# 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




Elevated homocysteine is observed in schizophrenia and associated with illness severity. The aim was to determine if vitamin B12, B6 and folic acid lowers homocysteine and improves symptomatology and neurocognition in first-episode psychosis. Whether baseline homocysteine, genetic variation, sex and diagnosis interact with b-vitamin treatment on outcomes was also examined.


Randomized, double-blind, placebo-controlled trial. One-hundred and twenty patients with first-episode psychosis were randomized to adjunctive b-vitamin supplement (containing folic acid 5mg, B12 0.4mg, B6 50mg) or placebo, taken once-daily for 12-weeks. Co-primary outcomes were change in total symptomatology (PANSS) and composite neurocognition. Secondary outcomes included additional measures of symptoms, neurocognition, functioning, tolerability and safety.


B-vitamin supplementation reduced homocysteine levels ( p= .003; ES=-0.65). B-vitamin supplementation had no significant effects on PANSS total ( p =.749) or composite neurocognition ( p =0.785). There were no significant group differences in secondary symptom domains. A significant group difference in the attention/vigilance domain ( p =.024; ES=0.49) showed the b-vitamin group remained stable and the placebo group declined in performance. 14% of the sample had elevated baseline homocysteine levels, which was associated with greater improvements in one measure of attention/vigilance following b-vitamins. Being female and having affective psychosis was associated with improved neurocognition in select domains following b-vitamins. Genetic variation did not influence b-vitamin treatment response.


While 12-week b-vitamin supplementation may not improve overall psychopathology and global neurocognition, it may have specific neuroprotective properties in attention/vigilance, particularly in patients with elevated homocysteine levels, affective psychosis and females. Results support a personalised medicine approach to vitamin supplementation in FEP.

Key words:

homocysteine, [folic acid](https://www.biologicalpsychiatryjournal.com/action/doSearch?searchType=quick&occurrences=all&ltrlSrch=true&searchScope=series&searchText=folic acid&seriesISSN=0006-3223), b-vitamins, [early psychosis](https://www.biologicalpsychiatryjournal.com/action/doSearch?searchType=quick&occurrences=all&ltrlSrch=true&searchScope=series&searchText=early psychosis&seriesISSN=0006-3223), attention, genetics



When I gave birth to a son with Down syndrome

many in my family wanted me to do the vitamin therapy

it was a big thing at the time, but I think the cost stopped me

and also I wasn’t sure it was really necessary, as I accepted him

the way he is. But even just starting to him a multi vit, I noticed

a difference right away, his attention was better.


I don’t like supplements unless they are absolutely necessary for me. This is an interesting article though. I have an interest in homocysteine since I think it’s associated with inflammation somehow.


My folate metabolism score from geneticoncept.


This was for first episode people, but seems like this would be important to start at diagnosis or at start of symptoms then.


There was one interesting trial published in 2014, in which folinic acid was used instead of folic acid. Unfortunately, this seems to be the only study of folinic acid in schizophrenia.


Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.



The jury is still out on the folinic acid and the whole issue of cerebral folate deficiency in schizophrenia. Just a single trial, and only one group (Ramaekers et al) investigating this issue. A larger trial would be needed to confirm the results. But it’s very interesting.


did you see my comments on research and study on human beings?

Perhaps you are prepared to make note?


If any hospital, agency, or gov study wants to conduct research

on another human being, it must include a stipend to the participant

and come with legality of their work in which such conclusions are released.

There should be no human test subject in the world that feels they were treated

like a guinea pig under extreme measure. We have ethics. We have laws.


Quote from a 2018 review titled " Antibodies in the Diagnosis, Prognosis, and Prediction of Psychotic Disorders" (in Schizophrenia Bulletin):

Where autoantibodies to specific receptors indicate dysfunction of the associated neurochemical system, these antibodies may represent an opportunity for treatments targeting that system. For example, folate receptor antibodies were described in 15 of 18 patients (83.3%) with refractory schizophrenia, compared with 3.3% of healthy controls. These antibodies were hypothesized to block the receptor and modulate flux of folic acid into and out of the brain in a manner analogous to that seen in infantile-onset cerebral folate deficiency syndrome. Eight seropositive patients were treated with folinic acid supplementation with improvement reported in 7 patients.106 No randomized study has yet attempted to replicate this interesting open-label study. In a similar vein, a single case study demonstrating improvement in psychotic symptoms in a woman with chronic schizophrenia, NMDAR antibodies and characteristic EEG abnormalities reported significant improvement with D-serine, an NMDAR co-agonist.107