Epigenetic Regulation of BDNF in Major Depression

Epigenetic Regulation of Brain-Derived Neurotropic Factor (BDNF) in Patients With Major Depression

The investigators will (1) detect the associations between brain-derived neurotrophic factor (BDNF) DNA methylation, histone modification, depressive symptoms, suicidal behavior and antidepressant responses in major depressive disorder (MDD) patients, (2) check the correlation between blood BDNF protein and RNA and BDNF rs6265 gene, and (3) discuss the possible mechanisms of epigenetic regulation of BDNF in Taiwanese major depressive patients.

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder

Detailed Description

Brain-derived neurotrophic factor (BDNF) had been chosen as a candidate gene for a development of major depressive disorder (MDD). BDNF had been reported to have an important role on neuronal plasticity, axonal growth and connectivity, and participating in the local response to various types of neuronal stressors. BDNF also influences the differentiation of neurons.

In the past studies, the investigators had found that major depressive women had lower serum BDNF protein levels than healthy controls, and their BDNF levels became significantly increased after antidepressant treatments. In addition, some authors had found that reduced expression of BDNF was noted in postmortem brain of completed suicide subjects. Suicidal major depressive patients also had lower plasma BDNF levels than non-suicidal major depressive patients. These findings suggested that BDNF might play an important role in the suicidal behavior.

However, in past studies, the results did not fully explain why major depressive patients with same genotypes had different clinical expression, including the severity of depression, with/without suicide, and the treatment response. Recently, some papers found that there were relationships between epigenetic regulation, including DNA methylation and histone modification, and psychopathology of major depression. Therefore, we try to investigate the relationships between epigenetic regulation of BDNF and major depression.

• Study Type: Observational
• Enrollment (Actual): 110

Contacts and Locations

Study Locations

• Taiwan
  • Kaohsiung, Taiwan, 833
    • Department of Psychiatry, Chang Gung Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This 2-year study will be conducted in our clinical setting. By a semi-structured interview for DSM-IV criteria, a total of 160 subjectes (80 healthy controls and 80 patients with major depression) will be recruited in this study. In the first year (recruiting 40 healthy controls and 40 patients with major depression), the data of BDNF DNA methylation in all subjects will be collected. In the second year (recruiting another 40 healthy controls and 40 patients with major depression), the data of BDNF histone modification in all subjects will be collected and the mechanism of epigenetic regulation of BDNF in major depression will be discussed.

Description

Inclusion Criteria:

The clinical screening and assessment in patients with major depression：

1. 40 major depression will be recruited in psychiatric inpatients according to DSM-IV criteria by a semi-structured interview. The assessment will be done by two senior psychiatrists. The intra-rater and inter-rater reliability will be done before this project started.
2. The patients had the ability to complete the written inform consent.
3. The choice of antidepressant drugs depended on the need of patients in natural treatment procedure. They included selective serotonin reuptake inhibitors (SSRI), eg. fluoxetine or paroxetine.
4. The 17-item Hamilton Depression Rating Scale (HAM-D) was used to assess severity of depression. The minimum baseline score of the 17-item HAM-D was 18.

Exclusion Criteria:

1. The patients had systemic diseases, including metabolic, heart, and liver diseases。
2. The patients had received any drugs before entering this protocol.
3. The patients were heavy smokers or dependent on alcohol.
4. The use of secondary generation anti-psychotic drugs and mood stabilizers.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Healthy subjects
Major depressive patients

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls	averaged percentage of methylation at each CpG site listed	2 years
Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls	Chromatin immunoprecipitation (ChIP) was used to measure histone modification. The unit of our given machine is relative quantification, and a higher value indicated increased histone modification. The detailed method could be found in: Huebert DJ, Kamal M, O'Donovan A, Bernstein BE: Genome-wide analysis of histone modifications by ChIP-on-chip. Methods 2006; 40: 365-369.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BDNF Levels of MDD Patients Before and After Treatment and Healthy Controls	Serum BDNF levels were measured. MDD patients received antidepressant treatment, a standard biological management. Nothing novel (such as experimental drugs or management) is introduced in the treatment, so the research design is observational (of standard treatment). The choice of antidepressant drugs depended on the need of patients in natural treatment procedure. They included selective serotonin reuptake inhibitors (SSRI), eg. fluoxetine or paroxetine.	2 years

Collaborators and Investigators

• Sponsor: Chang Gung Memorial Hospital
• Investigators: Principal Investigator: Tiao-Lai Huang, M.D., Chang-Gung Memorial Hospital, Kaohsiung

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: August 11, 2010
• First Submitted That Met QC Criteria: August 13, 2010
• First Posted (Estimate): August 16, 2010

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: July 24, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: Major depression; BDNF; DNA methylation; Histone modification
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: NSC99-2628-B-182-002-MY2