• Endothelial functioning [ Time Frame: Measured at baseline and after 3 months ] [ Designated as safety issue: No ]
• Metabolic syndrome diagnosis [ Time Frame: Measured at baseline and after 3 months ] [ Designated as safety issue: No ]

This study will examine possible causes of metabolic side effects in people taking atypical antipsychotic (AAP) medications.

Antipsychotic medications are used to treat some of the most severe symptoms of mental illness, such as hallucinations and irrational outbursts. Atypical antipsychotics (AAPs) are a group of newer, second generation antipsychotic medications that effectively treat psychotic symptoms but that also have severe side effects. One side effect is an increased risk of metabolic syndrome, which is a cluster of conditions that together increase the risk of heart disease, stroke, type 2 diabetes, and endothelial dysfunction—dysfunction of the cells that line the inner surface of blood cells. Schizophrenic patients taking atypical antipsychotics are more than twice as likely as the general population to experience metabolic syndrome. Certain genetic variants associated with folate metabolism, as well as low dietary folate, may lead to the development of metabolic syndrome and its associated diseases. These factors have been studied in the general population, but not in a group of schizophrenic patients taking antipsychotics. This study will examine the relationship among folic acid, variants in the gene methlenetrahydrofolate reductase, and metabolic syndrome and its associated diseases in people with schizophrenia who are taking atypical antipsychotics. The study will also evaluate the use of folic acid supplementation for treating metabolic syndrome in this population.

Participation in this study will involve two phases. The first phase will involve recruitment, screening, and testing of participants taking antipsychotics and will last 4 years. During this phase, participants will attend one study visit in which they will undergo a screening for metabolic syndrome and have the following measured: endothelial functioning, body size, diet, physical activity, medication history, and genetic makeup. Participants who have metabolic syndrome will be invited to participate in Phase 2.

Phase 2 will run concurrently with Phase 1, but will extend to 5 years, in order to give all participants an opportunity to continue from one phase to the next if they meet entry criteria. Participants in Phase 2 will attend four study visits over the course of 3 months: one at the beginning of the phase and one after each month of the study. After the first study visit, participants will be given folic acid to take daily for the 3 months. At each study visit, participants will be asked about thoughts, illness, functioning, diet, medication side effects, recent medication history, smoking history, alcohol intake, and exercise habits. On the first and last visits, participants will undergo additional tests of genetics, blood hormone levels, and blood vessel functioning, and additional measurements will be made of height, weight, vital signs, and body size.

Inclusion Criteria for Phase 1:

• DSM-IV diagnosis of schizophrenia, schizophreniform disorder, schizoaffective disorder, or psychosis not otherwise specified
• Treatment with one of the following atypical antipsychotics (AAPs) for at least 6 months: clozapine, olanzapine, risperidone, quetiapine, aripiprazole, or ziprasidone

Inclusion Criteria for Phase 2:

• Previous participation in Phase 1 pharmacogenomic study
• Meets metabolic syndrome criteria
• No medication changes for 6 months, including antipsychotic medication changes and changes in any other medications related to treating metabolic syndrome, diabetes, hypertension, or hyperlipidemia

Exclusion Criteria for Phases 1 and 2:

• Presence of any serious medical condition that would significantly affect weight changes, such as neoplastic or thyroid disease
• Diagnosis of active substance dependence or use of illicit substances within the past month
• History of type 2 diabetes mellitus prior to AAP use
• Past history of or currently has pernicious, aplastic, or normocytic anemia with a B12 deficiency