Exploring the potential of polyphenols in major depression: from molecular function to clinical therapy

Major depressive disorder (MDD) is a highly prevalent and debilitating psychiatric condition and remains a major contributor to global disease burden. Recent global burden of disease analyses indicate that both the incidence and prevalence of MDD have increased over the past decades, with projections suggesting continued growth worldwide. These trends highlight an urgent need to explore novel and complementary therapeutic strategies. MDD is a complex mental health condition characterized by disturbances in mood, cognition, and behavior, and its pathophysiology involves multiple biological systems. During depressive episodes, inflammatory pathways are activated, mitochondrial function is impaired, oxidative stress markers are increased, and antioxidant capacity is diminished. Approximately 30% of individuals with depression do not respond adequately to conventional pharmacological treatments. Consequently, increasing attention has been directed toward the impact of bioactive food components on neurological disorders, including MDD. Polyphenols, a class of bioactive compounds abundantly found in plant-based foods and beverages, have garnered significant interest for their potential role in mitigating MDD. While numerous animal studies suggest antidepressant-like effects of polyphenols, particularly catechins, curcumin, resveratrol, and quercetin, clinical research remains limited, with randomized controlled trials primarily focusing on curcumin and anthocyanins. In this paper, evidence from preclinical and clinical studies is reviewed to explain how polyphenols may act as antidepressant agents. Their effects are described through actions on neurotransmitter systems, reductions in inflammation and oxidative stress, and support of neuroplasticity. In conclusion, current findings indicate that polyphenols may provide meaningful benefits in managing MDD due to their wide-ranging biological effects. Integrating polyphenols into clinical practice therefore represents a promising approach for improving treatment outcomes. Future directions include expanding clinical trials to evaluate a broader spectrum of polyphenols, developing strategies to improve bioavailability, standardizing product formulations, examining potential interactions with conventional medications, and promoting public education on dietary strategies that support mental health.