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The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis

  • J. Firth (a1), B. Stubbs (a2) (a3), J. Sarris (a4) (a5), S. Rosenbaum (a6), S. Teasdale (a7) (a8), M. Berk (a9) (a10) and A. R. Yung (a1) (a11)...
  • Please note a correction has been issued for this article.



When used as an adjunctive with antipsychotics, certain vitamins and minerals may be effective for improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modulating neurological pathways.


We conducted a systematic review of all randomized controlled trials (RCTs) reporting effects of vitamin and/or mineral supplements on psychiatric symptoms in people with schizophrenia. Random-effects meta-analyses were used to calculate the standardized mean difference between nutrient and placebo treatments.


An electronic database search in July 2016 identified 18 eligible RCTs, with outcome data for 832 patients. Pooled effects showed that vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms significantly more than control conditions [g = 0.508, 95% confidence interval (CI) 0.01–1.01, p = 0.047, I 2 = 72.3%]. Similar effects were observed among vitamin B RCTs which used intention-to-treat analyses (g = 0.734, 95% CI 0.00–1.49, p = 0.051). However, no effects of B vitamins were observed in individual domains of positive and negative symptoms (both p > 0.1). Meta-regression analyses showed that shorter illness duration was associated with greater vitamin B effectiveness (p = 0.001). There were no overall effects from antioxidant vitamins, inositol or dietary minerals on psychiatric symptoms.


There is preliminary evidence that certain vitamin and mineral supplements may reduce psychiatric symptoms in some people with schizophrenia. Further research is needed to examine how the benefits of supplementation relate to nutrient deficits and the impact upon underlying neurobiological pathways, in order to establish optimal nutrient formulations for improving clinical outcomes in this population. Future studies should also explore the effects of combining beneficial nutrients within multi-nutrient formulas.


Corresponding author

*Address for correspondence: Mr J. Firth, Institute of Brain, Behaviour and Mental Health, University of Manchester, Room 3.306, Jean McFarlane Building, Oxford Road, Manchester M13 9PL, UK. (Email:


