There is growing interest in supplementing antipsychotics with complementary alternative medicine to treat schizophrenia. Although the importance of nutritional status is well documented,1 the strategic use of polyunsaturated fatty acids (PUFAs), folate, and ascorbic acid is an ongoing area of investigation. This article provides an update on the current state of knowledge of the role of fatty acids, folate, and ascorbic acid (vitamin C) in the development of schizophrenia, and their potential to improve treatment outcomes for patients taking antipsychotic medications.
Fatty Acid Supplementation
Supplementing antipsychotics with high doses of vitamins and fatty acids to treat schizophrenia has gained growing attention in recent years, but the mechanisms by which supplements improve schizophrenia symptoms remain relatively unknown. Recent literature, however, has suggested an anti-inflammatory, potential protective role of fatty acids against brain damage,1 although the precise mechanism, particularly at the molecular level, is unknown.
Randomized, placebo-controlled trials suggest that schizophrenia phase is important when assessing the potential benefit of fatty acids for improving symptoms. Pawelczyk et al.2 administered 2.2 g/day of eicosapentanoic acid (EPA) plus docosahexaenoic acid to patients experiencing first-episode schizophrenia for 6 months and saw a reduction in symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS) scores. In contrast to this, PUFA use in patients with chronic schizophrenia has resulted in mixed results, confirming that the success of PUFA supplementation is likely dependent on the phase of the disorder, which may potentially impact the level of oxidative stress and the overall response.3
In addition to acute treatment for people at high risk for schizophrenia, evidence regarding the use of fatty acids for preventing disease progression into full-blown schizophrenia is mixed.4 In a randomized, placebo-controlled trial conducted with people at ultra-high risk of developing psychiatric disorder, Amminger et al.5 demonstrated the preventive effects of PUFAs in the development of psychosis. In this investigation, participants were given 1.2 g/day of omega-3 PUFAs or a placebo for 12 weeks followed by a 40-week monitoring period. Overall, PUFAs significantly reduced positive, negative, and general symptoms while reducing the risk of progression to psychotic disorder.5 Interestingly, the effects of PUFAs at delaying progression into psychotic disorder and reducing psychiatric morbidity were sustained well after treatment ended.5 In a follow-up investigation conducted at an average time point of 6.7 years after fatty acid treatment, 9.8% of the participants in the fatty acid group developed psychosis compared to 40% in the placebo group.6 Ultimately, these findings suggest the potential for PUFAs to act as a safe, long-term preventive measure for people at ultra-high risk of psychosis. However, more recent investigations failed to reproduce this connection.7
Vitamin C Supplementation
Although fatty acid composition in the brain may not differ between patients with schizophrenia and healthy controls,8 those with schizophrenia have lower levels of ascorbate in serum,9 and recent literature suggests that vitamin C may have a regulatory function over glutamatergic and dopaminergic systems.10 Because many antipsychotics target various points of the dopamine signal cascade, vitamin C has the potential to serve as an effective adjunct treatment that poses minimal risk to patients.
