Metformin Treatment on Cognitive Impairment of Schizophrenia

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

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.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Metformin treatment; Drug: Placebo treatment; Other: Baseline assessments; Other: Volunteer assessments

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jing Huang, M.D.; Phone Number: 15874290980; Email: jinghuangserena001@csu.edu.cn
• Study Contact Backup: Name: Jingmei Xiao, M.D.; Phone Number: 17673129702; Email: xiaojingmei@csu.edu.cn

Study Locations

• China
  • Hunan
    • Changsha, Hunan, China, 410011
      • Recruiting
      • Mental Health Institute of Second Xiangya Hospital,CSU
      • Contact: Renrong Wu, PhD, M.D; Phone Number: 15874179855; Email: wurenrong2013@163.com
      • Contact: Jing Huang, MD; Email: jinghuangserena001@csu.edu.cn
      • Sub-Investigator: Jingmei Xiao, MD
  • Shandong
    • Jinan, Shandong, China, 250014
      • Recruiting
      • Shandong Mental Health Center
      • Contact: Ranran Li, MD; Phone Number: 18678777190
  • Yunnan
    • Dali, Yunnan, China, 671014
      • Recruiting
      • The Second People's Hospital of Dali Bai Autonomous Prefecture
      • Contact: Xuemei Li; Phone Number: 15894589720
  • Zhejiang
    • Ningbo, Zhejiang, China, 315201
      • Not yet recruiting
      • NingBo KangNing Hospital
      • Contact: Weiwei Xie, MD; Phone Number: 13738486800

