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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
120
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.
Parallel-dose adjustments will be made for the placebo group to maintain consistency in dosing between the two groups.
Schizophrenic participants who don't meet any of the diagnostic criteria for metabolic syndrome will only accept baseline evaluations.
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.
Mental Health Institute of Second Xiangya Hospital,CSU
Changsha, Hunan, China
The Third Peoples's Hospital of Jiangyin
Jiangyin, Jiangsu, China
Shandong Mental Health Center
Jinan, Shandong, China
The Second People's Hospital of Dali Bai Autonomous Prefecture
Dali, Yunnan, China
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).
Time frame: From baseline to 12th week；From baseline to 24th 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.
Time frame: From baseline to 12th week；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.
Time frame: From baseline to 12th week; 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)
Time frame: 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)
Time frame: 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)
Time frame: 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.
Time frame: From baseline to 24th 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.