23 Mar 2017
by Lesley McCollum
Supplementation with l-methylfolate (l-MF), the active form of folate, may help reduce negative symptoms in schizophrenia, according to a new randomized, double-blind trial published online March 14 in Molecular Psychiatry. The study was spearheaded by Donald Goff, now at the New York University School of Medicine and Nathan Kline Institute, and led by Joshua Roffman of Massachusetts General Hospital and Harvard Medical School in Boston.
In the study of 55 medicated patients with schizophrenia, 29 patients receiving 15 mg of oral l-MF for 12 weeks had high blood levels of l-MF, the primary outcome measure of the study, and also showed improved negative symptom scores compared with 26 patients receiving a placebo. l-MF treatment also generated structural and functional brain changes that may provide clues to the processes behind the supplement’s effects on negative symptoms.
Though preliminary because of the study’s small sample size, the findings add to the growing evidence supporting the idea that raising low folate levels present in schizophrenia may help treat negative symptoms. The ease of its potential implementation as an add-on therapy for schizophrenia makes it an enticing approach—as a "medical food" it’s readily available and doesn’t require specific indications for its use.
Large scale, placebo-controlled, randomized clinical trials are still needed before its implementation, said Robert Buchanan of the University of Maryland, US, who was not involved in the study, in an email interview with SRF. Specifically, he continued, the trials should be designed to allow interpretation of clinical outcomes, which would be a critical issue for negative symptoms.
Previous studies using folic acid have shown promising outcomes for negative symptoms, but variation in genes that regulate the body’s use of folic acid in the schizophrenia population have led to inconsistent responses (see SRF related news story). One gene in particular is MTHFR, which plays a key role in the conversion of folic acid to l-MF (Hill et al., 2011; see SRF related Q&A with Roffman). So in this study, Roffman and colleagues gave l-MF directly to circumvent the genetic variants that may interfere with thebioavailability or efficacy of folic acid.
“Unlike the previous studies of folic acid, there was no dependence on MTHFR or other genotype effects on negative symptom improvement,” said Roffman. “So for that reason we feel that this intervention may have a better chance of working in a larger component of the population with schizophrenia.”
The difference in the change in Positive and Negative Syndrome Scale (PANSS) negative score between l-MF and placebo was about three points—not a huge change, noted Roffman—which reflected a larger response in some patients and a more subtle response in others. “I wouldn’t say that this is a cure for negative symptoms, but it does appear to help,” he said.
Patients taking l-MF also showed improvement in PANSS total and general psychopathology scores, but these differences were dependent on specific genotypes. The treatment did not have any effect on positive symptoms or cognition.
“[T]he fact that changes in blood l-MF levels did not correlate with changes in clinical outcome measures is problematic,” said Buchanan, though he agreed with the authors that peripheral blood levels may not reflect levels in the central nervous system, as constraints on the transfer of l-MF across the blood-brain barrier cause levels in the brain to plateau.
A unique feature of this trial was the use of magnetic resonance imaging scans before and after treatment to observe potential brain changes. After treatment with l-MF, patients had increased thickness of the medial prefrontal cortex (mPFC), and were better able to deactivate the region during a working memory task, a process that is impaired in schizophrenia. Patients taking l-MF also showed reduced connectivity between the mPFC and limbic regions, suggesting potential restoration of the hyperconnectivity between these regions that is associated with schizophrenia. However, Buchanan cautions that the lack of a healthy control group also treated with l-MF makes it difficult to conclude if the changes reflect normalization of limbic dysfunction.
Though brain imaging measures did not correlate with symptom changes, a relationship that’s hard to draw for any study of this small size, said Roffman, “… all of these changes were interesting in that they were convergent around medial prefrontal structure and physiology in the context of significant genotype-independent effects on negative symptoms.”