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The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youth at Ultra-High Risk for Psychosis

32 Pages Posted: 28 May 2019

See all articles by G. Paul Amminger

G. Paul Amminger

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Barnaby Nelson

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Connie Markulev

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Hok Pan Yuen

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Miriam R. Schäfer

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Maximus Berger

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Nilufar Mossaheb

Medical University of Vienna

Monika Schlögelhofer

Medical University of Vienna

Stephan Smesny

Friedrich-Schiller-Universität Jena - University Hospital Jena

Ian B. Hickie

The University of Sydney

Gregor E. Berger

Child and Adolescent Psychiatric Service of the Canton of Zurich

Eric Y H Chen

The University of Hong Kong - Department of Psychiatry

Lieuwe de Haan

University of Amsterdam

Dorien H. Nieman

University of Amsterdam

Merete Nordentoft

University of Copenhagen - Department of Clinical Medicine

Anita Riecher-Rössler

University of Basel - Department of Psychiatry; University Psychiatric Clinics Basel

Swapna Verma

Institute of Mental Health

Andrew Thompson

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Alison Ruth Yung

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Patrick D. McGorry

Orygen Youth Health

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Abstract

Background: NEURAPRO was a multicenter, double-blind, randomised, placebo-controlled trial RCT of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) ('fish oil') therapy provided for 6 months in individuals at ultra-high risk (UHR) for psychotic disorders, followed by an additional 6-month follow-up period. The study was conducted in 10 specialized early psychosis treatment services in Australia, Asia, and Europe, in 304 participants who received either n-3 PUFA together with cognitive behavioral case management (CBCM) or placebo with CBCM. In the intention to treat analysis, NEURAPRO failed to replicate findings of a previous single-center study. Although the RCT design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil RCTs, since the test agent is not only present in the intervention group but n-3 PUFA are present in the diet and in the body tissue of all participants, potentially influencing outcomes.

Methods: We conducted a biomarker analysis in NEURAPRO participants to determine if n-3 PUFA (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; n-3 index; EPA+DHA) levels measured in erythrocyte membranes at baseline and at month 6 (end-of supplementation) predicted clinical outcomes 6 and 12 months after study entry in the participants irrespective of their original treatment group allocation in the trial.

Findings: Of the 304 participants, 285 (94%) had biomarker data at baseline and 218 (72%) participants had biomarker data at baseline and a subsequent time point (209 at month 6; 9 at transition to psychosis). Increases of the n-3 index, EPA and DHA consistently predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of the n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio (95%CI)=1.79 (1.30-2.48); n-3 PUFA increase: adjusted odds ratio (95%CI)=1.43 (1.16-1.76) and at month 12 (n-3 index baseline: adjusted odds ratio (95%CI)=2.60 (1.71-3.97); n-3 PUFA increase: adjusted odds ratio (95%CI)=1.36 (1.06-1.74). The transition to psychosis rate was lower than expected in this study (5.0% at month 6; 10.1% at month 12). No association was observed between n-3 PUFA measures and transition to psychosis.

Interpretation: These data suggest that n-3 PUFA can exert protective and therapeutic effects in UHR individuals. This finding may have implications for early intervention and clinical treatment guidelines since n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.

Trial Registration: The trial was registered at the Australia and New Zealand Clinical Trials Registry (ID 12608000475347).

Funding Statement: This work was supported by grant 07TGF-1102 from the Stanley Medical Research Institute, grant 566529 from the NHMRC Australia Program (Drs McGorry, Hickie, and Yung, and Amminger), and a grant from the Colonial Foundation. Drs Amminger and Yung were supported by NHMRC Senior Research Fellowships 1080963 and 566593, respectively; and Dr Nelson was supported by NHMRC Career Development Fellowship 1027532. Dr McGorry was supported by Senior Principal Research Fellowship 1060996 from the National Health and Medical Research Council of Australia (NHMRC).

