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Omega-3 Fatty Acids in the Prevention of Interferon-Alpha-Induced Depression: Results from a Randomized, Controlled Trial

      Background

      Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression.

      Methods

      We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis.

      Results

      Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.

      Conclusions

      EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.

      Key Words

      Finding the best strategy to prevent neuropsychiatric adverse effects induced by interferon (IFN)-α will improve clinical outcome and shed light on the pathogenesis of inflammation-induced depression, but previous studies have had mixed results (see below), especially in patients who receive IFN-α for chronic hepatitis C virus (HCV) infection. Chronic HCV infection is a major public health issue and has a high rate of progression to liver cirrhosis and hepatocellular carcinoma (
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      ). In addition, the use of antidepressants in patients receiving IFN-α therapy has been associated with rare, but severe, adverse effects, such as retinal hemorrhaging and cotton-wool spots (
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      ), bone marrow suppression, hepatotoxicity (
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      ), and manic episodes (
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      ). As most patients receiving IFN-α do not develop clinically significant depression, the routine pretreatment with antidepressant drugs might expose patients to unnecessary medications; it is thus important to find alternative strategies for the prevention of IFN-α-induced depression.
      Omega-3 polyunsaturated fatty acids (ω-3 or n-3 PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutritional compounds with potential preventive and therapeutic effects against depression. Patients with major depressive disorder have lower levels of omega-3 PUFAs (
      • Lin P.Y.
      • Huang S.Y.
      • Su K.P.
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      ), and societies that consume a larger amount of omega-3 PUFAs have a lower prevalence of major depressive disorder (
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      ). More importantly, meta-analyses and many clinical studies (
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      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ), if not all (
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      A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.
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      • Bloch M.H.
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      ), have shown that omega-3 PUFAs have antidepressant effects. Taken together also with the evidence discussed below, these studies support the use of omega-3 PUFAs as an effective depression prophylactic strategy in at-risk groups, such as indeed patients taking IFN-α.
      One of the hypothesized mechanisms underlying PUFAs’ antidepressant effects is their neuroprotective and anti-inflammatory action (
      • Su K.P.
      Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a ‘Mind-Body Interface’?.
      ,
      • Chalon S.
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      ). Indeed, EPA is important in regulating immune function by antagonizing membrane arachidonic acid (an n-6 PUFA), reducing prostaglandin E2 synthesis (
      • Farooqui A.A.
      • Ong W.Y.
      • Horrocks L.A.
      Inhibitors of brain phospholipase A2 activity: Their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders.
      ), and preventing the response to inflammatory stimuli (
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      Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus.
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      ). Moreover, omega-3 PUFAs have been found to have beneficial effects in animal models of cytokine-induced behavioral changes that resemble depressive behavior (
      • Song C.
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      Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats.
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      Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats.
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      Long-chain polyunsaturated fatty acids modulate interleukin-1 beta-induced changes in behavior, monoaminergic neurotransmitters, and brain inflammation in rats.
      ). Of particular relevance for the present study, we have recently demonstrated that lower DHA levels in the peripheral blood are associated with an increased risk of developing IFN-α-induced depression over the following weeks (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). We have hypothesized that this reflects less endogenous anti-inflammatory capability in those who later develop depression (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). Based on this and the other evidence discussed above, we have conducted this 2-week, double-blind, placebo-controlled trial to test the differential effects of the omega-3 PUFAs, EPA, and DHA against placebo in the prevention of IFN-α-induced depression.
      We have specifically prescribed a short (2 weeks) intervention before IFN-α therapy, to potentially correct the lower omega-3 fatty acid levels that we had previously identified as a risk factor for the development of IFN-α -induced depression (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). Indeed, we also have measured the levels of PUFAs in the erythrocytes before and after the trial and correlated these with treatment response. In addition, we have chosen to test a prophylactic intervention that would be acceptable to most patients because of its brevity and because it would precede, and not overlap with, the IFN-α (and ribavirin) therapy. According to most studies, the active antidepressant component from omega-3 PUFAs is EPA (
      • Martins J.G.
      • Bentsen H.
      • Puri B.K.
      Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: A critique of Bloch and Hannestad and updated meta-analysis.
      ,
      • Lin P.Y.
      • Mischoulon D.
      • Freeman M.P.
      • Matsuoka Y.
      • Hibbeln J.
      • Belmaker R.H.
      • Su K.P.
      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ), but we also wanted to test DHA because, as mentioned above, we have found that lower levels of this omega-3 PUFA predispose to IFN-induced depression (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ).

