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Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

ABSTRACT: This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ? 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were randomized between 18 May 2006 and 30 June 2011 to 8 weeks of double-blind treatment with eicosapentaenoic acid (EPA)-enriched n-3 1060 mg day(-1), docosahexaenoic acid (DHA)-enriched n-3 900 mg day(-1) or placebo. Outcomes were determined using mixed model repeated measures analysis for 'high' and 'low' inflammation groups based on individual and combined biomarkers. Results are presented in terms of standardized treatment effect size (ES) for change in HAM-D-17 from baseline to treatment week 8. Although overall treatment group differences were negligible (ES=-0.13 to +0.04), subjects with any 'high' inflammation improved more on EPA than placebo (ES=-0.39) or DHA (ES=-0.60) and less on DHA than placebo (ES=+0.21); furthermore, EPA-placebo separation increased with increasing numbers of markers of high inflammation. Subjects randomized to EPA with 'high' IL-1ra or hs-CRP or low adiponectin ('high' inflammation) had medium ES decreases in HAM-D-17 scores vs subjects 'low' on these biomarkers. Subjects with 'high' hs-CRP, IL-6 or leptin were less placebo-responsive than subjects with low levels of these biomarkers (medium to large ES differences). Employing multiple markers of inflammation facilitated identification of a more homogeneous cohort of subjects with MDD responding to EPA vs placebo in our cohort. Studies are needed to replicate and extend this proof-of-concept work.

SUBMITTER: Rapaport MH

PROVIDER: S-EPMC4581883 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

Rapaport M H MH Nierenberg A A AA Schettler P J PJ Kinkead B B Cardoos A A Walker R R Mischoulon D D

Molecular psychiatry 20150324 1

This study explores whether inflammatory biomarkers act as moderators of clinical response to omega-3 (n-3) fatty acids in subjects with major depressive disorder (MDD). One hundred fifty-five subjects with Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) MDD, a baseline 17-item Hamilton Depression Rating Scale (HAM-D-17) score ⩾ 15 and baseline biomarker data (interleukin (IL)-1ra, IL-6, high-sensitivity C-reactive protein (hs-CRP), leptin and adiponectin) were random ...[more]

PMID: 25802980

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Project description:Although major depressive disorder (MDD) is associated with altered functional coupling between disparate neural networks, the degree to which such measures are ameliorated by antidepressant treatment is unclear. It is also unclear whether functional connectivity can be used as a predictive biomarker of treatment response. Here, we used whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response. 163 MDD and 62 healthy individuals underwent functional MRI during pre-treatment baseline and 8-week follow-up sessions. Patients were randomized to escitalopram, sertraline or venlafaxine-XR antidepressants and assessed at follow-up for remission. Baseline measures of intrinsic functional connectivity between each pair of 333 regions were analyzed to identify pre-treatment connectomic features that distinguish remitters from non-remitters. We then interrogated these connectomic differences to determine if they changed post-treatment, distinguished patients from controls, and were modulated by medication type. Irrespective of medication type, remitters were distinguished from non-remitters by greater connectivity within the default mode network (DMN); specifically, between the DMN, fronto-parietal and somatomotor networks, the DMN and visual, limbic, auditory and ventral attention networks, and between the fronto-parietal and somatomotor networks with cingulo-opercular and dorsal attention networks. This baseline hypo-connectivity for non-remitters also distinguished them from controls and increased following treatment. In contrast, connectivity for remitters was higher than controls at baseline and also following remission, suggesting a trait-like connectomic characteristic. Increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression.

