Research report
BDNF promoter methylation and suicidal behavior in depressive patients

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Abstract

Introduction

Suicide is a major health problem, and depression is a major psychiatric cause of suicide. Suicide is influenced by the multifactorial interaction of many risk factors. Therefore, epigenetic research may lead to understandings that are applicable to suicide. This study investigated whether epigenetic changes are associated with suicidal behavior and evaluated the treatment outcome of suicidal ideation in depressive patients.

Methods

In 108 patients with major depression, the promoter methylation of the gene encoding brain-derived neurotrophic factor (BDNF) was measured. Sociodemographic and clinical characteristics including a history of previous depressive episodes, age at onset, duration of illnesses, family history of depression, and number of stressful life events as well as subjective perception of stress and assessment scales for depression (HAMD), anxiety (HAMA), function (SOFAS), disability (WHODAS-12), and quality of life (WHOQOL-BREF) were evaluated at baseline. Suicidal behavior was ascertained using a semistructured clinical interview with questions about severity and intent. Beck Scale for Suicide Ideation (BSS) was administered during 12 weeks of treatment with antidepressants.

Results

A higher BDNF promoter methylation status was significantly associated with a previous suicidal attempt history, suicidal ideation during treatment, and suicidal ideation at last evaluation as well as with higher BSS scores and poor treatment outcomes for suicidal ideation.

Limitations

Methylation status was investigated with limited area of the BDNF gene and sample size was relatively small.

Conclusions

BDNF methylation status could be a proxy marker for previous suicidal attempts and a clinical biomarker for poor treatment outcomes of suicidal ideation in depression.

Introduction

Suicide is a worldwide public health issue. Almost 1 million people die from suicide each year (World Health Organization, 2012). Additionally, suicide is one of the three leading causes of death among those in the most economically productive age group (15–44 years) (Patton et al., 2009). Given the magnitude of suicide as a public health problem, there is an urgent need to take action to prevent suicide. Assessment of suicide risk is the cornerstone of suicide management.

Suicidal behaviors are influenced by interacting biological, psychiatric, psychosocial, interpersonal, and cultural risk factors (Wasserman, 2001, Hawton and van Heeringen, 2009). Altered plasticity of neuronal pathways was recently proposed as an emerging hypothesis for suicide (Garcia, 2002, Duman et al., 2000). In this respect, alteration of the neurotrophin system, such as brain-derived neurotrophic factor (BDNF), has been considered as a risk indicator for suicide. BDNF is critical for the growth, survival, and differentiation of neuronal cells as well as neuronal plasticity (Huang and Reichardt, 2001). Recent studies found a decreased level of BDNF in the hippocampus and prefrontal cortex of suicidal patients (Dwivedi et al., 2003, Karege et al., 2005, Pandey et al., 2008). Plasma levels of BDNF are lower in suicidal depressive patients compared with nonsuicidal depressive patients (Kim et al., 2007a, Kim et al., 2007b). Moreover, a meta-analysis of the relationship between the functional BDNF marker Val66Met and suicidal behavior suggested a trend for MET-carrying genotypes and the Met allele associated with BDNF secretion that is dependent on reduced activity (Egan et al., 2003), conferring a risk for suicide (Zai et al., 2012).

BDNF expression is also regulated by epigenetic chromatin remodeling, including DNA methylation, histone acetylation, and other chemical alterations in gene promoter regions. In the central nervous system, DNA methylation of cytosines in cytosine–guanine (CpG) dinucleotides is regarded as the representative component of broader epigenetic modification at a given locus (Hochberg et al., 2010). It was reported that an increase in CpG methylation at promoter regions on the BDNF gene was correlated with decreased synthesis of BDNF in the neurons (Martinowich et al., 2003). Based on these findings, it can be postulated that BDNF DNA methylation is associated with suicidal behaviors. To our knowledge, only one epigenetic study has examined BDNF and its effect on gene transcription in completed suicide (Keller et al., 2010). The findings of this study showed that BDNF promoter/exon IV is frequently hypermethylated in Wernicke′s area in the postmortem brain of suicide patients irrespective of the genome-wide methylation level. This suggests that a gene-specific increase in DNA methylation could contribute to the down-regulation of BDNF expression in suicide patients. Although this epigenetic study is valuable, it has two limitations. First, the use of postmortem brain tissue resulted in challenges with respect to the time between exposure and outcome as well as possible epigenetic modification, such as acidosis, during death. Second, only the association of suicidal behavior with completed suicide was investigated. Suicidal behavior can be conceptualized as a complex process that can range from suicidal ideation to planning, attempting, and finally performing suicide.

Suicide is strongly associated with mental disorders, especially depressive disorder (Mann, 2002, Blackmore et al., 2008). Therefore, effective diagnosis and appropriate treatment of depression are crucial to the prevention of suicide. In this respect, investigation of the epigenetic risk factors of suicide in depressive patients who are at high risk of suicide might contribute to intensive and efficient suicide prevention. We investigated the association between BDNF promoter hypermethylation and suicidal behavior during 12 weeks of antidepressant treatment in depressive patients.

Section snippets

Subjects

Of patients with major depressive disorder receiving outpatient treatment at Chonnam National University Hospital Gwangju, Korea from January 2009 to July 2012, 108 who completed all 12-week follow-up evaluations participated in the study. Two psychiatrists (H.J.K. and J.M.K.) diagnosed all patients by applying the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association, 1994), with complementary information from the

Characteristics of the sample

The 108 patients with major depressive disorder who completed all 12-week evaluations formed the study sample. Sociodemographic and clinical characteristics of the 108 patients are summarized in the first column of Table 1. These characteristics are compared by the BDNF promoter methylation status in the second and fifth columns of Table 1. Higher BDNF promoter methylation was significantly associated with male gender and lower scores on the SOFAS and WHOQOL-BREF. Because we found no

Discussion

The principal finding of this study of major depressive patients was that greater BDNF methylation was significantly associated with a previous suicidal attempt history as well as with suicidal ideation during treatment and at the last evaluation in the 12-week antidepressant treatment. Furthermore, it predicted significantly less improvement in suicidal ideation during the treatment period independent of the change in depressive symptoms.

Most previous research on associations between suicide

Role of funding source

This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A120004). The Ministry of Health and Welfare had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. Prof. Stewart is part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Biomedical Research

Conflict of interest

Dr. J-M Kim has received research support from Ministry of Health & Welfare and National Research Foundation of Korea. Drs. Kang, Lee, S-Y Kim, S-W Kim, I-S Shin, H-R Kim, M-G Shin and Yoon report no additional financial or other relationships relevant to the subject of this article.

Acknowledgement

None

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