Abstract: Objective To investigate the effect of lacosamide monotherapy on peripheral blood interleukin-6 (IL-6) and 5-hydroxytryptamine (5-HT) expression in teenagers with focal epilepsy combined with depression. Methods Teenagers, aged 12-18 years, who were admitted to the Affiliated Hospital of Xuzhou Medical University and initially diagnosed with focal epilepsy from June 2022 to January 2023 were enrolled. Their Hamilton Depression Rating Scale (HAMD) scores were evaluated and those with a score of ≥8 points (with a tendency to depression) were included in the study. A total of 116 patients were included and divided into two groups: a lacosamide group (oral administration with lacosamide, n=53) and a oxcarbazepine group (oral administration with oxcarbazepine, n=63). Follow-ups were conducted at post-treatment 6 and 12 months, and the overall effective rate of epilepsy control, HAMD scores, peripheral blood IL-6 and 5-HT levels and adverse reactions were observed. Results The total effective rate of epilepsy control in the lacosamide group was 64.71% at post-treatment 6 months, without statistical difference compared with the oxcarbazepine group (P>0.05). The total effective rate of epilepsy control in the lacosamide group was 89.13% at post-treatment 12 months, which was higher than that in the oxcarbazepine group, with statistical difference (P<0.05). No statistical difference was found in HAMD scores, and IL-6 and 5-HT levels before and 6 and 12 months after treatment between the two groups (P>0.05). The lacosamide group showed remarkable decreases in HAMD scores and IL-6 levels and increases in 5-HT levels at post-treatment 6 and 12 months, compared with those before treatment (P<0.05). The incidence of adverse reactions at post-treatment 12 months was 15.09% in the lacosamide group, which was lower than that in the oxcarbazepine group, with statistical difference (P<0.05). Conclusions Lacosamide monotherapy is effective to control seizures for teenagers with focal epilepsy combined with depression and improve their depressive symptoms, which may be related to reduction of IL-6 and elevation of 5-HT, with a low incidence of adverse reactions.