      Methods and Materials

      Patient Selection

      Since 2005, a psychiatric team has been working together with the hepatologists to provide an integrated care package for HCV patients referred for IFN-α therapy at the Liver Centre of China Medical University Hospital, Taichung, Taiwan, where the Institutional Review Board approved the study. In the period between July 2009 and June 2012, the hepatologists identified eligible HCV patients before they started the combination therapy with peginterferon α-2b (1.5 µg per kilogram of body weight once weekly) and ribavirin (1000–1200 mg daily). Patients were excluded from this study if they had a major depressive episode at the initial assessment; a lifetime history of psychotic disorders (e.g., schizophrenia or bipolar disorder); a history of alcohol or drug dependence within 1 year before entry into the study; and evidence of any unstable chronic medical conditions (e.g., cardiovascular, endocrine, hematological, renal, or neurological diseases). The diagnoses of psychiatric disorders were based on the structured Mini-International Neuropsychiatric Interview (
      • Sheehan D.V.
      • Lecrubier Y.
      • Sheehan K.H.
      • Amorim P.
      • Janavs J.
      • Weiller E.
      • et al.
      The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.
      ). All patients who agreed to participate in this study provided their signed written informed consent before enrollment.

      Study Design and Recruitment

      Two hundred seven patients with HCV were screened, 162 of them consented to participate and were randomized to the study, and all of them completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. For allocation of the participants following simple double-blind randomization procedures, a computer-generated list of random numbers was used. The identical capsules were prepacked in bottles and consecutively numbered according to the randomization schedule by an independent nutritionist.
      Figure S1 in Supplement 1 provides a flow chart summarizing study recruitment. Ten subjects discontinued the IFN-α treatment; they did not differ from the completers in any demographic features, including gender, age, married status, education years, and past history of depression. While the noncompleters did have significantly higher baseline scores than completers in depressive symptoms (Hamilton Rating Scale for Depression [HAMD]: 8.6 ± 3.65 versus 4.5 ± 4.49; p = .018) and neurovegetative symptoms (Neurotoxicity Rating Scale [NTRS]: 52.9 ± 41.74 versus 26.9 ± 29.58; p = .010), they were equally distributed among the three groups (EPA, n = 4; DHA, n = 3; placebo, n = 3).
      The subjects were randomly assigned in double-blind fashion to EPA, DHA, or placebo, administered for 2 weeks before starting IFN-α therapy. Specifically, 2 weeks before the initiation of IFN-α therapy (week –2), patients started receiving a daily treatment of five identical capsules of EPA (3.5 g/day), DHA (1.75 g/day), or placebo (high oleic oil) in single or divided administration. The experimental capsules contained concentrated EPA (700 mg), DHA (350 mg), or high oleic oil (800 mg); they weighed 1000 mg, were deodorized with orange flavor, and were supplemented with tertiary-butyl hydroquinone (.2 mg/g) and tocopherols (2 mg/g) as antioxidants. The sources of EPA, DHA, and oleic acids were, respectively, anchovy fish body oil (purchased from AK BioTech, Ulsan, Korea), algal vegetable (purchased from DSM Nutritional Products, Basel, Switzerland), and safflower oil (purchased from Aarhus Karlshamn, Hull, England).
      The recruited participants were evaluated at weeks –2 (when omega-3 fatty acid prophylactic intervention started) and 0 (when the prophylactic intervention stopped and IFN-α therapy started) and during weeks 2, 4, 6, 8, 12, 16, 20, and 24 of IFN-α therapy to assess the occurrence of major depressive episode with the structured Mini-International Neuropsychiatric Interview. Sociodemographic factors, including gender, age, education, and marital status, as well as the past psychiatric history, substance use history, and family psychiatric history, were recorded at the initial assessment. Severity of depressive symptoms and of neurovegetative symptoms were measured using, respectively, the 21-item HAMD (
      • Hamilton M.
      A rating scale for depression.
      ), rated by trained psychiatrists, and the self-administered NTRS (
      • Valentine A.D.
      • Meyers C.A.
      • Talpaz M.
      Treatment of neurotoxic side effects of interferon-alpha with naltrexone.
      ), both administered at weeks –2, 0, 2, 4, 6, 8, 12, 16, 20, and 24. The NTRS is a checklist questionnaire that has been frequently used for the evaluation of neuropsychiatric symptoms related to cytokine therapy; the items are categorized into general symptoms, nonpainful somatic symptoms, and painful somatic symptoms, with each item rated from 0 to 10 on a visual analog scale, and the final score ranging 0 to 390 (
      • Musselman D.L.
      • Lawson D.H.
      • Gumnick J.F.
      • Manatunga A.K.
      • Penna S.
      • Goodkin R.S.
      • et al.
      Paroxetine for the prevention of depression induced by high-dose interferon alfa.
      ,
      • Valentine A.D.
      • Meyers C.A.
      • Talpaz M.
      Treatment of neurotoxic side effects of interferon-alpha with naltrexone.
      ,
      • Valentine A.D.
      • Meyers C.A.
      Cognitive and mood disturbance as causes and symptoms of fatigue in cancer patients.
      ,
      • Capuron L.
      • Gumnick J.F.
      • Musselman D.L.
      • Lawson D.H.
      • Reemsnyder A.
      • Nemeroff C.B.
      • Miller A.H.
      Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions.
      ). During IFN-α therapy, allowable concomitant medications included acetaminophen and other nonsteroidal anti-inflammatory agents for pain symptoms and fever; granisetron or ondansetron for nausea; lorazepam for severe anxiety; and zolpidem for insomnia. The results of routine biochemical laboratory examinations, the occurrence of adverse effects, and any reason for IFN-α discontinuation were recorded.

