Background: In recent decades, interest has grown in the link between lipid metabolism and mental health. Omega-3 fatty acids (EPA and DHA) play a crucial role in brain function, neuroplasticity, and emotional regulation. Deficiency or an imbalanced omega-6/omega-3 ratio, typical of Western diets, has been associated with an increased risk of mood disorders, such as major depression and bipolar disorder. Objective: This review critically synthesizes neurobiological and clinical evidence on the role of omega-3s in mood disorders, assessing mechanisms, randomized controlled trials, and meta-analyses, with a focus on inflammatory biomarkers and their integration into a personalized psychiatry framework. Methods: A narrative review of epidemiological studies, randomized controlled trials (RCTs), meta-analyses, and experimental research was conducted, evaluating mechanistic pathways (synaptic, inflammatory, neuroplastic, and redox) and clinical moderators (particularly inflammatory markers and dietary lipid profiles). Results: Consistent evidence indicates that EPA-enriched formulations (≥60%) exert antidepressant effects, particularly in patients with elevated inflammatory markers (CRP, IL-6, TNF-α). In contrast, DHA-only preparations show limited efficacy, and outcomes vary depending on dietary omega-6/omega-3 balance. However, the literature remains heterogeneous in design, sample size, and biomarker stratification, which limits generalizability and contributes to conflicting findings across studies. Conclusions: While omega-3 fatty acids represent promising adjunctive interventions for mood disorders, methodological weaknesses and inconsistent formulations hinder definitive conclusions. Future research should prioritize biomarker-guided, precision-based approaches to clarify therapeutic efficacy and optimize clinical use.
Lastretti et al. (Sat,) studied this question.