Effectiveness of Vitamin Supplementation in Treating People With Residual Symptoms of 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.

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