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Mood disorders such as depression and anxiety have a high prevalence in adult patients with epilepsy, and their evaluation is crucial in choosing the most appropriate antiepileptic drug (AED) with regard to side effects, which can account for long-term discontinuation, poor compliance, and ultimately, failure of seizure control. While more evidence is provided for older AEDs on their effect on mood changes, newer AEDs such as lacosamide have not yet been extensively studied. We performed a systematic review of the literature available on the impact of lacosamide on mood in adult patients with epilepsy. A literature search on MEDLINE, COCHRANE, Scielo, and Clinicaltrials.gov databases was performed, and articles where mood scales where specifically reported as primary or secondary outcome measures were included. Articles differed greatly in terms of inclusion criteria, concomitant AEDs, seizure reduction control, and outcome measures. If lacosamide is used as add-on, two studies point towards a beneficial effect on depressive and anxiety symptoms, two studies claim no effects on mood, and one reports a positive effect only in patients with major depressive symptoms at baseline. Additional evidence from either retrospective or comparative drug studies indicates no effects of lacosamide on mood. Even though presently, a negative effect on mood seems unlikely, whether lacosamide could exert a beneficial impact on mood remains controversial. Multicenter, randomized, controlled, double-blind studies are needed to assess the impact on lacosamide on mood disorders, given the low evidence level (Class III and IV) of currently available studies.