Metformin Treatment on Cognitive Impairment of Schizophrenia

Study Overview
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Brief Summary
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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. The specific aims are to compare metformin group versus controls on: 1) cognition; 2) clinical core symptoms. Biological samples also will be collected and stored to explore related mechanisms.

Detailed Description
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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, and serum insulin), 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 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.

Official Title
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The Effect of Metformin Treatment on Cognitive Impairment in Individuals With Schizophrenia: A 24-week Multicentre Randomised Controlled Trial

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Metformin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female with aged 18 to 50 years, who meet the Diagnostic and Statistical Manual (DSM-5) diagnostic criteria for schizophrenia; Duration of illness less than 15 years with current symptoms in a stable condition; 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; Have great compliance on medication and follow-up； 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. Signed the study consent for participation. Exclusion Criteria: Having history of substance dependence or abuse or whose symptoms are caused by the other diagnosable mental disorders; Having history of traumatic brain injury, seizures or other known neurological or organic diseases of the central nervous system; Taking antidepressants, stimulants, mood stabilizer or accepts electricity shock treatment; Having current suicidal or homicidal thoughts or any safety concern by research staff that cannot be manage in an inpatient setting; Taking dementia related drugs, minocycline, and other drugs that could affect cognitive function. The routine blood tests showing significant abnormal renal, liver function or other somatic disease. Pregnant or lactating women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two groups were observed longitudinally for 24 weeks.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin group<br>The goal is to investigate whether adding metformin will benefit the cognitive impairment in individuals with schizophrenia. | Drug: Metformin<br>* Take metformin 1500mg per day<br>|
| Placebo Comparator: Placebo group<br>The purpose of using placebo is to judge if the outcome is related to the study medication rather than other reasons. | Drug: Placebo<br>* Take placebo 1500mg per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of the MATRICS Consensus Cognitive Battery score | After assessment at each visit, evaluator convert raw scores to scale scores, then to normalized T scores. T scores of seven domains and composite score are further calculated. The changes of scores at different follow up timepoint will be used for assessing the improvement of cognitive function (higher score means better function). | 12 weeks | 
| Change of brain cerebral blood flow by arterial spin labeling | At each visit, whole brain cerebral blood flow (CBF) will be recorded by arterial spin labeling(ASL) before and 30 min after 160 units nasal insulin spray application, which will be performed at fasting state. The change of Insulin responsiveness of the brain will be partly reflected by the change of CBF before and after metformin treatment. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of the MATRICS Consensus Cognitive Battery (MCCB) composite score | After assessment at each visit, evaluator convert raw scores to scale scores, then to normalized T scores. T scores of seven domains and composite score are further calculated. The changes of scores at different follow up timepoint will be used for assessing the improvement of cognitive function (higher score means better function). | 24 week | 
| Change of brain cerebral blood flow by arterial spin labeling | At each visit, whole brain cerebral blood flow (CBF) will be recorded by arterial spin labeling(ASL) before and 30 min after 160 units nasal insulin spray application, which will be performed at fasting state. The change of Insulin responsiveness of the brain will be partly reflected by the change of CBF before and after metformin treatment. | 24 weeks | 
| Change of Resting-state functional MRI | At each visit, the Resting-state functional MRI(fMRI) will be recorded before and 30 min after 160 units nasal insulin spray application, which will be performed at fasting state. The change of fMRI indexes associated with Insulin responsiveness of the brain and/or metformin treatment will be used for exploring underlying mechanism. | 12 weeks and 24 weeks | 
| Change of social function by Personal and Social Performance Scale | The change of Personal and Social Performance Scale(PSP) at different follow up timepoint will be used for evaluating the improvement of personal life and social function.(higher score means better function) | 12 weeks and 24 weeks | 
| Change of clinical symptoms by Scale for Assessment of Negative Symptoms | The change of Scale for Assessment of Negative Symptoms(SANS) at different follow up timepoint will be used for recording the improvement of negative symptoms.(lower score means alleviation of symptoms) | 12 weeks and 24 weeks | 
| Change of clinical symptoms by Positive And Negative Syndrome Scale | The change of Positive And Negative Syndrome Scale (PANSS) at different follow up timepoint will be used for recording the improvement of psychiatric symptoms.(lower score means alleviation of symptoms) | 12 weeks and 24 weeks | 
| Changes of level of phosphorylated insulin receptor substrate 1 and its downstream mediators in Extracellular Vesicles of neuronal origin isolated from blood | Phosphorylated insulin receptor substrate 1 and its downstream mediators represent the state of neuronal insulin resistance, whose improvement means better insulin signaling. | 12 weeks and 24 weeks | 
| Changes of homoeostasis model assessment-estimated insulin resistance. | Homoeostasis model assessment-estimated insulin resistance(HOMA-IR) represents systemic insulin resistance(higher value means worse outcome). | 12 weeks and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Schizophrenia, Cognitive impairment, Metformin, Clinical trial