Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients
Effects of Adjunctive Metformin on Metabolic Profiles in Clozapine-treated Schizophrenic Patients
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.
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. In our recent study data showed that after 8 weeks treatment with
 metformin 1500 mg/day in 24 olanzapine-treated patients, the body weight, fasting levels of
 glucose, triglyceride, and insulin significantly decreased. Insulin secretion and insulin
 resistance also decreased significantly. Half of subjects with metabolic syndrome obtained
 improvement after metformin trial.

 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. We
 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.

 Patients are recruited in the first phase if they meet the following criteria (1) fulfilled
 DSM-IV criteria of schizophrenia or schizoaffective disorder; (2) 18-65 year of age (3)
 receiving clozapine for at least 6 months. We will check 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. In this study, we use
 the modified ATP III criteria for Asians to evaluate subjects for a diagnosis of metabolic
 syndrome.

 The inclusion criteria of second phase intervention will be first-phase participants who are
 (1) overweight and obese (BMI ≧ 24) or (2) 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: (1) current use of hypoglycemic or
 hypolipidemic agents (2) FPG levels ≥ 126 mg/dL; (3) women who are pregnant; (4) known
 allergy or contraindicated to metformin (including Creatine>1.4 ng/dl; abnormal liver
 function test; chronic cardiopulmonary insufficiency).

 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, we estimate to recruit 150 clozapine-treated patients in the first phase
 and 75 fulfill the second phase criteria. We estimate 60 patients complete the second phase
 intervention (staying in second phase at least 4 weeks).

 From this study, we 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.

 Key words: schizophrenia, clozapine, metabolic dysregulation, metformin
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).