Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study.

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Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study.

Hum Brain Mapp. 2019 Jan 11;:

Authors: Stenbaek DS, Kristiansen S, Burmester D, Madsen MK, Frokjaer VG, Knudsen GM, Fisher PM

Abstract
Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5-HT2A R) agonist psilocybin. However, no studies have investigated whether 5-HT2A R availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5-HT2A R binding in neocortex imaged with [18 F]altanserin or [11 C]Cimbi-36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory-Revised. No significant associations between neocortical 5-HT2A R binding and trait Openness were found for [18 F]altanserin (p = 0.5) or [11 C]Cimbi-36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5-HT2A R availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5-HT2A R with compounds such as psilocybin may contribute to long-term changes in trait Openness, there is no evidence in favor of an association between 5-HT2A R and trait Openness.

PMID: 30633430 [PubMed – as supplied by publisher]

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Three weeks of SSRI administration enhances the visual perceptual threshold – a randomized placebo-controlled study.

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Three weeks of SSRI administration enhances the visual perceptual threshold – a randomized placebo-controlled study.

Psychopharmacology (Berl). 2019 Jan 08;:

Authors: Lansner J, Jensen CG, Petersen A, Fisher PM, Frokjaer VG, Vangkilde S, Knudsen GM

Abstract
RATIONALE: The serotonergic system has been repeatedly linked to visual attention in general, but the effects of selective serotonin reuptake inhibitor (SSRI) on specific components of visual attention remain unknown. Changes in distinct perceptual and cognitive processes are not readily evident in most attention paradigms.
OBJECTIVE: In this study, we isolate basic components of visual attention to investigate potential effects of longer-term SSRI administration on non-emotional aspects of visual attention in healthy males.
METHODS: In a randomized double-blind placebo-controlled design, 32 young healthy males were tested on multiple attentional parameters, before and after a 3-week SSRI intervention with fluoxetine (40 mg daily) or placebo. Data were modeled with a computational theory of visual attention to derive independent estimates of five distinct components of visual attention.
RESULTS: The SSRI intervention selectively and significantly lowered the threshold for conscious visual perception. Specifically, we demonstrate that this improvement does not stem from a general increase in the speed of visual processing, as previously suggested, but specifically from a change in the perceptual threshold.
CONCLUSIONS: The study provides a novel description of the attentional dynamics affected by SSRI, while supporting previous findings on attentional effects of SSRI. Furthermore, it accentuates the utility of employing accuracy-based measures of attentional performance when conducting psychopharmacological research.

PMID: 30623228 [PubMed – as supplied by publisher]

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Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study.

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Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study.

Br J Psychiatry. 2018 Nov 20;:1-9

Authors: Mehta D, Rex-Haffner M, Søndergaard HB, Pinborg A, Binder EB, Frokjaer VG

Abstract
BACKGROUND: Enhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations.AimTesting if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes.
METHOD: We generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa.
RESULTS: Of the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up.
CONCLUSIONS: Our data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers.Declaration of interestV.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.

PMID: 30457060 [PubMed – as supplied by publisher]

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Neuroticism modulates mood responses to pharmacological sex hormone manipulation in healthy women.

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Neuroticism modulates mood responses to pharmacological sex hormone manipulation in healthy women.

Psychoneuroendocrinology. 2018 Oct 26;99:251-256

Authors: Stenbæk DS, Budtz-Jørgensen E, Pinborg A, Jensen PS, Frokjaer VG

Abstract
BACKGROUND: Women show increased risk of depressive symptoms during hormonal transition phases. The risk mechanisms may include changes in mood in response to fluctuating ovarian hormones moderated by predisposing risk factors for mood disorders, such as personality trait Neuroticism.
METHODS: A pooled sample of 92 mentally healthy women (28.3 ± 7.1, mean age ± SD) from two independent cohorts run in our lab, using gonadotropin-releasing hormone agonist (GnRHa) experimentally (n = 28) compared to placebo (n = 27) and as part in vitro fertilization (n = 37), were extracted from the Center for Integrated Molecular Brain Imaging database. All women filled in questionnaires of trait Neuroticism from the NEO personality Inventory-Revised (NEO PI-R) at baseline and self-reported levels of mood disturbances with the Profile of Mood States (POMS) daily during 14 days of GnRHa intervention or placebo. Effects of intervention by trait Neuroticism on serial daily reports of mood disturbances were examined using mixed model analyses.
RESULTS: Personality trait Neuroticism significantly modulated daily mood responses to GnRHa, but not placebo. Women with high and low scores on trait Neuroticism at baseline experienced more pronounced changes in mood when exposed to GnRHa, whereas women with medium trait Neuroticism scores remained relatively stable.
CONCLUSIONS: The susceptibility to hormone-triggered mood changes appears to depend upon women’s general tendency to experience distress and destabilization of mood, as captured by personality trait Neuroticism. This could aid clinicians evaluate hormone-related vulnerability for mood disorders in women and may guide targeted prevention in reproductive care.

PMID: 30390443 [PubMed – as supplied by publisher]

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Delirium assessment in neuro-critically ill patients: A validation study.

