Neurobiological Mechanisms of Mental Disorders in Relation to Epilepsy: A Narrative Review

Depression, anxiety and psychosis occur in people with epilepsy far more often than in the general population, and each can precede the first unprovoked seizure, which suggests shared neurobiology in addition to psychosocial reaction. This narrative review examined original human research published between 2016 and 2026, identified by keyword searching and selected purposively. Of eighteen included studies, thirteen provided direct mechanistic evidence, two provided prognostic clinical evidence and three were retained as adjacent evidence. Imaging findings differed by phenotype, with reduced network connectivity in depression and parietal grey matter and white matter changes in psychosis, but each phenotype was studied with different methods in small, separate cohorts. Peripheral brain-derived neurotrophic factor did not distinguish patients with and without comorbid depression and was strongly influenced by anti-seizure medication, which limits its biomarker value without excluding a central neurotrophic role. Serotonergic and hippocampal glutamatergic measures were associated with depression in single studies, and circulating cytokine findings were inconsistent in direction. Genome-wide analyses identified shared loci including SCN1A, Mendelian randomisation was consistent with major depressive disorder liability increasing epilepsy risk, and suicidality at diagnosis predicted treatment resistance. These findings generate hypotheses rather than establish mechanisms.