Disturbance of lipid, particularly omega-3 polyunsaturated fatty acid (PUFA), metabolism is associated with the etiology and symptoms of schizophrenia. Numerous clinical studies have tried to evaluate whether omega-3 PUFA supplementation can ameliorate the disorder, but the results are inconclusive.
Objectives:
This systematic review integrates and refines the research evidence of the effectiveness of omega-3 PUFA nutritional supplementation on schizophrenia during the different developmental phases of the disease (prodromal, first-episode, and chronic phases) and examines whether different developmental stages modulate the efficacy of omega-3 PUFA supplementation.
Data Sources:
Scientific articles from 2000 to 2020 in PubMed/Medline, Allied Health Literature, PsychINFO, and SCOPUS following the Preferred Reporting Items for Systematic Reviews guidelines.
Methods:
A systematic review was performed. We reviewed electronic databases and identified 1,266 clinical studies. Of these, 26 met the inclusion criteria.
Results:
The effectiveness of omega-3 dietary supplementation on symptoms varies among different phases of illness. Omega-3 supplementation significantly improves positive and negative symptoms at the prodromal phase, improves mainly the negative symptoms in patients with the first-episode, and effects symptoms partly in patients with chronic schizophrenia.
Discussion:
The effectiveness of omega-3 PUFA dietary supplementation is modulated by age, duration of untreated psychosis and illness, baseline levels of omega-3 fatty acids, and status of antioxidant capacity of patients. The important implications for psychiatric research and clinical practice developments as well as nursing care are presented and discussed.
AmmingerG. P.NelsonB.MarkulevC.YuenH. P.SchäferM. R.BergerM.MossahebN.SchlögelhoferM.SmesnyS.HickieI. B.BergerG. E.ChenE. Y. H.de HaanL.NiemanD. H.NordentoftM.Riecher-RösslerA.VermaS.ThompsonA.YungA. R.McGorryP. D. (2020). The NEURAPRO biomarker analysis: Long-chain omega-3 fatty acids improve 6-month and 12-month outcomes in youths at ultra-high risk for psychosis. Biological Psychiatry, 87(3), 243–252. https://doi.org/10.1016/j.biopsych.2019.08.030
2.
AmmingerG. P.SchaeferM. R.PapageorgiouK.BeckerJ.MossahebN.HarriganS. M.McGorryP.BergerG. (2007). Omega-3 fatty acids reduce the risk of early transition to psychosis in ultra-high risk individuals: A double-blind randomized, placebo-controlled treatment study. Schizophrenia Bulletin, 3(suppl), 418–419.
3.
AmmingerG. P.SchaferM. R.PapageorgiouK.KlierC. M.CottonS. M.HarriganS. M.MackinnonA.McGorryP. D.BergerG. E. (2010). Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: A randomized, placebo-controlled trial. Archives of General Psychiatry, 67(2), 146–154. https://doi.org/10.1001/archgenpsychiatry.2009.192
4.
AmmingerG. P.SchäferM. R.SchlögelhoferM.KlierC. M.McGorryP. D. (2015). Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nature Communications, 11(6), 7934. https://doi.org/10.1038/ncomms8934
5.
AndreasenN. C.NopoulosP.MagnottaV.PiersonR.ZiebellS.HoB. C. (2011). Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia. Biological Psychiatry, 70(7), 672–679. https://doi.org/10.1016/j.biopsych.2011.05.017
6.
ArvindakshanM.SitasawadS.DebsikdarV.GhateM.EvansD.HorrobinD. F.BennettC.RanjekarP. K.MahadikS. P. (2003). Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biological Psychiatry, 53, 56–64. https://doi.org/10.1016/S0006-3223(02)01443-9
7.
BentsenH.LandrøN. I. (2018). Neurocognitive effects of an omega-3 fatty acid and vitamins E+C in schizophrenia: A randomised controlled trial. Prostaglandins, Leukotrienes & Essential Fatty Acids, 136, 57–66. https://doi.org/10.1016/j.plefa.2017.10.002
8.
