An update on the pharmacokinetic and pharmacodynamic interactions between antidepressants and antiseizure medications

Introduction: This is an update of a prior review of clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) drug-drug interactions (DDIs) between antidepressants and antiseizure medications (ASMs). Area covered: Articles published between 1 January 2010 and 30 November 2025 were identified through structured searches in PubMedⓇ, Web of Science, SCOPUS, and Google Scholar using antidepressant- and ASM-related terms. Some antidepressants, including fluoxetine, paroxetine, fluvoxamine, are moderate to strong inhibitors of various cytochrome P450 (CYP) isoenzymes and may cause clinically relevant interactions with ASMs metabolized by these pathways. First-generation ASMs with enzyme-inducing properties (e.g. carbamazepine, phenobarbital, and phenytoin) or enzyme-inhibiting effects (e.g. valproic acid) may alter the PK profile of several antidepressants, potentially leading to reduced therapeutic efficacy or dose-dependent toxicity. The introduction of second- and third-generation ASMs has substantially improved the safety of combined pharmacotherapy. Potential PD DDIs between antidepressants and ASMs are less clearly defined and remain largely theoretical. Expert opinion: Antidepressants and ASMs are associated with a considerable risk of clinically significant DDIs. A thorough understanding of the underlying PK and PD mechanisms, combined with complementary strategies including therapeutic drug monitoring, consultation of interaction databases, and careful clinical monitoring, is essential to anticipate, prevent, and effectively manage adverse DDIs.