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First-Episode Psychosis? Take Your Vitamins

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Reducing homocysteine levels with a vitamin cocktail has potential benefits.

Elevated homocysteine levels have been reported in schizophrenia, and homocysteine reduction by higher vitamin doses has been reported to improve symptoms in schizophrenia. In a 12-week, randomized, double-blind, placebo-controlled Australian study, researchers provided a single pill combining standard supplement doses of vitamin B6, vitamin B12, and folic acid to 100 patients with a first episode of any psychotic disorder. All patients continued their usual treatment, including antipsychotic drugs.

Vitamins, but not placebo, increased red cell folate levels and decreased homocysteine levels. At 12 weeks, the two groups showed no differences in positive and negative symptoms or overall neurocognition. However, attention/vigilance declined in placebo patients while remaining stable in vitamin patients. This benefit with supplementation was mainly evident in patients with baseline elevated homocysteine levels, patients with affective psychoses, and women, who also showed improved processing speed. In a test of four genetic variants in folate-metabolizing enzymes, no group differences were seen.


These results, combined with other earlier findings, suggest that this vitamin preparation could be helpful in higher doses to patients with elevated homocysteine levels, particularly in those with affective psychoses. The other health benefits of lowering homocysteine levels are already known. It is sometimes claimed that methylfolate is more beneficial than folate, but in this study, folate did at least enter red cells, and its effect was independent of alleles of folate-metabolizing enzymes. Little seems to be lost by suggesting the addition of supplements in high doses to patients with affective psychoses, especially women (because an effect could have been evident in men with higher doses).

Allott K et al. The vitamins in psychosis study: A randomized, double-blind, placebo-controlled trial of the effects of vitamin B12, B6 and folic acid on symptoms and neurocognition in first-episode psychosis. Biol Psychiatry 2019 Jan 9; [e-pub]. (https://doi.org/10.1016/j.biopsych.2018.12.018)


Homocysteine is a sulphur amino acid that is synthesised from methionine, and its regulation depends on dietary intake of folic acid and b-vitamins. (1) Elevated homocysteine levels or severe deficiencies in folate and b-vitamins are risk factors for neurodevelopmental problems, heart disease, stroke, cognitive decline, and mood disorders. 234 Elevated prenatal homocysteine has been associated with a two-fold increased risk for schizophrenia. (5) Blood levels of homocysteine are also elevated in people with schizophrenia and higher levels of homocysteine are associated with younger age. (16) These elevated homocysteine levels are observed from illness onset, in first-episode psychosis (FEP) patients, independently of antipsychotic medication. (78)Furthermore, elevated homocysteine has been associated with higher negative symptomatology(9, 10) and poorer functioning. (11) The relationships between clinical disease presentation and higher levels of homocysteine suggest that reducing homocysteine levels may be therapeutic in schizophrenia. One method to achieve this is folate supplementation.

Impairments in folate metabolism can cause adverse consequences for genome structure, expression and stability, and can result from folate deficiency, secondary nutrient deficiencies (vitamins B and B 12 , iron), and single nucleotide polymorphisms (SNPs) in folate-dependent enzymes. A recent meta-analysis examining blood nutrient levels of vitamins in FEP found significant deficits in folate compared to healthy controls ( =−0.624).(12) Furthermore, lower folate levels were associated with more severe negative symptoms. (12) In humans, several common SNPs regulate folate. The 677C>T variant in the methylenetetrahydrofolate reductase (MTHFR) gene has been the most studied polymorphism in schizophrenia. (61314) Meta-analytic findings have shown an association between homozygosity of the 677C>T polymorphism in the MTHFR gene and schizophrenia, potentially suggesting a causal relationship between aberrant homocysteine metabolism and genotype. (16) The 677C>T MTHFR polymorphism is associated with variation in negative symptom severity in chronic schizophrenia. (14) Missense variants in methionine synthase (MTR 2756A), folate hydrolase 1 (FOLH1 484C), and catechol -methyltransferase (COMT 675A) have also been shown to be predictive of negative symptom severity. (15) These findings further support the hypothesis that folate supplementation may be beneficial in schizophrenia.