BentsenH.OsnesK.RefsumH.SolbergD. K.BohmerT. (2013). A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Translational Psychiatry, 3, e335. https://doi.org/10.1038/tp.2013.110
9.
BentsenH.SolbergD. K.RefsumH.BohmerT. (2012). Clinical and biochemical validation of two endophenotypes of schizophrenia defined by levels of polyunsaturated fatty acids in red blood cells. Prostaglandins, Leukotrienes & Essential Fatty Acids, 87, 35–41. https://doi.org/10.1016/j.plefa.2012.05.005
10.
BergerG. E.ProffittT.McConchieM.YuenH.WoodS. J.AmmingerG. P.BrewerW.McGorryP. D. (2007). Ethyl-eicosapentaenoic acid in first-episode psychosis: A randomized, placebo-controlled trial. The Journal of Clinical Psychiatry, 68(12), 1867–1875. https://doi.org/10.4088/jcp.v68n1206
11.
BergerG. E.WoodS. J.WellardR. M.ProffittT. M.McConchieM.AmmingerG. P.JacksonG. D.VelakoulisD.PantelisC.McGorryP. D. (2008). Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study. Neuropsychopharmacology, 33(10), 2467–2473. https://doi.org/10.1038/sj.npp.1301628
12.
BorovcaninM.JovanovicI.RadosavljevicG. (2013). Antipsychotics can modulate the cytokine profile in schizophrenia: Attenuation of the type-2 inflammatory response. Schizophrenia Research, 147(1), 103–109. https://doi.org/10.1016/j.schres.2013.03.027
13.
CadenheadK.AddingtonJ.CannonT.CornblattB.MathalonD.McGlashanT.PerkinsD.SeidmanL. J.TsuangM.WalkerE.WoodsS. (2017). Omega-3 fatty acid versus placebo in a clinical high-risk sample from the North American Prodrome Longitudinal Studies (NAPLS) consortium. Schizophrenia Bulletin, 43(suppl 1), S16. https://doi.org/10.1093/schbul/sbx021.042
14.
ChenA. T.ChibnallJ. T.NasrallahH. A. (2015). A meta-analysis of placebo-controlled trials of omega-3 fatty acid augmentation in schizophrenia: Possible stage-specific effects. Annals of Clinical Psychiatry, 27(4), 289–296.
15.
EmsleyR.ChilizaB.AsmalL.du PlessisS.PhahladiraL.van NiekerkE.van RensburgS. J.HarveyB. H. (2014). A randomized, controlled trial of omega-3 fatty acids plus an antioxidant for relapse prevention after antipsychotic discontinuation in first-episode schizophrenia. Schizophrenia Research, 158(1-3), 230–235. https://doi.org/10.1016/j.schres.2014.06.004
16.
EmsleyR.MyburghC.OosthuizenP.Van RensburgS. J. (2002). Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia. American Journal of Psychiatry, 159(9), 1596–1598. https://doi.org/10.1176/appi.ajp.159.9.1596
17.
EmsleyR.NiehausD. J.KoenL.OosthuizenP. P.TurnerH. J.CareyP.van RensburgS. J.MaritzJ. S.MurckH. (2006). The effects of eicosapentaenoic acid in tardive dyskinesia: A randomized, placebo-controlled trial. Schizophrenia Research, 84(1), 112–120. https://doi.org/10.1016/j.schres.2006.03.023
18.
FentonW. S.DickersonF.BoronowJ.HibbelnJ. R.KnableM. B. (2001). A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. American Journal of Psychiatry, 158(12), 2071–2074. https://doi.org/10.1176/appi.ajp.158.12.2071
19.
