| 1. |
- Furmark, Tomas, et al.
(författare)
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Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder
- 2016
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Ingår i: Journal of Psychopharmacology. - London, United Kingdom : SAGE Publications. - 0269-8811 .- 1461-7285. ; 30:10, s. 1028-1035
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Tidskriftsartikel (refereegranskat)abstract
- It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[ -C-11]tryptophan, [C-11]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [C-11]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions.
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| 2. |
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| 3. |
- Bas-Hoogendam, Janna Marie, et al.
(författare)
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Voxel-based morphometry multi-center mega-analysis of brain structure in social anxiety disorder
- 2017
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Ingår i: NeuroImage. - : Elsevier BV. - 2213-1582. ; 16, s. 678-688
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Tidskriftsartikel (refereegranskat)abstract
- Social anxiety disorder (SAD) is a prevalent and disabling mental disorder, associated with significant psychiatric co-morbidity. Previous research on structural brain alterations associated with SAD has yielded inconsistent results concerning the direction of the changes in gray matter (GM) in various brain regions, as well as on the relationship between brain structure and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new opportunities to investigate SAD-related alterations in brain structure in larger samples.An international multi-center mega-analysis on the largest database of SAD structural T1-weighted 3T MRI scans to date was performed to compare GM volume of SAD-patients (n = 174) and healthy control (HC)-participants (n = 213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, the amygdala-hippocampal complex, the prefrontal cortex, and the parietal cortex. SAD-patients had larger GM volume in the dorsal striatum when compared to HC-participants. This increase correlated positively with the severity of self-reported social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs. Thereby, the results of this mega-analysis suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Our findings emphasize the importance of large sample imaging studies and the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium.
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| 4. |
- Hjorth, Olof
(författare)
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Imaging serotonin and dopamine transporters in social anxiety disorder : Characterization, treatment and expectancy effects
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The monoamines serotonin and dopamine are likely to be involved in the pathophysiology of social anxiety and other affective disorders, but their respective contributions and putative interactions in the causes and cures of these disorders are still not well understood. It is also largely unknown if and how expectations of treatment success affect brain neurochemistry and neural activations, and if expectations interact with antidepressants like selective serotonin reuptake inhibitors (SSRIs). In this thesis some of these issues were addressed by use of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). Using the highly selective radiotracers [11C]DASB and [11C]PE2I to characterize the availability of serotonin (SERT) and dopamine (DAT) transporter proteins, study I compared non-displaceable binding potentials (BPND), probing the transporters, between patients with social anxiety disorder and healthy controls. Increased SERT binding was observed in the reward related region nucleus accumbens (NAcc), in the social anxiety group. Moreover, increased DAT binding was associated with severity of the disorder and social anxiety was also associated with higher SERT-DAT co-expression in fear- and reward-related areas, including the amygdala and NAcc. Study II showed that verbal instructions regarding expected treatment efficacy strongly affected the clinical outcome of SSRI-treatment. Overt treatment, when patients with social anxiety disorder were correctly informed, was vastly superior to covert SSRI treatment, when patients expected an ineffective placebo. Groups were also differentiated on objective brain activity measures. Study III further demonstrated different SERT and DAT binding changes in limbic and striatal areas with overt as compared to covert SSRI-treatment. Decreased DAT BPND in the striatum, as assessed with PET, correlated with improvement in the overt group, suggesting increased dopaminergic signalling. Study IV compared treatment-induced changes in SERT and DAT binding after cognitive-behavior therapy (CBT) combined with an SSRI or placebo in patients with social anxiety disorder. Both groups showed initial co-expression similar to study I. The SSRI+CBT and placebo+CBT combinations yielded dissimilar transporter change patterns. Higher SERT occupancy in the NAcc correlated with reduced symptoms and this relationship was moderated by the change in DAT BPND. The results of this thesis support that functional interactions between serotonin and dopamine modulate social anxiety symptomatology and are important brain targets for successful treatment. Further it demonstrates that the treatment success of SSRIs in social anxiety disorder depends on how the treatment is presented. These results can be informative for the practice of clinicians, but also highlights an ethical dilemma because a large portion of the total treatment effects is elicited by processes within the patient itself.
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| 5. |
- Olofsdotter, Susanne, et al.
(författare)
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Anxiety disorders among adolescents referred to general psychiatry for multiple causes : clinical presentation, prevalence, and comorbidity
- 2016
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Ingår i: Scandinavian Journal of Child and Adolescent Psychiatry and Psychology. - : Walter de Gruyter GmbH. - 2245-8875. ; 4:2, s. 55-64
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reports of anxiety disorder characteristics among youth in clinical settings typically include descriptions of patients who have been specifically referred for anxiety treatment. At odds with a large body of evidence which demonstrates these disorders to be most common among young people, prevalence studies in samples referred to general psychiatry for multiple causes are scarce and report highly discrepant estimates.Methods: For this study and regardless of their presenting symptoms, 125 adolescents (57.6% girls) between the ages of 12 and 18 years who were consecutively referred to two child and adolescent general psychiatry clinics in Sweden were assessed for anxiety disorders and comorbidity using the Schedule for Affective Disorders and Schizophrenia for School-Age Children. Self-ratings of anxiety symptoms and difficulties with family, school, friends, sleep, and body aches were also obtained.Results: At least one anxiety disorder was found in 46% of participants. Among anxious adolescents, homotypic comorbidity (concurrent anxiety) was observed in 43%, and heterotypic comorbidity (concurrent non-anxiety psychiatric disorders) was observed in 91%. No comorbidity was observed in 5%. Trauma, ache, and difficulties making friends were more common among anxious adolescents as compared with psychiatrically referred adolescents without anxiety.Conclusions: The finding that only 21% of adolescents diagnosed with anxiety disorders were referred for anxiety further supports the routine use of standardized and structured instruments—irrespective of referral cause—to improve both precision and detection rates in the clinical setting. Comprehensive assessments are of utmost importance to fully address the complexity of the symptoms in this patient group.