Project description:Background Omega-3 polyunsaturated fatty acids (n-3 PUFAs) augmentation of antidepressants has shown great potential in the prevention and treatment of major depressive disorders (MDD). Objective To investigate the effect of n-3 PUFAs plus venlafaxine in patients with first-diagnosed, drug-naïve depression. Method A total of 72 outpatients with first-diagnosed depression were recruited. The daily dose of 2.4 g/day n-3 PUFAs or placebo plus venlafaxine was used for over 12 weeks. The outcomes were assessed by the Hamilton depression scale (HAMD), Hamilton anxiety scale (HAMA), Beck depression inventory (BDI), and Self-rating anxiety scale (SAS). Results Both groups exhibited improvement on clinical characteristics at week 4 and week 12 compared with baseline. The rate of responders for anxiety in n-3 PUFAs group (44.44%) was significantly higher than that in placebo group (21.21%) at week 4 (χ2 = 4.182, p = 0.041), while week 12 did not show a difference (χ2 = 0.900, p = 0.343). The rate of responders for depression at both week 4 (χ2 = 0.261, p = 0.609) and week 12 (χ2 = 1.443, p = 0.230) showed no significant difference between two groups. Further analysis found that Childhood Trauma Questionnaire (CTQ) had positive correlation with HAMA (r = 0.301, p = 0.012), SAS (r = 0.246, p = 0.015), HAMD (r = 0.252, p = 0.038) and BDI (r = 0.233, p = 0.022) with Pearson correlation analysis. Social Support Rating Scale (SSRS) had negative correlation with SAS (r = −0.244, p = 0.015) and BDI (r = −0.365, p = 0.000). Conclusion This trial found that n-3 PUFAs supplementation in favor of venlafaxine alleviated the anxiety symptoms rather than depressive symptoms at the early stage of treatment (4 weeks) for first-diagnosed, drug-naïve depressed patients. However, the advantage disappeared in long-term treatment. Furthermore, childhood abuse and social support are closely related to the clinical and biological characteristics of depression. Both childhood trauma and lack of social support might be predictors of poor prognosis in depression. Clinical Trial Registration [clinicaltrials.gov], identifier [NCT03295708].

Project description:Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114-0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I(2)=73.36, P<0.001), meta-regression showed that higher EPA dose (?=0.00037 (0.00009-0.00065), P=0.009), higher percentage antidepressant users (?=0.0058 (0.00017-0.01144), P=0.044) and earlier publication year (?=-0.0735 (-0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:BackgroundThe prevalence of mood disorders in children is a growing global concern. Omega-3 fatty acids (FA) are emerging as a promising adjuvant therapy for depressive disorder (DD) in paediatric patients. The primary objective of this pilot, single-centre, randomized, double-blind controlled study was to compare the efficacy of an Omega-3 FA fish oil emulsion with a control oil emulsion alongside standard treatment for depressive symptoms in children and adolescents suffering from depressive disorder (DD) and mixed anxiety depressive disorder (MADD).Methods38 children (12 patients were treated and diagnosed for at least 1 month before enrolment, 26 patients were first-time diagnosed as DD) aged 11-17 years were randomised 1:1 to the intervention (Omega-3 FA, 19 patients) or active comparator (Omega-6 FA, 19 patients) groups. Children's depression inventory (CDI) ratings were performed at baseline, every 2 weeks for a 12-week intervention period and at 4-week post-intervention. 35 patients (17 in Omega-3 and 18 in Omega-6 groups) who completed the whole intervention period were evaluated. Patients from Omega-3 group were stratified according to diagnosis into two subgroups (DD-10/17 and mixed anxiety depressive disorder (MADD)-7/17 patients) and in the Omega-6 group into DD-10/18 and MADD-8/18 patients. Groups were evaluated separately. Differences between-groups were tested with the Student´s t test or non-parametric Mann-Whitney U test. Two-way ANOVA with repeated measures and Friedman test were used to analyse the Treatment effect for response in CDI score. p < 0.05 was considered significant in all statistical analyses.ResultsSignificant reductions in CDI scores in 35 analysed patients who completed 12 weeks intervention were observed after 12 weeks of intervention only in the Omega-3 group (p = 0.034). After stratification to depressive disorder and mixed anxiety depressive disorder subgroups, the DD subgroup receiving the Omega-3 FA fish oil showed statistically greater improvement (score reduction after 8 week treatment of -9.1 CDI, p = 0.0001) when compared to the MADD subgroup (score reduction after 8 week treatment -4.24 CDI, p = 0.271).ConclusionsCDI scores were reduced in the Omega-3 group and the depression subgroup had greater improvement than the mixed depressive/anxiety group. An Omega-3 fatty acid rich fish oil emulsion may be an effective adjuvant supplement during the treatment of depressive disorders in children. Trial registration ISRCTN81655012.

Dataset Information

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

Publications

Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study.

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