Fusar-PoliP.BergerG. (2012). Eicosapentaenoic acid interventions in schizophrenia: Meta-analysis of randomized, placebo-controlled studies. Journal of Clinical Psychopharmacology, 32(2), 179–185. https://doi.org/10.1097/JCP.0b013e318248b7bb
20.
Fusar-PoliP.BonoldiI.YungA. R.BorgwardtS.KemptonM. J.ValmaggiaL.BaraleF.CaverzasiE.McGuireP. (2012). Predicting psychosis: Meta-analysis of transition outcomes in individuals at high clinical risk. Archives of General Psychiatry, 69(3), 220–229. https://doi.org/10.1001/archgenpsychiatry.2011.1472
21.
HowesO. D.KapurS. (2009). The dopamine hypothesis of schizophrenia: Version III—The final common pathway. Schizophrenia Bulletin, 35(3), 549–562. https://doi.org/10.1093/schbul/sbp006
22.
HsuM. C.TungC. Y.ChenH. E. (2018). Omega-3 polyunsaturated fatty acid supplementation in prevention and treatment of maternal depression: Putative mechanism and recommendation. Journal of Affective Disorders, 238, 47–61. https://doi.org/10.1016/j.jad.2018.05.018
23.
JamilianH.SolhiH.JamilianM. (2014). Randomized, placebo-controlled clinical trial of omega-3 as supplemental treatment in schizophrenia. Global Journal of Health Science, 6(7), 103–108. https://doi.org/10.5539/gjhs.v6n7p103
24.
ManteghiyA.ShakeriM. T.KoohestaniL.SalariE. (2008). Beneficial antipsychotic effects of omega-3 fatty acids add-on therapy for the pharmacological management of patients with schizophrenia. Iranian Journal of Psychiatry & Behavioral Science, 2(2), 35–40.
25.
McEvoyJ.BaillieR. A.ZhuH.BuckleyP.KeshavanM. S.NasrallahH. A.DoughertyG. G.YaoJ. K.Kaddurah-DaoukR. (2013). Lipidomics reveals early metabolic changes in subjects with schizophrenia: Effects of atypical antipsychotics. PLoS One, 8(7), e68717. https://doi.org/10.1371/journal.pone.0068717
26.
McGorryP. D.NelsonB.MarkulevC.YuenH. P.SchäferM. R.MossahebN.SchlögelhoferM.SmesnyS.HickieI. B.BergerG. E.ChenE. Y.de HaanL.NiemanD. H.NordentoftM.Riecher-RösslerA. O.VermaS.ThompsonA.YungA. R.AmmingerG. P. (2017). Effect of ω-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders the NEURAPRO randomized clinical trial. JAMA Psychiatry, 74(1), 19–27. https://doi.org/10.1001/jamapsychiatry.2016.2902
27.
McNamaraR. K.JandacekR.RiderT.TsoP.HahnC. G.RichtandN. M.StanfordK. E. (2007). Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: Gender differences and partial normalization with antipsychotic medications. Schizophrenia Research, 91(1–3), 37–50. https://doi.org/10.1016/j.schres.2006.11.027
28.
MillerJ.DrostD. J.JensenE.ManchandaR.NorthcottS.NeufeldR. W.MenonR.RajakumarN.PavloskyW.DensmoreM.SchaeferB.WilliamsonP. (2012). Progressive membrane phospholipid changes in first episode schizophrenia with high field magnetic resonance spectroscopy. Psychiatry Research, 201(1), 25–33. https://doi.org/10.1016/j.pscychresns.2011.06.017
29.
MoherD.LiberatiA.TetzlaffJ.AltmanD. G., & The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Medicine, 6(7), e1000097. https://doi.org/10.1371/journal.pmed.1000097
30.
MossahebN.SchäferM. R.SchlögelhoferM.KlierC. M.CottonS. M.McGorryP. D.AmmingerG. P. (2013). Effect of omega-3 fatty acids for indicated prevention of young patients at risk for psychosis: When do they begin to be effective?Schizophrenia Research, 148(1-3), 163–167. https://doi.org/10.1016/j.schres.2013.05.027
31.
