Depression is a common occurrence among epileptic patients and constitutes, along with anxiety disorders, the most frequent psychiatric condition in these patients. The relationship between depression and epilepsy is two-directional, because patients with major depression also have a higher frequency of epilepsy. In epileptic patients, depressive disorders can present as unipolar, bipolar, or dysthymic disorders. More characteristically, however, they present as an atypical depression, which can often go unrecognized for long periods of time. In the diagnostic evaluation of these patients, clinicians must rule out the possibility that the depressive disorder resulted from the administration of antiepileptic drugs (AEDs; e.g., barbiturates) or from the discontinuation of an AED with mood-stabilizing properties that were masking an underlying affective disorder. Although antidepressant drugs have been used in epileptic patients for a long time, to date there has only been one controlled study. The antidepressants of the family of selective serotonin reuptake inhibitors (SSRIs) should be considered as initial therapy for depressive disorders in these patients.