BER: Berberine as Adjuvant Treatment for Schizophrenia Patients

Sponsor

The University of Hong Kong (Other)

Overall Status

Completed

CT.gov ID

NCT02983188

Collaborator

Queen Mary Hospital, Hong Kong (Other), Kowloon Hospital, Hong Kong (Other), Castle Peak Hospital (Other), Zhejiang Provincial Tongde Hospital (Other)

113

Enrollment

Location

Arms

32.4

Actual Duration (Months)

3.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

One double-blind, randomized, placebo-controlled trial is designed to examine whether berberine added to current antipsychotic drugs could produce significantly greater efficacy in reducing atypical antipsychotic-induced metabolic syndrome. To achieve this objective, 120 patients with schizophrenia spectrum disorders (SSD) who have developed metabolic syndrome will be recruited and randomly assigned to receive additional treatment with placebo (n = 60) or berberine (n = 60, 0.6 g/day, 0.3 g, b.i.d.) for 12 weeks. The primary outcome is changes in net weight gain; other outcomes include body mass index (BMI), waist circumference (WC), blood pressure, triglycerides (TG), total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), fasting glucose, glycated haemoglobin (HbA1c).

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Schizophrenia Spectrum and Other Psychotic Disorders Metabolic Syndrome x	Drug: Berberine Drug: Placebos Drug: Antipsychotic Agents	Phase 2/Phase 3

Detailed Description

Schizophrenia is a severe mental illness that affects about 1% of the worldwide population. Most patients develop a chronic course with frequent relapses and exacerbation of symptoms and required to have long-term treatment. Although antipsychotic therapy is the mainstay of the management of schizophrenia, the treatment outcomes are often unsatisfactory, largely due to adverse drug reactions. Metabolic syndrome is a highly prevalent side effect incurred in antipsychotic therapy, with a prevalence of 35% in patients with severe mental illness in Hong Kong. No effective therapies are available in treating antipsychotic-induced metabolic syndrome, although some antidiabetic medications may have limited benefits in controlling weight gain and increased glucose level.

Berberine is a natural plant alkaloid isolated from the Chinese herb, Coptis chinensis (Huang-Lian), which is traditionally used for diarrhea caused by bacterial and viral infections in clinical practice. Several lines of evidence suggest that berberine has body weight-lowering, anti-diabetic, and anti-hyperlipidemic effects. One recent study has further shown that the addition of berberine significantly prevented olanzapine (OLZ)-Induced weight gain in rats and modulated the expression of multiple key genes that control energy expenditure.

In addition to the peripheral effects, berberine also broadly modulates brain biogenic amines and related receptors that are involved in the pathogenesis of antipsychotic-induced metabolic syndrome. This suggests that it may be suitable for the treatment of antipsychotic-induced metabolic disturbance.

Over the past decade, a number of studies have demonstrated comparable efficacy of berberine as mono- and combination therapy in reducing metabolic symptoms, without serious side effect. The efficacy of berberine also has been well confirmed in patients with gastrointestinal, liver, heart, and ovary disease as well as in renal-transplant recipients and healthy volunteers. It is well tolerated and only minor digestive reactions were observed, mainly nausea, diarrhea, constipation, abdominal distension and pain.

The results obtained from the clinical and animal studies of the group strongly suggest the promising effects of berberine against OLZ-induced weight gain, without changing pharmacokinetic and pharmacodynamics profile of OLZ at peripheral and central levels. This warrants further evaluation in a larger randomized controlled trial.

The working hypothesis of the proposed study is that berberine as an adjuvant can control weight gain and other metabolic symptoms associated with antipsychotic therapy. To test this hypothesis, a 12-week, double-blind, randomized, placebo-controlled trial will be conducted in patients with schizophrenia spectrum disorders (SSD) to determine whether berberine adjunctive treatment could limit weight gain and improve other anthropometric and metabolic measures in patients with SSD who have developed metabolic syndrome.

