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Genotype Influences Improvement in Schizophrenia Patients Treated with Folate Plus Vitamin B12

Genotype Influences Improvement in Schizophrenia Patients Treated with Folate Plus Vitamin B12


June 17, 2013

Joshua L. Roffman, MD, MMSc


Assistant Professor of Psychiatry, Harvard Medical School, Massachusetts General Hospital Department of Psychiatry

First published in
Psychiatry Weekly, Volume 8, Issue 13, June 17, 2013




Folate deficiency is an important avenue of research in terms of pathogenesis and treatment mechanisms in several psychiatric disorders. In schizophrenia, folate deficiency is associated with elevated homocysteine levels (there is an inverse relationship between the two) and negative symptoms. As many as 20% of patients with schizophrenia have insufficient blood folate levels.

Genotype, Folate, and Negative Symptoms

Two older studies of folate supplementation and schizophrenia with relatively small sample sizes reported benefits for folate compared with placebo.1,2 More recently, in 2011, Drs. Donald Goff, Joshua Roffman and colleagues at Massachusetts General Hospital conducted a pilot study of folate supplementation vs placebo.3

“This study was different from others in that we were looking at specific gene variants that we know are important in controlling the way the body absorbs and metabolizes folic acid,” explains Dr. Roffman. “When we looked at one such variant in our pilot study (MTHFR 677C>T) we found that there did seem to be a difference in how individuals responded to folate supplementation based on genotype.”

The results of that pilot study led to a larger (n=140), 16-week, multi-site, randomized, placebo-controlled trial of folic acid plus B12 supplementation in schizophrenia patients, funded by NIMH.4

“Dr. Goff, the principal investigator of the current study, previously demonstrated a specific relationship between negative symptom severity and blood folic acid levels,”5 says Dr. Roffman. “Those findings, among others, led us to becoming most interested in negative symptoms for this trial.”

Goff, Roffman and colleagues used a stratified randomization process to ensure that blood folate levels at baseline would be comparable in the placebo and intervention groups. The intervention group received 2 mg of folate and 400 µg of B12 each day.

In their intent-to-treat analysis, the investigators observed a significant improvement in negative symptoms in the intervention group over the course of treatment, whereas there were no significant changes in symptoms in the placebo group. Direct comparison of the intervention and placebo groups, though, did not uncover a statistically significant advantage for the intervention group.

"FOLHI genotype strongly differentiated between patients who showed a good treatment response and those who did not."

“However, when we entered into the model four genetic variants of folate metabolism (in FOLH1, MTHFR, MTR, and COMT) that we had previously associated with variation in negative symptom severity, the difference between active treatment and placebo became significant,” says Dr. Roffman. “This suggested that these genes play an important role in individual responsiveness to treatment.”

While in the earlier pilot study MTHFR genotype predicted treatment response, Roffman and colleagues’ follow-up study found that the FOLH1 484T>C variant had an even stronger bearing on negative symptom improvement.

FOLH1 genotype strongly differentiated between patients who showed a good treatment response and those who did not,” says Dr. Roffman. “The FOLH1 variant also had a significant effect on baseline blood folate levels. Individuals with the low functioning FOLH1 variant (484C) had significantly lower baseline folate levels compared to those with the high functioning variant (484T). This may explain why patients with the low functioning variant failed to show a significant improvement in negative symptoms, as it took 8 weeks for their folate levels to catch up to those found in patients with the normal functioning version of the gene.”


Compared to other routine medical tests, some genetic tests are relatively inexpensive, although more time consuming. Dr. Roffman says, however, that the costs of genetic testing in this instance probably outweigh the potential benefit.

“These results alone would not prompt me to recommend that patients get tested for which FOLH1 or MTHFR variant they have before starting folate and B12 supplementation,” he says. “Although genotype may influence the level of benefit, the intervention is inexpensive, well tolerated, and carries little risk. Other potential interventions related to folic acid may not be as inexpensive or well tolerated as this one, and ongoing investigations may help us understand when genotyping will be cost-effective in patients who receive these types of treatments.”

Disclosure: This work was funded by a grant from the NIMH (R01MH070831) awarded to Dr. Donald Goff. Dr. Roffman has received grant/research support from Pamlab.


1. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336(8712):392-395.

2. Levine J, Stahl Z, Sela BA, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry. 2006;60:265-269.

3. Hill M, Shannahan K, Jasinski S, et al. Folate supplementation in schizophrenia: a possible role for MTHFR genotype. Schizophr Res. 2011;127:41-45.

4. Roffman JL, Lamberti JS, Achtyes E, et al. Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia. JAMA Psychiatry. 2013;70:481-489.

5. Goff DC, Bottiglieri T, Arning E, et al. Folate, homocysteine, and negativesymptoms in schizophrenia. Am J Psychiatry. 2004;161:1705-1708.