Genotype plays role in schizophrenia response to folate



Folate and vitamin B12 supplements may improve the negative symptoms of schizophrenia but only in patients with a genetic variant that influences folate metabolism, a study has shown.

"Although four such variants have previously been associated with negative symptom severity, the genotype that contributed most strongly to treatment response was FOLH1 484T>C," wrote Dr. Joshua L. Roffman, of the psychiatry department at Massachusetts General Hospital, Boston, and his colleagues.


Patients treated with folate plus vitamin B12 showed significant improvement on the Scale for the Assessment of Negative Symptoms (SANS), compared with placebo (group difference, –0.33 change in score per week; 95% confidence interval, –0.62 to –0.05), when genotype was taken into account.

Among patients homozygous for the 484T allele – a genetic variant in the folate hydrolase 1 (FOLH1) gene – the benefits of folate and vitamin B12 supplements were even greater (–0.59 change in SANS score per week; 95% CI, –0.99 to –0.18), according to results published in JAMA Psychiatry (formerly Archives of General Psychiatry) (2013 March 6 [doi: 10.1001/jamapsychiatry.2013.900]).

The double-blind, placebo-controlled study randomized 140 outpatients with schizophrenia, who had persistent symptoms despite treatment with antipsychotics, to 2 mg of folic acid and 400 mcg of vitamin B12 daily for 16 weeks or placebo. The patients were 18-68 years old, had been treated with an antipsychotic for at least 6 months, and were at a stable dose for at least 6 weeks. They also had to have scored at least 60 on the Positive and Negative Syndrome Scale.

The study found that only the high-functioning variant of FOLH1 (484T) was associated with a benefit from supplementation, while the effects of supplementation did not reach significance for either the low-functioning variant of FOLH1 (484C) or the MTHFR, MTR, or COMT genotypes.

While the treatment effects were modest, the researchers noted that even small effects could be clinically meaningful given the disability associated with negative symptoms, the paucity of available treatments for these symptoms, and the minimal side effects of vitamin supplements.

Folate deficiency is known to be a risk factor for schizophrenia, and all four genetic variants included in the study have been associated with increased severity of negative symptoms such as apathy, social withdrawal, and loss of emotional expressiveness.

"Thus, the finding that only patients homozygous for the T allele exhibited improvement in negative symptoms after 16 weeks of folate supplementation could reflect diminished folate absorption, and briefer exposure to higher folate levels, among C allele carriers," the researchers wrote.

The authors suggested that the findings could have implications for other health conditions associated with reduced folate and elevated homocysteine concentrations, such as stroke, cardiovascular disease, and dementia. "The current results suggest that individual differences in folate metabolism related to the presence of common functional genetic variants may have a bearing on treatment outcomes in these other disorders, as well as negative symptoms of schizophrenia," Dr. Roffman and his colleagues noted.

The research was funded by the National Institute of Mental Health and an award from the Howard Hughes Medical Institute, with support from Harvard Catalyst. The investigators disclosed receiving support and grants from a number of pharmaceutical companies and research organizations.

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