Metformin Treatment on Cognitive Impairment of Schizophrenia

In this study, the investigators will investigate the effect and the underlying mechanism of metformin treatment on cognitive impairment in individuals with schizophrenia. The study will recruit 120 individuals with schizophrenia at 4 sites, who will be randomized to metformin or placebo group for 24-week treatment. Clinical assessments will be done at screen/baseline, 12th week and 24th week. Participants who don't meet any of the diagnostic criteria for metabolic syndrome will only accept baseline evaluations. The specific aims are to compare healthy volunteers versus schizophrenic participants on:1) cognition; 2) MRI features, and to compare metformin group versus placebo group of 24-week treatment cohort on: 1) cognition; 2) clinical core symptoms; 3) MRI features. Biological samples also will be collected and stored to explore related mechanisms.

Participants screened through inclusion and exclusion criteria will be randomized to metformin or placebo group (2:1). The information of demographic data, medical history, previous and current medication regimen, and family history regarding psychotic and metabolic diseases will be collected at baseline. The assessments will be carried out at baseline, 12th week and 24th week, including physical examination, anthropometry, blood test(blood routine, liver function, renal function, blood lipids, fasting blood glucose, serum insulin and thyroid function), electrocardiogram, MRI scan( High-resolution T1-weighted Anatomical Images, Diffusion Tensor Imaging, Resting-state functional MRI and Arterial Spin Labeling) and psychiatry scales(Positive And Negative Syndrome Scale, Scale for Assessment of Negative Symptoms, Calgary Depressing Scale for Schizophrenia, Personal and Social Performance Scale, The Systematic Assessment for Treatment Emergent Events, the Simpson-Angus Extrapyramidal Side Effects Scale and the Barnes Akathisia Rating Scale); cognitive function will be assessed by the Measurement and Treatment Research to Improve Cognition in Schizophrenia(MATRICS) Consensus Cognitive Battery; biological samples also will be collected and stored to explore related mechanisms. Participants who don't meet any of the diagnostic criteria for metabolic syndrome will only accept baseline evaluations. In addition, we will recruit healthy volunteers, and collect their demographic data, and family history regarding psychotic and metabolic diseases. Apart from psychiatry scales(Hamilton Depression Scale, Young Mania Rating Scale and Self-reporting Inventory-90), other assessments for the healthy subjects are the same as the baseline for sczhiophrenic participants.

Eligibility Criteria:
Inclusion Criteria:

1. Male and female with aged 18 to 50 years, who meet the Diagnostic and Statistical Manual (DSM-5) diagnostic criteria for schizophrenia;
2. Duration of illness less than 15 years with current symptoms in a stable condition;
3. Participants must be receiving stable treatment with standard-of-care medications, with a maximum allowance of two antipsychotic medications. If additional anticholinergic agents are required for the management of extrapyramidal symptoms, they should be prescribed at low dosages;
4. Have great compliance on medication and follow-up；
5. Meet one of the diagnostic criteria for metabolic syndrome: 1)abdominal obesity (i.e. central obesity): waist circumference for male≥90 cm, for female ≥85 cm; 2)fasting blood glucose ≥110 mg/dl (6.1 mmol/l) and/or plasma glucose ≥140 mg/dl (7.8 mmol/l) after glucose load; 3)at fasting state, triglyceride ≥1.7 mmol/l; 4)at fasting state, HDL-C \<1.04 mmol/L.
6. Signed the study consent for participation.

Exclusion Criteria:

1. Having history of substance dependence or abuse or whose symptoms are caused by the other diagnosable mental disorders;
2. Having history of traumatic brain injury, seizures or other known neurological or organic diseases of the central nervous system;
3. Taking antidepressants, stimulants, mood stabilizer or accepts electricity shock treatment;
4. Having current suicidal or homicidal thoughts or any safety concern by research staff that cannot be manage in an inpatient setting;
5. Taking dementia related drugs, minocycline, and other drugs that could affect cognitive function.
6. The routine blood tests showing significant abnormal renal, liver function or other somatic disease.
7. Pregnant or lactating women.

For schizophrenic participants who don't meet any of the diagnostic criteria for metabolic syndrome will only accept baseline evaluations.