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| 6. |
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| 7. |
- Appel, Lieuwe, et al.
(författare)
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Altered NK1-receptor availability in patients with post traumatic stress disorder
- 2009
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Ingår i: [Biological Psychiatry 2009, 65(8), Suppl. 1, 118S, no. 394]. - : Elsevier BV. ; , s. 118S-
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Konferensbidrag (refereegranskat)abstract
- Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder that can develop after one or more traumatic events causing extreme stress or grave physical harm. The neurokinin-1 (NK1) receptor is the primary receptor for substance P (SP); a neuropeptide suggested being involved in anxiety and depression. The present study investigated differences in NK1-receptor availability between PTSD patients and healthy controls, using positron emission tomography (PET). Methods: Eleven male refugee patients (age: 41±10) with DSM-IV defined PTSD and nine healthy male control subjects (age: 33±10) were investigated using the PET-tracer [11C]GR205171, supplied by Uppsala Imanet. GR205171 is a highly selective NK1-receptor antagonist. Scans were performed during 60 minutes in the resting state. Parametric images were generated using the graphical reference Patlak method assuming irreversible binding of [11C]GR205171 from 20-60 minutes and having cerebellum as reference region. Exploratory whole brain analyses were performed using the statistical parametric mapping (SPM2) software. Results: PTSD patients had lower [11C]GR205171 binding compared to controls, in frontal cortical clusters encompassing bilaterally insula and left Brodmann area 11, reflecting lower NK1-receptor availability. No areas were found in which PTSD patients had higher [11C]GR205171 binding. Conclusions: This is the first study reporting differences in NK1-receptor availability in PTSD patients relative to controls. A tentative conclusion is that PTSD patients have a down regulation of the NK1-receptor system, which could be either a risk factor or due to emotional trauma processing.
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| 8. |
- Michelgård Palmquist, Åsa, 1973-, et al.
(författare)
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Enhanced neurokinin 1 receptor availability in the amygdala in posttraumatic stress disorder
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Posttraumatic stress disorder (PTSD) may result from experiencing severe distress, and is in part amygdala dependent. Animal studies demonstrate that stress and negative affect enhance the amygdala-release of the neuropeptide substance P (SP) which binds to the neurokinin 1 (NK1) receptor. This positron emission tomography (PET) study investigated if NK1 receptor availability in the amygdala of PTSD patients were different from healthy control subjects. Methods: Eleven male patients with DSM-IV defined PTSD and nine healthy male control subjects were PET scanned during 60 min at rest using the NK1 preferring tracer [11C]GR205171. Parametric Patlak images were generated and analyzed using statistical parametric mapping software. The effect of age was co-varied out because the amount of NK1 receptors decline with age. Results: PTSD patients had elevated uptake of [11C]GR205171 in the amygdala as compared to controls, also when anxiety differences were controlled for. Conclusions: We suggest that enhanced NK1 receptor availability could be a risk factor for developing PTSD rather than reflecting trauma induced alterations.
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| 9. |
- Månsson, Kristoffer N. T., et al.
(författare)
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Improvement in indices of cellular protection after psychological treatment for social anxiety disorder
- 2019
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.
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| 10. |
- Frick, Andreas, Docent, et al.
(författare)
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Neuroimaging, genetic, clinical, and demographic predictors of treatment response in patients with social anxiety disorder
- 2020
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Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 261, s. 230-237
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Tidskriftsartikel (refereegranskat)abstract
- Background: Correct prediction of treatment response is a central goal of precision psychiatry. Here, we tested the predictive accuracy of a variety of pre-treatment patient characteristics, including clinical, demographic, molecular genetic, and neuroimaging markers, for treatment response in patients with social anxiety disorder (SAD). Methods: Forty-seven SAD patients (mean±SD age 33.9 ± 9.4 years, 24 women) were randomized and commenced 9 weeks’ Internet-delivered cognitive behavior therapy (CBT) combined either with the selective serotonin reuptake inhibitor (SSRI) escitalopram (20 mg daily [10 mg first week], SSRI+CBT, n = 24) or placebo (placebo+CBT, n = 23). Treatment responders were defined from the Clinical Global Impression-Improvement scale (CGI-I ≤ 2). Before treatment, patients underwent functional magnetic resonance imaging and the Multi-Source Interference Task taxing cognitive interference. Support vector machines (SVMs) were trained to separate responders from nonresponders based on pre-treatment neural reactivity in the dorsal anterior cingulate cortex (dACC), amygdala, and occipital cortex, as well as molecular genetic, demographic, and clinical data. SVM models were tested using leave-one-subject-out cross-validation. Results: The best model separated treatment responders (n = 24) from nonresponders based on pre-treatment dACC reactivity (83% accuracy, P = 0.001). Responders had greater pre-treatment dACC reactivity than nonresponders especially in the SSRI+CBT group. No other variable was associated with clinical response or added predictive accuracy to the dACC SVM model. Limitations: Small sample size, especially for genetic analyses. No replication or validation samples were available. Conclusions: The findings demonstrate that treatment outcome predictions based on neural cingulate activity, at the individual level, outperform genetic, demographic, and clinical variables for medication-assisted Internet-delivered CBT, supporting the use of neuroimaging in precision psychiatry.
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