Trauma Disclosure Moderates the Effects of Oxytocin on Intrusions and Neural Responses to Fear

Scheele, Dirk; Lieberz, Jana; Goertzen-Patin, Alexandra; Engels, Christine; Schneider, Lía; Stoffel‐Wagner, Birgit; Becker, Benjamin; Hurlemann, René

doi:10.1159/000496056

Cited by 20 publications

(23 citation statements)

References 10 publications

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“…This pilot finding thus replicates and extends a previous observation of increased OXTR exon III methylation in OCD [12]. While increased methylation of the promoter/exon I gene region has been shown to entail silenced gene transcription, hypermethylation of the gene body has been linked to enhanced transcription [23]. Accordingly, the presently observed increased OXTR exon III methylationand thus presumably heightened oxytocinergic transmission -conferring impaired treatment response is furthermore in accordance with elevated plasma as well as cerebrospinal fluid oxytocin levels in OCD patients [15,16] and with oxytocin inducing OCD-like behavior in the rodent model [14].…”

Section: Discussionsupporting

confidence: 89%

“…Accordingly, the presently observed increased OXTR exon III methylationand thus presumably heightened oxytocinergic transmission -conferring impaired treatment response is furthermore in accordance with elevated plasma as well as cerebrospinal fluid oxytocin levels in OCD patients [15,16] and with oxytocin inducing OCD-like behavior in the rodent model [14]. Along these lines, oxytocin administration -although proposed as a treatment adjunct in other mental disorders [23][24][25][26] -has been shown to be ineffective in treating OCD [27,28]. A detrimental role of increased oxytocin in OCD pathogenesis and treatment response could be interpreted in the context of oxytocin having been linked to volitional and emotional ambivalence [29], and an observed strong ambivalence regarding apparently opposing interpersonal styles of prosocial attitudes and latent aggression in OCD [30].…”

Section: Discussionsupporting

confidence: 53%

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Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

Schiele¹,

Thiel²,

Kollert³

et al. 2020

Psychother Psychosom

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Introduction: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. Objective: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. Methods: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. Results: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. Conclusions: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 53%

Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

Schiele¹,

Thiel²,

Kollert³

et al. 2020

Psychother Psychosom

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“…Intranasal oxytocin (OT) has been proposed as a potential therapy for social dysfunction in psychiatric disorders in relation to autism spectrum disorder, schizophrenia and social anxiety [1][2][3] as well as in the context of fear-extinction [4] and as an adjunct to the placebo effect for working memory deficits [5]. To date the functional effects of intranasal OT administration have been based primarily on a single dose and there is evidence that a 24IU dose may be optimal [6].…”

