Early response to selective serotonin reuptake inhibitors in panic disorder is associated with a functional 5-HT1A receptor gene polymorphism

Yevtushenko, Olga O.; Oros, Mykhaylo M.; Reynolds, Gavin P.

doi:10.1016/j.jad.2009.09.007

Cited by 52 publications

(32 citation statements)

References 16 publications

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“…In addition to its association with depression, we and others have found that the G(−1019) allele associates with reduced response to chronic SSRI or SSRI/pindolol treatment (Lemonde et al, 2004a; Le François et al, 2008; Villafuerte et al, 2009; Yevtushenko et al, 2010). Interestingly, antidepressant response to flibanserin, a 5-HT1A agonist which directly targets 5-HT1A receptor desensitization, was the most attenuated in subjects with the G/G genotype.…”

Section: Transcriptional Regulation Of the 5-ht1a Receptor Gene In Mementioning

confidence: 79%

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Albert¹

2010

Front. Neurosci.

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Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT) neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a “brake” to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone) that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(−1019)G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

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Section: Transcriptional Regulation Of the 5-ht1a Receptor Gene In Mementioning

confidence: 79%

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Albert¹

2010

Front. Neurosci.

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“…This may reflect a difference in ethnicity in which the G-allele is infrequent in oriental populations, or may suggest the presence of additional polymorphisms, which could potentiate the effects of rs6295 [140]. Recently, the presence of the GG(-1019) genotype was found to associate with a lack of rapid response to SSRI treatment in panic disorder patients compared to patients with the C(-1019) allele [141]. Interestingly, a report shows that the CC-genotype also confers a better response to transcranial magnetic stimulation [142], suggesting that modulation of the 5-HT1A receptor may also participate in treatments that target cortical processes, perhaps via induced expression of the 5-HT1A receptor in cortex and amygdala [143].…”

Section: -Ht1a Promoter Polymorphisms and Mental Illnessmentioning

confidence: 99%

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Albert¹,

Fiori

2014

CPD

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The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5-HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as postsynaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto-and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto-and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto-and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression. KeywordsSerotonin; repressor; enhancer; antidepressant; raphe; autoreceptor SEROTONIN AND MAJOR DEPRESSIONDepression continues to grow as a major health challenge with a lifetime prevalence for major depressive disorder (MDD) estimated at 16 % [1, 2] (Box 1). In developed countries, MDD currently accounts for the second highest lifetime burden of disease, and is predicted

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“…However, these compounds have insufficient specificity since they affect both pre-and post-synaptic receptors, and display only partial specificity for 5-HT1A autoreceptors [210,211]. We and others have found that the G(-1019) allele associates with reduced antidepressant response [174,212-214], suggesting that regulation by Deaf1 could facilitate antidepressant response. Successful treatment of panic disorder patients with chronic SSRIs correlates with a normalization of pre- and post-synaptic 5-HT1A receptors, suggesting that down-regulation of pre-synaptic receptors concomitant with an up-regulation of post-synaptic 5-HT1A receptors may be critical for treatment response [45,215].…”

Section: -Ht1a Autoreceptors In Human Depressionmentioning

confidence: 99%

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

2011

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The serotonin-1A (5-HT1A) receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A) using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019)G (rs6295) polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

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Early response to selective serotonin reuptake inhibitors in panic disorder is associated with a functional 5-HT1A receptor gene polymorphism

Cited by 52 publications

References 16 publications

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity

Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

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