Epilepsy Risk with Depression

Depression may increase the risk of developing epilepsy and having worse seizures outcomes, according to a study published in JAMA Neurology.¹

The study is the first to evaluate the risk of epilepsy after being treated for depression for the first time, and whether the severity of depression affects this risk.

“These preliminary 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 counselling and management,” wrote first author Colin Josephson, MD, of the University of Calgary (Calgary, Alberta, Canada) and colleagues.

The results suggest depression-specific interventions could help decrease the effect of depression on risk of epilepsy, they also mentioned.

Depression ranks high among a number of psychiatric conditions associated with epilepsy. Community-based studies have suggested that almost one in four people with epilepsy may have comorbid depression.² While the reasons for this overlap are unclear, some researchers have hypothesized that the two conditions share underlying pathophysiology, such as overlapping neuroanatomical regions and changes in certain neurotransmitters.   

To study the link between depression and epilepsy, researchers used the Health Improvement Network (THIN) database, which contains prospective data on people seen in primary care clinics in the United Kingdom. The analysis included data from 10,595,709 patients, of whom 229,164 were treated for depression for the first time (2.2%) and 97,177 developed epilepsy (0.9%) between 2007 and 2015. Researchers used antidepressant treatment type as a surrogate for depression severity, with counseling assumed to be for less severe cases and antidepressants for more severe cases.

To evaluate whether depression was associated with worse seizure outcomes, researchers used the Calgary Comprehensive Epilepsy Programme (CEP), which contains data on 1.3 million people seen at epilepsy clinics in Calgary, Canada. The analysis included 2573 patients, 504 (20%) of whom achieved one year of seizure freedom in the past year, and 738 (28.7%) of whom had current or past depression.

Results were controlled for age, sex, comorbidities, and socioeconomic status.

Key Results:

• Significantly more women than men developed depression (63% vs 37%, respectively, P<0.001) and epilepsy (56% vs 44%, P<0.001)

• Incident epilepsy was significantly associated with increased risk of developing depression compared to no epilepsy (hazard ratio [HR], 2.04 [95% CI, 1.97-2.09]; P<0.001)

• Incident depression was significantly associated with increased risk of developing epilepsy, compared to no depression (HR, 2.55 [95% CI, 2.49-2.60]; P<0.001)

• Risk of epilepsy increased with increasing severity of depression:

♦ Counseling alone: Lowest risk of epilepsy (HR, 1.84 [95% CI, 1.30-2.59]; P<0.001)

♦ Antidepressants alone: Intermediate risk (HR, 3.43 [95% CI, 3.37-3.47]; P<0.001)

♦ Both counseling and antidepressants: Highest risk (HR, 9.85 [95% CI, 5.74-16.90]; P<0.001)

• Depression was linked to significantly higher odds of not achieving one year of seizure freedom, compared to no depression (odds ratio, 1.75 [95% CI, 1.06-2.94]; P=0.03)

The authors noted several limitations. The databases lacked information on etiology, epilepsy subtype, other conditions linked to both epilepsy and depression, antidepressant dose, duration or frequency of therapy sessions, and whether patients continued antidepressants. Also, depression treatment may not actually indicate severity, but could be related to patient/physician preference and resource availability. Finally, the study design could not evaluate whether depression has a causal effect on risk of epilepsy, and vice versa.

“However, the strong, specific, and temporal association between the exposure (depression) and the outcome (epilepsy) provides compelling evidence suggestive of a causal association… This assertion is corroborated by the incremental hazard of epilepsy among those receiving counselling alone (lowest hazard), antidepressants alone (intermediate hazard), and a combination of counselling and antidepressants (highest hazard),” they wrote.

Alternatively, antidepressants could increase the risk of epilepsy. However, this explanation is less plausible, according to the authors, given that counseling alone was linked to increased risk for epilepsy. 

“This association is clearly counterintuitive from a pathophysiological perspective,” they added, “Rather, it is entirely more congruent with the notion that treatment is acting as a proxy for depression severity and is thus consistent with the existence of a biological dose-response relationship.”

They noted that more studies evaluating the causative role of depression on epilepsy, and vice versa, are needed.

Take-home Points

• A database study found that incident epilepsy was significantly associated with increased risk of developing depression, compared to no epilepsy.

• Incident depression was significantly associated with increased risk of developing epilepsy, compared to no depression.

• Risk of epilepsy increased with increasing severity of depression.

• Depression was linked to significantly higher odds of not achieving one year of seizure freedom, compared to no depression.

• More studies are needed to evaluate the causative role of depression on epilepsy, and vice versa, are needed.

The authors report no conflicts of interest.

The authors report no conflicts of interest.

References:

1. Josephson CB, et al. Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis. JAMA Neurol. 2017 Feb 27.

2. Fiest  KM, et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology. 2013;80(6):590-599.