      Laboratory Methods

      Fatty acid composition of erythrocyte membranes was analyzed by thin-layer chromatography, and the level of individual fatty acid was measured with gas chromatography of methyl esters (Lipid Standards, FAMEs, Sigma Co., St. Louis, Missouri). Fatty acid profiles were identified by comparing the retention times with those of appropriate standard fatty acid methyl esters. The detailed step-by-step procedures have been published and described elsewhere (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ,
      • Chiu C.C.
      • Huang S.Y.
      • Su K.P.
      • Lu M.L.
      • Huang M.C.
      • Chen C.C.
      • Shen W.W.
      Polyunsaturated fatty acid deficit in patients with bipolar mania.
      ,
      • Su K.P.
      • Huang S.Y.
      • Chiu C.C.
      • Shen W.W.
      Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial.
      ). The levels of each fatty acid were expressed as a percentage of total fatty acids. Laboratory measures were conducted on coded samples by workers who were blind to subjects’ information.

      Data Analyses and Statistics

      All participants who were recruited into the study (n = 162) completed the 2-week, double-blind, randomized-controlled trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. The primary outcome measurement of efficacy was the incidence of major depressive episode in the three groups at any time point during 24 weeks of IFN-α therapy, while the HAMD and NTRS were secondary outcome measurements. The power was calculated a priori: a sample size of 50 in each group would have had 80% of power (at p < .05) to detect a reduction of 10% in the risk of depression. The categorical data (occurrence of major depressive episode or not) were analyzed using χ2 (chi-squared) test. Changes in HAMD and NTRS scores as a function of time were assessed using repeated measures analysis of variance using mixed linear modeling, and at each time point, the mean scores of HAMD and NTRS were compared among the three groups by analysis of variance and post hoc analyses when appropriate. Furthermore, Kaplan-Meier estimates, survival curves, and log-rank test were used to compare the cumulative time free from depression between groups. All probabilities were two-tailed, with p less than .05 considered statistically significant. We used the SPSS statistical software version 15 (SPSS Inc., Chicago, Illinois).

      Results

      Demographics

      There were no statistical differences between the three groups (EPA, DHA, or placebo) in demographics (age, gender, education, and marriage status) (Table 1), psychiatric characteristics (past history of depression, baseline HAMD and NTRS scores) (Table 1), and HCV-relevant biological markers (alanine aminotransferase and HCV genotypes and HCV RNA titers) (Table 1, Table 2).
      Table 1Demographics and Clinical Characteristics Among EPA, DHA, and Placebo Groups
      The results are from analysis of variance unless otherwise specified.
      EPADHAPlacebop
      n505151
      Age (Years), Mean ± SD53.1 ± 10.553.6 ± 9.452.3 ± 11.8.81
      Sex (Male), %48%49%47%.98
      Indicates the results of χ2 (chi-squared) tests.
      Education (Years), Mean ± SD10.3 ± 3.89.8 ± 4.310.5 ± 4.4.63
      Marriage (Married), %96%95%89%.95
      Indicates the results of χ2 (chi-squared) tests.
      History of Major Depressive Disorder, %4%6%8%.72
      Indicates the results of χ2 (chi-squared) tests.
      Psychological Assessments at Week −2
       Baseline HAMD, mean ± SD4.4 ± 4.34.5 ± 5.04.6 ± 4.2.98
       Baseline NTRS, mean ± SD27.6 ± 33.627.3 ± 29.725.8 ± 25.5.95
      Physiological Assessments at Week −2
       Alanine aminotransferase (U/L)92.3 ± 59.6106.9 ± 65.299.4 ± 61.6.77
       Type 1 HCV genotype (%)72%63%60%.45
      Indicates the results of χ2 (chi-squared) tests.
      DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HAMD, the 21-item Hamilton Depression Rating Scale; HCV, hepatitis C virus; NTRS, Neurotoxicity Rating Scale.
      a The results are from analysis of variance unless otherwise specified.
      b Indicates the results of χ2 (chi-squared) tests.
      Table 2Primary and Secondary Outcome Measures Among EPA, DHA, and Placebo Groups
      The results are from analysis of variance unless otherwise specified.
      EPADHAPlacebop
      IFN-Induced MDE, n (%)5 (10%)14 (28%)15 (30%).037
      Indicates the results of χ2 (chi-squared) tests.
      Time to MDE (Weeks), Mean ± SD12.0 ± 5.811.7 ± 6.35.3 ± 3.2.002
      EPA Levels (%)
       Week −22.34 ± .682.43 ± 1.002.29 ± .92.69
       Week 03.08 ± 1.312.31 ± .732.47 ± 1.04.017
      DHA Levels (%)
       Week −24.37 ± 1.514.62 ± 1.084.34 ± 1.40.81
       Week 05.10 ± 1.335.85 ± 1.274.64 ± 1.39.002
      HAMD Score, Mean ± SD
       Week 04.5 ± 4.74.4 ± 4.84.4 ± 4.3.93
       Week 249.7 ± 6.212.1 ± 8.412.3 ± 7.3.19
      NTRS Score, Mean ± SD
       Week 030.2 ± 33.827.9 ± 25.728.9 ± 25.4.92
       Week 2443.8 ± 35.849.4 ± 46.453.1 ± 45.8.62
      HCV RNA (≥200,000 IU/mL) (%)
       Week 078%84%78%.32
      Indicates the results of χ2 (chi-squared) tests.
       Week 244%4%6%.87
      Indicates the results of χ2 (chi-squared) tests.
      DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HAMD, the 21-item Hamilton Depression Rating Scale;HCV, hepatitis C virus; IFN, interferon; MDE, major depressive episode; NTRS, Neurotoxicity Rating Scale.
      a The results are from analysis of variance unless otherwise specified.
      b Indicates the results of χ2 (chi-squared) tests.

