Metformin Treatment on Cognitive Impairment of Schizophrenia

Sponsor

Central South University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05838573

Collaborator

NINGBO KANGNING HOSPITAL (Other), Shandong Mental Health Center (Other), The Second People's Hospital of Dali Bai Autonomous Prefecture (Other)

120

Enrollment

Locations

Arms

31.9

Anticipated Duration (Months)

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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:

cognition; 2) clinical core symptoms. Biological samples also will be collected and stored to explore related mechanisms.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Metformin Drug: Placebo	Phase 3

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, 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, and The Systematic Assessment for Treatment Emergent Events); 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Two groups were observed longitudinally for 24 weeks.Two groups were observed longitudinally for 24 weeks.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

May 5, 2023

Anticipated Primary Completion Date :

Jul 30, 2025

Anticipated Study Completion Date :

Dec 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Metformin group The goal is to investigate whether adding metformin will benefit the cognitive impairment in individuals with schizophrenia.	Drug: Metformin Take metformin 1500mg per day
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 Take placebo 1500mg per day

Arm

Intervention/Treatment

Experimental: Metformin group

The goal is to investigate whether adding metformin will benefit the cognitive impairment in individuals with schizophrenia.

Drug: Metformin

Take metformin 1500mg per day

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

Take placebo 1500mg per day

Outcome Measures

Primary Outcome Measures

The change of the MATRICS Consensus Cognitive Battery score [12 weeks]
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).
Change of brain cerebral blood flow by arterial spin labeling [12 weeks]
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.

Secondary Outcome Measures

The change of the MATRICS Consensus Cognitive Battery (MCCB) composite score [24 week]
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).
Change of brain cerebral blood flow by arterial spin labeling [24 weeks]
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.
Change of Resting-state functional MRI [12 weeks and 24 weeks]
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.
Change of social function by Personal and Social Performance Scale [12 weeks and 24 weeks]
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)
Change of clinical symptoms by Scale for Assessment of Negative Symptoms [12 weeks and 24 weeks]
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)
Change of clinical symptoms by Positive And Negative Syndrome Scale [12 weeks and 24 weeks]
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)
Changes of level of phosphorylated insulin receptor substrate 1 and its downstream mediators in Extracellular Vesicles of neuronal origin isolated from blood [12 weeks and 24 weeks]
Phosphorylated insulin receptor substrate 1 and its downstream mediators represent the state of neuronal insulin resistance, whose improvement means better insulin signaling.
Changes of homoeostasis model assessment-estimated insulin resistance. [12 weeks and 24 weeks]
Homoeostasis model assessment-estimated insulin resistance(HOMA-IR) represents systemic insulin resistance(higher value means worse outcome).

Other Outcome Measures

High-resolution T1-weighted anatomical images and Diffusion Tensor Imaging by MRI at baseline for predicting efficacy [12 weeks and 24 weeks]
The high-resolution T1-weighted anatomical images and Diffusion Tensor Imaging(DTI) scanned by MRI at baseline will be analysed for predicting efficacy of metformin on cognitive function.
Change of the level of blood lipids [12 weeks and 24 weeks]
Blood lipids include total cholesterol, low-density lipoprotein-cholesterol, triglyceride and high-density lipoprotein-cholesterol.
Safety evaluation through the Systematic Assessment for Treatment Emergent Events [12 weeks and 24 weeks]
The participants will be asked to score the occurred side effects using the Systematic Assessment for Treatment Emergent Events(SAFTEE) at 12th week and 24th week. (higher score means worse side effect）
Score of Calgary Depressing Scale for Schizophrenia [12 weeks and 24 weeks]
Calgary Depressing Scale for Schizophrenia(CDSS) which be assessed at every visit will be used for excluding the impact of depressive symptoms on cognitive function. (higher score means bigger impact)
Change of Body Mass Index [12 weeks and 24 weeks]
To some extent, Body Mass Index(BMI) can represent the situation of peripheral metabolism.
Change of waist-hip circumference [12 weeks and 24 weeks]
To some extent, waist-hip circumference can represent the situation of peripheral metabolism.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 10 years with current symptoms in a stable condition;
Participants are required to be on stable treatment with standard-of-care medications; first-generation antipsychotics will be allowed, but only in the context of no concomitant anticholinergic agents and minimal extrapyramidal symptoms; and antipsychotic medication should be no more than 2;
The sum score of PANSS Marder negative factor items is at least 20;
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)systolic blood pressure/diastolic blood pressure ≥130/85 mmHg; 4)at fasting state, total cholesterol ≥1.7 mmol/l; 5)at fasting state, HDL-C <1.04 mmol/L. Otherwise, participant who is at high risk of metabolic syndrome will also be recruited.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mental Health Institute of Second Xiangya Hospital,CSU	Changsha	Hunan	China	410011
2	Shandong Mental Health Center	Jinan	Shandong	China	250014
3	The Second People's Hospital of Dali Bai Autonomous Prefecture	Dali	Yunnan	China	671014
4	Ningbo Kangning Hospital	Ningbo	Zhejiang	China	315201