Abstract
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 points to shared neurobiology rather than psychosocial reaction. This narrative review examined original human research published between 2016 and 2026, identified by keyword searching and selected purposively, spanning eighteen studies across neuroimaging, neurotransmitter and neuroendocrine systems, neuroinflammation, genetic architecture and psychiatric phenotype. Imaging separated the psychiatric phenotypes: depression was associated with reduced connectivity across salience, attention and default mode networks, whereas psychosis was associated with parietal grey matter loss and disrupted long association tracts, although temporal lobe epilepsy, hippocampal sclerosis and family history of schizophrenia predicted psychosis. Brain-derived neurotrophic factor separated epilepsy from health but not comorbid depression, and anti-seizure medication accounted for much of its variance, whereas serotonergic and hippocampal glutamatergic measures tracked depression specifically. The hypothalamic-pituitary-adrenal axis showed elevated basal cortisol with abolished stress reactivity, whereas inflammatory findings were inconsistent. Genome-wide analyses identified shared loci including SCN1A, and Mendelian randomisation supported major depressive disorder as an antecedent of epilepsy; psychiatric polygenic burden and suicidality at diagnosis each predicted treatment resistance. Depression and psychosis appear to have separable substrates and should not be pooled.