Study Design

Study Type:

Interventional

Actual Enrollment :

113 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Double-blind, Randomized, Placebo-controlled Trial of Berberine as an Adjuvant to Treat Antipsychotic-induced Metabolic Syndrome in Patients With Schizophrenia Spectrum Disorders

Actual Study Start Date :

Apr 25, 2018

Actual Primary Completion Date :

Dec 30, 2020

Actual Study Completion Date :

Jan 4, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Berberine Patients will receive berberine pills in additional to current atypical antipsychotic agents	Drug: Berberine Berberine tablets, 0.3g every time, two times daily Drug: Antipsychotic Agents Antipsychotic agents prescribed at the discretion of the patients' psychiatrists with respect to patients' conditions. Concomitant use of other psychotropic drugs, including antidepressants, anxiolytics, and mood stabilizers for mood disorders, benzodiazepines and non-benzodiazepines for insomnia, and anticholinergics for extrapyramidal symptoms, was allowed as usual. For those who were under anti-hyperlipidemic, antihypertensive and anti-diabetic treatment, they were allowed to continue their current medications throughout the study.
Placebo Comparator: Placebo Patients will receive placebos pills in additional to current atypical antipsychotic agents	Drug: Placebos Placebo tablets, 0.3g every time, two times daily Other Names: Placebo Drug: Antipsychotic Agents Antipsychotic agents prescribed at the discretion of the patients' psychiatrists with respect to patients' conditions. Concomitant use of other psychotropic drugs, including antidepressants, anxiolytics, and mood stabilizers for mood disorders, benzodiazepines and non-benzodiazepines for insomnia, and anticholinergics for extrapyramidal symptoms, was allowed as usual. For those who were under anti-hyperlipidemic, antihypertensive and anti-diabetic treatment, they were allowed to continue their current medications throughout the study.

Arm

Intervention/Treatment

Active Comparator: Berberine

Patients will receive berberine pills in additional to current atypical antipsychotic agents

Drug: Berberine

Berberine tablets, 0.3g every time, two times daily

Drug: Antipsychotic Agents

Antipsychotic agents prescribed at the discretion of the patients' psychiatrists with respect to patients' conditions. Concomitant use of other psychotropic drugs, including antidepressants, anxiolytics, and mood stabilizers for mood disorders, benzodiazepines and non-benzodiazepines for insomnia, and anticholinergics for extrapyramidal symptoms, was allowed as usual. For those who were under anti-hyperlipidemic, antihypertensive and anti-diabetic treatment, they were allowed to continue their current medications throughout the study.

Placebo Comparator: Placebo

Patients will receive placebos pills in additional to current atypical antipsychotic agents

Drug: Placebos

Placebo tablets, 0.3g every time, two times daily

Other Names:

Placebo

Drug: Antipsychotic Agents

Outcome Measures

Primary Outcome Measures

Changes in net weight gain [Baseline, 3 week, 6 week, 9 week, 12 week]
Assessments will be conducted at baseline and once every three weeks thereafter.

Secondary Outcome Measures

Changes in body mass index (BMI) [Baseline, 3 week, 6 week, 9 week, 12 week]
Assessments will be conducted at baseline and once every three weeks thereafter.
Changes in waist circumference (WC) [Baseline, 3 week, 6 week, 9 week, 12 week]
Assessments will be conducted at baseline and once every three weeks thereafter.
Changes in blood pressure [Baseline, 6 week, 12 week]
Assessments will be conducted at baseline and once every six weeks thereafter.
Changes in triglycerides (TG) [Baseline, 12 week]
Triglycerides (TG) level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in total cholesterol [Baseline, 12 week]
Total cholesterol level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in high-density lipoprotein (HDL) [Baseline, 12 week]
High-density lipoprotein (HDL) level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in low-density lipoprotein (LDL) [Baseline, 12 week]
Low-density lipoprotein (LDL) level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in fasting glucose [Baseline, 12 week]
Fasting glucose level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in glycated haemoglobin (HbA1c) [Baseline, 12 week]
Glycated haemoglobin (HbA1c) level will be determined from blood samples collected at baseline and 12 weeks. The collection of blood will be conducted between 08:00 and 09:00 after an overnight fast.
Changes in positive and Negative Syndrome Scale (PANSS) [Baseline, 6 week, 12 week]
The severity of psychotic symptoms will be also assessed using the Positive and Negative Syndrome Scale (PANSS). Assessments will be conducted at baseline and once every six weeks thereafter.
Changes in extrapyramidal Symptom Rating Scale (ESRS) [Baseline, 6 week, 12 week]
The Extrapyramidal Symptom Rating Scale (ESRS) will be used to evaluate antipsychotic-induced movement symptoms. Assessments will be conducted at baseline and once every six weeks thereafter.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

a primary diagnosis of SSD, including schizophrenia, schizoaffective disorder, schizophreniform disorder, and psychotic disorder not otherwise specified according to the Classification of Mental and Behavior Disorders (10th version);
have been under atypical antipsychotic treatment for at least 3 months and current conditions are stable, indicated by no difficulty to communicate with investigators and give informed consent; and
have developed metabolic syndrome according to the International Diabetes Federation criteria for metabolic syndrome in Asian/Chinese population.