Comorbid Depression in Epilepsy: Challenges in Diagnosis and Treatment

Epilepsy drug for stroke
Epilepsy drug for stroke
Psychiatric comorbidities including depression are a common complication of epilepsy in both children and adults.

In addition to the significant, multifaceted burden that people with epilepsy often face, they are also much more likely than the general population to suffer from depression. This comorbidity has been linked with diminished quality of life and worse outcomes in the course of the disease.1

“Psychiatric comorbidities including depression are a common complication of epilepsy in both children and adults,” Bruce P. Hermann, PhD, professor of neurology and director of the Charles Matthews Neuropsychology Lab at the University of Wisconsin School of Medicine and Public Health in Madison, told Neurology Advisor. He points to numerous findings, such as a 2013 systematic review and meta-analysis showing an overall prevalence of current or past-year depression in 23.1% in people with epilepsy.2 Of the studies reviewed, 4 studies reported an overall lifetime prevalence of depression of 13% in such individuals. The review researchers concluded that epilepsy “was significantly associated with depression and depression was observed to be highly prevalent in” people with epilepsy.

A Bidirectional Link?

This comorbidity has been observed for millennia. For example, Hippocrates speculated that both illnesses share an underlying cause, which was also mentioned in a 2015 paper in Epilepsy & Behavior.3 “We think there is actually a bidirectional relationship between the 2 conditions,” said co-investigator Jay A. Salpekar, MD, FANPA, medical director of the Neuropsychiatry in Epilepsy Program at Kennedy Krieger Institute in Baltimore, Maryland, and a pediatric neuropsychiatrist in the department of psychiatry there; he is also an assistant professor of psychiatry at the Johns Hopkins University School of Medicine. “You can understand how epilepsy may lead to depression, but what is surprising is that depression may lead to epilepsy,” he told Neurology Advisor.

In addition to the elevated risk of depression in people with epilepsy, individuals with depression are 3 to 7 times more likely to develop epilepsy, according to a 2011 review that explored potential overlapping mechanisms.4 While these pathways have yet to be identified, possibilities include “a hyperactive hypothalamic–pituitary-adrenal (HPA) axis and its neuroanatomic and neuropathologic complications, as well as disturbances in serotonergic, noradrenergic, γ-aminobutyric acid (GABA)ergic, and glutamatergic neurotransmitter systems, all of which may be interrelated,” the researchers wrote. Dr Salpekar pointed out that the same medications are often used in the treatment of both epilepsy and psychiatric disorders, which adds further support to the possibility of shared mechanisms.

Detection and treatment of comorbid depression in patients with epilepsy is critical. “If they have depression, you’d better address it, or their epilepsy won’t improve,” Dr Salpekar cautioned. “They won’t have as good of a response to epilepsy treatment, and their quality of life will be lower.” Previous research found that depression and anxiety independently predicted health-related quality of life in people with epilepsy, even more so than the severity, frequency, and chronicity of seizures.2 Underscoring the need for timely detection and treatment is the recent finding by the Centers for Disease Control and Prevention (CD C) that the risk of suicide is 22% higher in people with epilepsy, especially in the 40 to 49 age bracket. The investigators  cite the importance of evidence-based treatment to decrease comorbid mental illness in such patients.5


“Depression can be screened in a clinic setting with brief questionnaires or structured interviews,” according to Dr Hermann. While there are numerous such measures, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) is particularly short and efficient.6 “This 6-item test designed to screen for major depression in epilepsy is the most commonly validated screening tool, free to the public, validated in multiple languages, and easy to administer, although selection of the best tool may vary depending on the setting and available resources.” A 2017 review determined that, across 12 studies, the NDDI-E had a median sensitivity of 80.5% (range 64.0-100.0) and specificity of 86.2 (range 81.0-95.6) at the most common cut-point of >15.

Although these screening tools for depression can be useful, Dr Salpekar emphasized that the most important thing is simply to ask patients about it: “Just ask, ‘Are you depressed?’” Doctors may be hesitant to inquire about depression if they are unclear about how to deal with it, but the patient’s answer will give you a better idea of what to do next. For example, if they indicate that they are depressed, you might offer to refer them back to their primary care physician or to a psychiatrist for further evaluation and treatment. Or, if they are unsure whether or not they are depressed, you may ask additional questions or ask if they would like a referral to a mental health counselor to further explore the topic.


If depression is in fact diagnosed, there are obviously many variables that inform the appropriate course of treatment in each patient. “Start by trying to optimize the epilepsy – lamotrigine, valproate sodium, and oxcarbazepine are particularly effective in treating mood instability,” Dr Salpekar suggested. If that strategy proves inadequate, an adjunctive antidepressant may be appropriate. Generally, most antidepressants are safe for use in epilepsy and will not make seizures worse. If necessary, refer the patient to a physician “who has experience treating with antidepressants and understands the basic rules – to start with a very low dose, and have the patient come back and follow-up every 1 or 2 weeks.”

“Depression is commonly treated successfully with medications, but it can also be treated non-pharmacologically – an excellent example is the PEARLS program developed by the CDC,” Dr Hermann added. This approach program consists of 6 to 8 in-home sessions that focus on behavioral and problem-solving techniques. In 2 randomized controlled trials, this community-based approach effectively decreased symptoms of depression and improved quality of life in adults with epilepsy.7,8 A combination of medication and psychotherapy may represent the optimal treatment approach in some patients.

“Detecting and treating depression in epilepsy, as well as other comorbidities, is important in comprehensive quality of care,” said Dr Hermann.


  1. Kanner AM. Is depression a risk factor of worse response to therapy in epilepsy? Epilepsy Curr. 2011;11(2):50-51. doi:10.5698/1535-7511-11.2.50
  2. Fiest KM, Dykeman J, Patten SB, et al. Depression in epilepsy: a systematic review and meta-analysis. Neurology. 2013;80(6):590-599. doi:10.1212/WNL.0b013e31827b1ae0
  3. Salpekar JA, Mishra G, Hauptman AJ. Key issues in addressing the comorbidity of depression and pediatric epilepsy. Epilepsy Behav. 2015;46:12-18. doi:10.1016/j.yebeh.2015.02.036
  4. Kanner, AM. Depression and epilepsy: A bidirectional relation? Epilepsia. 2011;52:21-27. doi:10.1111/j.1528-1167.2010.02907
  5. Tian N, Cui W, Zack M, Kobau R, Fowler KA, Hesdorffer DC. Suicide among people with epilepsy: A population-based analysis of data from the US National Violent Death Reporting System, 17 states, 2003-2011. Epilepsy Behav. 2016; 61:210-7. doi:10.1016/j.yebeh.2016.05.028
  6. Gill, SJ, Lukmanji S, Fiest KM, Patten SB, Wiebe S, Jetté, N. Depression screening tools in persons with epilepsy: A systematic review of validated tools [published online January 8, 2017]. Epilepsia. doi:10.1111/epi.13651
  7. Ciechanowski P, Wagner E, Schmaling K, et al. Community-integrated home-based depression treatment in older adults: a randomized controlled trial. JAMA. 2004;291(13):1569-1577.
  8. Schmaling KB, Williams B, Schwartz S, Ciechanowski P, LoGerfo J. The content of behavior therapy for depression demonstrates few associations with treatment outcome among low-income, medically ill older adults. Behav Ther. 2008;39(4):360-365. doi:10.1016/j.beth.2007.10.004

This article originally appeared on Neurology Advisor