      Efficacy Outcomes

      As shown in Table 2, the incident rates of IFN-induced depression were significantly different among EPA, DHA, and placebo groups (10% vs. 28% vs. 30%, respectively; χ2 = 6.62, p = .037). The post hoc analyses showed that incident rate was significantly lower following EPA (χ2 = 5.99, p = .014) but not following DHA (χ2 = .05, p = .8), as compared with placebo. Both EPA and DHA significantly delayed the onset of IFN-induced depression as compared with placebo (mean 12.0 vs. 11.7 vs. 5.3 weeks, respectively; F = 7.80, p = .002).
      Figure 1 shows the Kaplan-Meier survival curves of IFN-induced depression comparing EPA, DHA, and placebo groups. Log-rank tests showed a significant overall effect for treatment group (χ2 = 6.74, df = 2, p = .034). Specifically, subjects receiving EPA prophylactic treatment showed a lower risk of IFN-α-induced depression as compared with placebo treatment (χ2 = 6.52, df = 1, p = .011) or DHA treatment (χ2 = 3.23, df = 1, p = .072). However, there was no significant difference between DHA and placebo groups (χ2 = .95, df = 1, p = .3). The hazard ratios were 2.9 (confidence interval: 1.0–7.9, p = .044) for the comparison between EPA and DHA and 3.5 (confidence interval: 1.3–9.6, p = .015) for the comparison between EPA and placebo.
      Figure thumbnail gr1
      Figure 1Survival curves (Kaplan-Meier estimates) of cumulative incidences of interferon (IFN)-induced depression of 152 patients with hepatitis C viral infection who were pretreated with eicosapentaenoic acid (EPA) (n = 50), docosahexaenoic acid (DHA) (n = 51), or placebo (n = 51) for 2 weeks before a 24-week IFN-α therapy. Using the log-rank test, we examined whether the curves displayed the risks of developing IFN-induced depression among EPA, DHA, and placebo groups were identical during a 24-week IFN-α therapy. Subjects that received EPA prophylactic treatment were associated with a significantly lower risk of IFN-induced depression as compared with placebo treatment (χ2 = 6.52, p = .011) and a trend of lower risk to DHA treatment (χ2 = 3.23, p = .072).
      The HAMD and NTRS scores during the IFN-α therapy are shown in Figure 2A and 2B, respectively. The mixed model analyses showed significant effects on time of repeated measurements (F = 63.8, df = 198, p < .001 for HAMD and F = 19.3, df = 184, p < .001 for NTRS), confirming the IFN-α-induced changes over time, but there were no significant effects of group (F = 1.4, df = 189, p = .2 for HAMD and F = .4, df = 153, p = .6 for NTRS) and no group by time interaction (F = 1.2, df = 198, p = .3 for HAMD and F = .7, df = 184, p = .8 for NTRS).
      Figure thumbnail gr2
      Figure 2Changes in scores on the 21-item Hamilton Depression Rating Scale (HAMD) (A) and the Neurotoxicity Rating Scale (NTRS) (B) from baseline to week 24 among eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo groups. Using a double-blind, placebo-controlled, randomized design, we examined the changes in HAMD (A) and NTRS (B) scores in a mixed-effects model for repeated measures analysis of 152 patients with hepatitis C viral infection who were pretreated with EPA (n = 50), DHA (n = 51), or placebo (n = 51) for 2 weeks before a 24-week interferon-α therapy. There was a significant effect of time with three groups exhibiting significant increases in HAMD (A) and NTRS (B) scores across interferon-α therapy. However, there was no main effect of treatment assignment and no treatment × time interaction. In HAMD (A), subjects in the EPA group had lower HAMD scores at week 4 (than those of the placebo group*; p = .013) and at week 8 (than those of the placebo* and DHA groups+; p = .022 and p = .002, respectively). There was no significant difference in the NTRS (B) at weeks 2, 4, 8, 12, 16, and 20 among the three groups. The error bars indicate SEM.
      As shown also in Table 2, participants in both omega-3 PUFA groups did not differ from those on placebo at weeks 0 and 24 during IFN-α therapy for either HAMD or NTRS. There were significantly lower HAMD scores in the EPA group only at week 4 (compared with placebo group; p = .013) and at week 8 (compared with both DHA and placebo; p = .022 and p = .002, respectively). However, there were no significant differences between the three groups in the HAMD at weeks 2, 12, 16, and 20 and in the NTRS at any week of assessment.

