Phytochemicals and Depression: Plant-Powered Pathways Preventing Neuroinflammation, Oxidative Overload, and Mitochondrial Malfunction in Major Depressive Disorder

Background/Objectives: Major depressive disorder (MDD), a debilitating psychiatric condition, is intricately linked to neuroinflammation, oxidative stress, mitochondrial dysfunction, disrupted tryptophan–kynurenine pathways, and an urgent need for novel, plant-based therapeutics such as curcumin and other natural antidepressants. Emerging evidence further highlights altered brain-derived neurotrophic factor (BDNF) signaling in MDD, making the search for integrative, phytomedicine-oriented interventions more critical than ever. Methods: This systematic review critically analyzed 62 articles initially retrieved from PubMed, Cochrane, EMBASE, and Google Scholar databases, with 19 studies deemed eligible for comprehensive synthesis. Results: The included investigations spanned diverse populations and examined the therapeutic potential of phytochemicals to modulate neuroimmune interactions, reduce oxidative injury, and enhance mood-related biomarkers. Among the promising candidates, curcumin, polyphenols, and flavonoid-rich extracts consistently demonstrated improvements in depressive symptoms, often by targeting pro-inflammatory mediators and promoting neuroplasticity. These findings reinforce the notion that bioactive compounds from plants may serve as effective adjunctive or standalone strategies in MDD management, particularly for individuals who experience limited benefit from conventional approaches. Conclusions: This study demonstrates the growing feasibility of phytomedicine as a powerful complement to existing treatment paradigms. Future work should focus on standardized dosing, long-term safety, and mechanistic studies that clarify how plant-derived compounds can be leveraged for more robust, personalized depression care. Such integrative approaches promise to broaden therapeutic horizons and spark novel research pathways in translational neuroscience.