The new study finds that adding folate and vitamin B12 to a standard antipsychotic treatment regime led to significant improvements in symptomatic components of schizophrenia - including apathy, social withdrawal, and a lack of emotional expressiveness.
Led by Dr Joshua Roffman from Massachusetts General Hospital (MGH), USA, the research team noted that while the level of improvement across all participants was modest, their results were more significant in individuals carrying specific variants in genes involved in folate metabolism.
"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness," explained Roffman. "These include negative symptoms, which can be particularly devastating."
"Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia," he said.
Writing in JAMA,Roffman and his team said the current study was designed specifically to investigate whether supplementation with folate and B12 – which can magnify the effects of folate – reduced negative symptoms of schizophrenia after previous research suggested that folate status may be linked to the condition.
Folate, or folic acid, is an essential nutrient that is required for the synthesis of DNA and neurotransmitters, whilst it also plays a role in the control of gene expression.
It is known that increasing folate intake during pregnancy can reduce the risk of birth defects – in particular neural tube defects. However research has also suggested that folate deficiency during pregnancy can significantly increase the risk of schizophrenia among offspring.
Recent research by the MGH-based team has suggested that low blood folate levels may be linked with more severe negative symptoms among patients with schizophrenia.
The new study enrolled 140 patients with schizophrenia at community mental health centres, and randomised them to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks.
Participants were all taking antipsychotic medications – which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms. The participants' blood samples were also analysed to determine the variants they carried of the MTHFR gene, and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.
Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine - an amino acid that tends to rise when folate levels drop.
Roffman and his team revealed that those receiving folate and vitamin B12 showed improvement in negative symptoms, however they said that the degree of improvement was not statistically significant compared with the placebo group.
However, when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, they said.
"For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear," Roffman said.
"While we don't know why this is the case, changes in gene expression – which take time – are a likely explanation," he speculated. "Folate plays a critical role in DNA methylation, which regulates gene expression, so it's plausible that its effects on negative symptoms act through gene expression changes."
He added that, while the benefits of supplementation for the overall group were modest, the lack of effective treatment for negative symptoms and the safety of folate and vitamin B12 supplementation support the need for larger-scale trials.