Declaration of Interests: Drs Amminger, Hickie, Yung, and Nelson have received National Health and Medical Research Council (NHMRC) funding. Dr McGorry reported receiving grant funding from National Alliance for Research on Schizophrenia and Depression and unrestricted research funding from AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, and Novartis, as well as honoraria for educational activities with AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, Bristol-Myers Squibb, Roche, and the Lundbeck Institute. No other conflicts were reported.

Ethics Approval Statement: The National Health and Medical Research Council of Australia (NHMRC) National Statement on Human Research was adhered to and appropriate ethical approval was obtained by each site (Melbourne, Australia: Melbourne Health Research Ethics Committee; Sydney, Australia: Sydney South West Area Health Service Ethics Review Committee; Basel, Switzerland: Ethics Commission for Basel; Zurich, Switzerland: Cantonal Ethics Commission Zurich; Jena, Germany: University Clinic Jena Ethics Commission; Copenhagen, Denmark: Capital Region Research Ethics Committee; Hong Kong: Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster; Vienna, Austria: Medical University of Vienna Ethics Commission; Singapore: National Healthcare Group Domain Specific Review Board; and Amsterdam, the Netherlands: Academic Medical Centre Medical Ethics Committee). Written informed consent was obtained for those younger than 17 years, parental or guardian consent was sought. Participants received financial compensation.

Keywords: Ultra-high risk for psychotic disorders; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; omega-3 index; biomarker analysis; randomised, placebo-controlled trial; NEURAPRO

Suggested Citation

Amminger, G. Paul and Nelson, Barnaby and Markulev, Connie and Yuen, Hok Pan and Schäfer, Miriam R. and Berger, Maximus and Mossaheb, Nilufar and Schlögelhofer, Monika and Smesny, Stephan and Hickie, Ian B. and Berger, Gregor E. and Chen, Eric Y H and de Haan, Lieuwe and Nieman, Dorien H. and Nordentoft, Merete and Riecher-Rössler, Anita and Verma, Swapna and Thompson, Andrew and Yung, Alison Ruth and McGorry, Patrick D., The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youth at Ultra-High Risk for Psychosis (05/24/2019 05:56:01). Available at SSRN: https://ssrn.com/abstract=3393730 or http://dx.doi.org/10.2139/ssrn.3393730

G. Paul Amminger (Contact Author)

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health ( email )

Melbourne
Australia

Barnaby Nelson

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Connie Markulev

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Hok Pan Yuen

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Miriam R. Schäfer

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Maximus Berger

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Nilufar Mossaheb

Medical University of Vienna

Vienna
Austria

Monika Schlögelhofer

Medical University of Vienna

Vienna
Austria

Stephan Smesny

Friedrich-Schiller-Universität Jena - University Hospital Jena

Jena
Germany

Ian B. Hickie

The University of Sydney

University of Sydney
Sydney, NSW 2006
Australia

Gregor E. Berger

Child and Adolescent Psychiatric Service of the Canton of Zurich

Switzerland

Eric Y H Chen

The University of Hong Kong - Department of Psychiatry

Pokfulam Road
Hong Kong, Pokfulam HK
China

Lieuwe De Haan

University of Amsterdam

Spui 21
Amsterdam, 1018 WB
Netherlands

Dorien H. Nieman

University of Amsterdam

Spui 21
Amsterdam, 1018 WB
Netherlands

Merete Nordentoft

University of Copenhagen - Department of Clinical Medicine

Nørregade 10
Copenhagen, København DK-1165
Denmark

Anita Riecher-Rössler

University of Basel - Department of Psychiatry

Switzerland

University Psychiatric Clinics Basel

Switzerland

Swapna Verma

Institute of Mental Health

Singapore

Andrew Thompson

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Alison Ruth Yung

University of Melbourne - Orygen, The National Centre of Excellence in Youth Mental Health

Melbourne
Australia

Patrick D. McGorry

Orygen Youth Health ( email )

Department of Management
Babel Building
Melbourne, 3010
Australia

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