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Adler, LA, Rotrosen, J, Edson, R, Lavori, P, Lohr, J, Hitzemann, R, Raisch, D, Caligiuri, M, Tracy, K (1999). Vitamin E treatment for tardive dyskinesia. Archives of General Psychiatry 56, 836841.
Alvarez-Jimenez, M, Gleeson, J, Henry, L, Harrigan, S, Harris, M, Killackey, E, Bendall, S, Amminger, G, Yung, A, Herrman, H (2012). Road to full recovery: longitudinal relationship between symptomatic remission and psychosocial recovery in first-episode psychosis over 7.5 years. Psychological Medicine 42, 595606.
Álvarez-Jiménez, M, Parker, AG, Hetrick, SE, McGorry, PD, Gleeson, JF (2011). Preventing the second episode: a systematic review and meta-analysis of psychosocial and pharmacological trials in first-episode psychosis. Schizophrenia Bulletin 37, 619630.
Andreasen, NC (1989). Scale for the Assessment of Negative Symptoms (SANS). British Journal of Psychiatry.
Arroll, MA, Wilder, L, Neil, J (2014). Nutritional interventions for the adjunctive treatment of schizophrenia: a brief review. Nutrition Journal 13, 91.
Arvindakshan, M, Ghate, M, Ranjekar, PK, Evans, DR, Mahadik, SP (2003). Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophrenia Research 62, 195204.
Barnes, TR (2011). Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 25, 567620.
Bentsen, H, Osnes, K, Refsum, H, Solberg, DK, Bohmer, T (2013). A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E + C in schizophrenia.
Berk, M, Brnabic, A, Dodd, S, Kelin, K, Tohen, M, Malhi, GS, Berk, L, Conus, P, McGorry, PD (2011). Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention. Bipolar Disorders 13, 8798.
Berk, M, Copolov, D, Dean, O, Lu, K, Jeavons, S, Schapkaitz, I, Anderson-Hunt, M, Judd, F, Katz, F, Katz, P, Ording-Jespersen, S (2008). N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biological Psychiatry 64, 361368.
Borenstein, M, Hedges, L, Higgins, J, Rothstein, H (2005). Comprehensive meta-analysis version 2. Englewood, NJ: Biostat 104.
Brown, HE, Roffman, JL, Wood, JK (2016). Emerging treatments in schizophrenia: highlights from recent supplementation and prevention trials. Harvard Review of Psychiatry 24, e1e7.
Dakhale, GN, Khanzode, SD, Khanzode, SS, Saoji, A (2005). Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacology 182, 494498.
Dipasquale, S, Pariante, CM, Dazzan, P, Aguglia, E, McGuire, P, Mondelli, V (2013). The dietary pattern of patients with schizophrenia: a systematic review. Journal of Psychiatric Research 47, 197207.
Dorfman-Etrog, P, Hermesh, H, Prilipko, L, Weizman, A, Munitz, H (1999). The effect of vitamin E addition to acute neuroleptic treatment on the emergence of extrapyramidal side effects in schizophrenic patients: an open label study. European Neuropsychopharmacology 9, 475477.
Duval, S, Tweedie, R (2000). Trim and fill: a simple funnel-plot–based method of testing and adjusting for publication bias in meta-analysis. Biometrics 56, 455463.
Fusar-Poli, P, Berger, G (2012). Eicosapentaenoic acid interventions in schizophrenia: meta-analysis of randomized, placebo-controlled studies. Journal of Clinical Psychopharmacology 32, 179185.
Gesch, CB, Hammond, SM, Hampson, SE, Eves, A, Crowder, MJ (2002). Influence of supplementary vitamins, minerals and essential fatty acids on the antisocial behaviour of young adult prisoners. British Journal of Psychiatry 181, 2228.
Godfrey, P, Toone, B, Bottiglien, T, Laundy, M, Reynolds, E, Carney, M, Flynn, T, Chanarin, I (1990). Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392395.
Graham, KA, Keefe, RS, Lieberman, JA, Calikoglu, AS, Lansing, KM, Perkins, DO (2015). Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first-episode schizophrenia. Early Intervention in Psychiatry 9, 397405.
Guallar, E, Stranges, S, Mulrow, C, Appel, LJ, Miller, ER (2013). Enough is enough: stop wasting money on vitamin and mineral supplements. Annals of Internal Medicine 159, 850851.
Guy, W (1976). Clinical global impression scale. The ECDEU Assessment Manual for Psychopharmacology-Revised Volume DHEW Publication No. ADM 76, 218222.
Heald, A, Sein, K, Anderson, S, Pendlebury, J, Guy, M, Narayan, V, Gibson, M, Haddad, P, Livingston, M (2015). Diet, exercise and the metabolic syndrome in schizophrenia: a cross-sectional study. Schizophrenia Research 169, 494495.
Higgins, JP, Altman, DG, Gøtzsche, PC, Jüni, P, Moher, D, Oxman, AD, Savović, J, Schulz, KF, Weeks, L, Sterne, JA (2011). The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. British Medical Journal 343, d5928.
Hill, M, Shannahan, K, Jasinski, S, Macklin, EA, Raeke, L, Roffman, JL, Goff, DC (2011). Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophrenia Research 127, 4145.
Hockney, RA, Montgomery, P, Williams, C, Geddes, JR, Cowen, PJ (2006). Lack of effect of chromium supplementation on mental state and body weight in people with schizophrenia. Journal of Clinical Psychopharmacology 26, 544545.
Jauhar, S, McKenna, P, Radua, J, Fung, E, Salvador, R, Laws, K (2014). Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. British Journal of Psychiatry 204, 2029.
