Findings Support a Personalized Approach to Treatment
Mar 08, 2013
Supplementing antipsychotic medication with folate plus vitamin B12 as an adjunctive treatment can improve negative symptoms of schizophrenia, a new study shows.
However, the randomized clinical trial also suggests that the level of treatment response is more significant in individuals with specific gene variants involved in folate metabolism.
"Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia. Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia," study investigator Joshua Roffman, MD, said in a release.
The study was published online March 6 in JAMA Psychiatry.
According to investigators, there is a need for more effective treatments for the negative symptoms of schizophrenia, which include apathy, social withdrawal, loss of emotional expressiveness, and cognitive impairment.
"The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness. These include negative symptoms, which can be particularly devastating," said Dr. Roffman.
The investigators also note that negative symptoms of schizophrenia have previously been associated with folate deficiency, particularly in patients with low-functioning variants in genes that regulate folate metabolism.
To determine whether supplementation with folate and B12 — which can augment the effects of folate — reduced the negative symptoms of schizophrenia, the investigators conducted a parallel-group, randomized, double-blind, placebo-controlled, 16-week treatment trial that included 140 outpatients with chronic schizophrenia.
Participants were psychiatrically stable but, despite antipsychotic treatment, had persistent symptoms and scored 60 or more on the Positive and Negative Syndrome Scale (PANSS).
Patients were randomly assigned to receive daily oral folic acid (2 mg) and B12 (400 µg) or placebo.
Genotype Dictates Response
The study's primary outcome measure was change in negative symptoms, assessed using the Scale for the Assessment of Negative Symptoms (SANS), as well as positive and total symptoms, as reflected by scores on PANSS.
Participants' medical and psychiatric status was evaluated every 2 weeks. Adherence was monitored by pill count and fasting blood levels of vitamin B12, homocysteine, and folate, measured at baseline and weeks 2, 4, 8, 12, and 16.
In addition, DNA extracted from whole blood samples was genotyped for variants in 4 genes that have previously been associated with negative symptom severity in schizophrenia. These included FOLH1, MTHFR, MTR, and COMT.
Although patients in the active treatment group had improved SANS scores, the degree of improvement was not statistically significant compared with those receiving placebo.
However, when genotype was taken into account, the folate plus B12 group had significant symptom improvement (group difference, -.33 change in SANS score per week; 95% confidence interval, -0.62 to 0.05).
Although in a previous study it was a low-functioning variant of FOLH1 (484C) that was associated with increased negative symptoms, the investigators found it was the high-functioning FOLH1 (484T) variant that predicted a better treatment outcome.
The investigators speculate that this unexpected finding may be due to the fact that those with the low-functioning variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption.
Although supplementation enabled blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was likely too late to produce symptom improvement during the 16-week trial period.
"For participants who did not show benefit, it took the full 16 weeks of treatment for that benefit to appear. While we don't know why this is the case, changes in gene expression, which take time, are a likely explanation," said Dr. Roffman.
"Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies," he added.
Implications for Other Diseases
The investigators conclude that although the treatment effects were "modest," the disability associated with negative symptoms, coupled with a lack of available treatments and the safety of vitamin supplementation, may make it a treatment worth trying.
In addition, said Dr. Roffman, there is a need for larger scale trials.
He also noted that the impact of genotype that was demonstrated in this study highlights the need to examine the role of folate pathway variants in conditions in which low folate increases risk, such as 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," the authors write.
Dr. Roffman reports no relevant financial relationships. The disclosures of the other authors can be found in the original article.
JAMA Psychiatry. Published online March 6, 2013.