Bipolar disorder, affecting 0.5-1% of the general population and characterized by episodes of mania/hypomania and depression, significantly impacts cognitive function and quality of life. While its pathogenesis remains unclear, inflammatory signaling plays a crucial role, with increased levels of pro-inflammatory cytokines like TNF-α, IL-6, and hs-CRP observed in patients compared to healthy individuals. Reducing inflammation is thus a potential therapeutic target. Omega-3 polyunsaturated fatty acids, known for their anti-inflammatory properties through mechanisms such as inhibiting leukocyte chemotaxis and eicosanoid/cytokine production, have shown promise in treating various inflammatory conditions. Meta-analyses have demonstrated their effectiveness in reducing inflammatory markers in heart failure and gestational diabetes. However, their impact on inflammatory factors in metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease has yielded mixed results. Given the potential of omega-3s to mitigate inflammation in bipolar disorder and the limited research directly addressing this in the context of pro-inflammatory cytokines and depression, this study aimed to investigate the efficacy of omega-3 fatty acid supplementation in these patients.

Existing literature highlights the association between inflammation and bipolar disorder, with elevated levels of pro-inflammatory cytokines like TNF-α, IL-6, and hs-CRP correlating with the severity of the disorder. Studies have explored the potential therapeutic role of omega-3 fatty acids, demonstrating their anti-inflammatory effects in various conditions, though their impact on bipolar disorder specifically is not fully established. Some studies suggest beneficial effects of omega-3 supplementation in reducing symptoms and inflammatory markers, while others show inconsistent or null findings. This disparity underscores the need for further investigation into the precise role of omega-3 fatty acids in managing the inflammatory aspects of bipolar disorder and their potential influence on depressive symptoms.

This randomized, double-blind, placebo-controlled clinical trial was conducted in 2021 in Zahedan, Iran, enrolling 60 patients with bipolar disorder in the depressive phase (aged 16-60). Patients were randomly assigned (using permuted block stratified randomization based on age and gender) to either an omega-3 fatty acid group (n=30, 15 men, 15 women) receiving 2g/day (180mg EPA, 120mg DHA) for two months or a placebo group (n=30) receiving 2g/day of paraffin oil. Depression status was assessed using the Persian version of the Hamilton Depression Rating Scale (reliability 81%), and serum levels of TNF-α, IL-6, and hs-CRP were measured before and after the intervention. Data normality was assessed using the Kolmogorov-Smirnov test and Q-Q plot. Intragroup comparisons were performed using paired t-tests, while intergroup comparisons used independent t-tests due to the normality of the data. Pearson correlation assessed the relationship between cytokine levels and depression scores. Statistical significance was set at P<0.05. The study was approved by the Ethical Committee of Zahedan University of Medical Sciences and registered at the Iranian Registry of Clinical Trials.

Following the two-month intervention, the omega-3 group exhibited significant reductions in depression scores (P<0.001) and serum concentrations of TNF-α, IL-6, and hs-CRP (P<0.001 for all) compared to baseline. In contrast, the placebo group showed no significant changes in these parameters. A significant difference between the omega-3 and placebo groups was observed for all inflammatory markers after the intervention (P<0.001). The omega-3 group experienced reductions of 50%, 32%, and 43% in IL-6, TNF-α, and hs-CRP levels respectively. A positive correlation was observed between depression scores and serum concentrations of IL-6, TNF-α, and hs-CRP both before and after the intervention in both groups.

The findings support a positive correlation between pro-inflammatory cytokine levels (TNF-α, IL-6, and hs-CRP) and depression severity in bipolar disorder, aligning with previous research demonstrating the involvement of cytokines in the pathogenesis and progression of the disorder. The significant reduction in both depression scores and inflammatory markers in the omega-3 group underscores the potential therapeutic benefit of omega-3 supplementation. This aligns with other studies showing omega-3s' ability to decrease inflammatory markers and improve cognitive performance. While some studies have reported inconsistent results, the current study demonstrates a clear reduction in inflammatory cytokines and depression scores with omega-3 supplementation. The mechanism of action is likely related to the ability of omega-3s to downregulate inflammatory cytokines and enzymes and to attenuate the production of pro-inflammatory cytokines. The reduction in depression scores alongside the decrease in inflammatory markers highlights the potential anti-depressant effect through the anti-inflammatory pathway.

This study demonstrates a strong positive correlation between serum levels of TNF-α, IL-6, hs-CRP, and depression scores in bipolar disorder patients. Omega-3 fatty acid supplementation effectively reduced both depression scores and inflammatory markers, suggesting its potential as an adjunctive therapy for managing inflammation and depression in bipolar disorder. Future research should explore the long-term effects, investigate the relationship between peripheral and central cytokine levels, and assess the impact of omega-3s on other inflammatory markers and clinical symptoms.

Limitations of the study include the assessment of cytokines in serum rather than brain tissue, which may not fully reflect central nervous system inflammation. The study investigated only three inflammatory markers, limiting the scope of inflammatory assessment. A longer follow-up period would provide a more comprehensive understanding of the long-term effects of omega-3 supplementation. The sample size, while sufficient for statistical analysis, could be expanded to enhance the generalizability of findings.