Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine

Gassó, Patricia; Rodríguez, Natàlia; Blázquez, Alicia; Monteagudo, Ana; Boloc, Daniel; Plana, María Teresa; Lafuente, Amàlia; Lázaro, Luisa; Arnáiz, Joan Albert; Mas, Sergi

doi:10.1016/j.pnpbp.2016.12.003

Cited by 39 publications

(29 citation statements)

References 52 publications

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“…This may reveal one of the mechanisms of action of escitalopram in treating depressive symptoms, potentially decreasing expression of these serotonin transporters and potentiating serotonin in the synapse. Gassó et al 2017 found that lower pre-treatment average HTR1B promoter methylation is associated with increased patient functioning after fluoxetine treatment [78]. Their hypothesis was that patients with lower pre-treatment methylation had high HTR1B expression and lower serotonin, so they were able to gain more clinical improvement from fluoxetine than those with lower initial HTR1B expression.…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-four articles met full inclusion criteria. The articles described the relationship between antidepressant administration and DNA methylation in the following genes: Brain-derived neurotrophic factor (BDNF) [49][50][51][52][53][54][55][57][58][59] (Table 1), monoamine oxidase A (MAOA) [64,65] (Table 2), 5-hydroxytryptamine (serotonin) transporter (SLC6A4) [67][68][69][70][71] (Table 3), norepinephrine transporter (SLC6A2) [72] (Table 3), 5-hydroxytryptamine transporters 1A and 1B (5HTR1A/1B) [77,78] (Table 4), interleukin-6 (IL6) [82], and interleukin-11 (IL11) [85] (Table 5). Two papers reported antidepressant effects on global DNA methylation [86,88] (Table 6).…”

Section: Methodsmentioning

confidence: 99%

“…Gassó et al 2017 studied HTR1B promoter methylation in eighty-three child and adolescent subjects treated for 12 weeks with fluoxetine for MDD (n = 57), obsessive compulsive disorder (n = 16), and generalized anxiety disorder (n = 10) [78]. Lower HTR1B promoter methylation after treatment was associated with increased psychosocial functioning [78].…”

Section: Htr1a/1bmentioning

confidence: 99%

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The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review

Webb

Phillips

et al. 2020

IJMS

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Major depressive disorder (MDD) is the leading cause of disability worldwide and is associated with high rates of suicide and medical comorbidities. Current antidepressant medications are suboptimal, as most MDD patients fail to achieve complete remission from symptoms. At present, clinicians are unable to predict which antidepressant is most effective for a particular patient, exposing patients to multiple medication trials and side effects. Since MDD’s etiology includes interactions between genes and environment, the epigenome is of interest for predictive utility and treatment monitoring. Epigenetic mechanisms of antidepressant medications are incompletely understood. Differences in epigenetic profiles may impact treatment response. A systematic literature search yielded 24 studies reporting the interaction between antidepressants and eight genes (BDNF, MAOA, SLC6A2, SLC6A4, HTR1A, HTR1B, IL6, IL11) and whole genome methylation. Methylation of certain sites within BDNF, SLC6A4, HTR1A, HTR1B, IL11, and the whole genome was predictive of antidepressant response. Comparing DNA methylation in patients during depressive episodes, during treatment, in remission, and after antidepressant cessation would help clarify the influence of antidepressant medications on DNA methylation. Individuals’ unique methylation profiles may be used clinically for personalization of antidepressant choice in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Htr1a/1bmentioning

confidence: 99%

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The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review

Webb

Phillips

et al. 2020

IJMS

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“…A similar decrease of 5-HT 1B receptor binding has also been found in patients with MDD (Murrough et al, 2011b). Moreover, a polymorphism of the HTR1B gene has been associated with the antidepressant effect of SSRIs (Villafuerte et al, 2009), and the methylation level of the HTR1B gene is negatively correlated with clinical improvement after fluoxetine (Gasso et al, 2016). As shown in this study, 5-HT 1B acts to decrease glutamate release from cortical and thalamic inputs onto BLA projection neurons.…”

Section: Discussionmentioning

confidence: 99%

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala

2017

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The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

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“…rs13212041 is located in the 3' regulatory region of HTR1B. The rs13212041 G allele attenuates microRNA-directed mRNA silencing of HTR1B [12]. Individuals with the rs13212041 AA homozygous genotype are more aggressive than those that are G allele carriers.…”

Section: Introductionmentioning

confidence: 99%

Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

Xia

Ding

Xuan

et al. 2020

Preprint

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Background The 5-hydroxytryptamine 1B receptor (5-HT1B) plays an essential role in the serotonin (5-HT) system and is widely involved in a variety of brain activities. HTR1B is the gene encoding 5-HT1B. Genome-wide association studies have shown that HTR1B polymorphisms are closely related to multiple mental and behavioral disorders; however, the functional mechanisms underlying these associations are unknown. This study investigated the effect of several HTR1B haplotypes on regulation of gene expression in vitro and the functional sequences in the 5' regulatory region of HTR1B to determine their potential association with mental and behavioral disorders.Methods Six haplotypes consisting of rs4140535, rs1778258, rs17273700, rs1228814, rs11568817, and rs130058 and several truncated fragments of the 5' regulatory region of HTR1B were transfected into SK-N-SH and HEK-293 cells. The relative fluorescence intensities of the different haplotypes and truncated fragments were detected using a dual-luciferase reporter assay system.Results Compared to the major haplotype T-G-T-C-T-A, the relative fluorescence intensities of haplotypes C-A-T-C-T-A, C-G-T-C-T-A, C-G-C-A-G-T, and C-G-T-A-T-A were significantly lower, and that of haplotype C-G-C-A-G-A was significantly higher. Furthermore, the effects of the rs4140535T allele, the rs17273700C-rs11568817G linkage combination, and the rs1228814A allele made their relative fluorescence intensities significantly higher than their counterparts at each locus. Conversely, the rs1778258A and rs130058T alleles decreased the relative fluorescence intensities. In addition, we found that regions from -1587 to -1371 bp (TSS, +1), -1149 to -894 bp, -39 to +130 bp, +130 to +341 bp, and +341 to +505 bp upregulated gene expression. In contrast, regions -603 to -316 bp and +130 to +341 bp downregulated gene expression. Region +341 to +505 bp contained the core promoter region and played a decisive role in gene transcription.Conclusions HTR1B 5' regulatory region polymorphisms have regulatory effects on gene expression and potential correlate with several pathology and physiology conditions. This study suggests that the core promoter sequence of HTR1B is located in region +341~+505 bp. Regions -1587 to -1371 bp, -1149 to -894 bp, -603 to -316 bp, -39 to +130 bp, and +130 to +341 bp contain functional sequences that can promote or suppress the HTR1B gene expression.

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Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine

Cited by 39 publications

References 52 publications

The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review

The Relationship between DNA Methylation and Antidepressant Medications: A Systematic Review

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala

Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

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