Kale, A, Naphade, N, Sapkale, S, Kamaraju, M, Pillai, A, Joshi, S, Mahadik, S (2010). Reduced folic acid, vitamin B 12 and docosahexaenoic acid and increased homocysteine and cortisol in never-medicated schizophrenia patients: implications for altered one-carbon metabolism. Psychiatry Research 175, 4753.
Kaplan, BJ, Rucklidge, JJ, Romijn, A, McLeod, K (2015). The emerging field of nutritional mental health inflammation, the microbiome, oxidative stress, and mitochondrial function. Clinical Psychological Science 3, 964980.
Kay, SR, Flszbein, A, Opfer, LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261.
Kirkpatrick, B, Fenton, WS, Carpenter, WT, Marder, SR (2006). The NIMH-MATRICS consensus statement on negative symptoms. Schizophrenia Bulletin 32, 214219.
Lally, J, Gardner-Sood, P, Firdosi, M, Iyegbe, C, Stubbs, B, Greenwood, K, Murray, R, Smith, S, Howes, O, Gaughran, F (2016). Clinical correlates of vitamin D deficiency in established psychosis. BMC Psychiatry 16.
Lam, LC, Chiu, HF, Hung, S (1994). Vitamin E in the treatment of tardive dyskinesia: a replication study. Journal of Nervous and Mental Disease.
Lerner, V, Bergman, J, Statsenko, N, Miodownik, C (2004). Vitamin B6 treatment in acute neuroleptic-induced akathisia: a randomized, double-blind, placebo-controlled study. Journal of Clinical Psychiatry 65, 15501554.
Lerner, V, Miodownik, C, Kaptsan, A, Cohen, H, Loewenthal, U, Kotler, M (2002). Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study. Journal of Clinical Psychiatry 63, 5458.
Levine, J, Goldberger, I, Rapaport, A, Schwartz, M, Schield, C, Elizur, A, Belmaker, R, Shapiro, J, Agam, G (1994). CSF inositol in schizophrenia and high-dose inositol treatment of schizophrenia. European Neuropsychopharmacology 4, 487490.
Levine, J, Gonsalves, M, Babur, I, Stier, S, Elizur, A, Kofman, O, Belmaker, R (1993 a). Inositol 6 g daily may be effective in depression but not in schizophrenia. Human Psychopharmacology: Clinical and Experimental 8, 4953.
Levine, J, Stahl, Z, Sela, BA, Ruderman, V, Shumaico, O, Babushkin, I, Osher, Y, Bersudsky, Y, Belmaker, RH (2006). Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biological Psychiatry 60, 265269.
Levine, J, Umansky, R, Ezrielev, G, Belmaker, R (1993 b). Lack of effect of inositol treatment in chronic schizophrenia. Biological Psychiatry 33, 673675.
Lohr, JB, Cadet, JL, Lohr, MA, Larson, L, Wasli, E, Wade, L, Hylton, R, Vidoni, C, Jeste, DV, Wyatt, RJ (1988). Vitamin E in the treatment of tardive dyskinesia: the possible involvement of free radical mechanisms. Schizophrenia Bulletin 14, 291.
McGrath, J (2010). Editorial: is it time to trial vitamin D supplements for the prevention of schizophrenia? Acta Psychiatrica Scandinavica 121, 321324.
McGrath, JJ, Burne, TH, Féron, F, Mackay-Sim, A, Eyles, DW (2010 a). Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. Schizophrenia Bulletin sbq101.
McGrath, JJ, Eyles, DW, Pedersen, CB, Anderson, C, Ko, P, Burne, TH, Norgaard-Pedersen, B, Hougaard, DM, Mortensen, PB (2010 b). Neonatal vitamin D status and risk of schizophrenia: a population-based case-control study. Archives of General Psychiatry 67, 889894.
Meyer, U, Schwarz, MJ, Müller, N (2011). Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacology & Therapeutics 132, 96110.
Miller, BJ, Buckley, P, Seabolt, W, Mellor, A, Kirkpatrick, B (2011). Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological Psychiatry 70, 663671.
Miodownik, C, Lerner, V, Statsenko, N, Dwolatzky, T, Nemets, B, Berzak, E, Bergman, J (2006). Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study. Clinical Neuropharmacology 29, 6872.
Misiak, B, Frydecka, D, Slezak, R, Piotrowski, P, Kiejna, A (2014). Elevated homocysteine level in first-episode schizophrenia patients – The relevance of family history of schizophrenia and lifetime diagnosis of cannabis abuse. Metabolic Brain Disease 29, 661670.
Moher, D, Liberati, A, Tetzlaff, J, Altman, DG (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Annals of Internal Medicine 151, 264269.
Mondelli, V, Cattaneo, A, Murri, MB, Di Forti, M, Handley, R, Hepgul, N, Miorelli, A, Navari, S, Papadopoulos, AS, Aitchison, KJ (2011). Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. Journal of Clinical Psychiatry 72, 16771684.
Mortazavi, M, Farzin, D, Zarhghami, M, Hosseini, SH, Mansoori, P, Nateghi, G (2015). Efficacy of zinc sulfate as an add-on therapy to risperidone versus risperidone alone in patients with schizophrenia: a double-blind randomized placebo-controlled trial. Iranian Journal of Psychiatry and Behavioral Sciences 9.
Moustafa, AA, Hewedi, DH, Eissa, AM, Frydecka, D, Misiak, B (2014). Homocysteine levels in schizophrenia and affective disorders-focus on cognition. Frontiers in Behavioral Neuroscience 8, 343.
NICE (2010). Schizophrenia: the NICE guideline on core interventions in the treatment and management of schizophrenia in adults in primary and secondary care , updated edition. The British Psychological Society and the Royal College of Psychiatrists: London.
