People with epilepsy have a high risk of developing depressive disorders, and people with primary depressive disorders have a high risk of developing epilepsy. Furthermore, a lifetime history of depressive disorders has been associated with a poor response of the seizure disorder to pharmacotherapy and epilepsy surgery. The aim of this Review is to identify the principal neurobiological pathogenic mechanisms of depressive disorders with the potential to facilitate the epileptogenic process or cortical hyperexcitability in experimental animal studies or those that can aggravate known pathogenic mechanisms of epilepsy in human beings. These mechanisms include (1) a hyperactive hypothalamic-pituitary-adrenal axis; (2) structural and functional abnormalities of cortical structures; (3) increased glutamatergic and decreased GABAergic and serotonergic activity; and (4) immunological abnormalities. The data presented in this Review provide experimental evidence that might begin to explain the bidirectional relation between depressive disorders and epilepsy and that can be regarded as a source for future research.
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