The Omega-3 Fatty Acid Paediatric Depression Trial (Omega-3-pMDD)

OMEGA-3 FATTY ACIDS AS FIRST-LINE TREATMENT IN PAEDIATRIC DEPRESSION. A Phase III, 36-week, Multi-centre, Double-blind, Placebo-controlled Randomized Superiority Study

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.

Study Overview

• Status: Completed
• Conditions: Depression
• Intervention / Treatment: Drug: Omega 3 fatty acid; Drug: Placebo oil

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.

• Study Type: Interventional
• Enrollment (Actual): 257
• Phase: Phase 3

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland
    • University Psychiatric Services
  • Saint Gallen, Switzerland
    • Stiftung Kinder- und Jugendpsychiatrische Dienste St.Gallen
  • Baselland
    • Liestal, Baselland, Switzerland
      • Psychiatric Services Baselland
  • St.Gallen
    • Ganterschwil, St.Gallen, Switzerland
      • Klinik Sonnenhof
  • Thurgau
    • Littenheid, Thurgau, Switzerland
      • Clienia Littenheid
    • Weinfelden, Thurgau, Switzerland
      • Spital Thurgau Kinder- und Jugendpsychiatrischer Dienst
  • ZH
    • Zurich, ZH, Switzerland, 8032
      • Psychiatric University Clinics, Department of Child and Adolescent Psychiatry

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female in- or outpatients of a participating centre
• Children aged 8 <13 years or teenager aged 13 to < 18 years
• Major depressive disorder with depressive symptoms of at least moderate severity
• Written informed consent of the parents / legal representatives and patients' assent

Exclusion Criteria:

• contraindications to the drug
• more than 4 weeks of regular omega-3 supplementation
• pregnant or breastfeeding or intention to become pregnant
• pre-existing neurological or medical conditions likely to be responsible for depressive symptoms
• laboratory screening values considered clinically relevant
• known or suspected non-compliance
• other psychiatric diagnoses (substance dependency, schizophrenia, bipolar affective disorder, eating disorder, mental retardation, pervasive developmental disorder)
• inability to follow the procedures of the study
• Participation in another study with omega-3, previous enrolment in the current study, or dependent persons of the investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Omega-3 fatty acid oil; 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, respectively, will be added to standardized treatment according to the German S3 Guidelines for the treatment of depression in children and adolescents	Drug: Omega 3 fatty acid; Omega-3 fatty acids in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines; Other Names: Eicosapentaenoic acid (EPA) / docosahexaenoic acid (DHA)
Placebo Comparator: Placebo oil; Placebo capsules will contain mostly medium chain triglycerides (MCT) and also a small amount of fish oil to mimic the fishy flavour and taste. Placebo will be added to standardized treatment according to the German S3 Guidelines for the treatment of depression in children and adolescents	Drug: Placebo oil; medium chain triglycerides in addition to standard treatment for depression in children and adolescents according to the German S3 Guidelines; Other Names: medium chain triglycerides

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic improvement	Change of the (continuous) Children's Depression Rating Scale-revised (CDRS-R) total score analyzed using using a linear random coefficient regression model	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recovery rate	(dichotomous) rates of recovery defined by the absence of pMDD for >4months at 36 weeks according to the Kiddie-Schedule (K-SADS)	9 months
Remission rate	remission is defined as a CDRS total score <28	3 months
Remission rate	remission is defined as a CDRS total score <28	9 months
Response rate	Response is defined as a 30% decrease in total baseline CDRS sum score	6 weeks
Antidepressant medication	Differences in antidepressant medication between the treatment groups	9 months
Children's global assessment scale (CGAS)	Differences in the scores of the CGAS between treatment groups	9 months
Kidscreen quality of life measure for children and adolescents	Differences in the scores of the Kidscreen between treatment groups	9 months
Hospitalization	Differences in hospital admissions between the treatment groups	9 months
Retention rate	Differences in retention rate between the treatment groups	9 months
Inflammatory mediators as predictors of response	Omega-3 fatty acid response wil be predicted by the ratio between pro- and anti-inflammatory markers	Baseline values as predictors for response across the trial
Omega-3 index as predictors of response	Omega-3 fatty acid response will be predicted by the omega-3 index	Baseline values as predictors for response across the trial
Metabolites of EPA as predictors for response	Omega-3 fatty acid response will be predicted by the levels of direct metabolites of EPA	Baseline values as predictors for response across the trial
Depressive Symptoms	Correlation between severity of depressive symptoms and pro-inflammatory state and omega-3 index	9 months
Suicidal ideation Questionnaire (SIQ)	Inverse correlation between omega-3 fatty acids and scores in the SIQ	9 months
Scale of Impulsivity and Emotion Dysregulation (IES-27)	Correlation between omega-3 index and the overall score of the Scale of Impulsivity and Emotion Dysregulation (IES-27)	9 months
Relationship between stress, omega-3 fatty acids and saliva cortisol	Correlation between omega-3 fatty acid levels, scores in the perceived stress scale and saliva cortisol	9 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Verbal learning and memory test (VLMT)	Differences in the overall score between the treatment groups	9 months
Behavior Rating Inventory of Executive Function (BRIEF)	Differences in the scores of the BRIEF between the treatment groups	9 months
Tolerability assessed by the Self-reported Antidepressant Side-Effect Checklist (ASEC)	ASEC total score shows no significant differences between active and placebo	9 months
Digit span measured by the Wechsler Intelligence Scale for Children (WISC-IV)	Differences in the overall score of the digit span between the treatment groups	9 months
Emotion recognition measured with the Amsterdam Neuropsychological Task (ANT) Program	Significant better scores in emotion recognition of the active compared to the placebo group	9 months
Attentional flexibility measured with the shifting attentional set of the Amsterdam Neuropsychological Task (ANT) program	Differences in the reaction times between the treatment groups	9 months
Regensburg Word Fluency Test (RWT)	Differences in the number of generated words in the RWT between treatment groups	9 months

Collaborators and Investigators

• Sponsor: Gregor Berger
• Collaborators: Swiss National Science Foundation
• Investigators: Principal Investigator: Susanne Walitza, MD, Psychiatrische Universitätsklinik Zürich KJPP; Principal Investigator: Klaus Schmeck, MD, Universitäre Psychiatrische Kliniken (UPK) Basel

Publications and helpful links

General Publications

• Haberling I, Berger G, Schmeck K, Held U, Walitza S. Omega-3 Fatty Acids as a Treatment for Pediatric Depression. A Phase III, 36 Weeks, Multi-Center, Double-Blind, Placebo-Controlled Randomized Superiority Study. Front Psychiatry. 2019 Nov 27;10:863. doi: 10.3389/fpsyt.2019.00863. eCollection 2019.

Helpful Links

• Study website (online from Mai 2017)

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2017
• Primary Completion (Actual): March 24, 2022
• Study Completion (Actual): March 24, 2022

Study Registration Dates

• First Submitted: February 24, 2017
• First Submitted That Met QC Criteria: May 24, 2017
• First Posted (Actual): May 25, 2017

Study Record Updates

• Last Update Posted (Actual): April 6, 2023
• Last Update Submitted That Met QC Criteria: April 4, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: cognition; antidepressants; suicidality; omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid; childhood depression; pediatric depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder
• Other Study ID Numbers: SNF 33IC30_166826; 2016-02116 (Other Identifier: Swissethics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: A BioBank will be established. Access to the Biobank can be requested upon completion of the trial contacting the sponsor-investigator Dr. Gregor Berger

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No