Long-Chain ω-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial | Psychiatry and Behavioral Health | JAMA Psychiatry | JAMA Network
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    2 Comments for this article
    Omega-3 Fatty Acid Deficiency as a Risk Factor for Schizophrenia
    Robert K. McNamara, Ph.D. | University of Cincinnati College of Medicine
    The Amminger et al (1) study demonstrates a significant benefit of omega-3 fatty acid supplementation for preventing or delaying transition to psychosis in ultra-high risk adolescents. One important implication of this finding that deserves elaboration is that it provides support for omega-3 fatty acid deficiency as a ‘risk factor’ for schizophrenia. A risk factor, unlike a risk marker, implies a causal link with the illness, correction of which reduces the risk of developing the illness. This study provides three key pieces of evidence in support of omega- 3 fatty acid deficiency as a ‘risk factor’ for schizophrenia. First, this study demonstrates that subjects at ultra-high risk for developing psychosis exhibit very low erythrocyte levels of the two principal long- chain omega-3 fatty acids, eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), in the prodromal phase. Specifically, mean erythrocyte EPA+DHA composition was 3.1%, a value that is approximately 40% lower than healthy subjects (4.9%) (2). Second, this EPA+DHA deficit is consistent with prior case-control studies finding significantly lower erythrocyte omega-3 fatty acid levels in medication- naïve first-episode or early-episode psychotic patients (3). Third, this study demonstrates that increasing erythrocyte EPA+DHA composition through dietary EPA+DHA supplementation prevents or delays the onset of psychosis in ultra-high risk subjects. Together, these findings satisfy the ‘prediction’, ‘consistency’, and ‘response to treatment’ criteria, respectively (4).
    Not reported in the Amminger et al. study, however, is evaluation of the ‘dose-response’ relationship between erythrocyte EPA+DHA composition and risk of transitioning to psychosis (i.e., lowest erythrocyte EPA+DHA levels associated with greatest risk for transitioning to psychosis). Nevertheless, preliminary support for this criterion is provided by the finding that supplementation with EPA+DHA, but not placebo, increased erythrocyte EPA+DHA composition and reduced psychosis transition rates. Unfortunately, the authors did not report erythrocyte EPA+DHA composition following the 12-week intervention so that protective levels could be extrapolated. The ‘specificity’ criterion (i.e., specific to schizophrenia) cannot be met because omega-3 fatty acid deficiency has also been implicated as a risk factor in other psychiatric disorders (5). Finally, the ‘biological plausibility’ criterion is satisfied by several findings linking omega-3 fatty acid deficiency during development and a long-standing dysregulation in dopamine and serotonin neurotransmitter systems.
    Taken collectively, the study by Amminger et al provides new evidence that strengthens the validity of omega-3 fatty acid deficiency as a ‘risk factor’ (vs. risk marker) for schizophrenia. As in other areas of medicine, identification of a valid risk factor holds tremendous promise for understanding underlying pathoetiological mechanisms as well as developing targeted interventions. Fortunately, omega-3 fatty acid deficiency is a diagnosable, preventable, and reversible condition.
    1. Amminger GP, Schäfer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67:146-154.
    2. Jakobik V, Burus I, Decsi T. Fatty acid composition of erythrocyte membrane lipids in healthy subjects from birth to young adulthood. Eur J Pediatr. 2009;168:141-147.
    3. Reddy RD, Keshavan MS, Yao JK: Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline. Schizophr Bull. 2004;30:901-911.
    4. Hill, AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58:295-300.
    5. McNamara, R. K. Evidence-based evaluation of omega-3 fatty acid deficiency as a risk factor for recurrent neuropsychiatric illness: Current status and future directions. In: E. P. Heikkinen (Ed.), Fish Oils and Health. Nova Science Publishers, Inc. U.S.A. pp. 7-67, 2008.
    No relevant conflicts of interest
    Fish oil to prevent psychosis
    Scott W. Woods M.D., Thomas H. McGlashan M.D. | Yale University School of Medicine and Connecticut Mental Health Center
    Originally posted February 23, 2010

