Comparative efficacy of agomelatine and escitalopram in people with epilepsy and comorbid major depressive disorder: A double-blind randomized controlled trial.

Major depressive disorder (MDD) is the most common psychiatric comorbidity in epilepsy but is often undertreated due to concerns about antidepressant effects on seizure frequency. This study evaluated the efficacy of agomelatine versus escitalopram in people with epilepsy (PwE) and comorbid MDD, including effects on seizure frequency, sleep, cognition, and quality of life (QoL). In this double-blind, randomized, phase IV study across three centers, 64 PwE and comorbid MDD were screened, and 51 were randomized to agomelatine (25 mg) or escitalopram (10 mg). Outcome measures were Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), QoL in Epilepsy Inventory-31, Mental Deterioration Battery, and seizure frequency. Depression scores did not differ between groups, although both groups improved over time. No significant between-group differences were found for QoL or cognitive performance. However, QoL improved significantly only in the escitalopram group. After correction for multiple comparisons, verbal memory improved significantly only in the agomelatine group, whereas the cognitive changes observed with escitalopram did not remain significant after correction. No significant differences in seizure frequency, PSQI, or ESS scores were observed in either group. Adverse events were mild to moderate (7.8%), and no serious adverse event occurred. In conclusion, agomelatine and escitalopram improved depressive symptoms in PwE, without worsening seizure frequency, sleep, or daytime alertness. Escitalopram showed a more consistent pattern of benefit on mood and QoL, whereas cognitive effects were limited after correction for multiple testing. Larger studies are needed to confirm these findings.