Multiple randomized controlled trials (RCTs) have investigated the effects of homocysteine-lowering agents (e.g., folic acid, vitamins B 12 and B ) on clinical outcomes in long-term schizophrenia. An early study showed that 6-month l-methylfolate (15mg) administration in folate-deficient patients significantly reduced symptomatology compared with placebo. (16) A larger study of 12-weeks of l-methylfolate (15mg) in individuals with schizophrenia recently replicated these findings, showing moderate-large reductions in total, general and negative symptomatology. (17) Findings were moderated by folate-related genetic variation. (17) Other RCTs using combined b-vitamin supplements have revealed various benefits, including significant decreases in homocysteine levels, total psychopathology and cognitive deficits(7) and reduced negative symptoms specifically in people homozygous for the 484T allele in the 484C>T variant of FOLH1. (13) A recent meta-analysis of data pooled from seven b-vitamin RCTs in schizophrenia found a moderate positive effect ( =0.51) of vitamin supplementation on total symptom levels. (18) Studies that used a combination of b-vitamins were most effective, and effectiveness was associated with shorter illness duration. (18) However, no study has investigated the effectiveness of b-vitamins in FEP.

This is the first study to examine the efficacy of vitamins B (folate), B 12 and B supplementation in a FEP population and to examine the potential interaction effects associated with baseline homocysteine, genetic variation, sex and diagnosis on effectiveness. The b-vitamin supplement resulted in significantly lowered homocysteine (and increased folate) blood levels. However, b-vitamins resulted in no significant benefit over placebo with respect to total symptoms or composite neurocognition (co-primary outcomes), nor in most of the secondary outcomes over 12-weeks. One exception was for attention/vigilance, in which the mean performance of the placebo group declined over 12-weeks, whereas performance in the vitamin group remained stable. Attention/vigilance was the most sensitive domain to the neurocognitive effects of b-vitamins, with large improvements in this domain in response to vitamins more likely in females, those with affective psychosis and the subgroup of participants who had elevated baseline homocysteine levels. B-vitamins were well tolerated and had minimal side-effects, consistent with previous research. (13)

Our finding that adjunctive b-vitamins were ineffective for improving psychiatric symptoms is in contrast to previous trials. (7131617) Notably, the participants in previous studies had chronic schizophrenia with much higher baseline levels of symptomatology than the participants in the current study. (71317) Heterogeneity of psychotic diagnosis and participants’ symptom levels in the current study may have limited the range for an overall effect to be shown. Furthermore, baseline blood levels of folate and vitamin B 12 on average were lower and baseline levels of homocysteine were much higher in previous studies compared to the current study(13, 16), where homocysteine was on average in the normal range. Indeed, the improvement on the Identification test in the b-vitamin subgroup of FEP patients with elevated homocysteine suggests that individuals who have abnormal homocysteine or blood vitamin levels may be the most responsive to adjuvant vitamin treatment, strongly supporting a precision medicine or biomarker-guided treatment approach. (44)

Furthermore, recent RCTs in other psychiatric conditions (i.e., major depression) have demonstrated that significant benefits of vitamin supplementation are achieved at higher doses than used in our study. For instance, 15mg daily of l-methylfolate (a more bioavailable version of folic acid) significantly reduced symptoms of treatment-resistant major depression, whereas 7.5mg daily did not. (45) Symptomatic benefits from l-methylfolate may also occur from the anti-inflammatory (rather than homocysteine-reducing) effects, as greatest reductions in depression were observed in patients with elevated inflammatory cytokines. (46) A recent study in long-term schizophrenia also found significant reductions in negative symptoms, along with improvements in white matter, from 15mg l-methylfolate after just 12-weeks. (17) Thus, the generally null results of this trial could suggest that higher doses of more bioactive versions of folate supplementation are required to produce noticeable benefits for symptomatology within 12-weeks in FEP.

Secondary analysis showed that b-vitamins may have some neuroprotective properties, with evidence that they prevented a decline in attention/vigilance over 12-weeks. Previous research suggests that a dose-response relationship exists between increases in homocysteine and risk of schizophrenia, providing a rational for using homocysteine levels as a biological parameter for intervention studies. (1) Our findings partially support this with high homocysteine levels being associated with better neurocognitive outcomes following vitamin treatment. Hyperhomocysteinemia has been proposed to cause oxidative stress in schizophrenia, which may have negative effects on the brain and neurocognition. (1) Support for this comes from trials of older people with mild cognitive impairment (MCI). In one study, MCI patients showed that two-months of folic acid increased attention and this effect was strongest in those with low baseline plasma folate. (47) A study of 24-months of b-vitamin supplementation in MCI patients showed that slower brain atrophy due to treatment was correlated with baseline plasma homocysteine levels. (48) Finally, a large study of healthy older adults showed that 3-years of folic acid supplementation resulted in better memory and processing speed compared with placebo, with greatest benefits observed in those with elevated baseline homocysteine. (49) Together, these findings suggest that a simple blood test showing elevated homocysteine at entry to treatment for FEP may indicate that vitamin supplementation at an adequate dose is warranted to prevent neurocognitive decline. Future trials that select participants with high homocysteine levels are now needed to confirm these findings and investigate generalization to other clinical and brain measures.