NICE (2014). Psychosis and schizophrenia in adults. The National Institute for Health and Care Excellence.
O'Donnell, CP, Allott, KA, Murphy, BP, Yuen, HP, Proffitt, TM, Papas, A, Moral, J, Pham, T, O'Regan, MK, Phassouliotis, C, Simpson, R (2016). Adjunctive taurine in first-episode psychosis: a phase 2, double-blind, randomized, placebo-controlled study. Journal of Clinical Psychiatry. doi:10.4088/JCP.15m10185.
Orwin, RG (1983). A fail-safe N for effect size in meta-analysis. Journal of Educational Statistics 157159.
Overall, JE, Gorham, DR (2004). BPRS. Klinische Interviews und Ratingskalen, 50.
Pawelczyk, T, Grancow-Grabka, M, Kotlicka-Antczak, M, Trafalska, E, Pawelczyk, A (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, 3444.
Rietjens, IM, Boersma, MG, de Haan, L, Spenkelink, B, Awad, HM, Cnubben, NH, van Zanden, JJ, van der Woude, H, Alink, GM, Koeman, JH (2002). The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids. Environmental Toxicology and Pharmacology 11, 321333.
Roffman, JL, Brohawn, DG, Nitenson, AZ, MacKlin, EA, Smoller, JW, Goff, DC (2013 a). Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophrenia Bulletin 39, 330338.
Roffman, JL, Lamberti, JS, Achtyes, E, Macklin, EA, Galendez, GC, Raeke, LH, Silverstein, NJ, Smoller, JW, Hill, M, Goff, DC (2013 b). Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry 70, 481489.
Rucklidge, JJ, Andridge, R, Gorman, B, Blampied, N, Gordon, H, Boggis, A (2012). Shaken but unstirred? Effects of micronutrients on stress and trauma after an earthquake: RCT evidence comparing formulas and doses. Human Psychopharmacology: Clinical and Experimental 27, 440454.
Rucklidge, JJ, Frampton, CM, Gorman, B, Boggis, A (2014). Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. British Journal of Psychiatry 204, 306315.
Rucklidge, JJ, Johnstone, J, Kaplan, BJ (2013). Magic bullet thinking-why do we continue to perpetuate this fallacy? British Journal of Psychiatry 203, 154154.
Rucklidge, JJ, Kaplan, BJ (2013). Broad-spectrum micronutrient formulas for the treatment of psychiatric symptoms: a systematic review. Expert Review of Neurotherapeutics 13, 4973.
Sarris, J, Logan, AC, Akbaraly, TN, Amminger, GP, Balanzá-Martínez, V, Freeman, MP, Hibbeln, J, Matsuoka, Y, Mischoulon, D, Mizoue, T (2015). Nutritional medicine as mainstream in psychiatry. Lancet Psychiatry 2, 271274.
Sarris, J, Murphy, J, Mischoulon, D, Papakostas, GI, Fava, M, Berk, M, Ng, CH (2016). Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. American Journal of Psychiatry. doi:10.1176/appi.ajp.2016.1509122.
Schardt, C, Adams, MB, Owens, T, Keitz, S, Fontelo, P (2007). Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Medical Informatics and Decision Making 7, 1.
Schizophrenia Commission (2012). The Abandoned Illness: A Report from the Schizophrenia Commission. Rethink Mental Illness: London.
Shivakumar, V, Kalmady, SV, Amaresha, AC, Jose, D, Narayanaswamy, JC, Agarwal, SM, Joseph, B, Venkatasubramanian, G, Ravi, V, Keshavan, MS, Gangadhar, BN (2015). Serum vitamin D and hippocampal gray matter volume in schizophrenia. Psychiatry Research: Neuroimaging 233, 175179.
Sivrioglu, EY, Kirli, S, Sipahioglu, D, Gursoy, B, Sarandol, E (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, 14931499.
Soares, K, McGrath, J (1999). The treatment of tardive dyskinesia – a systematic review and meta-analysis. Schizophrenia Research 39, 116.
Teasdale, SB, Ward, PB, Rosenbaum, S, Watkins, A, Curtis, J, Kalucy, M, Samaras, K (2016). A nutrition intervention is effective in improving dietary components linked to cardiometabolic risk in youth with first-episode psychosis. British Journal of Nutrition 115, 19871993.
Valipour, G, Saneei, P, Esmaillzadeh, A (2014). Serum vitamin D levels in relation to schizophrenia: a systematic review and meta-analysis of observational studies. Journal of Clinical Endocrinology and Metabolism 99, 38633872.
Van Berckel, BN, Bossong, MG, Boellaard, R, Kloet, R, Schuitemaker, A, Caspers, E, Luurtsema, G, Windhorst, AD, Cahn, W, Lammertsma, AA, Kahn, RS (2011). Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biological Psychiatry 64, 820822.
van der Kemp, WJM, Klomp, DWJ, Kahn, RS, Luijten, PR, Hulshoff Pol, HE (2012). A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia. Schizophrenia Research 141, 153161.
Woods, SW (1899). Chlorpromazine equivalent doses for the newer atypical antipsychotics. Journal of Clinical Psychiatry 64, 663667.
Yanik, M, Kocyigit, A, Tutkun, H, Vural, H, Herken, H (2004). Plasma manganese, selenium, zinc, copper, and iron concentrations in patients with schizophrenia. Biological Trace Element Research 98, 109117.


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The effects of vitamin and mineral supplementation on symptoms of schizophrenia: a systematic review and meta-analysis

  • J. Firth (a1), B. Stubbs (a2) (a3), J. Sarris (a4) (a5), S. Rosenbaum (a6), S. Teasdale (a7) (a8), M. Berk (a9) (a10) and A. R. Yung (a1) (a11)...
  • Please note a correction has been issued for this article.


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