In one double-blind study, patients with schizophrenia taking olanzapine (10 mg/day), quetiapine (200 mg/day), or ziprasidone (40 mg/day) were given 500 mg/day of vitamin C or a placebo for 8 weeks.11 At the end of treatment, patients given vitamin C experienced reduced oxidative stress and improvements in Brief Psychiatric Rating Scale scores.11 Moreover, no serious adverse event was reported in either the treatment or control group. Despite conflicting reports on the value of vitamin C to patients with schizophrenia, there is consistent evidence that it is well tolerated, even at doses as high as 2,000 mg/day.10
In another randomized clinical trial, fatty acids and other vitamins, when administered together, did not appear to positively or negatively impact psychotic symptoms for patients with schizophrenia with low levels of polyunsaturated fatty acids.4 Bentsen et al.4 administered ethyl-eicosapentaenoate (2 g/day) or vitamin E (364 mg/day) plus vitamin C (1,000 mg/day) for 16 weeks to patients with a clinical diagnosis of schizophrenia who were prescribed an antipsychotic. Given separately, these dietary substances resulted in detrimental effects on disease progression for patients as measured by PANSS. However, when administered together, EPA and vitamin E and vitamin C did not appear to positively or negatively impact psychotic symptoms for patients with low PUFA levels.4 Although findings suggest that intake of vitamin E and vitamin C in conjunction with fatty acids is safe for patients with schizophrenia, evidence of their inefficacy at improving and preventing the symptoms associated with schizophrenia is misaligned with prior research.12
Folate (or vitamin B9) is necessary for the formation of nucleic acids and cell division. The commercially available supplements of folate are converted to the bioactive form L-methylfolate, which can cross the blood-brain barrier. Key enzymes involved in this conversion are methylenetetrahydrofolate reductase (MTHFR) and folic acid synthesis protein (FOLH1). Insufficient dietary intake of folate can be a risk factor for the development of psychosis1 as well as the weight gain and altered metabolism of glucose and lipids seen with atypical antipsychotic use.13 Patients with schizophrenia have long been shown to exhibit lower levels of folate in serum compared to those without psychiatric disorders; therefore, current work in this area has been examining the impact of folic acid and L-methylfolate supplementation on improving symptomology and the metabolic deficiencies seen in these patients.14
Several clinical studies have examined the effect of vitamin B supplementation on the symptoms of schizophrenia. Levine et al.15 conducted a double-blind, randomized, placebo-controlled study in which highly symptomatic patients with schizophrenia were prescribed a daily supplement containing 2 mg of folic acid, 400 mcg of vitamin B12, and 25 mg of pyridoxine for 3 months. Compared to the placebo group, supplementation resulted in significant decreases in clinical symptoms as measured by PANSS.15 However, the effect of folate and/or vitamin B12 at improving symptoms of schizophrenia may depend, at least to some extent, on genetic variants in the genes coding for MTHFR and FOLH1. Roffman et al.16 found that negative symptoms improved for patients with chronic schizophrenia when given an oral dose of 2 mg of folic acid and 400 mcg of vitamin B12 daily for 16 weeks only when genotype was considered. Interactions were observed between the 484C>T variant of FOLH1 (rs202676), and patients homozygous for the 484T allele incurred the greatest improvement in negative symptoms during the course of treatment.16 In more recent clinical trials, significant reductions in PANSS scores occurred regardless of genotype for patients treated with 15 mg of L-methylfolate for 12 weeks, which is not surprising given the fact that L-methylfolate bypasses the normal metabolic process for folic acid.17 Nevertheless, supplementation aimed at augmenting conventional efforts with folic acid should consider genotype to develop the most effective strategies for improving treatment outcomes.
Overall, there is conflicting evidence surrounding the efficacy of vitamins at improving positive and negative symptoms associated with schizophrenia. As such, the strategic use of PUFAs, ascorbic acid, and folic acid supplementation has been slow to integrate into clinical practice. It appears that fatty acid supplementation may be most effective for young patients who are at ultra-high risk and those experiencing first-episode schizophrenia. On the other hand, the efficacy of vitamin B supplementation may be dependent on certain genotypic variants and the specific agent supplemented. A lack of published studies involving human participants limits our ability to recommend specific dosages and duration, but future clinical research should work to identify the doses of folic acid and other vitamins that are most effective, as well as the neurochemical impact on disease etiology. At this time, clinicians can still consider augmenting conventional antipsychotic medications with supplements for interested patients given evidence demonstrating minimal side effects associated with these supplements at doses used in clinical trials.
- Mitra S, Natarajan R, Ziedonis D, Fan X. Antioxidant and anti-inflammatory nutrient status, supplementation, and mechanisms in patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:1–11. doi:. doi:10.1016/j.pnpbp.2017.05.005 [CrossRef]
- Pawelczyk T, Grancow-Grabka M, Kotlicka-Antczak M, Trafalska E, Pawelczyk A. 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. J Psychiatr Res. 2016;73:34–44. doi:. doi:10.1016/j.jpsychires.2015.11.013 [CrossRef]
- Chen AT, Chibnall JT, Nasrallah HA. A meta-analysis of placebo-controlled trials of omega-3 fatty acid augmentation in schizophrenia: possible stage-specific effects. Ann Clin Psychiatry. 2015;27(4):289–296.