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Delirium assessment in neuro-critically ill patients: A validation study.

Acta Anaesthesiol Scand. 2018 Oct 16;:

Authors: Larsen LK, Frøkjaer VG, Nielsen JS, Skrobik Y, Winkler Y, Møller K, Petersen M, Egerod I

Abstract
BACKGROUND: Delirium is underinvestigated in the neuro-critically ill, although the harmful effect of delirium is well established in patients in medical and surgical intensive care units (ICU).To detect delirium, a valid tool is needed. We hypothesized that delirium screening would be feasible in patients with acute brain injury and we aimed to validate and compare the Confusion Assessment Method for the ICU and the Intensive Care Delirium Screening Checklist against clinical International Classification of Diseases-10 criteria as reference.
METHODS: Nurses assessed delirium using the Confusion Assessment Method for the ICU and Intensive Care Delirium Screening Checklist in adult patients with acute brain injury admitted to the Neurointensive care unit (Neuro-ICU), Copenhagen University Hospital, if their Richmond agitation-sedation scale score was -2 or above. As the reference, a team of psychiatrist assessed patients using the International Classification of Diseases-10 criteria.
RESULTS: We enrolled 74 patients, of whom 25 (34%) were deemed unable to assess by the psychiatrists, leaving 49 (66%) for final analysis. Sensitivity and specificity for the Confusion Assessment Method for the ICU was 59% (95% CI: 41-75) and 56% (95% CI: 32-78), respectively, and 85% (95% CI: 70-94) and 75% (95% CI: 51-92), respectively, for the Intensive Care Delirium Screening Checklist.
CONCLUSIONS: Our findings suggest that the Intensive Care Delirium Screening Checklist may be a valid tool and the Confusion Assessment Method for the ICU is less suitable for delirium detection for patients in the Neuro-ICU. In the neuro-critically ill, delirium screening is challenged by limited feasibility.

PMID: 30324653 [PubMed – as supplied by publisher]

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Seasonality-resilient individuals downregulate their cerebral 5-HT transporter binding in winter – A longitudinal combined 11C-DASB and 11C-SB207145 PET study.

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Seasonality-resilient individuals downregulate their cerebral 5-HT transporter binding in winter – A longitudinal combined 11C-DASB and 11C-SB207145 PET study.

Eur Neuropsychopharmacol. 2018 Aug 01;:

Authors: Mc Mahon B, Nørgaard M, Svarer C, Andersen SB, Madsen MK, Baaré WFC, Madsen J, Frokjaer VG, Knudsen GM

Abstract
We have recently shown that the emergence and severity of seasonal affective disorder (SAD) symptoms in the winter is associated with an increase in cerebral serotonin (5-HT) transporter (SERT) binding. Intriguingly, we also found that individuals resilient to SAD downregulate their cerebral SERT binding in the winter. In the present paper, we provide an analysis of the SERT- and 5-HT dynamics as indexed by 5-HT4 receptor (5-HT4R) binding related to successful stress coping. We included 46 11C-DASB positron emission tomography (PET) scans (N = 23, 13 women, age: 26 ± 6 years) and 14 11C-SB207145 PET scans (7 participants, 3 women, age: 25 ± 3 years) from 23 SAD-resilient Danes. Data was collected longitudinally in summer and winter. We found that compared to the summer, raphe nuclei and global brain SERT binding decreased significantly in the winter (praphe = 0.003 and pglobal = 0.003) and the two measures were positively correlated across seasons (summer: R2 = 0.33, p = .004, winter: R2 = 0.24, p = .018). A voxel-based analysis revealed prominent changes in SERT in clusters covering both angular gyri (0.0005 < pcorrected < 0.0016), prefrontal cortices (0.00087 < pcorrected < 0.0039) and the posterior temporal and adjacent occipital cortices (0.0001 < pcorrected < 0.0066). We did not observe changes in 5-HT4R binding, suggesting that 5-HT levels remained stable across seasons. We conclude that resilience to SAD is associated with a global downregulation of SERT levels in winter which serves to keep 5-HT levels across seasons.

PMID: 30077433 [PubMed – as supplied by publisher]

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Paroxetine blunts the corticosterone response to swim-induced stress and increases depressive-like behavior in a rat model of postpartum depression.

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Paroxetine blunts the corticosterone response to swim-induced stress and increases depressive-like behavior in a rat model of postpartum depression.

Psychoneuroendocrinology. 2017 Oct 31;:

Authors: Overgaard A, Lieblich SE, Richardson R, Galea LAM, Frokjaer VG

Abstract
Perinatal depression (PND) affects 15% of women. During the perinatal period both stress- and gonadal hormones fluctuate widely. Putatively, these fluctuations are involved in PND disease mechanisms. The serotonin system is sensitive to such hormone fluctuations, and serotonin reuptake inhibitors (SSRIs) are used to treat PND, although treatment is suboptimal and it is not known at which peripartum time-point SSRI treatment may be most efficacious. In this study, we investigate the effect of the SSRI paroxetine (5mg/kgs.c.) on swim stress-induced corticosterone in a rat model of postpartum depression. In the rat model corticosterone (CORT; 40mg/kgs.c.) was administered in Sprague Dawley rats across postpartum day (PD)2 to PD14. Stress response was measured during the first exposure to the forced swim test (FST1), and depressive-like behavior was measured in both FST1 and FST2. We found that paroxetine completely blunted the swim stress-induced CORT response and increased depressive-like behavior in both FST1 and FST2. Our findings suggest that in the postpartum context, SSRIs compromise stress axis dynamics, which are needed for a healthy stress response. This is likely unfavorable for reversing depressive-like behavior and may provide a rationale for augmentation strategies beyond SSRIs alone to optimize the clinical management of PND.

