L-Methylfolate for Schizophrenia: Does it Help?

randomized-controlled-trial PMID: 28289280

Quick Summary: Research suggests L-methylfolate, a form of folate (Vitamin B9), may help reduce some symptoms of schizophrenia, particularly negative symptoms like social withdrawal. The study found it also improved brain function in some areas.

What The Research Found

This study looked at how L-methylfolate affects people with schizophrenia. Here's what they discovered:

Improved Symptoms: People taking L-methylfolate showed improvement in some schizophrenia symptoms, especially those related to negative symptoms (like lack of motivation or social withdrawal).

Brain Changes: The study also found that L-methylfolate seemed to change how the brain works in areas related to thinking and emotions.

Folate Levels: L-methylfolate increased the levels of folate in the blood.

Study Details

Who was studied: 55 adults with schizophrenia who were already taking medication for their condition.

How long: The study lasted for 12 weeks (about 3 months).

What they took: Half the group took 15mg of L-methylfolate daily, and the other half took a placebo (a "dummy" pill).

What This Means For You

Potential Benefit: If you have schizophrenia, this research suggests L-methylfolate might help with some of your symptoms, especially negative symptoms.

Talk to Your Doctor: It's important to talk to your doctor before taking L-methylfolate or any new supplement. They can help you understand if it's right for you and if it could interact with any medications you're already taking.

Not a Cure: This study doesn't mean L-methylfolate is a cure for schizophrenia. It's a potential tool that may help manage some symptoms.

Study Limitations

Small Study: The study only included a small number of people, so more research is needed to confirm these findings.

Short Duration: The study was only 3 months long. We don't know if the benefits would last longer.

Specific Group: The study focused on people already taking medication. The results might be different for people with different types of schizophrenia or who aren't taking medication.

More Research Needed: While promising, more research is needed to fully understand how L-methylfolate works and who might benefit the most.

Key Findings

L-Methylfolate (15 mg/day) significantly increased plasma methylfolate levels (effect size d=1.00, P=0.0009) and improved schizophrenia symptoms, particularly the PANSS Negative (d=0.61, P=0.03) and General Psychopathology subscales. Genetic variants in the folate pathway influenced PANSS Total and General Psychopathology outcomes but not Negative subscale improvements. MRI revealed physiological changes in the ventromedial prefrontal cortex, including increased task-induced deactivation, altered limbic connectivity, and cortical thickening. No significant effects were observed on cognitive composite scores or depression/anxiety scales.

Study Design

This was a 12-week, randomized, double-blind, placebo-controlled trial involving 55 outpatients with schizophrenia stabilized on antipsychotic medications. Primary outcome: change in plasma methylfolate levels. Secondary outcomes: symptom severity (PANSS, Calgary Depression Scale, Scale for Assessment of Negative Symptoms), cognition, and MRI-based brain physiology. Analyses were adjusted for six genetic variants in the folate pathway (e.g., MTHFR C677T), with post hoc evaluations excluding covariates to assess genotype independence.

Dosage & Administration

Participants received 15 mg/day of L-methylfolate orally (once daily) or placebo for 12 weeks. Supplementation was administered alongside stable antipsychotic regimens.

Results & Efficacy

Physiological: L-Methylfolate increased plasma methylfolate levels by 1.00 standard deviation (P=0.0009) compared to placebo.
Symptoms:
PANSS Total score improved (d=0.61, P=0.03), driven by genotype-dependent effects on General Psychopathology (P=0.02) but genotype-independent reductions in Negative symptoms (P=0.01).
No significant changes in depression, anxiety, or cognitive composite scores.
MRI: Treatment induced increased ventromedial prefrontal cortex deactivation during working memory tasks, altered resting-state limbic connectivity, and localized cortical thickening.

Limitations

Small sample size (n=55) limits power and generalizability.
Short duration (12 weeks) precludes assessment of long-term efficacy or sustained physiological changes.
Participants were outpatients on stable antipsychotics; results may not apply to treatment-resistant or acute cases.
Genotype covariates were preselected, potentially missing other genetic or metabolic modifiers.
Lack of functional outcome measures (e.g., social/occupational functioning) and unmeasured mechanistic pathways (e.g., neurotransmitter interactions).

Clinical Relevance

L-Methylfolate (15 mg/day) may offer targeted benefits for negative symptoms and brain physiology in schizophrenia patients, independent of genetic variants affecting folate metabolism. However, its effects on broader symptom domains and cognition remain inconclusive. Clinicians should consider genotype status when evaluating symptom response but note that Negative subscale improvements occurred universally. Larger trials are needed to confirm these findings and explore long-term clinical outcomes. Patients should consult healthcare providers before supplementation, as interactions with antipsychotics or other nutrients (e.g., B12) require monitoring.

Source: PubMed | Trial Registration: NCT01091506

L-Methylfolate for Schizophrenia: Does it Help?