Relationships of One-Carbon Cycle Pathways with Psychopathology and Metabolic Abnormalities in Patients with Schizophrenia and Potential Intervention Strategy with 5-Methyltetrahydrofolate and Vitamin B12

Project: A - Government Institutionb - National Science and Technology Council

Project Details


Background: Gene and environment interaction has been proposed to contribute to the vulnerability to schizophrenia. One-carbon cycle pathway is one example of gene-environment interaction. Patients with schizophrenia have lower serum folate and higher homocysteine. In addition, genetic variants of enzymes in one-carbon cycle pathway may be associated with schizophrenia. Some studies showed that genetic polymorphisms of one-carbon cycle pathway are associated with symptomatology, metabolic abnormalities, and folate treatment response in patients with schizophrenia, especially those with low folate level. Study Aims Our study aims are: 1. To investigate folate, vitamin B12, and homocysteine levels in patients with schizophrenia. 2. To evaluate the relationships among folate, vitamin B12, and homocysteine levels, genetic variants of one-carbon cycle pathway, psychopathology, including positive symptoms, negative symptoms, and cognition, and metabolic abnormalities in patients with schizophrenia. 3. For patients with low folate levels, we would like to conduct a 24-week double-blinded, placebo-controlled of 5-methyltetrahydrofolate (5-MTHF) (15 mg/d) and vitamin B12 (400 ug/d) supplementation study to know whether combination of 5-MTHF and vitamin B12 can improve patients’ psychopathology or metabolic profiles, and the effects of genetic variants in one-carbon cycle pathway on treatment response. Methods This is a two-phase study. The first phase is to investigate nutritional status, including folate, vitamin B12, homocysteine, and metabolic profiles in patients with schizophrenia. The second phase is a 24-week double-blinded, placebo-controlled study to use 5-MTHF (15 mg/d) and vitamin B12 (400 ug/d) supplementation for those patients with folate deficiency or insufficiency. First phase screening: Inclusion criteria: 1. Age 20-65 year-old. 2. Fulfill DSM-IV-TR diagnosis of schizophrenia. 3. Be treated with an antipsychotic agent for at least 6 months or at a stable dose for at least 3 months. Exclusion criteria: 1. Medically unstable. 2. Currently taking vitamin supplementation. 3. Pregnancy or lactation. 4. Test positive of urine drug screen. Clinical assessments include physical examination and psychiatric evaluation, including height, body weight, blood pressure, waist circumference, PANSS, SANS, HAMD-17, CogState, AIMS etc. Laboratory assays include 1. general biochemical assay: including serum and RBC folate and vitamin B12 and homocysteine levels, and other metabolic profiles. 2. DNA assays: Genetic variants in one-carbon cycle pathway, such as FOLH1; MTHFR C677T; MTR G1298A; COMT G675A; etc. Second phase intervention: Inclusion criteria: 1. Patients with folate deficiency or insufficiency, and PANSS score at least 60 or more in the first phase screening. Folate deficiency and insufficiency (low folate level) are defined as serum folate < 6.8 nmol/L (3 ng/mL) and <= 13.5 nmol/L (6 ng/mL), respectively. Exclusion criteria: 1. Megaloblastic anemia due to folate deficiency; 2. Patients with parkinsonism (score of > 12 on the Simpson-Angus Scale); 3. History of alcohol or other substances use disorder in past 3 months; 4. History of significant neurological illness; 5. Creatine>1.4 ng/dl. We adopt the 2 : 1 ratio of randomization to increase sample size in active arm. Each active pill contains 15 mg of 5-MTHF and 400 ug of vitamin B12. Patients will be visited clinics at week 2, 4, 8, 12, 16, 20, and 24. Psychiatric evaluation except for cognitive function and Udvalg for Kliniske Undersogelser Side Effect Rating Scale questionnaire will be assessed at every visit. Cognitive function will be evaluated at week 12 and 24. Adherence will be monitored by pill counts at each visit. Laboratory assays including serum and RBC folate and vitamin B12 levels, homocysteine, metabolic profiles will be performed at week 4, 12, and 24. We estimate to screen 220 patients with schizophrenia in the first phase to get about 88 patients with folate deficiency or insufficiency.
Effective start/end date8/1/147/31/15


  • one-carbon cycle
  • folate
  • 5-MTHF
  • schizophrenia
  • psychopathology
  • metabolic abnormality


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.