Investigating potential molecular mechanisms of antiepileptic drug-induced depression through network toxicology and...

Antiepileptic drugs (AEDs) are essential for epilepsy management but frequently induce adverse effects including depression. This study employs network toxicology and molecular docking to investigate molecular mechanisms underlying AED-induced depression. After identifying eight AEDs (Topiramate, Zonisamide, Phenobarbital, Primidone, Levetiracetam, Gabapentin, Tiagabine, and Perampanel) potentially associated with depression via a literature review, further analysis integrating drug and disease target databases revealed 25 targets relevant to AED-induced depression. Gene ontology analysis conducted with DAVID, indicated that biological processes including synaptic transmission and plasticity, glutamate receptor signaling, and calcium ion regulation are critical to this phenomenon. KEGG pathway analysis demonstrated that AEDs primarily affect neuroactive ligand-receptor interactions, which are essential for synaptic transmission and plasticity, and disrupt calcium, cAMP, MAPK, and oxytocin signaling pathways. These pathways are vital for the proper functioning of the central nervous system, as neurotransmitter interactions activate crucial signaling pathways. The drug-target interaction network analysis identified 12 candidate targets that directly interact with the eight AEDs, and GeneMANIA network expansion provided deeper insights into their functional associations. Molecular docking results revealed the interactions between AEDs and their respective direct targets, with Zonisamide exhibiting significant potential to induce depression through strong binding to multiple targets. In vitro experiments demonstrated that Zonisamide treatment elevated the expression and activity of MAOA protein in the prefrontal cortex of mice, which may influence monoaminergic neurotransmission through MAO pathway regulation, potentially leading to depression. Collectively, this integrated approach elucidates the mechanisms underlying AED-induced depression, thereby establishing a foundation for future therapeutic strategies.