Examining Risk Factors for Atypical Antipsychotic Metabolic Side Effects

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

Detailed Description
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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.

Official Title
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Folate Pharmacogenomics and Risk of Atypical Antipsychotic Metabolic Side Effects

Conditions
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Schizophrenia

Intervention / Treatment
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* Dietary Supplement: Folic Acid
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Folate<br>During Phase 1, participants will undergo screening for metabolic syndrome and have genetic makeup, body size, and endothelial functioning measured. During Phase 2, participants will receive daily folic acid as a treatment for metabolic syndrome. Phase 2B participants will receive either daily folic acid or placebo as a treatment for metabolic syndrome. | Dietary Supplement: Folic Acid<br>* 5 mg of folic acid taken daily for 3 months in an open label fashion<br>* Other names: Folate;|
| Placebo Comparator: Placebo<br>During Phase 1, participants will undergo screening for metabolic syndrome and have genetic makeup, body size, and endothelial functioning measured. During Phase 2, participants will receive daily folic acid as a treatment for metabolic syndrome. Phase 2B participants will receive either daily folic acid or placebo as a treatment for metabolic syndrome. | Other: Placebo<br>* Subjects may receive placebo (a sugar pill) for 4 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelial functioning | Using the EndoPAT machine (Itamar) we will measure the Reactive hyperemia index (RHI) | Measured at baseline and after 3 months, and then at a two month follow up visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| metabolic syndrome | Metabolic Syndrome is defined as having any 3 of the following: 1) abdominal obesity characterized by waist circumference of >40 inches for men or >35 inches for women, 2) triglycerides ≥150 mg/dL, 3) HDL cholesterol <40 mg/dL for men and <50 mg/dL for women or receiving a lipid lowering agent), 4) blood pressure ≥130/≥85 mmHg or treatment for hypertension, or 5) fasting glucose ≥100 mg/dL or treatment of diabetes. | measured at baseline, endpoint, and follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antipsychotic, Metabolic Syndrome, Insulin Resistance, Endothelial Function