The effects of omega 3 fatty acids on the serum concentrations of pro inflammatory cytokines and depression status in patients with bipolar disorder: A randomized double-blind controlled clinical trial

Bipolar disorder affects approximately 0.5%–1% of the general population and is associated with increased pro-inflammatory markers (e.g., TNF-α, IL-6, hs-CRP). Inflammation is implicated in the pathogenesis and progression of bipolar disorder, and reducing inflammation may aid treatment. Omega-3 polyunsaturated fatty acids have anti-inflammatory properties through mechanisms such as inhibiting leukocyte chemotaxis and reducing eicosanoid and cytokine production. Prior studies show mixed effects of omega-3 supplementation on inflammatory markers across populations. This study investigates whether omega-3 supplementation reduces pro-inflammatory cytokines (TNF-α, IL-6, hs-CRP) and improves depression status in patients with bipolar disorder, addressing gaps due to limited data in this population.

The authors note elevated pro-inflammatory cytokines in bipolar disorder compared with healthy controls and associations with mood states. Meta-analyses and trials in other conditions (heart failure, gestational diabetes) report reductions in TNF-α, IL-6, and/or hs-CRP with omega-3 supplementation, while studies in metabolic syndrome and type 2 diabetes with NAFLD show no significant effects, highlighting inconsistencies possibly due to population differences, doses, and durations. Prior psychiatric literature links inflammatory dysregulation with bipolar disorder course and depressive symptoms, supporting the hypothesis that anti-inflammatory interventions like omega-3s may improve outcomes.

Design: Randomized, double-blind, placebo-controlled clinical trial conducted in 2021 in Zahedan, Iran. Participants: 60 patients with bipolar disorder in the depressive phase (15 men and 15 women per group) from Baharan Psychiatric Clinic under supervision of a university psychiatrist. Inclusion criteria: Age 16–60 years; ≥6 months history of bipolar disorder; willingness to participate; no omega-3 supplement use for several months prior; no planned surgery in the next 3 months; not receiving drugs that interfere with omega-3s (e.g., anticoagulants); no severe hypertension; non-alcohol users. Exclusion criteria: Change in medication dosage/type; hypersensitivity to omega-3; compliance <80%; infectious/inflammatory disorders; unwillingness to continue; delusional bipolar patients. Randomization and blinding: Permuted block stratified randomization by age and gender (R software v4.0.2). Double blinding; interventionists and technicians were blinded to allocation. Groups matched on sex and age by frequency matching. Intervention: Omega-3 group received 2 capsules/day of 1000 mg omega-3 fatty acids (each capsule: 180 mg EPA, 120 mg DHA; total 2 g/day; EPA 360 mg/day, DHA 240 mg/day) for 2 months, taken after meals with water. Placebo group received 2 capsules/day of edible paraffin oil identical in appearance. Products supplied by Barij Essence Company. Participants were advised to avoid omega-3-rich foods and anti-inflammatory diets; adherence monitored weekly; consumption with main meals recommended to minimize GI side effects. Outcomes: - Primary biochemical outcomes: Serum TNF-α, IL-6, hs-CRP measured before and after intervention using commercial kits (LDN, Germany). Blood drawn (5 mL), centrifuged at 3500 rpm for 10 min. - Clinical outcome: Depression status measured by the 24-item Hamilton Depression Rating Scale (Persian version; reliability 0.81). Categories: 0–6 remission; 7–17 mild; 18–24 moderate; ≥25 severe. Demographics collected (age, marital status, job). Diagnosis confirmed by psychiatrist. Sample size: Calculated from prior study parameters with α=0.05, power=0.80, κ=1, σ2=88.5, ε=2.2, δ=5, yielding 30 per group. Statistical analysis: Normality assessed by Kolmogorov–Smirnov and Q-Q plots. Within-group comparisons by paired t-test; between-group comparisons by independent t-test. Demographics compared by independent t-test (continuous) and chi-square (categorical). Pearson correlations assessed relationships between cytokines and depression scores. Significance threshold P<0.05. Data expressed as mean±SD or frequencies. Ethics: Approved by Zahedan University of Medical Sciences Ethics Committee (IR.ZAMUS.REC.1400.319). Registered at Iranian Registry of Clinical Trials (IRCT20211220053469N1). Informed consent obtained from all participants.