PMID: 29146408 [PubMed – as supplied by publisher]

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No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

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No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study.

PLoS One. 2017;12(9):e0184403

Authors: Stenbæk DS, Dam VH, Fisher PM, Hansen N, Hjordt LV, Frokjaer VG

Abstract
Serotonin (5-HT) brain architecture appears to be implicated in normal personality traits as supported by genetic associations and studies using molecular brain imaging. However, so far, no studies have addressed potential contributions to variation in normal personality traits from in vivo serotonin 4 receptor (5-HT4R) brain availability, which has recently become possible to image with Positron Emission Tomography (PET). This is particularly relevant since availability of 5-HT4R has been shown to adapt to synaptic levels of 5-HT and thus offers information about serotonergic tone in the healthy brain. In 69 healthy participants (18 females), the associations between personality traits assessed with the five-factor NEO Personality Inventory-Revised (NEO PI-R) and regional cerebral 5-HT4R binding in neocortex, amygdala, hippocampus, and anterior cingulate cortex (ACC) were investigated using linear regression models. The associations between each of the five personality traits and a latent variable construct of global 5-HT4R levels were also evaluated using latent variable structural equation models. We found no significant associations between the five NEO personality traits and regional 5-HT4R binding (all p-values > .17) or the latent construct of global 5-HT4R levels (all p-values > .37). Our findings indicate that NEO personality traits and 5-HT4R are not related in healthy participants. Under the assumption that global 5-HT4R levels index 5-HT tone, our data also suggest that 5-HT tone per se is not directly implicated in normal personality traits.

PMID: 28880910 [PubMed – in process]

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Neuroticism associates with cerebral in vivo serotonin transporter binding differently in males and females.

Neuroticism associates with cerebral in vivo serotonin transporter binding differently in males and females.

Int J Neuropsychopharmacol. 2017 Aug 07;:

Authors: Tuominen L, Miettunen J, Cannon DM, Drevets WC, Frokjaer VG, Hirvonen J, Ichise M, Jensen PS, Keltikangas-Järvinen L, Klaver JM, Knudsen GM, Takano A, Suhara T, Hietala J

Abstract
Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter (5-HTT), which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and 5-HTT have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and 5-HTT, but this question has not been investigated by previous studies.
Methods: Here, we combined data from four different positron emission tomography imaging centers to address whether neuroticism is related to 5-HTT binding in vivo. The data set included 5-HTT binding potential (BPND) values from the thalamus and striatum, and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and 5-HTT is different in females and males.
Results: We found that neuroticism and thalamic 5-HTT BPND were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher 5-HTT BPND in males (standardized beta 0.292, p = .008), whereas in females, higher neuroticism associated with lower 5-HTT BPND (standardized beta -0.288, p = .014).
Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic 5-HTT to the risk of affective disorders depends on sex.

PMID: 29020405 [PubMed – as supplied by publisher]

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Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding.

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Testosterone levels in healthy men correlate negatively with serotonin 4 receptor binding.

Psychoneuroendocrinology. 2017 Mar 22;81:22-28

Authors: Perfalk E, Cunha-Bang SD, Holst KK, Keller S, Svarer C, Knudsen GM, Frokjaer VG

Abstract
The serotonergic system integrates sex steroid information and plays a central role in mood and stress regulation, cognition, appetite and sleep. This interplay may be critical for likelihood of developing depressive episodes, at least in a subgroup of sensitive individuals. The serotonin 4 receptor (5-HT4R) indexes central serotonergic tonus, which may be related to endogenous sex-steroid levels in the mentally healthy state even though this remains elusive. Here we evaluate if peripheral levels of estradiol and testosterone are associated with 5-HT4R binding as imaged by [(11)C]SB207145 positron emission tomography in a group of 41 healthy men. We estimated global 5-HT4R binding using a latent variable model framework, which models shared correlation between 5-HT4R across multiple brain regions (hippocampus, amygdala, posterior and anterior cingulate, thalamus, pallidostriatum and neocortex). We tested whether testosterone and estradiol predict global 5-HT4R, adjusting for age. We found that testosterone, but not estradiol, correlated negatively with global 5-HT4R levels (p=0.02) suggesting that men with high levels of testosterone have higher cerebral serotonergic tonus. Our findings corroborate the link between sex hormone levels and serotonin signalling. Future longitudinal studies in clinical relevant populations are needed to elucidate the potential importance of testosterone in the pathophysiology of e.g. major depression and its treatment.

PMID: 28426945 [PubMed – as supplied by publisher]

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