      Fatty Acid Biomarkers

      As shown in Table 2, there was no significant difference in DHA and EPA levels between the three groups before the trial intervention (at week −2). However, there were significant effects of EPA and DHA intervention on the PUFA levels at the end of the trial (week 0) (Table 2). Specifically, the EPA intervention significantly increased EPA (+32%, p = .009) and DHA levels (+17%, p = .016). The DHA intervention significantly increased DHA (+27%, p = .002) but not EPA levels (−5%, p = .6). When the three groups were compared at week 0, analyses of variance followed by post hoc tests found that the EPA intervention group had higher levels of EPA (p = .002 vs. DHA intervention and p = .03 vs. placebo groups), while the DHA intervention group had only higher levels of DHA (p = .035 vs. EPA intervention and p = .001 vs. placebo groups). The complete profile of erythrocyte composition in fatty acids is shown in Table S1 in Supplement 1.
      In the overall sample, a total of 34 patients (22%) developed IFN-α-induced depression at some point during the 24-week therapy, while 118 (78%) patients did not develop IFN-α-induced depression. At week −2 (before the intervention), subjects who later developed IFN-α-induced depression had lower baseline EPA levels (2.00 ± .63) than those who did not (2.47 ± .92; p = .031) but not DHA levels (4.17 ± 1.02 for depressed vs. 4.53 ± 1.41 for nondepressed, p = .28). However, at week 0 (before IFN-α therapy, after the 2 weeks of omega-3 PUFA intervention), there were no significant differences in EPA or DHA levels between subjects who subsequently did or did not develop IFN-α-induced depression (EPA: 2.64 ± 1.16 for depressed vs. 2.50 ± .78 for nondepressed, p = .6; DHA: 5.22 ± 1.32 for depressed vs. 5.11 ± 1.64 for nondepressed, p = .8).

      Adverse Events

      EPA and DHA were found well tolerated in this HCV population. No participant was withdrawn because of adverse events by investigators’ decision, and reported events were all very mild and self-limited. There was no effect found in any blood laboratory parameter, such as abnormal bleeding time or liver function. In addition, there were no significant differences in the proportions of high HCV RNA levels (≥200,000 IU/mL) before and after IFN therapy among the three groups, showing no effects of the PUFA treatments on viral load.

