• Cognitive deficits, as measured by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) cognitive battery composite score [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• Psychotic symptoms, as measured by the PANSS psychosis subscale score [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• Negative symptoms, as measured by the modified Scale for Assessment of Negative Symptoms (SANS) total score [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• Relationship among PANSS total score; negative and positive symptoms; cognitive performance; baseline serum and red blood cell (RBC) folate, plasma homocysteine, and B12 concentrations; tobacco intake; and MTHFR C677T gene status [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]
• Relationship between response of negative and positive symptoms and the change in RBC folate, serum folate, serum B12, and plasma homocysteine concentrations [ Time Frame: Measured at Week 16 ] [ Designated as safety issue: No ]

This study will evaluate the effectiveness of folate and B12 supplementation in reducing negative symptoms in people with schizophrenia.

About 30% of people with schizophrenia suffer from treatment-resistant psychotic symptoms, which may include social withdrawal, apathy, and depression. These negative symptoms can produce substantial distress for those affected, often disrupting social and occupational functioning and resulting in hospitalization. Although atypical antipsychotic medications have demonstrated some success in treating negative symptoms, the degree to which many negative symptoms respond is unclear. Depression and poor response to antidepressant medication have been linked to deficiency in the vitamins folate and B12. It is believed that vitamin supplementation with folate and B12 may offer a safe and inexpensive approach to improve outcomes for people with schizophrenia who have residual negative symptoms and have exhibited poor treatment response. This study will compare the effectiveness of folate and B12 versus placebo in reducing negative symptoms in people with schizophrenia.

Participation in this double-blind study will last 19 weeks. Potential participants will undergo initial screening, which will include a medical and psychiatric evaluation, physical exam, blood draw, urine sampling, and questionnaires. Participants will also be asked for permission to use a portion of the blood sample for genetic analysis. Eligible participants will be randomly assigned to take folate with B12 or placebo. Participants will first complete a 2-week stabilization phase, followed by the 16-week treatment study. Medication visits, occurring every 2 weeks during treatment, will include questions about medication side effects and the distribution of study medication. During specified medication visits, participants will complete various assessments, which will include questionnaires about schizophrenia, tests of learning and memory, repeat blood tests, and pregnancy tests. The medication visits will last between 15 minutes and 4 hours, depending on the scheduled assessments for that visit.

• Dietary Supplement: Folic acid with B12
• Drug: Placebo

• Experimental: Participants will take folic acid plus B12 for 18 weeks.
• Placebo Comparator: Participants will take placebo for 18 weeks.

Inclusion Criteria:

• Diagnosis of schizophrenia, any subtype
• Treated with an antipsychotic medication for at least 6 months at a stable dose for at least 6 weeks before study entry
• PANSS total score of at least 60, with a score of at least 3 (moderate) on one negative symptom item or on one positive symptom item
• Simpson Angus Scale (SAS) for Extrapyramidal Syndrome (EPS) total score of 12 or less
• A score of 2 (mild) or less on all items of the Calgary Depression Scale (CDS)
• Speaks English adequately enough to complete cognitive testing

Exclusion Criteria:

• Serum B12 concentration less than 300 ug/L
• Complete blood count results consistent with megaloblastic anemia
• Serum creatinine concentration greater than 1.4
• Current use of folate or B12 supplementation
• Current use of any of the following medications: phenobarbital, phenytoin, carbamazepine, valproic acid, fosphenytoin, primidone, or pyrimethamine
• Alcohol or other substance abuse within 3 months before study entry (nicotine allowed)
• Positive baseline urine toxic screen
• Unstable medical illness
• Unstable psychiatric illness
• Seizure disorder
• Pregnant or breastfeeding