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Serotonin transporter polymorphism related to amygdala excitability and symptom severity in patients with social phobia. Neurosci Lett

Department of Psychology, Uppsala University, Uppsala, Sweden.
Neuroscience Letters (Impact Factor: 2.06). 06/2004; 362(3):189-92. DOI: 10.1016/j.neulet.2004.02.070
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ABSTRACT A functional polymorphism in the promoter region of the human serotonin transporter (5-HTT) gene has been related to negative affect and amygdala activity. We studied amygdala activation during social anxiety provocation in relation to affective ratings and 5-HTT genetic variation. [H2(15)O]positron emission tomography was used to estimate amygdala blood flow during private and public speaking (baseline and anxiety conditions) in 17 patients with social phobia. Genotyping identified patients with long and short alleles in the promoter region of the 5-HTT. Individuals with one or two copies of the short allele exhibited significantly increased levels of anxiety-related traits, state anxiety, and enhanced right amygdala responding to anxiety provocation, compared with subjects homozygous for the long allele. Thus, 5-HTT genetic variation was associated with symptom severity and amygdala excitability in social phobia.

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Available from: Tomas Furmark, Mar 17, 2015
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    • "The short form has been associated with a reduced transcriptional efficiency of SLC6A4, resulting in decrease SLC6A4 expression and serotonin reuptake compared to the long form (Lesch et al., 1996; Gerretsen and Pollock, 2008). The short form has also been associated with the presence of social phobia (Furmark et al., 2004), obsessive-compulsive disorder (Hasler et al., 2006), posttraumatic stress disorder and depression (Kilpatrick et al., 2007), and with anxiety-related traits such as neuroticism and danger avoidance (Lesch et al., 1996). However, a meta-analysis did not confirm the association of the short form with depression (Risch et al., 2009). "
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    ABSTRACT: Environmental effects and personal experiences could be expressed in individuals through epigenetic non-structural changes such as DNA methylation. This methylation could up- regulate or down-regulate corresponding gene expressions and modify related phenotypes. DNA methylation increases with aging and could be related to the late expression of some forms of mental disease. The objective of this study was to evaluate the association between anxiety disorders and/or depression in older women and DNA methylation for four genes related to anxiety or depression. Women aged 65 and older with (n = 19) or without (n = 24) anxiety disorders and/or major depressive episode (DSM-IV), were recruited. DNA methylation and single nucleotide variant (SNV) were evaluated from saliva, respectively by pyrosequencing and by PCR, for the following genes: brain-derived neurotrophic factor (BDNF; rs6265), oxytocin receptor (OXTR; rs53576), serotonin transporter (SLC6A4; rs25531), and apolipoprotein E (APOE; rs429358 and rs7412). A greater BDNF DNA methylation was observed in subjects with anxiety/depression compared to control group subjects (Mean: 2.92 SD ± 0.74 vs. 2.34 ± 0.42; p= 0.0026). This difference was more pronounced in subjects carrying the BDNF rs6265 CT genotype (2.99 ± 0.41 vs. 2.27 ± 0.26; p= 0.0006) than those carrying the CC genotype (p= 0.0332); no subjects with the TT genotype were observed. For OXTR, a greater DNA methylation was observed in subjects with anxiety/depression, but only for those carrying the AA genotype of the OXTR rs53576 SNV, more particularly at one out of the seven CpGs studied (7.01 ± 0.94 vs. 4.44 ± 1.11; p= 0.0063). No significant differences were observed for APOE and SLC6A4. These results suggest that DNA methylation in interaction with SNV variations in BDNF and OXTR, are associated with the occurrence of anxiety/depression in older women.
    Frontiers in Genetics 06/2015; 6:230. DOI:10.3389/fgene.2015.00230
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    • "The s-allele of 5-HTTLPR is associated with reduction of serotonin uptake and 5-HTT expression [18]. Having the s-allele is associated with increased amygdala reactivity [10], [19]–[21] and poorer treatment response to selective serotonin reuptake inhibitors (SSRIs) for social anxiety disorder (SAD) [22] and panic disorder [23]. In another study persistent higher symptoms in panic disorder patients carrying either an s-allele or an LG-allele, were reported by Lonsdorf et al. [24]. "
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    ABSTRACT: The role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients. Participants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report. At long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials. None of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD. ClinicalTrials.gov (ID-NCT0056496).
    PLoS ONE 11/2013; 8(11):e79015. DOI:10.1371/journal.pone.0079015 · 3.23 Impact Factor
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    • "Recent genetic association studies have also explored the influence of 5-HTTLPR on social anxiety. The low-expressing alleles of 5-HTTLPR polymorphisms (e.g., S or L G ) have been significantly associated with symptoms such as state-anxiety escalation and amygdala hyperactivity during public speaking (Furmark et al., 2004), increased shyness and reduced discrimination of angry and neutral faces (Battaglia et al., 2005), and blushing propensity (Domschke et al., 2009) in SAD patients. In addition, these lowexpressing alleles also predicted reduced responses to SSRI (Stein, Seedat, & Gelernter, 2006) and placebo treatments that reduce amygdala hyperactivity during public speaking in SAD (Furmark et al., 2008). "
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    ABSTRACT: Social anxiety symptoms have been related to (a) polymorphisms in the serotonin-transporter gene-promoter region (also, serotonin-transporter-linked polymorphic region; 5-HTTLPR) and (b) reduced use of adaptive forms of emotion regulation such as reappraisal. It is not known, however, whether reappraisal functions as a mediator in the link between 5-HTTLPR and social anxiety. To address this issue, 182 unselected community volunteers were tested for 5-HTTLPR status, and self-report measures of social anxiety symptoms and reappraisal use were obtained. Relative to other participants, those with two low-expressing alleles displayed increased social anxiety and decreased reappraisal. As predicted, the influence of 5-HTTLPR on social anxiety symptoms was transmitted via reappraisal, and this effect of 5-HTTLPR was observed using two different measures of reappraisal. These findings suggest that cognitive reappraisal may be an intermediate phenotype of the social anxiety spectrum, and that individuals with low-expressing 5-HTTLPR genotypes may benefit the most from cognitive-behavioral psychotherapy because they do not appear to engage as frequently as others in reappraisal. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
    Emotion 06/2013; DOI:10.1037/a0033383 · 3.88 Impact Factor
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