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Healthy volunteer	Other: Volunteer assessments; 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.
Experimental: Metformin group; The goal is to investigate whether adding metformin will benefit the cognitive impairment in individuals with schizophrenia.	Drug: Metformin treatment; Participants assigned to the metformin group will receive 500mg metformin three times daily (tid) for 24 weeks. The initial dose will be 500 mg orally in the evening for the first two days, followed by an increase to 500mg twice a day for the subsequent two days. By day 5, the dosage will be further increased to 500mg tid. The highest tolerated dosage will be maintained for participants who could not tolerate the maximum dosage.
Placebo Comparator: Placebo group; The purpose of using placebo is to judge if the outcome is related to the study medication rather than other reasons.	Drug: Placebo treatment; Parallel-dose adjustments will be made for the placebo group to maintain consistency in dosing between the two groups.
Other: Cross-sectional participants; Participants do not meet any 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. the other inclusion criteria and exclusion criteria are same as the intervention group.	Other: Baseline assessments; Schizophrenic participants who don't meet any of the diagnostic criteria for metabolic syndrome will only accept baseline evaluations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of the score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery of interventional participants	At baseline and 12th week, the cognitive function of interventional participants will be assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. 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 after 12-week metformin treatment will be used for assessing the improvement of cognitive function (higher score means better function).	From baseline to 12th week
Changes of brain cerebral blood flow by arterial spin labeling of interventional participants	At baseline and 12th week, whole brain cerebral blood flow (CBF) will be recorded by arterial spin labeling (ASL). For interventional participants, the changes in CBF (c-CBF) before and after the application of 160 units nasal insulin spray of interventional participants will be calculated. The changes of c-CBF after 12-week metformin treatment will be reported.	From baseline to 12th week
Changes of resting-state functional MRI of interventional participants	At baseline and 12th week, the resting-state functional MRI(fMRI) will be conducted at fasting state. For interventional participants, the changes in fMRI (c-fMRI) before and after the application of 160 units nasal insulin spray will be analysed. The changes of c-fMRI after 12-week metformin treatment will be used for exploring underlying mechanism.	From baseline to 12th week
The difference of cerebral blood flow between schizophrenic participants and healthy volunteers	At baseline, whole brain cerebral blood flow (CBF) will be recorded by arterial spin labeling (ASL) for every participants, the changes in CBF (c-CBF) before and after the application of 160 units nasal insulin spray will be calculated. The difference of c-CBF of the brain between schizophrenic participants and healthy volunteers will be reported.	Baseline
The difference of resting-state functional MRI between schizophrenic participants and healthy volunteers	At baseline, the resting-state functional MRI(fMRI) will be conducted at fasting state. For every participants, the changes in fMRI (c-fMRI) before and after the application of 160 units nasal insulin spray will be analysed. The c-fMRI between schizophrenic participants and healthy volunteers may reflect the underlying mechanism of disease.	Baseline
The difference of the score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery between schizophrenic participants and healthy volunteers	At baseline, the cognitive function will be assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery, including schizophrenic participants and healthy volunteers. Evaluator convert raw scores to scale scores, then to normalized T scores. T scores of seven domains and composite score are further calculated(higher score means better function). The difference of scores and their relationships with cerebral blood flow (CBF) and resting-state functional MRI(fMRI) will be used for exploring underlying mechanism.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of the score of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery of interventional participants	At every visit, the cognitive function of interventional participants will be assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. 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 after 24-week metformin treatment will be used for assessing the improvement of cognitive function (higher score means better function).	From baseline to 24th week
Changes of brain cerebral blood flow by arterial spin labeling of interventional participants	At each visit, whole brain cerebral blood flow (CBF) will be recorded by arterial spin labeling (ASL). For interventional participants, the changes in CBF (c-CBF) before and after the application of 160 units nasal insulin spray of interventional participants will be calculated. The changes of c-CBF after 24-week metformin treatment will be reported.	From baseline to 24th week
Changes of resting-state functional MRI of interventional participants	At each visit, the resting-state functional MRI(fMRI) will be conducted at fasting state. For interventional participants, the changes in fMRI (c-fMRI) before and after the application of 160 units nasal insulin spray will be analysed. The changes of c-fMRI after 24-week metformin treatment will be used for exploring underlying mechanism.	From baseline to 24th week
Changes of social function by Personal and Social Performance Scale	The changes of Personal and Social Performance Scale of interventional participants at different follow up timepoint will be used for evaluating the improvement of personal life and social function.(higher score means better function)	From baseline to 24th week
Changes of clinical symptoms by Scale for Assessment of Negative Symptoms	The changes of Scale for Assessment of Negative Symptoms of interventional participants at different follow up timepoint will be used for recording the improvement of negative symptoms.(lower score means alleviation of symptoms)	From baseline to 24th week
Changes of clinical symptoms by Positive And Negative Syndrome Scale	The changes of Positive And Negative Syndrome Scale of interventional participants at different follow up timepoint will be used for recording the improvement of psychiatric symptoms.(lower score means alleviation of symptoms)	From baseline to 24th week
Changes of level of phosphorylated insulin receptor substrate 1 and its downstream mediators in Extracellular Vesicles of neuronal origin (NEVs) isolated from blood of interventional participants	Phosphorylated insulin receptor substrate 1 and its downstream mediators represent the state of neuronal insulin resistance, whose improvement means better insulin signaling. For interventional participants, blood samples will be collected and stored at -80℃ at every visit. The NEVs isolation and biomarker measurements will be processed uniformly at the end, the changes of the level of biomarkers will partly reflect the changes of central insulin resistance after metfromin treament.	From baseline to 24th week
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). For interventional participants, the changes of HOMA-IR will partly reflect the changes of peripheral insulin resistance after metfromin treament.	From baseline to 24th week
The difference of the level of phosphorylated insulin receptor substrate 1 and its downstream mediators in Extracellular Vesicles of neuronal origin isolated from blood between schizophrenic participants and healthy volunteers	Phosphorylated insulin receptor substrate 1 and its downstream mediators represent the state of neuronal insulin resistance, whose improvement means better insulin signaling. For schizophrenic participants and healthy volunteers, blood samples will be collected and stored at -80℃ at baseline. The NEVs isolation and biomarker measurements will be processed uniformly, and the difference of the level of phosphorylated insulin receptor substrate 1 and its downstream mediators between two groups will be used for exploring underlying mechanism of disease.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
High-resolution T1-weighted anatomical images and Diffusion Tensor Imaging by MRI at baseline for predicting efficacy	T1-weighted images will be acquired using 3D inversion recovery-prepared fast spoiled gradient-echo sequences, while Diffusion Tensor Imaging (DTI) will be performed using diffusion-weighted echo planar imaging sequences. The T1-weighted mages and DTI acquired at baseline will be analysed for predicting efficacy of metformin on cognitive function for interventional participants.	From baseline to 24th week
The difference of Diffusion Tensor Imaging scanned by MRI between schizophrenic participants and healthy volunteers	Diffusion Tensor Imaging (DTI) will be performed using diffusion-weighted echo planar imaging sequences. The analysis of DTI will be conducted to investigate the difference of brain structure and morphology between schizophrenic participants and healthy volunteers.	Baseline
Changes of Diffusion Tensor Imaging scanned by MRI	Diffusion Tensor Imaging (DTI) will be performed using diffusion-weighted echo planar imaging sequences. The analysis of DTI changes following a 24-week treatment will be conducted to investigate the impact of metformin on brain structure and morphology.	From baseline to 24th week
Changes of the level of blood lipids	Blood lipids include total cholesterol, low-density lipoprotein-cholesterol, triglyceride and high-density lipoprotein-cholesterol. For interventional participants, the changes of the level of blood lipids will represent the effects of metformin on metabolism.	From baseline to 24th week
Safety evaluation through the Systematic Assessment for Treatment Emergent Events	The participants will be asked to score the occurred side effects using the Systematic Assessment for Treatment Emergent Events at every visit. (higher score means worse side effect)	From baseline to 24th week
Score of Calgary Depressing Scale for Schizophrenia	Calgary Depressing Scale for Schizophrenia which be assessed at every visit will be used for excluding the impact of depressive symptoms on cognitive function. (higher score means bigger impact)	From baseline to 24th week
Changes of Body Mass Index	To some extent, Body Mass Index(BMI) can represent the situation of peripheral metabolism.	From baseline to 24th week
Changes of waist-hip circumference	To some extent, waist-hip circumference can represent the situation of peripheral metabolism.	From baseline to 24th week
Score of the Barnes Akathisia Rating Scale	At every visit, the Barnes Akathisia Rating Scale will be used to evaluate akathisia caused by antipsychotic drugs. (higher score means worse side effect）	From baseline to 24th week
Score of the Simpson-Angus Extrapyramidal Side Effects Scale	At every visit, the Simpson-Angus Extrapyramidal Side Effects Scale will be used to evaluate extrapyramidal symptoms. (higher score means worse side effect）	From baseline to 24th week

Collaborators and Investigators

• Sponsor: Central South University
• Collaborators: Shandong Mental Health Center; NINGBO KANGNING HOSPITAL; The Second People's Hospital of Dali Bai Autonomous Prefecture
• Investigators: Study Chair: Renrong Wu, M.D., Ph.D., Mental Health Institute of Second Xiangya Hospital,CSU

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2023
• Primary Completion (Estimated): July 30, 2025
• Study Completion (Estimated): December 30, 2025

Study Registration Dates

• First Submitted: March 22, 2023
• First Submitted That Met QC Criteria: April 28, 2023
• First Posted (Actual): May 1, 2023

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Schizophrenia; Metformin; Cognitive impairment; Clinical trial
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Cognition Disorders; Schizophrenia; Cognitive Dysfunction; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: WU202211MET

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No