This study is a 12-week, randomized, blank-controlled, assessor-blinded trial. Eligible patients were randomized in a 1:1 ratio to receive either berberine hydrochloride or blank control as an add on to their stable antipsychotic regimen for 12 weeks. Randomization was performed using a computer-generated random number table, and allocation was concealed using sequentially numbered, opaque, sealed envelopes. The trial included four visits: baseline (visit 1), week 4 (visit 2), week 8 (visit 3) and week 12 (visit 4). Patients in the berberine group received berberine hydrochloride tablets (100 mg/tablet), three tablets three times daily. The control group received no intervention (blank control) and continued their usual care.
Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS); cognitive symptoms were evaluated using the MATRICS Consensus Cognitive Battery (MCCB); depressive symptoms were assessed using the 24-item Hamilton Depression Rating Scale (HAMD-24); and anxiety symptoms were evaluated using the Hamilton Anxiety Rating Scale (HAMA). All assessments were administered by trained research personnel. The MCCB assessment was performed only at baseline and Week 12, whereas the PANSS, HAMD, and HAMA assessments were conducted at baseline, Week 4, Week 8, and Week 12. The primary outcome measure was the uncorrected T-score of the MCCB Overall Composite Score, which was derived by standardizing and summing the T-scores across seven cognitive domains: processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. Since commercially available berberine is only formulated as yellow tablets with a marked bitter taste, which makes it difficult to prepare an indistinguishable placebo, a blank control design was adopted to maintain feasibility while ensuring the integrity of the study. We acknowledge that this open-label design may introduce potential placebo effects. Nevertheless, the cognitive assessments are less susceptible to expectancy effects, and both the raters and statisticians were blinded to group assignment to minimize bias.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
124
Patients in the berberine group received berberine hydrochloride tablets (100 mg/tablet), three tablets three times daily.
Tianjin Anding Hospital
Tianjin, China
Change in the MCCB Overall Composite Score
MCCB is a standardized measurement tool for assessing cognitive function in schizophrenia. There are 9 subtests, which mainly assess 7 cognitive domains, including information processing speed, attention/alertness, Working memory, word learning, visual memory, reasoning and problem solving, and social cognition. After the evaluation is completed, the MCCB rough score is converted into the total score T score obtained after correction for age, gender, years of education, and untreated period. The T score is then converted into a defect score, with T scores ≥ 40, 35-39, 30-34, 25-29, 20-24, and ≤ 19 corresponding to defect scores 0, 1, 2, 3, 4, and 5, respectively. Among them, 1 represents mild defects, 2 represents mild to moderate defects, 3 represents moderate defects, 4 represents moderate to severe defects, and 5 represents severe defects. In this study, a defect score of ≥ 3 was used as the boundary for significant cognitive impairment.
Time frame: changes within 0, 12weeks
Change from baseline in scores on the remaining MCCB domains
MCCB is a standardized measurement tool for assessing cognitive function in schizophrenia. There are 9 subtests, which mainly assess 7 cognitive domains, including information processing speed, attention/alertness, Working memory, word learning, visual memory, reasoning and problem solving, and social cognition. After the evaluation is completed, the MCCB rough score is converted into the total score T score obtained after correction for age, gender, years of education, and untreated period.
Time frame: changes within 0, 12weeks
Psychiatric Symptoms
The psychiatric symptoms of schizophrenia were assessed in all enrolled patients using the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30-item clinician-rated scale yielding a total score ranging from 30 (least symptomatic) to 210 (symptomatic), where higher scores indicate more severe psychopathology.
Time frame: changes within 0, 4, 8,12weeks
Depressive Symptoms
The Hamilton Depression Scale-24 (HAMD-24) was used to assess the severity of depressive symptoms. Each item was scored on a scale of 0 (none) to 4 (severe); the total score ranged from 0 to 76, with higher scores indicating more severe depressive symptoms.
Time frame: changes within 0, 4, 8,12weeks
Anxiety Symptoms
The Hamilton Anxiety Scale (HAMA) is used to assess the severity of anxiety symptoms. Each item is scored on a scale of 0 (none) to 4 (very severe), with a total score range of 0-56. Higher scores indicate more severe anxiety symptoms.
Time frame: changes within 0, 4, 8, 12weeks
Changes of Fecal Macrogene Sequencing(FMS)
Total genomic DNA was extracted from patient fecal samples and subjected to quality control. Qualified DNA was then randomly fragmented to approximately 350 bp using a Covaris ultrasonic disruptor to generate libraries, which were quantified by Qubit and qPCR. Following library QC, pooled libraries were sequenced on an Illumina NovaSeq platform (PE150). Raw sequencing data underwent quality control, followed by assembly and gene prediction to construct a non-redundant gene set. Genes were then annotated for taxonomic and functional classification and abundance statistics were computed. Statistical analyses, including similarity clustering, group ordination, and differential comparisons, were performed on samples and sample groups.
Time frame: changes within 0, 12weeks
Changes in plasma levels of short-chain fatty acids.
Week 12 changes in plasma short-chain fatty acid levels from baseline.
Time frame: changes within 0, 12weeks
Changes in plasma bile acid levels
Week 12 changes in plasma bile acid from baseline.
Time frame: changes within 0, 12weeks
Changes in plasma tryptophan levels
Week 12 changes in plasma tryptophan from baseline.
Time frame: changes within 0, 12weeks
Changes of CRP
The concentration of C-reactive protein (CRP) is measured in venous blood. CRP is an acute-phase reactant protein synthesized by the liver, primarily functioning to recognize and clear pathogens or damaged cells. It plays a crucial role in inflammatory responses, infection surveillance, and disease monitoring.
Time frame: changes within 0, 4, 8, 12weeks
Changes in glycolipid levels
Glucose and lipid levels were measured at Weeks 0, 4, 8, and 12.
Time frame: Baseline, week 4, week 8 and week 12
Weight changes
Weight was measured at Weeks 0, 4, 8, and 12.
Time frame: Baseline, week4, week8, week12
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