      Discussion

      To our knowledge, this is the first study to demonstrate the beneficial effects of omega-3 fatty acids in the prevention of IFN-α-induced depression. The main finding is that EPA pretreatment significantly decreased the incidence of IFN-α-induced depression in HCV patients. In addition, both EPA and DHA pretreatment significantly delayed the onset of IFN-α-induced depression as compared with placebo pretreatment. Omega-3 fatty acids have been shown to have prophylactic effects in bipolar disorder (
      • Stoll A.L.
      • Severus W.E.
      • Freeman M.P.
      • Rueter S.
      • Zboyan H.A.
      • Diamond E.
      • et al.
      Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial.
      ,
      • Su K.P.
      • Shen W.W.
      • Huang S.Y.
      Are omega3 fatty acids beneficial in depression but not mania?.
      ), psychotic transition in ultra high-risk individuals (
      • Amminger G.P.
      • Schafer M.R.
      • Papageorgiou K.
      • Klier C.M.
      • Cotton S.M.
      • Harrigan S.M.
      • et al.
      Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial.
      ), and the development of posttraumatic stress disorder following accidental injury (
      • Matsuoka Y.
      • Nishi D.
      • Yonemoto N.
      • Hamazaki K.
      • Hashimoto K.
      • Hamazaki T.
      Omega-3 fatty acids for secondary prevention of posttraumatic stress disorder after accidental injury: An open-label pilot study.
      ). Therefore, our findings confirm and extend the notion that this nutritional intervention can have preventive effects in mental health and corroborate the evidence that anti-inflammatory strategies may have antidepressant effects, especially in the context of depression associated with inflammation.
      The results of the current study support our previous findings showing that omega-3 PUFAs play a role in the risk of IFN-α-induced depression (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). In our previous study, we measured the erythrocyte levels of DHA and EPA and analyzed genetic variation in the phospholipase A2 (PLA2) and cyclooxygenase 2 (COX2) genes, the two key enzymes in the metabolism of omega-3 PUFAs. We found that participants with PLA2 BanI GG or COX2 rs4648308 AG genotypes have a higher risk of IFN-α-induced depression. In addition, the at-risk PLA2 polymorphism is associated with lower EPA levels and the at-risk COX2 polymorphism is associated with lower levels of both DHA and EPA during IFN-α therapy; furthermore, in the whole sample, having lower baseline DHA levels before IFN-α therapy is associated with a higher risk of developing depression during IFN-α therapy (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). This evidence is consistent with the present study, where we find that EPA pretreatment, increasing both EPA and DHA erythrocyte levels, is effective in preventing IFN-α-induced depression.
      Previous clinical trials and meta-analyses have shown that the efficacy of omega-3 fatty acids might be dependent on the ratio of EPA and DHA (
      • Lin P.Y.
      • Mischoulon D.
      • Freeman M.P.
      • Matsuoka Y.
      • Hibbeln J.
      • Belmaker R.H.
      • Su K.P.
      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ) and have suggested that EPA, rather than DHA, might be the most active component of omega-3 PUFAs’ antidepressant effects (
      • Lin P.Y.
      • Su K.P.
      A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids.
      ,
      • Martins J.G.
      • Bentsen H.
      • Puri B.K.
      Eicosapentaenoic acid appears to be the key omega-3 fatty acid component associated with efficacy in major depressive disorder: A critique of Bloch and Hannestad and updated meta-analysis.
      ,
      • Lin P.Y.
      • Mischoulon D.
      • Freeman M.P.
      • Matsuoka Y.
      • Hibbeln J.
      • Belmaker R.H.
      • Su K.P.
      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ,
      • Martins J.G.
      EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: Evidence from a meta-analysis of randomized controlled trials.
      ). Indeed, clinical trials using only DHA monotherapy as antidepressant strategy have shown conflicting findings: Marangell et al. (
      • Marangell L.B.
      • Martinez J.M.
      • Zboyan H.A.
      • Kertz B.
      • Kim H.F.
      • Puryear L.J.
      A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression.
      ) found no benefit over placebo for 2 g/day DHA, but Mischoulon et al. (
      • Mischoulon D.
      • Best-Popescu C.
      • Laposata M.
      • Merens W.
      • Murakami J.L.
      • Wu S.L.
      • et al.
      A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder.
      ) found a dose-response effect supporting 1 g/day as superior to 2 g/day or 4 g/day, though the latter study was limited by the lack of a placebo arm. A recent meta-analysis has suggested that both EPA and DHA contribute to antidepressant effects but that the effects of EPA are stronger (
      • Sublette M.E.
      • Ellis S.P.
      • Geant A.L.
      • Mann J.J.
      Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression.
      ). Our current study, showing that EPA reduces the incidence of depression while DHA only delays the onset of depression, further supports this notion. Moreover, EPA can be metabolized into DHA, and EPA intervention can increase blood and brain levels of DHA (
      • Brenna J.T.
      Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man.
      ), which is particularly relevant in this context, as we have identified lower endogenous DHA as a risk factor for IFN-α-induced depression (
      • Su K.P.
      • Huang S.Y.
      • Peng C.Y.
      • Lai H.C.
      • Huang C.L.
      • Chen Y.C.
      • et al.
      Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.
      ). Indeed, it is interesting to highlight that the EPA intervention in our study increased both EPA and DHA levels. Incidentally, in our previous animal study, we demonstrated that a PUFA dietary intervention is able to increase PUFA levels in both erythrocytes and the brain, thus supporting the notion that PUFA changes measureable in the periphery reflect changes in the brain (
      • Huang S.Y.
      • Yang H.T.
      • Chiu C.C.
      • Pariante C.M.
      • Su K.P.
      Omega-3 fatty acids on the forced-swimming test.
