Please select the eligibility criteria that correspond to the clinical trial below.
Title: Prevalence of Metabolic Syndrome and Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients
Brief Summary: Background: Several studies have suggested that clozapine has the greatest propensity of all available atypical antipsychotics to induce weight gain and metabolic dysregulation. So it is necessary to conduct some interventions to prevent or treat metabolic dysregulation induced by clozapine.

Metformin has been reported to achieve weight loss in several groups of patients characterized by insulin resistance. Several studies evaluated the effects of metformin on antipsychotics-induced weight gain and study period lasted from 8 to 16 weeks. Long-term metformin use had more robust effect on metabolic dysregulation and body weight in non-psychiatric field.

Goals: The study goals are two-fold. The first goal is to estimate the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients in Taiwan. The second goal is to assess the reversal effect of metformin on metabolic disturbance among clozapine-treated schizophrenic patients in a 24-week double-blind, placebo-control trial. The investigators will use metformin 1500 mg/d or placebo in the second phase trial.

Methods: This study will be divided into two phases. The first phase is to estimate the prevalence of metabolic disturbances among clozapine-treated patients. The second will be a randomized, double-blind, and placebo-controlled study of adjunctive metformin for non-DM clozapine-treated patients.

The clozapine dosage was maintained unchanged during the study period. The eligible patients will be randomly assigned to either metformin or identical placebo pills. Metformin will be titrated to 1500 mg/day in 4 weeks. Patients' blood pressure (BP), waist circumference, body weight, fasting plasma glucose (FPG), triglyceride (TG), high-density lipoprotein cholesterol (HDL), insulin, and leptin will be measured at 2, 4, 8, 16, and 24 weeks after the start of metformin.

In a 3-year period, the investigators estimate to recruit 150 clozapine-treated patients in the first phase and 75 fulfill the second phase criteria. The investigators estimate 60 patients complete the second phase intervention (staying in second phase at least 4 weeks).

From this study, the investigators would like to know the prevalence of metabolic dysregulation among clozapine-treated schizophrenic patients and to know the effect of metformin on metabolic profile among non-DM clozapine treated patients.


Options:
A: Inclusion Criteria:

* Outpatients with a diagnosis of schizophrenia or schizoaffective disorder, as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV (SCID)
* Duration of illness greater than 1 year, as defined by having initiated antipsychotic treatment at least 1 year prior to study entry
* Adequate decisional capacity to make a choice about participating in this research study
* Body mass index (BMI) at or greater than 27
* Currently being treated with one or a combination of two antipsychotic medications (typical or atypical) and on that drug regimen for at least 2 months prior to study entry, with stable dosages for at least 1 month
* If taking antidepressants, mood stabilizers, or anxiolytics, the dose must be stable for at least 1 month prior to study entry
* Willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study. Acceptable methods include oral, injectable, or implanted contraceptives; intrauterine devices or barrier methods such as condoms; and diaphragms and spermicides.

Exclusion Criteria:

* Inpatient status
* Clinical Global Impression Severity (CGI-S) score greater than 6
* Currently being treated with more than two antipsychotic medications
* Fasting glucose greater than 125
* Diagnosis of diabetes mellitus or treatment with insulin or oral hypoglycemics
* Previous or current treatment with metformin
* Diagnosis of congestive heart failure
* Renal impairment, as defined by a serum creatinine level greater than 1.5 in males or greater than 1.4 in females, or creatinine estimated glomerular filtration rate (GFR) outside of normal limits
* Hepatic disease, as defined by aspartate transaminase (AST), alanine transaminase (ALT), or c-glutamyl transferase (CGT) greater than 1.5 times upper limit of normal (ULN), or total bilirubin greater than 1.2 times ULN
* Metabolic acidosis, as defined by serum carbon dioxide less than the lower limit of normal
* Known hypersensitivity to metformin
* Pregnant or breastfeeding
* Recent (in the past 30 days) or scheduled radiological studies involving iodinated contrast material
* Alcohol abuse or dependence within the past month, as determined by the SCID
* Other serious and unstable medical condition in the judgment of the investigator
* Diagnosis of mental retardation, delirium, or dementia, as defined by DSM-IV-TR
* Failed to discontinue 4 weeks prior to study entry any medication used for weight loss
* Concurrent treatment with certain drugs that are known to increase metformin blood levels should be discussed with the Project Medical Officer.
B: Inclusion Criteria:

1. patients diagnosed with schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
2. aged 20-65 years
3. had taken clozapine for at least 3 months
4. had at least one of the following metabolic abnormalities: BMI ≥ 24; WC \> 90 cm (men) or 80 cm (women); fasting serum TG level ≥ 150 mg/dL; fasting serum HDL-C level ≤ 40 mg/dL (men) or 50 mg/dL (women); systolic BP ≥ 130 or diastolic BP ≥ 85 mm Hg; current use of antihypertensive agents; and FPG level = 100-126 mg/dL.

Exclusion Criteria:

1. history of diabetes mellitus
2. current use of hypoglycemic or hypolipidemic agents
3. pregnancy
4. allergy to metformin
5. a creatinine level \> 1.4 ng/dL
6. an abnormal liver function test result
7. chronic cardiopulmonary insufficiency.
C: Inclusion Criteria:

* You must have been diagnosed with schizophrenia or schizoaffective disorder
* You must be able to visit the doctor's office once every two weeks for three months, then once every four weeks for the next three months with a possible bi-weekly visit during the fifth month
* If you are currently taking a medication for schizophrenia or schizoaffective disorder, you have been taking it for at least 30 days without any changes
* If you are a female, you must have a negative pregnancy test and be using an effective method of contraception

Exclusion Criteria:

* You have a diagnosis of bipolar I disorder, diabetes, very high triglyceride level (fasting triglycerides greater than or equal to 500 mg/dL), recent heart attack, stroke, uncontrolled seizures, serious infection, unstable heart disease (such as ischemic heart disease or congestive heart failure), an uncorrected narrow angle glaucoma or human immunodeficiency virus (HIV)
* You have diseases of the intestinal tract, lungs, liver, kidney, nervous or endocrine systems, or blood
* You have a diagnosis of an eating disorder
* You have a history of Parkinson's Disease or any related disorders
* You are allergic to sulfa drugs or any of the medications involved in this study
D: Inclusion Criteria:

phase 1

* fulfilled DSM-IV criteria of schizophrenia or schizoaffective disorder
* 18-65 year of age
* receiving clozapine for at least 6 months.

phase 2 are those in phase 1 and met the following

* overweight and obese (BMI ≧ 24)
* one or more metabolic dysregulation, such as abdominal obesity (waist circumference \> 90 cm, in men and \> 80 cm, in women
* fasting hypertriglyceridemia, (≥ 150 mg/dL)
* low fasting HDL levels (\< 40 mg/dL in men and \< 50 mg/dL in women)
* high blood pressure (≥ 130/ ≥ 85 mm Hg or current treatment with antihypertensive medication).

The exclusion criteria are the following:

* current use of hypoglycemic or hypolipidemic agents
* FPG levels ≥ 126 mg/dL
* women who are pregnant
* known allergy or contraindicated to metformin (including Creatine\>1.4 ng/dl abnormal liver function test; chronic cardiopulmonary insufficiency).

Exclusion Criteria:

phase 2

* current use of hypoglycemic or hypolipidemic agents
* FPG levels ≥ 126 mg/dL
* women who are pregnant
* known allergy or contraindicated to metformin (including Creatine\>1.4 ng/dl abnormal liver function test
* chronic cardiopulmonary insufficiency).

Answer: D