Berberine in Treating Negative Symptoms of Schizophrenia: Clinical Efficacy and Mechanisms

Overview

"Negative" symptoms are a major challenge for people with schizophrenia (SZ) and are a key reason why they struggle with everyday functioning. While current medications work well for the "positive" symptoms (like hallucinations or delusions), they aren't very effective at improving these "negative" symptoms, which include things like a lack of motivation or emotion. This study plans to conduct a large, randomized, double-blind, placebo-controlled trial to see if a compound called berberine (BBR) can safely and effectively improve these negative symptoms in SZ. The investigators will also examine how BBR affects gut bacteria, their byproducts in stool, and levels of general inflammation in the body. By looking at these different biological markers before and after BBR treatment, the investigators aim to understand how BBR influences negative symptoms and identify its main targets for improvement. This could lead to new ways to treat negative symptoms in schizophrenia in the future.

Detailed description

The investigators will enroll at least 120 patients with schizophrenia (SZ) meeting the inclusion criteria, randomized 1:1 to either the experimental group receiving antipsychotic medication plus berberine (BBR) or the control group receiving antipsychotic medication plus placebo, for a clinical intervention of 12 weeks. The primary outcome measures will be the change in the Negative Symptom Scale (SANS) total score and the log50 result of the skin nicotine test throughout the 12-week period. Secondary outcome measures include the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), the Global Assessment of Functioning (GAF), the Extrapyramidal Symptom Rating Scale, and cognitive assessments (MATRICS Consensus Cognitive Battery - MCCB). Other study indicators will involve the collection of sociodemographic and general clinical data. Blood and stool samples will be collected at pre-intervention (baseline), at 12 weeks of intervention, or at study termination. For safety assessments, participants' vital signs will be monitored at baseline, 4 weeks, 8 weeks, and 12 weeks, along with physical parameters (height, weight, blood pressure). Laboratory investigations will include complete blood count, comprehensive biochemical panel, and electrocardiogram (ECG). The Treatment Emergent Symptom Scale (TESS) will be used to assess drug side effects, and any adverse events will be recorded. Ultimately, the collected data will be used to investigate the clinical efficacy and safety of BBR on negative symptoms in SZ, its impact on the gut microbiota and their metabolic small molecules, its effect on peripheral blood inflammatory factors in SZ patients, and the longitudinal and cross-sectional correlations between gut microbiota and their metabolic small molecules, blood parameters, and negative symptoms in SZ patients under BBR treatment. This will facilitate the identification of early predictive biomarkers for BBR efficacy and key gut microbiota targets responsible for improving negative symptoms in SZ.

Interventions

• Drug Berberine
  Berberine 300 mg by mouth each dose# three times a day# plus any stable antipsychotic drug
• Drug Placebo
  The placebo were matched to Berberine in shape, smell and colour and tablets were sealed in identical bottles

Primary outcome measures

• Change in the total score of the Scale for Assessment of Negative Symptoms (SANS) [Time frame: Baseline, week4, week8, week12]
• log50 of the cutaneous niacin flush [Time frame: Baseline, week4, week8, week12]

Secondary outcome measures (7)

• Cognitive Function [Time frame: Baseline, week4, week8, week12]
• Psychiatric Symptoms [Time frame: Baseline, week4, week8, week12]
• Clinical efficacy [Time frame: Baseline, week4, week8, week12]
• Depressive Symptoms [Time frame: Baseline, week4, week8, week12]
• Functional capacity [Time frame: Baseline, week4, week8, week12]
• Changes of CRP [Time frame: Baseline, week12]
• Fecal 16S rRNA sequencing [Time frame: Baseline, week12]

Eligibility criteria

Inclusion criteria

• Subjects met the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The diagnosis was confirmed by two psychiatrists who interviewed enrolled patients using the Structured Clinical Interview for DSM-5 Disorders, Clinician Version (SCID-5-CV).
• Age between 18 and 60 years, inclusive.
• Gender: Not restricted.
• Ethnicity: Han Chinese.
• Subjects were receiving a stable dose of antipsychotic medication for at least 3 months prior to enrollment and had no dose adjustments in the month preceding enrollment.
• Subjects exhibited significant negative symptoms, defined as: A total score of ≤ 70 on the Positive and Negative Syndrome Scale (PANSS). Scores of ≤ 4 on the PANSS items for delusions, conceptual disorganization, hallucinations, and excitement. A score > 0 on the Negative Symptom Subscale-Positive Symptom Subscale.
• The patient or their legal representative provided informed consent and signed the informed consent form agreeing to participate in the study.

Exclusion criteria

• Individuals meeting DSM-5 criteria for other psychiatric disorders.
• Current severe neurological disease, uncontrolled metabolic disease, infectious disease, or autoimmune disease.
• History of gastrointestinal surgery.
• Use of antibiotics, other immunomodulatory agents, hormones, microecological agents, or probiotic medications within the past 1 month.
• Allergy to BBR (if "BBR" is a known abbreviation, otherwise it should be spelled out or defined).
• Receipt of physical therapies such as electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) within the past 1 month.
• Individuals with hemolytic anemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Pregnant or lactating females.
• Any factor that would prevent the participant from providing informed consent or participating in the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Tianjin Anding Hospital — Tianjin

Identifiers

NCT: NCT07356765 · BBR-SCH-NS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