ParikhV.KhanM. M.MahadikS. P. (2003). Differential effects of antipsychotics on expression of antioxidant enzymes and membrane lipid peroxidation in rat brain. Journal of Psychiatric Research, 37(1), 43–51. https://doi.org/10.1016/s0022-3956(02)00048-1.
32.
PawełczykT.Grancow-GrabkaM.Kotlicka-AntczakM.TrafalskaE.PawełczykA. (2016). A randomized controlled study of the efficacy of six-month supplementation with concentrated fish oil rich in omega-3 polyunsaturated fatty acids in first episode schizophrenia. Journal of Psychiatric Research, 73, 34–44. https://doi.org/10.1016/j.jpsychires.2015.11.013
33.
PawełczykT.Grancow-GrabkaM.TrafalskaE.SzemrajJ.PawełczykA. (2017). Oxidative stress reduction related to the efficacy of n-3 polyunsaturated fatty acids in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized trial. Prostaglandins, Leukotrienes & Essential Fatty Acids, 121(1), 7–13. https://doi.org/10.1016/j.plefa.2017.05.004
34.
PawełczykT.TrafalskaE.PawełczykA.Kotlicka-AntczakM. (2015). Differences in omega-3 and omega-6 polyunsaturated fatty acid consumption in people at ultra-high risk of psychosis, first-episode schizophrenia, and in healthy controls. Early Intervention in Psychiatry, 11(6), 498–508. https://doi.org/10.1111/eip.1226
35.
PeetM.BrindJ.RamchandC. N.ShahS.VankarG. K. (2001). Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Schizophrenia Research, 49(3), 243–251. https://doi.org/10.1016/S0920-9964(00)00083-9
36.
PeetM.HorrobinD. F., & E-E Multicentre Study Group. (2002). A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. Journal of Psychiatric Research, 36(1), 7–18. https://doi.org/10.1016/S0022-3956(01)00048-6
37.
QiaoY.MeiY.HanH.LiuF.YangX. M.ShaoY.XieB.LongB. (2018). Effects of Omega-3 in the treatment of violent schizophrenia patients. Schizophrenia Research, 195, 283–285. https://doi.org/10.1016/j.schres.2017.08.026
38.
RichardsonA. J.EastonT.PuriB. K. (2000). Red cell and plasma fatty acid changes companying symptom remission in a patient with schizophrenia treated with eicosapentaenoic acid. European Neuropsychopharmacology, 10(3), 189–193. https://doi.org/10.1016/S0924-977X(00)00068-7
39.
RobinsonD. G.GallegoJ. A.JohnM.HannaL. A.ZhangJ. P.BirnbaumM. L.GreenbergJ.NaraineM.PetersB. D.McNamaraR. K.MalhotraA. K.SzeszkoP. R. (2019). A potential role for adjunctive omega-3 polyunsaturated fatty acids for depression and anxiety symptoms in recent onset psychosis: Results from a 16 week randomized placebo-controlled trial for participants concurrently treated with risperidone. Schizophrenia Research, 204, 295–303. https://doi.org/10.1016/j.schres.2018.09.006
40.
SamaraM. T.NikolakopoulouA.SalantiG.LeuchtS. (2019). How many patients with schizophrenia do not respond to antipsychotic drugs in the short term? An analysis based on individual patient data from randomized controlled trials. Schizophrenia Bulletin, 45(3), 639–646. https://doi.org/10.1093/schbul/sby095
41.
SarrisJ.MurphyJ.MischoulonD.PapakostasG. I.FavaM.BerkM.NgC. H. (2016). Adjunctive nutraceuticals for depression: A systematic review and meta-analyses. American Journal of Psychiatry, 173(6), 575–587. https://doi.org/10.1176/appi.ajp.2016.15091228
42.
