This chapter presents evidence for underlying shared pathogenic mechanisms in epilepsy and psychiatric disorders, as it has direct implications for the safety and efficacy of psychotropic medications in the context of epilepsy. From a treatment perspective, it is necessary to first differentiate primary depression from the iatrogenic depressive effects of the antiepileptic drugs (AED) regimen. AEDs can affect the metabolism of co-prescribed medications that affect mood, through inhibition or induction of CYP450 isoenzymes, altering their blood levels. The association of tricyclic and related antidepressants with seizure induction has largely been fostered by reports of seizures with overdoses and toxic blood levels. The most studied comorbid psychiatric illness, depression, was most effectively treated in the context of primary care through collaborative care. A steppedcare model would involve a psychiatrist directly intervening only at higher levels of adverse outcome or complexity of disease.