Berberine as Adjuvant Treatment for Schizophrenia Patients

Schizophrenia Clinical Trial

— BER  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02983188
• Other study ID #: UW 17-020
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 25, 2018
• Est. completion date: January 4, 2021

Study information

• Verified date: January 2021
• Source: The University of Hong Kong
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: January 4, 2021
• Est. primary completion date: December 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Exclusion Criteria:

• serious comorbid gastrointestinal or other unstable medical conditions;

• have suicidal ideas or attempts or aggressive behavior;

• have a history of alcohol abuse in the past 3 months;

• have a history of drug abuse in past 3 months;

• had an investigational drug treatment within the previous 6 months; or

• pregnant and lactation.

Related Conditions & MeSH terms

• Mental Disorders
• Metabolic Syndrome
• Metabolic Syndrome x
• Psychotic Disorders
• Schizophrenia
• Schizophrenia Spectrum and Other Psychotic Disorders
• Syndrome

Intervention

Drug:
• Berberine
Berberine tablets, 0.3g every time, two times daily
• Placebos
Placebo tablets, 0.3g every time, two times daily
• 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.

Locations

Country	Name	City	State
Hong Kong	Castle Peak Hospital - The Department of General Adult Psychiatry	Tuen Mun

Sponsors (5)

Lead Sponsor	Collaborator
The University of Hong Kong	Castle Peak Hospital, Kowloon Hospital, Hong Kong, Queen Mary Hospital, Hong Kong, Zhejiang Provincial Tongde Hospital

Country where clinical trial is conducted

Hong Kong, 

References & Publications (14)

Bressington DT, Mui J, Cheung EF, Petch J, Clark AB, Gray R. The prevalence of metabolic syndrome amongst patients with severe mental illness in the community in Hong Kong--a cross sectional study. BMC Psychiatry. 2013 Mar 18;13:87. doi: 10.1186/1471-244X-13-87. — View Citation

Gharabawi GM, Bossie CA, Lasser RA, Turkoz I, Rodriguez S, Chouinard G. Abnormal Involuntary Movement Scale (AIMS) and Extrapyramidal Symptom Rating Scale (ESRS): cross-scale comparison in assessing tardive dyskinesia. Schizophr Res. 2005 Sep 15;77(2-3):119-28. — View Citation

Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes Care. 1997 Jul;20(7):1087-92. — View Citation

Harsing LG Jr, Lonart G, Vizi SE. Berbanes: search for novel alpha-2 adrenoceptor antagonists. Pol J Pharmacol Pharm. 1988 Nov-Dec;40(6):697-708. Review. — View Citation

Hu Y, Young AJ, Ehli EA, Nowotny D, Davies PS, Droke EA, Soundy TJ, Davies GE. Metformin and berberine prevent olanzapine-induced weight gain in rats. PLoS One. 2014 Mar 25;9(3):e93310. doi: 10.1371/journal.pone.0093310. eCollection 2014. — View Citation

Kane JM. Pharmacologic treatment of schizophrenia. Biol Psychiatry. 1999 Nov 15;46(10):1396-408. Review. — View Citation

Kawano M, Takagi R, Kaneko A, Matsushita S. Berberine is a dopamine D1- and D2-like receptor antagonist and ameliorates experimentally induced colitis by suppressing innate and adaptive immune responses. J Neuroimmunol. 2015 Dec 15;289:43-55. doi: 10.1016/j.jneuroim.2015.10.001. Epub 2015 Oct 14. — View Citation

Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. — View Citation

Kulkarni SK, Dhir A. On the mechanism of antidepressant-like action of berberine chloride. Eur J Pharmacol. 2008 Jul 28;589(1-3):163-72. doi: 10.1016/j.ejphar.2008.05.043. Epub 2008 Jun 3. — View Citation

Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G. Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol. 2015 Feb 23;161:69-81. doi: 10.1016/j.jep.2014.09.049. Epub 2014 Dec 10. Review. — View Citation

Peng WH, Wu CR, Chen CS, Chen CF, Leu ZC, Hsieh MT. Anxiolytic effect of berberine on exploratory activity of the mouse in two experimental anxiety models: interaction with drugs acting at 5-HT receptors. Life Sci. 2004 Oct 1;75(20):2451-62. — View Citation

Pirillo A, Catapano AL. Berberine, a plant alkaloid with lipid- and glucose-lowering properties: From in vitro evidence to clinical studies. Atherosclerosis. 2015 Dec;243(2):449-61. doi: 10.1016/j.atherosclerosis.2015.09.032. Epub 2015 Sep 30. Review. — View Citation

Salehi S, Filtz TM. Berberine possesses muscarinic agonist-like properties in cultured rodent cardiomyocytes. Pharmacol Res. 2011 Apr;63(4):335-40. doi: 10.1016/j.phrs.2010.12.004. Epub 2010 Dec 17. — View Citation

Wang HH, Cai M, Wang HN, Chen YC, Zhang RG, Wang Y, McAlonan GM, Bai YH, Wu WJ, Guo L, Zhang YH, Tan QR, Zhang ZJ. An assessor-blinded, randomized comparison of efficacy and tolerability of switching from olanzapine to ziprasidone and the combination of both in schizophrenia spectrum disorders. J Psychiatr Res. 2017 Feb;85:59-65. doi: 10.1016/j.jpsychires.2016.11.002. Epub 2016 Nov 4. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in net weight gain	Assessments will be conducted at baseline and once every three weeks thereafter.	Baseline, 3 week, 6 week, 9 week, 12 week
Secondary	Changes in body mass index (BMI)	Assessments will be conducted at baseline and once every three weeks thereafter.	Baseline, 3 week, 6 week, 9 week, 12 week
Secondary	Changes in waist circumference (WC)	Assessments will be conducted at baseline and once every three weeks thereafter.	Baseline, 3 week, 6 week, 9 week, 12 week
Secondary	Changes in blood pressure	Assessments will be conducted at baseline and once every six weeks thereafter.	Baseline, 6 week, 12 week
Secondary	Changes in triglycerides (TG)	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.	Baseline, 12 week
Secondary	Changes in total cholesterol	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.	Baseline, 12 week
Secondary	Changes in high-density lipoprotein (HDL)	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.	Baseline, 12 week
Secondary	Changes in low-density lipoprotein (LDL)	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.	Baseline, 12 week
Secondary	Changes in fasting glucose	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.	Baseline, 12 week
Secondary	Changes in glycated haemoglobin (HbA1c)	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.	Baseline, 12 week
Secondary	Changes in positive and Negative Syndrome Scale (PANSS)	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.	Baseline, 6 week, 12 week
Secondary	Changes in extrapyramidal Symptom Rating Scale (ESRS)	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.	Baseline, 6 week, 12 week