    Amminger et al(1) have made a valuable contribution to the prevention of psychotic disorders. Three additional points are worthy of discussion. First, the authors studied only one dose of the ω-3 preparation, and other doses or other preparations may not be as effective. From April 2002 to November 2003, we enrolled 7 subjects meeting criteria for risk syndromes for psychosis(2) similar to those used by Amminger et al in an 12-week, open - label study of an ω-3 preparation. None were receiving antipsychotic medication. Visits were weekly for 8 weeks and then biweekly; extension out
    to one year was permitted for patients who improved. Response was defined based on achieving no positive symptoms in the at-risk range on the Scale of Psychosis-risk Symptoms (SOPS).(3) In our sample (5M, 2F, 18.1±3.6 years), 2 patients completed at least 12 weeks and responded (at 4 and 16 weeks); however, 2 patients converted to psychosis while on protocol (to schizophreniform disorder at 2 weeks and to psychotic disorder NOS at 6 weeks), and a third converted (to schizophrenia at 6 weeks) one week after dropping out due to worsening depressive symptoms. The remaining two patents dropped out, one due to improvement after 3 weeks (a responder) and one after 6 weeks for reasons related to leaving college. Based on the three conversions among seven patients, we suspended the study. Our ω-3 preparation was purified ethyl-eicosapentaenoic acid (EPA) 500 mg, two tablets twice daily, the same preparation and dose that produced mixed findings in the authors’ previous first-episode antipsychotic augmentation study.(4) It is possible that the 700 mg/d of EPA that Amminger et al delivered in the current study to the at-risk patients is effective on average but the 2000 mg/d we gave is not. Also possible is that docosohexaenoic acid and other ω-3 fatty acids in the Amminger et al mixture are required for efficacy, a suggestion recently put forth in a systematic review to explain mixed findings with ω-3 fatty acids in bipolar disorder.(5) Other possibilities for the discrepant findings are that that we discontinued our study prematurely, given that 3/7 patients responded to treatment, or that we recruited a more severe and perhaps a “later” at-risk sample: SOPS total scores at baseline were 45±18, compared to 40±16 in our previous trial.(6) Second, it is worth noting that the signature “fish burp” side effect of ω-3 fatty acids, which can occur in as many as 75% of subjects,(7) risks compromising the blind.(8) Assessment of the blind through patient “guesses” is worthwhile to incorporate into future studies. Newer, more highly refined fish oil preparations may minimize this issue. Third, the authors emphasize that therapeutic effects persisted after cessation of the 12-week intervention. Given the ready availability of ω-3 preparations over-the-counter and the resourcefulness of patients and their families, the possibility that some or many patients continued ω-3 preparations on their own during follow-up should not be discounted.

    Scott W. Woods
    Thomas H. McGlashan
    Yale University School of Medicine


    1. Amminger GP, Schafr MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE. Long-chain ω-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67(2):146-154.

    2. Woods SW, Addington J, Cadenhead KS, Cannon TD, Cornblatt BA, Heinssen R, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, McGlashan TH. Validity of the prodromal risk syndrome for psychosis: findings from North American Prodrome Longitudinal Study. Schizophrenia Bulletin. 2009;35:894-908.

    3. Miller TJ, McGlashan TH, Woods SW, Stein K, Driesen N, Corcoran CM, Hoffman R, Davidson L. Symptom assessment in schizophrenic prodromal states. Psychiatr Q. 1999;70(4):273-87.

    4. Berger GE, Proffitt TM, McConchie M, Yuen H, Wood SJ, Amminger GP, Brewer W, McGorry PD. Ethyl-eicosapentaenoic acid in first-episode psychosis: a randomized, placebo-controlled trial. J Clin Psychiatry. 2007;68(12):1867-75.

    5. Turnbull T, Cullen-Drill M, Smaldone A. Efficacy of omega-3 fatty acid supplementation on improvement of bipolar symptoms: a systematic review. Arch Psychiatr Nurs. 2008;22(5):305-11.

    6. McGlashan TH, Zipursky RB, Perkins D, Addington J, Miller T, Woods SW, Hawkins KA, Hoffman RE, Preda A, Epstein I, Addington D, Lindborg S, Trzaskoma Q, Tohen M, Breier A. Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis. Am J Psychiatry. 2006;163(5):790-9.

    7. Marangell LB, Martinez JM, Zboyan HA, Kertz B, Kim HF, Puryear LJ. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160(5):996-8.

    8. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry. 1999;56(5):407- 12.
    CONFLICT OF INTEREST: Dr. Woods received a small grant from Laxdale Limited to conduct the open label trial. In the past ten years he has received investigator-initiated grant support from Eli Lilly, Janssen, Bristol Myers-Squib, Pfizer, Schering Plough, and Glytech Inc and speaking or consultant fees from Schering Plough and Otsuka. Dr. McGlashan has received investigator-initiated grant support from Eli Lilly.
    Original Article
    February 2010

    Long-Chain ω-3 Fatty Acids for Indicated Prevention of Psychotic Disorders: A Randomized, Placebo-Controlled Trial

    Author Affiliations

    Author Affiliations: Department of Child and Adolescent Psychiatry, Medical University of Vienna, Vienna, Austria (Drs Amminger, Schäfer, Papageorgiou, and Klier); Orygen Research Centre, Centre for Youth Mental Health, The University of Melbourne, Melbourne, Australia (Drs Amminger, Cotton, Mackinnon, and McGorry and Ms Harrigan); and Department of Research and Education, The Schlössli Clinic, Oetwil am See, Switzerland (Dr Berger).

    Arch Gen Psychiatry. 2010;67(2):146-154. doi:10.1001/archgenpsychiatry.2009.192

    Context  The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Long-chain ω-3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that ω-3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation.

    Objective  To determine whether ω-3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.

    Design  Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007.

    Setting  Psychosis detection unit of a large public hospital in Vienna, Austria.

    Participants  Eighty-one individuals at ultra-high risk of psychotic disorder.

    Interventions  A 12-week intervention period of 1.2-g/d ω-3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months.

    Main Outcome Measures  The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of ω-6 to ω-3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition.

    Results  Seventy-six of 81 participants (93.8%) completed the intervention. By study's end (12 months), 2 of 41 individuals (4.9%) in the ω-3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). ω-3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups.

    Conclusions  Long-chain ω-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.

    Trial Registration  clinicaltrials.gov Identifier: NCT00396643