People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.