BDNF promoter methylation and suicidal behavior in depressive patients

Kang, Hee‐Ju; Kim, Jae-Min; Lee, Ju‐Yeon; Kim, Seon‐Young; Bae, Kyung‐Yeol; Kim, Sung‐Wan; Shin, Il‐Seon; Kim, Hye‐Ran; Shin, Myung‐Geun; Yoon, Jin‐Sang

doi:10.1016/j.jad.2013.08.001

Cited by 199 publications

(120 citation statements)

References 55 publications

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“…Further corroborating the involvement of these mechanisms in depression neurobiology, increased DNMT expression (23) and increased DNA methylation in specific genomic loci have been reported in the brain of depressed individuals (24)(25)(26)(27)(28). Moreover, our research group has recently shown that decreasing DNA methylation by means of pharmacological treatment with 5-AzaD, a DNMT inhibitor (DNMTi) induces antidepressant-like effects in different preclinical models (29).…”

Section: Introductionsupporting

confidence: 62%

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Sales

Joca

2015

Acta Neuropsychiatr.

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Sales AJ, Joca SRL. Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels.Objective: Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressantlike effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated. Methods: Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants). Results: Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/ kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT. Conclusion: These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression. Significant outcomesThe results as given below further support a possible antidepressant-like profile for drugs that inhibit DNA methyltransferases.• Systemic administration of different classes of DNA methyltransferase inhibitors induces antidepressantlike effects.• The association of subeffective doses of DNA methyltransferase inhibitors with subeffective doses of conventional antidepressant drugs induces antidepressant-like effects.

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Section: Introductionsupporting

confidence: 62%

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Sales

Joca

2015

Acta Neuropsychiatr.

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“…However, despite this between-species discordance, it is striking that BDNF DNA methylation differences in humans that may serve as a predictor of behavioral vulnerability could be detected as early as at birth. In addition to promoter IV (34,43), other BDNF gene regions such as promoters I (13,14) and VI (10) can also be sensitive to epigenetic effects of early-life adversity and may confer psychiatric risk. Therefore, although our study provides a proof of principle that BDNF DNA methylation in the blood may predict behavioral vulnerability, future more comprehensive epigenetic analyses of the BDNF gene in response to other early-life exposures and in psychiatric patients are warranted.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

357

244

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Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.epigenetics | biomarker | BDNF | bisphenol A | early life

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“…Hypermethylation of the BDNF gene promoter was reported in Wernicke's area (Keller et al 2010) and peripheral blood (Kang et al 2013a) of subjects who com-mitted suicide. The CpG island of the BDNF gene upstream of exon I was found as a possible diagnostic biomarker of MDD (Fuchikami et al 2011), and higher methylation status of the BDNF promoter was associated with MDD (D 'Addario et al 2013;Carlberg et al 2014;Dell'Osso et al 2014;Januar et al 2015) and post-stroke depression ).…”

Section: Gene Methylationmentioning

confidence: 99%

“…The effect of antidepressant drugs on BDNF promoter methylation levels is still scarcely investigated and available data suggested a possible higher methylation status in treated versus untreated patients (Carlberg et al 2014), but an enhanced reduction in suicidal ideation after treatment in subjects with low methylation levels (Kang et al 2013a). Methylation levels may also be reduced in patients receiving combination treatments of antidepressants plus mood stabilisers compared to patients on antidepressant drugs alone (D'Addario et al 2013).…”

Section: Gene Methylationmentioning

confidence: 99%

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Fabbri

Hosák

Mößner

et al. 2016

The World Journal of Biological Psychiatry

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Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under-or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in anti-depressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-a receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

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BDNF promoter methylation and suicidal behavior in depressive patients

Cited by 199 publications

References 55 publications

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

DNA methylation of BDNF as a biomarker of early-life adversity

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

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