Section: Introductionmentioning

confidence: 99%

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Kou

Zhang

Zhou

et al. 2018

Preprint

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23Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy 24 for social dysfunction but some clinical trials have reported small or no beneficial 25 96 promising key neural mechanisms: attenuated amygdala fear responses and increased 97 resting state functional connectivity between the amygdala and medial prefrontal 98 cortex (Kendrick et al., 2017; Spengler et al., 2017). Both neural markers have been 99 primarily associated with attenuated anxiety in terms of reduced responses to social 100 threat and enhanced top-down control of emotion (Zhao et al., 2019), although OT 101 effects on the amygdala may also mediate its actions on a range of social cognition 102 6 domains (Kendrick et al., 2017; Meyer-Lindenberg et al., 2011; Spengler et al., 2017; 103 Young and Barrett, 2015). 104In order to determine optimal treatment protocols for chronic intranasal OT 105 administration the current pre-registered double-blind, randomized between subject 106 placebo (PLC)-controlled pharmacological neuroimaging trial (see Fig. 1) in 138 107 adult male subjects therefore aimed at determining the effects of acute (single dose) 108 and repeated doses (daily or every other day for 5 days) of 24IU OT versus PLC on 109 amygdala-centered neural and behavioral (valence, arousal and intensity ratings of 110 fear faces) mechanisms of OT. To identify individuals with the most promising 111 treatment sensitivity we additionally assessed the influence of OXTR rs53576 and 112 rs2254298 polymorphisms on acute and repeated dose OT effects. 113 Results 114 Acute effects of OT on neural responses to emotional faces 115 In accordance with the primary outcome measure of the trial analyses focused on the 116 neural responses to fearful faces, however no significant effects of OT were found for 117 happy or angry faces. Comparison of single-dose OT-(combined OT3 and OT5 groups) 118 and PLC-treated subjects (1 st day) revealed significantly decreased right amygdala 119 reactivity towards fearful faces on the whole brain level (k = 78, pFWE = 0.043, x=27, 120 y=-4, z=-13) (Fig.2A). Cytoarchitectonic probabilistic localization (Anatomy toolbox 121 V1.8 (Eickhoff et al., 2005)) mapped the peak coordinate with >80% probability to 122 the basolateral amygdala sub-region. In addition, OT also decreased fear-reactivity in 123 7 the right superior frontal gyrus and bilateral primary visual cortex (see SI and Table 124 S1). There were no significant differences between the OT3 and OT5 groups on the 1 st 125 day. 126 Primary outcome measures: effects of repeated doses on OT-evoked 127 changes 128 Mixed ANOVAs with treatment (PLC, OT3, OT5) and time point (1 st day, acute 129 effects; 5 th day, chronic effects) as factors and right amygdala fear reactivity as 130 dependent variable revealed a significant main effect of treatment (F2, 135 = 7.85, p = 131 0.001, η 2 p = 0.104) and a treatment x time point interaction (F2, 135 = 5.74, p = 0.004, 132 η 2 p =0.078). Post-hoc Bonferroni corrected comparisons between group...

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“…One of the clinical core symptoms of PTSD is intrusive reexperiencing, which can be modeled over days in healthy volunteers exposed to filmed violence. Based on this paradigm, it was shown that IN-OT (24 IU) not only enhanced functional connectivity between the amygdala and mPFC, but also diminished intrusions, at least in subjects who deliberately talked to their peers about what had scared them (Scheele et al, 2019).…”

Section: Clinical Translation Of the Fear-modulating Effects Of Oxytocinmentioning

confidence: 99%

Limbic Neuropeptidergic Modulators of Emotion and Their Therapeutic Potential for Anxiety and Post-Traumatic Stress Disorder

et al. 2021

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Post-traumatic stress disorder (PTSD) is characterized by hypervigilance, increased reactivity to unpredictable versus predictable threat signals, deficits in fear extinction, and an inability to discriminate between threat and safety. First-line pharmacotherapies for psychiatric disorders have limited therapeutic efficacy in PTSD. However, recent studies have advanced our understanding of the roles of several limbic neuropeptides in the regulation of defensive behaviors and in the neural processes that are disrupted in PTSD. For example, preclinical studies have shown that blockers of tachykinin pathways, such as the Tac2 pathway, attenuate fear memory consolidation in mice and thus might have unique potential as early post-trauma interventions to prevent PTSD development. Targeting this pathway might also be beneficial in regulating other symptoms of PTSD, including trauma-induced aggressive behavior. In addition, preclinical and clinical studies have shown the important role of angiotensin receptors in fear extinction and the promise of using angiotensin II receptor blockade to reduce PTSD symptom severity. Additional preclinical studies have demonstrated that the oxytocin receptors foster accurate fear discrimination by facilitating fear responses to predictable versus unpredictable threats. Complementary human imaging studies demonstrate unique neural targets of intranasal oxytocin and compare its efficacy with well-established anxiolytic treatments. Finally, promising data from human subjects have demonstrated that a selective vasopressin 1A receptor antagonist reduces anxiety induced by unpredictable threats. This review highlights these novel promising targets for the treatment of unique core elements of PTSD pathophysiology.

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Trauma Disclosure Moderates the Effects of Oxytocin on Intrusions and Neural Responses to Fear

Cited by 20 publications

References 10 publications

Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

Genotype and dose-frequency determine acute and chronic effects of oxytocin on amygdala fear responses in humans: therapeutic implications

Limbic Neuropeptidergic Modulators of Emotion and Their Therapeutic Potential for Anxiety and Post-Traumatic Stress Disorder

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