Major Depressive Disorder
Conditions
Keywords
Major depression, BDNF, DNA methylation, Histone modification
Brief summary
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.
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.
Interventions
None listed
Sponsors
Chang Gung Memorial Hospital
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | 2 years | averaged percentage of methylation at each CpG site listed |
| Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | 2 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BDNF Levels of MDD Patients Before and After Treatment and Healthy Controls | 2 years | 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. |
Countries
Taiwan
Participant flow
Recruitment details
From August 1st, 2000 to July 31st, 2012, major depressive disorder patients were recruited from Kaohsiung Chang Gung Memorial Hospital, a tertiary medical center.
Participants by arm
| Arm | Count |
|---|---|
| Major Depressive Patients | 48 |
| Healthy Subjects | 62 |
| Total | 110 |
Baseline characteristics
| Characteristic | Healthy Subjects | Major Depressive Patients | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 48 Participants | 110 Participants |
| Age, Continuous | 30.18 years STANDARD_DEVIATION 5.6 | 42.44 years STANDARD_DEVIATION 12.09 | 35.53 years STANDARD_DEVIATION 10.81 |
| Region of Enrollment Taiwan | 62 participants | 48 participants | 110 participants |
| Sex: Female, Male Female | 38 Participants | 32 Participants | 70 Participants |
| Sex: Female, Male Male | 24 Participants | 16 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 48 | 0 / 62 |
| serious Total, serious adverse events | 0 / 48 | 0 / 62 |
Outcome results
Primary
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
Time frame: 2 years
Population: Only 39 out of the 48 MDD patients provided enough blood sample for this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 24 | 92 percent | Standard Deviation 5 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 57 | 75 percent | Standard Deviation 5.4 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 80 | 65 percent | Standard Deviation 7.6 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 134 | 87 percent | Standard Deviation 4.2 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 140 | 49 percent | Standard Deviation 23.2 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 177 | 93 percent | Standard Deviation 3.9 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 203 | 88 percent | Standard Deviation 5.2 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 217 | 61 percent | Standard Deviation 8 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 324 | 95 percent | Standard Deviation 4.8 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 327 | 88 percent | Standard Deviation 4.7 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 345 | 97 percent | Standard Deviation 5 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 348 | 90 percent | Standard Deviation 6 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 362 | 89 percent | Standard Deviation 4.4 |
| Major Depressive Patients | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 391 | 84 percent | Standard Deviation 4.8 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 345 | 98 percent | Standard Deviation 3 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 24 | 92 percent | Standard Deviation 3 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 217 | 51 percent | Standard Deviation 11.4 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 57 | 75 percent | Standard Deviation 4.8 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 362 | 91 percent | Standard Deviation 2 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 80 | 63 percent | Standard Deviation 6.2 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 324 | 95 percent | Standard Deviation 2.4 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 134 | 86 percent | Standard Deviation 3.8 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 348 | 91 percent | Standard Deviation 4.1 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 140 | 41 percent | Standard Deviation 24.7 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 327 | 90 percent | Standard Deviation 2.5 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 177 | 94 percent | Standard Deviation 2.3 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 391 | 85 percent | Standard Deviation 3.1 |
| Healthy Subjects | Brain-derived Neurotrophic Factor (BDNF) DNA Methylation of Major Depressive Disorder (MDD) Patients and Healthy Controls | CpG site 203 | 90 percent | Standard Deviation 2.9 |
p-value: <0.05t-test, 2 sided
Primary
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.
Time frame: 2 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H4 | 1.7433 relative quantification | Standard Deviation 2.66175 |
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H3 | 1.6356 relative quantification | Standard Deviation 2.33692 |
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H3 | 3.8960 relative quantification | Standard Deviation 1.9445 |
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H3 | 3.5610 relative quantification | Standard Deviation 2.79865 |
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H4 | 2.2795 relative quantification | Standard Deviation 2.66175 |
| Major Depressive Patients | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H4 | 2.6346 relative quantification | Standard Deviation 2.66175 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H4 | .4676 relative quantification | Standard Deviation 0.54543 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H3 | .2564 relative quantification | Standard Deviation 0.36703 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H4 | .3784 relative quantification | Standard Deviation 0.54543 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H4 | .2105 relative quantification | Standard Deviation 0.30502 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H3 | .3124 relative quantification | Standard Deviation 0.53231 |
| Healthy Subjects | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H3 | .4059 relative quantification | Standard Deviation 0.43157 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H4 | .2540 relative quantification | Standard Deviation 0.5305 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H3 | .4321 relative quantification | Standard Deviation 0.32039 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor I acetyl-H4 | .4659 relative quantification | Standard Deviation 0.62056 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H3 | .4303 relative quantification | Standard Deviation 0.70365 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor IV acetyl-H4 | .4988 relative quantification | Standard Deviation 0.62056 |
| Major Depressive Patients After Treatment | Histone Modification of MDD Patients Before and After Treatment and With Healthy Controls | BDNF promotor X acetyl-H3 | .3640 relative quantification | Standard Deviation 0.34533 |
p-value: <0.05t-test, 2 sided
Secondary
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.
Time frame: 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Major Depressive Patients | BDNF Levels of MDD Patients Before and After Treatment and Healthy Controls | 7.9386 ng/ml | Standard Deviation 3.244 |
| Healthy Subjects | BDNF Levels of MDD Patients Before and After Treatment and Healthy Controls | 5.6014 ng/ml | Standard Deviation 4.46981 |
| Major Depressive Patients After Treatment | BDNF Levels of MDD Patients Before and After Treatment and Healthy Controls | 6.2803 ng/ml | Standard Deviation 5.58535 |
p-value: <0.05t-test, 2 sided