The Omega-3 Fatty Acid Paediatric Depression Trial
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      This study investigates the therapeutic efficacy and safety of omega-3 fatty acids rich in
      eicosapentaenoic acid / docosahexaenoic acid in pediatric depression in a nine months
      double-blind multi-centre study in 220 children and adolescents between 8 and 17 years of
      age. Inflammatory and bioactive lipid markers as predictors of response are evaluated. The
      relationship between omega-3 fatty acids with psychopathology, illness course and cognitive
      parameters will be further investigated.
    

Detailed description: 
      Background: About 10% teenagers report moderate to marked depressive symptoms and between
      1-6% will develop a paediatric major depressive disorder (pMDD) until adulthood. However,
      evidence-based treatment approaches are sparse and the use of selective serotonin reuptake
      inhibitors (SSRIs) is heavily debated due to reports of an increase in suicidal ideation and
      limited efficacy in this age group. Growing evidence suggests that omega-3 fatty acids may be
      a beneficial treatment in adult MDD (aMDD) with no published study in teenagers, despite of
      its face validity as a valuable first-line treatment. Meta-analyses of published randomized
      controlled trials (RCTs) in aMDD show moderate effect sizes, if the proportion of
      eicosapentaenoic acid (EPA) is >60% of the total omega-3 fatty acids. One small RCT in
      prepubertal children shows an even larger effect size in favour of omega-3 fatty acids.
      Higher inflammatory mediators (e.g. c-reactive protein, interleukins and others) have been
      reported in aMDD and pMDD. Preliminary data suggests that a proinflammatory state may serve
      as predictor for omega-3 fatty acids response. Furthermore, low levels of omega-3 fatty acids
      have been found in aMDD and pMDD potentially also serving as EPA-response predictors. As MDD
      is a heterogeneous disease entity, such response predictors should be incorporated into MDD
      RCTs.

      Objective: 1) To investigate the therapeutic efficacy and safety of omega-3 fatty acids rich
      in EPA in pMDD, 2) to demonstrate clinical meaningful effects of omega-3 fatty acid
      treatment, 3) to investigate inflammatory and bioactive lipid markers as response predictors,
      and 4) to investigate the relationship between psychopathology (in particular suicidal
      ideation), illness course and cognition in relation to inflammatory and bioactive lipid
      markers. 5.) To establish a tissue repository of phenotypically well characterised children
      and adolescents with pMDD.

      Outcome: The German S3 Guidelines for the treatment of depression in children and youth
      define the background treatment for all participants. All clinical partners will be trained
      and monitored accordingly. The primary outcomes are the (continuous) Children's Depression
      Rating Scale-revised (CDRS-R) total score and the (dichotomous) rates of recovery defined by
      the absence of pMDD for >4months at 36 weeks, as well as response and remission rates at 12
      and 36 weeks. Inflammatory mediators in serum using immunoassays, red blood cell omega-3, 6,
      9 and trans fatty acids using gas chromatography (GC) and bioactive lipid mediators (e.g.
      E-series resolvin) using mass spectrometry (LC-MS/MS) will be measured as potential response
      predictors. Adverse events/ harm endpoints (in particular suicidality) will be coded using
      MedDRA. Adherence measurements are pill counts, as well as n-3 EPA/DHA levels across the
      study. Blood samples will be taken at study entry, week 12 and 36.

      Study design:A Swiss, multicentre, randomised, double-blind, placebo-controlled clinical
      trial.

      Inclusion / Exclusion criteria:The study aims to recruit a sample of 220 individuals aged 8
      -17 years, who are in- or outpatients of a participating centre and have a present primary
      diagnosis of major depressive disorders with depressive symptom of at least moderate
      severity. Participants with pre-existing neurological or medical conditions likely to be
      responsible for the depressive symptoms or other psychopathological diagnoses are excluded.

      Measurement and procedures: The study design incorporates a 1-2week screening, a 1-week
      lead-in and a 36-week double-blind placebo-controlled treatment phase. The severity of the
      depression and psychosocial functioning will be assessed at baseline and at each study visit
      (twice in the acute phase and twice in the maintenance phase) using a variety of different
      questionnaires and rating scales. Cognitive testing and biological markers (blood, urine and
      saliva) will be sampled at baseline and at 12 and 36 weeks. Adherence to the study will be
      checked by pill count at each study visit and polyunsaturated fatty acid (PUFA) level
      measurements in red blood cell membranes at baseline, 12 and 36 weeks will be performed.

      Study product / Intervention: In the proposed study a daily dose of 500mg EPA/ 250mg DHA in
      the 8 to <13 year olds and 1000mg EPA / 500mg DHA in the 13 to <18 years olds (which
      corresponds with the omega-3 fatty acid doses used in adult MDD RCTs) is used as an active
      treatment, respectively. The drug will be administered for 36 weeks. Placebo capsules will
      contain mostly medium chain triglycerides (MCT) and also a small amount of fish oil to mimic
      the fishy flavour and taste. All study medication (active and placebo) will use fish derived
      gelatine capsules and natural orange flavor.

      Sample size justification: This clinical trial aims to include 220 participants in total,
      resulting in 110 participants per treatment group. A sample size calculation was performed
      based on the effect size of 0.54 found in a previous meta-analysis on the effect of omega-3
      fatty acids in aMDD. Sample size calculations were then adjusted for an expected higher
      placebo-response rate in minors and given the multi-centre design. The analysis resulted that
      the inclusion of 108 patients per treatment group will achieve 80% or greater power to detect
      a difference of 20% in response rates between the two treatment groups. The sample of 220
      participants exceeds therefore the projected sample size needed to detect a clinical
      meaningful difference. Participants with no psychopathological follow up data at all will be
      replaced.

      Study duration: The study duration is projected to be about four years and (April 2017 -
      2021) for patient recruitment and assessment and another year to finish up all the analysis
      and generate the final study report.
    

Intervention name(s): Omega 3 fatty acid; Placebo oil
Intervention type(s): Drug; Drug
Intervention description(s): Omega-3 fatty acids in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines; medium chain triglycerides in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines
Other intervention name(s): Eicosapentaenoic acid (EPA) / docosahexaenoic acid (DHA); medium chain triglycerides
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A 36-week, multi-centre, double-blind, placebo-controlled randomized superiority Study.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid; antidepressants; suicidality; cognition; childhood depression; pediatric depression