For aging-related cognitive decline, the beneficial neurological effects of b-vitamin supplementation are dependent upon polyunsaturated fatty acid levels; with improvements in brain structure and function from b-vitamin supplementation only occurring in individuals with high omega-3. (5051) Omega-3 levels are often low in FEP, and supplementation has been shown to improve neurological markers of brain health(52), introducing the possibility of using b-vitamins alongside omega-3 supplements for synergistic effects on neurological and psychological outcomes. Given the high tolerability and low side-effect profiles of nutritional supplements, future research could explore using targeted multi-nutrient interventions for synergistic action in FEP.

Although previous evidence suggested that males may preferentially benefit from vitamin supplementation(53), secondary analysis of the effects according to sex found that b-vitamins had no significant effect on symptoms or neurocognition in males with FEP. Our sample comprised a larger proportion of females than previous studies of long-term schizophrenia. (717) Unexpectedly, we found that the vitamin-treated females significantly improved in the neurocognitive domain of speed of processing and attention/vigilance. Supplementary analysis showed that the effect in females was not due to a higher compliance with the trial supplement (data not shown). It is unclear why females benefited more than males; this novel finding should be considered tentative and requires replication.

Finally, variants in the genes involved in the folate metabolic pathway did not interact with the effect of b-vitamins on psychopathology or neurocognition in this FEP sample. While there is evidence suggesting a possible link between genetic polymorphisms (e.g., in MTHFR), elevated homocysteine and schizophrenia, this link has not yet been definitively established. (9) Only two previous studies in schizophrenia have examined the role of genetic polymorphisms in response to vitamin supplementation and findings were mixed. One study showed that negative symptom improvement was seen in individuals homozygous for the 484T allele of FOLH1(13), whereas another showed that total and general symptom improvement was influenced by the MTR 2756A4G variant.

B-Vitamins for Schizophrenia

Decades of research have investigated the possible treatment of the symptoms of schizophrenia with several of the B vitamins.

Thiamine (Vitamin B1):

When taken with acetazolamide (more usually prescribed for glaucoma or epilepsy), this vitamin may improve a variety of symptoms of schizophrenia.

Niacin (Vitamin B3):

Once thought to manage schizophrenia, this claim has since been questioned. However, symptoms, as assessed by the Global Assessment of Functioning (GAF), are associated with lower niacin sensitivity; this may indicate a potential therapeutic use of niacin.

Pyridoxine (Vitamin B6): 

Has shown promise by decreasing movement disorders such as akathisia (extreme restlessness) and tardive dyskinesia (involuntary movements). B6 has also been proposed as a general adjunct to antipsychotics.

Folate/Folic Acid (Vitamin B9): 

The most recent study has discovered a link between those with a variation of a gene important in metabolizing folate and its effect on negative symptoms of schizophrenia. Researchers at Massachusetts General Hospital followed 140 people with schizophrenia over 4 months and found those with a high-functioning FOLH1 gene responded better to folate (2 mg) and B12 (400 mcg) supplements. This was attributed to better processing of the supplements, resulting in a reduction of apathy, withdrawal, and inability to display emotion. One researcher stated the study results are important since to date, there has been nothing widely accepted shown to work.

Vitamin B9 may also reduce metabolic syndrome (which, among other things, includes cardiovascular changes and weight gain) that some people develop while taking newer antipsychotics.

Cobalamin (Vitamin B12):

When taken with folic acid, it can improve negative symptoms of schizophrenia, perhaps because B12 metabolism is altered in some people with schizophrenia.

There is little recent research regarding other B vitamins and their potential roles in the development, progress, or side effect management of schizophrenia.

Selected references

1) Miodownik C, et al. Vitamin B6 versus mianserin and placebo in acute neuroleptic-induced akathisia: a randomized, double-blind, controlled study. Clinical Neuropharmacol. 2006.;29: 68-72.

2) Lerner VMiodownik CKaptsan ACohen HLoewenthal U, and Kotler M . Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study. J Clin Psych. 2002; 63: 54-58.

3) Lerner VMiodownik CKaptsan A, et al.  Vitamin B(6) in the treatment of tardive dyskinesia: a double-blind, placebo-controlled, crossover study. American J Psych. 2011;58: 1511-1514.

4) Burghardt KJ, and Ellingrod VL.Detection of metabolic syndrome in schizophrenia and implications for antipsychotic therapy: is there a role for folate? Mol Diag  Therapy. 2013; 17: 21-30.

5) Roffman JLLamberti JSAchtyes E, et al.  Randomized Multicenter Investigation of Folate Plus Vitamin B12 Supplementation in Schizophrenia. JAMA. Psychiatry [2013[Epub ahead of print].

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