Examining Risk Factors for Atypical Antipsychotic Metabolic Side Effects

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 methylenetetrahydrofolate 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. The Phase 2 study is now
inactive.

Phase 2B is active and currently recruiting participants. This is a randomized, placebo
controlled study of folate supplementation. Participants in phase 2B will attend 6 study
visits over the course of 6 months. At the first study visit they will be randomized to
either folic acid 5mg daily for 4 months or placebo. This 4 month period is followed by a 2
month follow up visit, when no supplementation is given. 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

Inclusion criteria for Phase 2B:

- At least 18 years old and presence of a DSM-IV diagnosis of schizophrenia,
schizophreniform disorder, schizoaffective disorder, or psychosis NOS

- Receiving atypical antipsychotic medication for at least 6 months

- Currently meet ≥ 2 of the NCEP-ATP-III criteria for metabolic syndrome

- No medication changes within the last two months

- Vitamin B12 levels within normal laboratory levels

- No illicit drug use in the past month

Exclusion Criteria for Phase 2B

- Inability to give informed consent or unwillingness to participate

- Presence of any serious medical conditions that would significantly affect weight
changes (i.e. neoplastic or uncontrolled thyroid disease)

- Blood pressure lower than 90/60 mmHg

- History of Type 2 Diabetes Mellitus prior to AAP use

- History of hypersensitivity or allergic reaction to folic acid or any of the product
ingredients

- Current pregnancy or nursing

- Current substance dependence diagnosis