- Bentsen H, Osnes K, Refsum H, Solberg DK, Bohmer T. A randomized placebo-controlled trial of an omega-3 fatty acid and vitamins E+C in schizophrenia. Transl Psychiatry. 2013;3:e335. doi:. doi:10.1038/tp.2013.110 [CrossRef]
- Amminger G, Schafer M, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders. Arch Gen Psychiatry. 2010;67(2):146–154. doi:. doi:10.1001/archgenpsychiatry.2009.192 [CrossRef]
- Amminger G, Schafer M, Schlogelhofer M, Klier C, McGorry P. Longer-term outcome in the prevention of psychotic disorders by the Vienna omega-3 study. Nat Commun. 2015;6:7934. doi:. doi:10.1038/ncomms8934 [CrossRef]
- McGorry P, Nelson B, Markulev C, et al. Effect of omega-3 polyunsaturated fatty acids in young people at ultrahigh risk for psychotic disorders: the NEURAPRO randomized clinical trial. JAMA Psychiatry. 2017;74(1):19–27. doi:. doi:10.1001/jamapsychiatry.2016.2902 [CrossRef]
- Beasley CL, Honer WG, Ramos-Miguel A, Vila-Rodriguez F, Barr AM. Prefrontal fatty acid composition in schizophrenia and bipolar disorder: association with reelin expression [published online ahead of print June 2, 2017]. Schizophr Res. doi:10.1016/j.schres.2017.05.033 [CrossRef].
- Dadheech G, Mishra S, Gautam S, Sharma P. Oxidative stress, alpha-tocopherol, ascorbic acid and reduced glutathione status in schizophrenics. Indian J Clin Biochem.2006;21(2):34–38. doi:. doi:10.1007/BF02912908 [CrossRef]
- Moretti M, Fraga D, Rodrigues A. Ascorbic acid to manage psychiatric disorders. CNS Drugs. 2017;31(7):571–583. doi:. doi:10.1007/s40263-017-0446-8 [CrossRef]
- Dakhale G, Khanzode S, Khanzode S, Saoji A. Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophrenia. Psychopharmacology. 2005;182:494–498. doi:. doi:10.1007/s00213-005-0117-1 [CrossRef]
- Kocot J, Luchowska-Kocot D, Kielczykowska M, Musik I, Kurzepa J. Does vitamin C influence neurodegenerative diseases and psychiatric disorders?Nutrients. 2017;9(7):e659. doi:10.3390/nu9070659 [CrossRef]
- Lieberman JA, Stroup TS, Hsiao JK, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223. doi:. doi:10.1056/NEJMoa051688 [CrossRef]
- Martone G. Enhancement of recovery from mental illness with L-methylfolate supplementation. Perspect Psychiatr Care. 2018;54(2):331–334. doi:. doi:10.1111/ppc.12227 [CrossRef]
- Levine J, Stahl Z, Sela B, et al. Homocysteine-reducing strategies improves symptoms in chronic schizophrenia patients with hyperhomocysteinemia. Biol Psychiatry. 2006;60:265–269. doi:10.1016/j.biopsych.2005.10.009 [CrossRef]
- Roffman J, Lamberti J, Achtyes E, Macklin E, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70(5):481–489. doi:. doi:10.1001/jamapsychiatry.2013.900 [CrossRef]
- Roffman J, Petruzzi L, Tanner A, et al. Biochemical, physiological and clinical effects of L-methylfolate in schizophrenia: a randomized controlled trial. Mol Psychiatry. 2017;23:316–322. doi:. doi:10.1038/mp.2017.41 [CrossRef]