of generalized tonic-clonic seizures, and current antiepileptic drug use.

Overall, the results “indicate a shared relationship between depression and epilepsy, with each appearing to act as a risk factor for the other, and, therefore, should have a direct effect on counseling and management,” Dr. Josephson and colleagues said.

Limitations

The researchers noted that they were unable to control for etiology, epilepsy subtype, or conditions that could cause epilepsy and depression, and they did not have information about the duration, dose, or frequency of depression treatments. Although depression severity may not necessarily determine treatment type, primary care guidelines recommend counseling as first-line treatment for mild depression and combination therapy for severe depression, the researchers said.

Other possible interpretations of the results, such as the idea that antidepressant treatment augments the risk of epilepsy or that patients are more severely depressed because they have not achieved one-year seizure freedom, are less likely. “Counseling interacted with antidepressant exposure and resulted in a threefold increase in the hazard of epilepsy over that of medications alone,” which suggests that “treatment is acting as a proxy for depression severity and is thus consistent with the existence of a biological dose-response relationship,” the researchers said. In addition, “a recent review has indicated that virtually all antidepressants are safe for patients with epilepsy, thereby debunking the notion that these medications increase the risk of seizures.”

—Jake Remaly

Suggested Reading

Josephson CB, Lowerison M, Vallerand I, et al. Association of depression and treated depression with epilepsy and seizure outcomes: A multicohort analysis. JAMA Neurol. 2017;74(5):533-539.

Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. Epilepsy Behav. 2016;61:282-286.