Is depression associated with an increased risk of treatment-resistant epilepsy? Research strategies to investigate this question

- Depressive disorders increase the risk of developing epilepsy.
- Common pathogenic mechanisms shared by depression and epilepsy may explain this risk.
- Depressive disorders are associated with a lower GABAergic activity in the brain.
- Depressive disorders are associated with a higher glutamatergic activity in the brain.
- In major depressive disorders, high serum cortisol is associated with structural changes in the brain.

Persons with epilepsy (PWE) have a higher risk of developing depressive disorders (DDs), and people with primary DD have an increased risk of developing epilepsy. Furthermore, a lifetime history of DD has been associated with a worse response of the seizure disorder to pharmacotherapy and epilepsy surgery. The first part of this article reviews the literature of this problem with the intention of highlighting the neurobiologic pathogenic mechanisms operant in DD with a potential to facilitate the epileptogenic process and/or cortical hyperexcitability in humans and experimental animal studies of depression. They include the following: (i) a hyperactive hypothalamic-pituitary-adrenal axis and the associated structural and functional abnormalities of limbic structures, (ii) increased glutamatergic activity and decreased GABAergic and serotonergic activity, and (iii) immunologic disturbances. In the second part of this article, we suggest research strategies to test the hypothesis of whether depression worsens the course of epilepsy and identify the pathogenic mechanisms operant in this process.This article is part of a Special Issue entitled “NEWroscience 2013”.