February 4, 2015

Essential Fatty Acids Block the Depressive Effect of Interferon Therapy

Study suggests fatty acids may prevent medication-induced depression
In this Taiwanese study, researchers found that adding omega-3 fatty acids to the diet of patients undergoing interferon-alpha therapy decreased their depressive symptoms significantly.


Su KP, Lai HC, Yang HT, et al. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biol Psychiatry. 2014;76(7):559-566. 


A single institution (Liver Centre of China Medical University Hospital, Taichung, Taiwan), double-blind, placebo-controlled trial 


A total of 162 subjects, all of whom were being treated for hepatitis C infection, were randomized to the study. Exclusions included major depressive episode at time of assessment, alcohol or drug use within 1 year, and unstable or chronic medical (eg, cardiovascular, renal, endocrine) conditions. 


The study compared supplementation with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or placebo for the prevention of interferon alpha (IFN α)‒induced depression. Two weeks before starting peginterferon α-2b therapy, patients were given a daily treatment of 5 identical capsules of EPA (3.5 g/d), DHA (1.75 g/d), or placebo (high oleic oil, 3.5 g/d). One hundred and fifty-two patients were evaluable throughout the entire 24 weeks of INT-α therapy. 

Outcome Measures

Using the structured Mini-International Neuropsychiatric Interview, patients were assessed at baseline (before supplementation or placebo intervention); just prior to INF-α treatment; at weeks 2, 4, 6, 8, 12, 16, and 20; and at the conclusion of treatment with INF-α (week 24). Primary endpoint was incidence of major depressive episode any time throughout the treatment. Fatty acid composition of erythrocyte membranes and the level of individual fatty acid were measured by chromatography. 

Key Findings

The incident rates of depression were significantly lower in EPA-treated patients but not in DHA-treated patients (P=.037). Incidence of depression in the placebo group was 30%, while in the EPA group, it was 10%, and in the DHA group, it was 28%. Both supplementation of EPA or DHA significantly delayed the onset of IFN α‒induced depression, with the week of onset at week 12 and week 11.7, respectively, vs week 5.3 for placebo (P=.002). EPA and DHA were both well tolerated in this population. Regarding laboratory findings, EPA treatment increased both EPA and DHA erythrocyte levels, but DHA increased only DHA erythrocyte levels. There was no difference in the proportions of high hepatitis C virus (HCV) viral loads between the groups before or after treatment. 

Practice Implications

Belonging to the cytokine class of proteins, interferons are glycoproteins known for their ability to “interfere” with viral replication in an effort to control hepatitis C infection. As a testament to the importance of the cytokine cascade in depressive illness, there is a high rate of IFN α‒induced depression.1
This simple intervention of 2 weeks of eicosapentaenoic acid could reduce the need to prescribe antidepressants that may have detrimental side effects. 
The role of inflammation and the involvement of cytokines directly as a causative factor in depression is gaining acceptance.2,3 Essential fatty acids are natural candidates for therapeutic use given their low toxicity and known antiinflammatory effects. Indeed, the use of fish oil on depressive symptoms has been validated in clinical trials.4,5
This trial is interesting in that the cause of depression in this population is better defined than usual. Peginterferon causes a rapid and dramatic rise in proinflammatory cytokines. This provides a well-defined framework to assess the short-term use of EPA and DHA. It also has basis in animal studies, which have shown the benefits of essential fatty acids to mitigate cytokine-induced sickness behavior and other behavioral changes.6 These all point to beneficial effects that can help balance common cytokine alterations that lead to depressive symptoms and behaviors. 
Note that EPA seems to have a greater benefit over DHA in this study, a finding that is supported by previous research as well.7 It is unclear whether a combination (as found in natural fish oil) over a longer period time might have similar or even better results. 
This simple intervention of 2 weeks of EPA could reduce the need to prescribe antidepressants that may have detrimental side effects. For example, serotonin reuptake inhibitors are well known to increase the risk of gastrointestinal bleeding.8
There are a couple of caveats regarding the current study. The study population was ethnically homogenous, with all Taiwanese participants. Taiwan is also a country with a high fish intake, so this may have affected participants’ baseline levels of fatty acids as well as metabolism of fatty acids. Another limitation is that the placebo contained 15% linoleic acid along with 75% oleic acid. While the authors believe this small quantity is not enough to have proinflammatory effects, perhaps this confounding factor can be removed in future studies.
From a clinical perspective, this study suggests natural medicine practitioners have a safe, effective and easy-to-use option to offer HCV patients preparing to begin interferon therapy. The use of EPA may help lower the incidence of depression and may preclude the need for more toxic medications to control depressive side effects. 

Categorized Under


  1. Udina M, Castellví P, Moreno-España J, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012;73(8):1128-1138.
  2. Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience.  2013 Aug 29;246:199-229.
  3. Delarue J, Matzinger O, Binnert C, Schneiter P, Chiolero R, Tappy L. Fish oil prevents the adrenal activation elicited by mental stress in healthy men. Diabetes Metab. 2003;29(3):289-295.
  4. Lespérance F, Frasure-Smith N, St-André E, Turecki G, Lespérance P, Wisniewski SR. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry. 2011;72(8):1054-1062.
  5. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584
  6. Song C, Manku MS, Horrobin DF. Long-chain polyunsaturated fatty acids modulate interleukin-1 beta-induced changes in behavior, monoaminergic neurotransmitters, and brain inflammation in rats. J Nutr. 2008;138(5):954-96.3
  7. Freeman MP. Omega-3 fatty acids in psychiatry: a review. Ann Clin Psychiatry. 2000;12(3):159-165.
  8. Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64.