      ). These results therefore indicate possible synergetic effects of EPA and DHA on depressive symptomatology.
      The anti-inflammatory action of EPA is likely to be particularly important in this context, where depression is triggered by an immune challenge. The prevailing model for IFN-α-induced depression points to a pivotal role of increased pro-inflammatory cytokines both in the periphery and in the brain (cerebrospinal fluid) of patients, with subsequent activation of the indoleamine 2,3-dioxygenase (IDO) pathway and the production of potentially depressogenic tryptophan metabolites, such as quinolinic acid (
      • Raison C.L.
      • Dantzer R.
      • Kelley K.W.
      • Lawson M.A.
      • Woolwine B.J.
      • Vogt G.
      • et al.
      CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression.
      ). EPA has numerous anti-inflammatory properties by antagonizing membrane arachidonic acid formation, inhibiting COX2 enzyme activity, and reducing prostaglandin E2 synthesis (
      • Su K.P.
      Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a ‘Mind-Body Interface’?.
      ). In turn, a reduction in COX2 activity not only has a general anti-inflammatory action but also can specifically downregulate the IDO enzymes cascade and the production of its metabolites (
      • Cesario A.
      • Rocca B.
      • Rutella S.
      The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer.
      ). Therefore, these findings confirm and extend recent studies showing that pro-inflammatory cytokines and the IDO cascade are involved in depressogenic mechanisms (
      • Zunszain P.A.
      • Anacker C.
      • Cattaneo A.
      • Choudhury S.
      • Musaelyan K.
      • Myint A.M.
      • et al.
      Interleukin-1beta: A new regulator of the kynurenine pathway affecting human hippocampal neurogenesis.
      ) and that high inflammation identifies depressed patients that are less likely to respond to standard antidepressants (
      • Carvalho L.A.
      • Torre J.P.
      • Papadopoulos A.S.
      • Poon L.
      • Juruena M.F.
      • Markopoulou K.
      • et al.
      Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system.
      ,
      • Cattaneo A.
      • Gennarelli M.
      • Uher R.
      • Breen G.
      • Farmer A.
      • Aitchison K.J.
      • et al.
      Candidate genes expression profile associated with antidepressants response in the GENDEP study: Differentiating between baseline ‘predictors’ and longitudinal ‘targets’.
      ) and more likely to respond to anti-inflammatory drugs (
      • Raison C.L.
      • Rutherford R.E.
      • Woolwine B.J.
      • Shuo C.
      • Schettler P.
      • Drake D.F.
      • et al.
      A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers.
      ). In addition to this anti-inflammatory action, EPA and DHA may both exert their preventive effects also through neuroplasticity effects (
      • Bazan N.G.
      Cell survival matters: Docosahexaenoic acid signaling, neuroprotection and photoreceptors.
      ,
      • Rao J.S.
      • Ertley R.N.
      • Lee H.J.
      • DeMar Jr, J.C.
      • Arnold J.T.
      • Rapoport S.I.
      • Brazinet R.P.
      n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism.
      ,
      • Beltz B.S.
      • Tlusty M.F.
      • Benton J.L.
      • Sandeman D.C.
      Omega-3 fatty acids upregulate adult neurogenesis.
      ), which is a relevant molecular mechanism for antidepressant actions (
      • Eisch A.J.
      • Petrik D.
      Depression and hippocampal neurogenesis: A road to remission?.
      ,
      • Castren E.
      • Hen R.
      Neuronal plasticity and antidepressant actions.
      ,
      • Duman R.S.
      • Heninger G.R.
      • Nestler E.J.
      A molecular and cellular theory of depression.
      ).
      Our findings have direct clinical relevance for HCV patients receiving IFN-α. Although prophylactic effects of SSRI antidepressants have been studied in several randomized-controlled clinical studies (
      • Schaefer M.
      • Sarkar R.
      • Knop V.
      • Effenberger S.
      • Friebe A.
      • Heinze L.
      • et al.
      Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: A randomized trial.
      ,
      • Raison C.L.
      • Woolwine B.J.
      • Demetrashvili M.F.
      • Borisov A.S.
      • Weinreib R.
      • Staab J.P.
      • et al.
      Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.
      ,
      • de Knegt R.J.
      • Bezemer G.
      • Van Gool A.R.
      • Drenth J.P.
      • Hansen B.E.
      • Droogleever Fortuyn H.A.
      • et al.
      Randomised clinical trial: Escitalopram for the prevention of psychiatric adverse events during treatment with peginterferon-alfa-2a and ribavirin for chronic hepatitis C.
      ,
      • McNutt M.D.
      • Liu S.
      • Manatunga A.
      • Royster E.B.
      • Raison C.L.
      • Woolwine B.J.
      • et al.
      Neurobehavioral effects of interferon-alpha in patients with hepatitis-C: Symptom dimensions and responsiveness to paroxetine.
      ), the use of such medications needs to be weighed against the risks of adverse effects and complications. Omega-3 fatty acid intervention, however, is a safe and well-accepted alternative antidepressant treatment (
      • Lin P.Y.
      • Su K.P.
      A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids.
      ,
      • Lin P.Y.
      • Mischoulon D.
      • Freeman M.P.
      • Matsuoka Y.
      • Hibbeln J.
      • Belmaker R.H.
      • Su K.P.
      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ,
      • Su K.P.
      Biological mechanism of antidepressant effect of omega-3 fatty acids: How does fish oil act as a ‘Mind-Body Interface’?.
      ). Omega-3 PUFAs have been shown to be well tolerated for patients with chronic medical illnesses and mental disorders (
      • Su K.P.
      Inflammation in psychopathology of depression: Clinical, biological, and therapeutic implications.
      ), and adverse reactions are rare (
      • Bays H.
      Clinical overview of Omacor: A concentrated formulation of omega-3 polyunsaturated fatty acids.
      ). It has been suggested that the potential antithrombotic effect of omega-3 PUFAs may theoretically increase the risk for bleeding: clinical trials have, however, shown that high-dose omega-3 PUFAs consumption is safe, even when concurrently administered with other agents that may increase bleeding, including aspirin and warfarin (
      • Bays H.E.
