Elsevier

Brain Research

Volume 1415, 30 September 2011, Pages 119-126
Brain Research

Research Report
The brain-derived neurotrophic factor is associated with alcohol dependence-related depression and antidepressant response

https://doi.org/10.1016/j.brainres.2011.08.005Get rights and content

Abstract

Brain-derived neurotrophic factor (BDNF) plays an essential role in neuronal survival, proliferation, and synaptic remodeling and modulates the function of many other neurotransmitters. Additionally, it likely underlies neurodegenerative and psychiatric disorders, including alcohol dependence-related depression (AD-D). Here, we investigated the possible association between three single nucleotide polymorphisms (SNPs) of the BDNF gene (rs13306221, rs6265, rs16917204) and AD-D. Of 548 patients with alcohol dependence (AD), 166 had AD-D and 312 healthy controls. Response to 8-week sertraline treatment was also assessed. The frequency of the A allele of rs6265 (Val66Met) was significantly higher in AD-D patients than in the healthy controls (p = 0.009 after Bonferroni correction). The analysis revealed a strong association between the rs6265 genotype distribution and AD-D (p = 0.005 after Bonferroni correction), and the A allele of rs6265 was significantly overrepresented in AD-D patients compared to AD without depression (AD-nD) patients (p = 0.001 after Bonferroni correction). Additionally, carriers of the A allele of rs6265 responded better to sertraline treatment (p = 0.001). Our results suggested a novel association between BDNF rs6265 and AD-D. These findings might lead to earlier detection of AD-D, perhaps providing better tools for clinical care of these patients in the future.

Highlights

► Genotypes at rs6265 were associated with dependence-related depression (AD-D). ► The A allele of rs6265 was significantly more common among AD-D patients than in the AD-nD. ► Carriers of the A allele of rs6265 responded better to sertraline treatment.

Introduction

Alcohol dependence (AD) is a complex neuropsychiatric disorder that is characterized by recurring cycles of chronic drinking, abstinence and relapse, and behavioral impairments. A number of epidemiological studies have shown that AD is frequently comorbid with major depression (MD) (Gilman and Abraham, 2001, Grant and Harford, 1995, Grant et al., 2009, Hasin and Grant, 2002, Patten and Charney, 1998, Schuckit et al., 1997). Both AD and MD are clinically and etiologically heterogeneous conditions with moderate to high heritability (37-70%) (Heath et al., 2002, Kendler et al., 2006). Twin studies support a common genetic liability for the two disorders (Prescott et al., 2000).

Brain-derived neurotrophic factor (BDNF), a growth factor enriched in brain, is altered by commonly abused drugs, such as alcohol. BDNF regulates the phosphatidylinositol 3′-kinase (PI3K), mitogen-activated protein kinase (MAPK), phospholipase Cγ (PLCγ) and nuclear factor kappa B (NFκB) signaling pathways. These pathways influence a range of cellular functions, including neuronal survival, growth, differentiation, and structure (Russo et al., 2009) and are involved in neuroadaptive changes in the dopaminergic and glutamate systems that underlie psychostimulant abuse and dependence (Corominas et al., 2007, Grimm et al., 2003). Thus, BDNF is a candidate locus for association with drug (Ghitza et al., 2010) and alcohol (Janak et al., 2006, Yoon et al., 2006) dependence.

Animal studies and clinical observations suggest that BDNF is involved in the etiology of MD. For example, animal models of depression displayed decreased BDNF levels during hippocampal formation (Angelucci et al., 2005). Decreased BDNF mRNA levels have been reported in the hippocampus and anterior cingulate cortex in MD patients (Dwivedi et al., 2003). Furthermore, post-mortem studies have documented decreased BDNF level in the brains of MD patients (Chen et al., 2001). Serum BDNF levels might be relevant in MD patients (Lee and Kim, 2009). Antidepressant treatment normalizes BDNF expression in rats (Dias et al., 2003) and may even induce BDNF expression in human subjects (Chen et al., 2001).

The BDNF single nucleotide polymorphism (SNP) rs6265 (G196A, Val66Met) adversely affects prefrontal and hippocampal anatomy and function (Frey et al., 2007). Some evidence suggests that rs6265 may affect the intracellular trafficking and activity-dependent secretion of BDNF (Egan et al., 2003), even in neuronal cell cultures where BDNF is secreted in depolarization-induced manner (Chen et al., 2004). Association of rs6265 with depression was reported in some (Kocabas et al., 2011, Ozan et al., 2010, Verhagen et al., 2010) but not all (Hong et al., 2003, Tsai et al., 2003) studies. Other BDNF SNPs have been found outside of the coding region. The putative promoter region contains a SNP rs13306221 (G-712A, 712 bp upstream of the first exon) associated with substance dependence (Zhang et al., 2006) and MD patients (Sun et al., 2011). In the 3′UTR, rs16917204 (G11757C) has also been associated with bipolar affective disorder and Alzheimer's disease-related depression (Borroni et al., 2009, Sklar et al., 2002).

The aims of this study were to investigate if these three known BDNF SNPs determine susceptibility for alcohol dependence-related depression (AD-D) and to explore the relationship between these SNPs and treatment response to selective serotonin reuptake inhibitors (SSRIs).

Section snippets

Results

We compared demographic and clinical characteristics of the participants including age, marital status, education years, family history, age of first intake, age of regular drinking, duration of dependence years, average alcohol consumption, Michigan Alcoholism Screening Test score, Alcohol Use Questionnaire score, numbers of suicide attempt and Hamilton Depression Rating Scale score. The results are presented in Table 1. A higher number of suicide attempts, and HAMD (Hamilton Rating Scale for

Discussion

MD is one of the most frequent neuropsychiatric comorbidities of AD (Grant et al., 2004, Kuo et al., 2010). AD patients with depressive symptoms reduces the chance for treatment success, increases risk of relapse, inhibits long-term social and functional adjustment, and increases the chance of dire outcomes, such as suicide (Preuss et al., 2002). Of the 548 AD participants in this study, 166 (30.29%) had prominent depressive symptoms, consistent with previous estimates of about one-third of AD

Subjects

The study was conducted in accordance with local clinical research regulations. All participants are unrelated Han Chinese. Written informed consent was obtained from each participant. The study was approved by the Ethical Committee of Xi'an, China. Three-hundred and seventy-eight AD male patients were consecutively recruited from Xi'an Mental Health Center from 2006 to 2011. This study was limited to males for two reasons. First, AD is more common in males. For example, Su et al. (2003) found

Acknowledgments

We thank the patients and families for participation and the medical staff for collecting specimens. This work was sponsored by the National Natural Science Foundation of China (NNSFC) (Grant No. 30930093).

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      A polymorphism, rs6265 or Val66Met, has been associated with more severe depressive illness.51 However, the findings that these same patients do less well with antidepressants has not be readily replicated.52,53 Potassium channel, KCNK2, codes for a potassium channel that leaks potassium out of the cell to control resting membrane potential (http://www.ncbi.nlm.nih.gov/gene/3776).

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    Sources of support: This research was supported by National Natural Science Foundation (30930093).

    1

    The first two authors contributed equally to this study.

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