SethomM. M.FaresS.BouazizN.MelkiW.JemaaR.FekiM.HechmiZ.KaabachiN. (2010). Polyunsaturated fatty acids deficits are associated with psychotic state in schizophrenia. Prostaglandins, Leukotrienes & Essential Fatty Acids, 83(3), 131–136. https://doi.org/10.1016/j.plefa.2010.07.001
43.
SivriogluE. Y.KirliS.SipahiogluD.GursoyB.SarandolE. (2007). The impact of omega-3 fatty acids, vitamins E and C supplementation on treatment outcome and side effects in schizophrenia patients treated with haloperidol: An open-label pilot study. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 31(7), 1493–1499. https://doi.org/10.1016/j.pnpbp.2007.07.004
44.
SommerI. E.BeardenC. E.Van DellenE.BreetveltE. J.DuijffS. N.MaijerK.van AmelsvoortT.de HaanL.GurR. E.ArangoC.Díaz-CanejaC. M.VinkersC. H.VorstmanJ. A. (2016). Early interventions in risk groups for schizophrenia: What are we waiting for?NPJ Schizophrenia, 2, 16003. https://doi.org/10.1038/npjschz.2016.3
45.
StillwellW.ShaikhS. R.ZerougaM.SiddiquiR.WassallS. R. (2005). Docosahexaenoic acid affects cell signaling by altering lipid rafts. Reproduction Nutrition Development, 45(4), 559–579. https://doi.org/10.1051/rnd:2005046
46.
SuK. P.ShenW. W.HuangS. Y. (2001). Omega-3 fatty acids as a psychotherapeutic agent for a pregnant schizophrenic patient. European Neuropsychopharmacology, 11(4), 295–299. https://doi.org/10.1016/S0924-977X(01)00098-0
47.
TahaA. Y.CheonY.MaK.RapoportS. I.RaoJ. S. (2013). Altered fatty acid concentrations in prefrontal cortex of schizophrenic patients. Journal of Psychiatric Research, 47(5), 636–643. https://doi.org/10.1016/j.jpsychires.2013.01.016
48.
Van der KempW. J.KlompD. W.KahnR. S.LuijtenP. R.HulshoffH. E. (2012). A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia. Schizophrenia Research, 141(2-3), 153–161. https://doi.org/10.1016/j.schres.2012.08.014
49.
van RensburgS. J.SmutsC. M.HonD.KiddM.van der MerweS.MyburghC.OosthuizenP.EmsleyR. (2009). Changes in erythrocyte membrane fatty acids during a clinical trial of eicosapentaenoic acid (EPA) supplementation in schizophrenia. Metabolic Brain Disease, 24(4), 659–672. https://doi.org/10.1007/s11011-009-9160-7
50.
Vik-MoA. O.BirkenaesA. B.FernøJ.JonsdottirH.AndreassenO. A.SteenV. M. (2008). Increased expression of lipid biosynthesis genes in peripheral blood cells of olanzapine-treated patients. International Journal of Neuropsychopharmacology, 11(5), 679–684. https://doi.org/10.1017/S1461145708008468
51.
WatariM.HamazakiK.HirataT.HamazakiT.OkuboY. (2010). Hostility of drug-free patients with schizophrenia and n−3 polyunsaturated fatty acid levels in red blood cells. Psychiatry Research, 177(1), 22–26. https://doi.org/10.1016/j.psychres.2010.02.016
52.
WoodS. J.CocchiL.ProffittT. M.McConchieM.JacksonG. D.TakahashiT.PantelisC.McGorryP. D.BergerG. E. (2010). Neuroprotective effects of ethyl-eicosapentaenoic acid in first episode psychosis: A longitudinal T2 relaxometry pilot study. Psychiatry Research: Neuroimaging, 182(2), 180–182. https://doi.org/10.1016/j.pscychresns.2009.12.003