- Baseline comparability: No significant between-group differences at baseline for IL-6 (P=0.652), TNF-α (P=0.196), hs-CRP (P=0.083), or depression score (P=0.128). Demographics (age, height, weight, disease duration, education/job) were similar. - Inflammatory markers (mean±SD): • IL-6 (pg/mL): Omega-3 3.46±0.54 to 2.30±0.40 (Δ −1.16±0.68; P<0.001 within; P<0.001 vs placebo post); Placebo 3.39±0.61 to 3.51±0.64 (P=0.124). • TNF-α (pg/mL): Omega-3 7.23±1.02 to 5.46±1.05 (Δ −1.76±0.75; P<0.001 within; P<0.001 vs placebo post); Placebo 6.94±0.66 to 6.95±0.91 (P=0.865). • hs-CRP (pg/mL): Omega-3 2.82±1.02 to 1.97±0.57 (Δ −0.85±0.68; P<0.001 within; P<0.001 vs placebo post); Placebo 3.02±0.40 to 3.04±0.29 (P=0.641). • Reported percent reductions in omega-3 group: IL-6 −50%, TNF-α −32%, hs-CRP −43% versus baseline. - Depression (Hamilton score, mean±SD): Omega-3 18.93±9.04 to 13.70±5.32 (Δ −5.23±3.22; P<0.001 within; P<0.001 vs placebo post); Placebo 19.36±9.72 to 20.43±8.26 (P=0.590). - Correlations: Depression scores positively correlated with IL-6, TNF-α, and hs-CRP before and after intervention in both groups. Reported Pearson r values ranged approximately 0.351–0.811 with P-values mostly <0.001 (e.g., after omega-3: IL-6 r=0.414, P=0.012; TNF-α r=0.365, P=0.039; hs-CRP r=0.811, P<0.001).

Findings show that adjunctive omega-3 supplementation in bipolar disorder reduces pro-inflammatory cytokines (TNF-α, IL-6) and hs-CRP and improves depressive symptoms relative to placebo over 2 months. The positive correlations between inflammatory markers and depression support the role of inflammation in bipolar pathophysiology. The anti-inflammatory actions of omega-3s likely contribute to antidepressant effects, potentially via modulation of cytokine signaling, attenuation of HPA axis activation, and preservation of neuronal membrane integrity and neurotransmission (dopaminergic/serotonergic). Results align with meta-analytic evidence of omega-3 reducing inflammatory biomarkers in other conditions and with prior psychiatric studies showing associations between inflammatory dysregulation and mood states in bipolar disorder. This trial addresses a gap by directly linking biomarker reductions to symptom improvements in bipolar depression, suggesting clinical relevance for using omega-3s as an adjunct to standard care.

Omega-3 fatty acid supplementation reduced serum TNF-α, IL-6, and hs-CRP and improved depression scores in patients with bipolar disorder, with positive correlations observed between inflammatory markers and depressive symptoms. These results support omega-3s as a potential adjunctive treatment targeting inflammation to alleviate depressive symptoms in bipolar disorder. Future research should include longer follow-up, broader panels of inflammatory and neuroimmune markers, and investigations into relationships between peripheral and central cytokine changes to clarify mechanisms and optimize dosing and patient selection.

- Serum cytokine measurements may not reflect central (brain) cytokine levels. - Only three inflammatory markers (TNF-α, IL-6, hs-CRP) were assessed; broader profiling was not performed. - No post-intervention follow-up to assess durability of effects. - Dietary intake was advised (to avoid omega-3-rich/anti-inflammatory foods) but not rigorously controlled, which could introduce variability.