      Safety considerations with omega-3 fatty acid therapy.
      ,
      • Harris W.S.
      Expert opinion: Omega-3 fatty acids and bleeding-cause for concern?.
      ). Another potential safety concern is the susceptibility of omega-3 fatty acids to undergo oxidation, which may potentially contribute to toxicity; however, the conclusions are inconsistent (
      • Chiu C.C.
      • Liu J.P.
      • Su K.P.
      The use of omega-3 fatty acids in treatment of depression: The lights and shadows.
      ), and adding antioxidant vitamin E to omega-3 PUFAs reduces oxidation.
      In this study, we chose 3.5 grams of EPA and 1.7 grams of DHA per day, because our previous studies conducted in Taiwan using PUFAs as antidepressants showed the effective EPA dose to be between 2.2 g/day and 4.4 g/day and the effective DHA dose to be between 1.2 g/day and 2.2 g/day (
      • Su K.P.
      • Huang S.Y.
      • Chiu C.C.
      • Shen W.W.
      Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial.
      ,
      • Su K.P.
      • Huang S.Y.
      • Chiu T.H.
      • Huang K.C.
      • Huang C.L.
      • Chang H.C.
      • Pariante C.M.
      Omega-3 fatty acids for major depressive disorder during pregnancy: Results from a randomized, double-blind, placebo-controlled trial.
      ). These doses are relatively high, which is consistent with the fact that the baseline dietary content of fish is much higher in Taiwan than in many Western countries (
      • Hibbeln J.R.
      Fish consumption and major depression.
      ). We used an animal source for EPA and a vegetal source for DHA because of the availability; therefore, we cannot exclude that the reduced effectiveness of DHA might be linked to its vegetal source. The placebo contained 15% of linoleic acid, which may exert pro-inflammatory effects and theoretically worsen depression (
      • Su K.P.
      Inflammation in psychopathology of depression: Clinical, biological, and therapeutic implications.
      ); however, the placebo also contained 75% of oleic acid, which could be converted to oleamide and potentially improve depression (
      • Sugiura T.
      • Kondo S.
      • Kodaka T.
      • Tonegawa T.
      • Nakane S.
      • Yamashita A.
      • et al.
      Enzymatic synthesis of oleamide (cis-9, 10-octadecenoamide), an endogenous sleep-inducing lipid, by rat brain microsomes.
      ,
      • Logan A.C.
      Omega-3 and depression research: Hold the olive oil.
      ,
      • Puri B.K.
      • Richardson A.D.
      The effects of olive oil on omega3 fatty acids and mood disorders.
      ). Therefore, on balance, we believe that this was a truly inactive placebo.
      The fact that EPA prevents the occurrence of depression without affecting the HAMD and NTRS scores of the whole group confirms the notion that EPA main effect is confined to subjects with clinically significant depression and does not extend to subjects with no or minimal depressive symptoms (
      • Lin P.Y.
      • Mischoulon D.
      • Freeman M.P.
      • Matsuoka Y.
      • Hibbeln J.
      • Belmaker R.H.
      • Su K.P.
      Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression.
      ). Indeed, patients in this study developed clinically significant depression at any time points between week 2 and week 24 and the prophylactic effects are limited to around 20% of the sample and thus too diluted to statistically affect the scores of the whole group. It is worth highlighting, however, that Figure 2 clearly shows that the scores of both scales are numerically lower in the EPA groups than in the other two groups; moreover, HAMD scores are significantly lower in the EPA group compared with placebo at weeks 4 and 8 and compared with DHA at week 8. The effects of DHA are simply less strong than those of EPA, as shown by the fact that DHA delays the onset of depression: basically, it prevents depression up to week 10 (Figure 1), but the effects are not sustained. Obviously, it is possible that both EPA and DHA effects might have been more pronounced if the treatments had been continued beyond 2 weeks. Finally, this study is limited by its relatively small sample size, the lack of information on prescription of hypnotic agents, and the fact that noncompleters had higher depression scores at baseline, although they were equally distributed among the three groups.
      In conclusion, EPA was beneficial for the prevention of IFN-α-induced depression, while DHA had only modest effects on delaying the onset. The data suggest that EPA or EPA/DHA combination is the best preventive strategy in this group of patients and potentially a suitable strategy for the wider pool of patients with depression associated with inflammation.
      This work was supported by the following grants: 102-2911-I-039-501, 101-2628-B-039-001-MY3, and 101-2320-B-038-020-MY2 from the National Science Council; NHRI-EX101-10144NI from the National Health Research Institute; and CMR99-114 and DMR-101-081 from the China Medical University in Taiwan; National Alliance for Research on Schizophrenia and Depression Young Investigator Award; and Royal Society Joint Research Projects for Taiwan and United Kingdom. Professor Pariante is also supported by the United Kingdom Medical Research Council (MR/J002739/1) and the South London and Maudsley National Health Service Trust and King’s College Hospital National Institute for Health Research Biomedical Research Centre for Mental Health.
      Drs Su and Pariante created the concept. Drs Su, Lai, Yang designed the study, acquired the data, and take responsibility for the integrity and accuracy of the data. Drs Su and Pariante drafted and revised the manuscript. All the authors had full access to all the data in the study.
      Professor Pariante has received research funding from companies interested in developing anti-inflammatory strategies for depression, such as Janssen Pharmaceuticals, but the current study is unrelated to this funding. All other authors report no biomedical financial interests or potential conflicts of interest.
      ClinicalTrials.gov: N-3 Polyunsaturated Fatty Acids in the Prevention and Treatment for IFN-induced Depression; https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0003K57&selectaction=View&uid=U0000KV0&ts=11&cx=-4rg5aa; NCT01620502.

      Appendix A. Supplementary Materials

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