The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders

Figures & data

Table 1 Epigenetic Changes in Animal Models of Anxiety Disorders

Tissue	Epigenetic Change	References
Rat developing hippocampus, amygdala	DNA methylation changes	[^Citation23]
Rat basolateral amygdala	Hypermethylation in GAD1 gene	[^Citation24]
Mouse basolateral amygdal	Hypermethylation of GAD1 gene	[^Citation25]
Rat hippocampus	Hypermethylation of Nr3c1 gene	[^Citation26]
Rat amygdala	Hypermethylation of developing brain	[^Citation27]
Rat amygdala	BDNF gene hypermethylation	[^Citation28]
Rat amygdala	Aberrant HDAC2-mediated histone modifications	[^Citation29]
Rat hippocampus	Differential histone acetylation and methylation	[^Citation30]
Rat hippocampus	H3 histone acetylation; modulation of methyl-CpG-binding	[^Citation31]
Mouse cerebral cortex	Down-regulation of HDAC2 associated with BDNF gene	[^Citation32]
Rat hippocampus	Reduces H3K14 acetylation due to prenatal dexamethasone	[^Citation33]
Rat hippocampus	Decreases H3K9 and H4K12 acetylation due to social isolation	[^Citation34]
Rat PFC	Reduces H3/H4 acetylation after extinction training	[^Citation35]
Rat nucleus accumbens	Inhibition of G9a/GLP HMT	[^Citation36]
Mouse medulla oblongata	Histone modifications of genes affecting neurodevelopment and emotionality	[^Citation37]
Mouse hippocampus and amygdala	Dysregulation of miR-132/212	[^Citation38]
Rat amygdala	Over-expression of miR-101a and its target Ezh2	[^Citation39]
Rat PFC and hippocampus	Changes in miRNA-135a and miRNA-16	[^Citation40]
Rat amygdala and PFC	Microbial regulation of miRNA expression	[^Citation41]
Mouse PFC	lncRNA Gomafu associated with anxiety	[^Citation42]

Abbreviations: BDNF, brain-derived neurotrophic factor; GAD1, glutamic acid decarboxylase1; HDACi, histone deacetylase inhibitor; HMT, histone methyltransferase; lncRNA, long non-coding RNA; miRNA, microRNA; PFC, prefrontal cortex.

Table 2 Epigenetic Changes in Human Peripheral Cells in Anxiety Disorders

Tissue	Epigenetic Change	References
Whole blood	183 differentially methylated loci	[^Citation46]
Blood cells	GAD1 gene hypomethylation	[^Citation47]
Buccal cells	Hypomethylation of SERT gene	[^Citation48]
Whole blood	MAOA gene hypomethylation	[^Citation49]
Whole blood	Several CpG sites hypomethylated	[^Citation50]
Saliva cells	Hypomethylation of MAOA gene	[^Citation51]
Whole blood	Hypomethylation of oxytocin receptor gene	[^Citation52]
Saliva	Hypermethylation in AA genotype of OXTR rs53576	[^Citation53]
PBMCs	Global DNA hypermethylation	[^Citation54]
Leukocytes	Glucocorticod receptor gene hypermethylation	[^Citation55]
Whole blood	Hypermethylation of FOXP3 promoter	[^Citation56]
Whole blood	Hypermethylation of HECA gene in females	[^Citation57]
Saliva cells	Neurodevelopmental pathway gene hypermethylation	[^Citation58]
Whole blood	Hypermethylation of STK32B promoter	[^Citation59]
Peripheral venous blood	Hypermethylation of BDNF gene	[^Citation60]
Peripheral blood	Hypermethylation of NR3C1 gene	[^Citation61]
Saliva	Hypermethylation of NR3C1 gene	[^Citation62]
Peripheral blood	Hypermethylation of FKBP5 gene	[^Citation63]
Saliva	Hypermethylation of BDNF and oxytocin receptor genes	[^Citation64]
Whole blood	hsa-miR-579-3P upregulates fear and anxiety	[^Citation65]
PBMCs	Increases miR-663 expression	[^Citation66]
Sperm	Reduces levels of miRNAs 449 and 34	[^Citation67]
Peripheral blood	Moderating effect of miRNAs on workplace bullying	[^Citation68]

Abbreviations: GAD1, glutamic acid decarboxylase1; miRNA, microRNA; PBMCs, peripheral blood mononuclear cells.

Table 3 Preclinical Trials of Epigenetic Drugs in Anxiety Disorders

Drug	Class	HDAC Class Target of Drugs	Effect	References
MS-275	HDACi	I, III	Reduces anxiety in S1 mice	[^Citation82]
TSA	HDACi	I, II	Has anxiolytic effects in rats	[^Citation83]
TSA	HDACi	I, II	Reduces anxiety-like behavior in rats	[^Citation84]
TSA, SAHA	HDACi	I, II,IV	Reduces anxiety-like behavior in Fischer rats	[^Citation85]
SAHA	HDACi	I, II,IV	Reduces stress-related behavior in rats	[^Citation86]
MS-275	HDACi	I,III	Rescues enhanced innate anxiety in mice	[^Citation87]
TSA	HDACi	I,II	Reverses anxiety due to maternal binge drinking	[^Citation88]
SB,VA	HDACi	I,IIa	Reduces anxiety in mice	[^Citation89]
SAHA	HDACi	I,II, IV	Reduces corticosterone-induced stress in mice	[^Citation90]
Lactate	Natural drug	–	Promotes resilience to stress in C57BL/6 mice	[^Citation91]

Abbreviations: HDACi, histone deacetylase inhibitor; SAHA, suberoylanilide hydroxamic acid; SB, sodium butyrate; TSA, trichostatin A; VA, valproic acid.

Table 4 Clinical Trials of Epigenetic Drugs in Anxiety Disorders

Drug	Class	HDAC Class Target of Drugs	Finding	References
Valproate	HDACi	I, IIa	Decreases panic disorder	[^Citation93]
Valproate	HDACi	I, IIa	Ameliorates panic disorder	[^Citation94]
Valproate	HDACi	I, IIa	Decreases panic disorder	[^Citation95]
Valproate	HDACi	I, IIa	Decreases social anxiety	[^Citation96]
Valproate	HDACi	I, IIa	Reduces anxiety	[^Citation97]
Valproate	HDACi	I,IIa	Decreases anxiety in healthy subjects	[^Citation98]

Abbreviation: HDACi, histone deacetylase inhibitor.

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