Placebo may yield beneficial effects that are indistinguishable from those of active medication, but the factors underlying proneness to respond to placebo are widely unknown. Here, we used functional neuroimaging to examine neural correlates of anxiety reduction resulting from sustained placebo treatment under randomized double-blind conditions, in patients with social anxiety disorder. Brain activity was assessed during a stressful public speaking task by means of positron emission tomography before and after an 8 week treatment period. Patients were genotyped with respect to the serotonin transporter-linked polymorphic region (5-HTTLPR) and the G-703T polymorphism in the tryptophan hydroxylase-2 (TPH2) gene promoter. Results showed that placebo response was accompanied by reduced stress-related activity in the amygdala, a brain region crucial for emotional processing. However, attenuated amygdala activity was demonstrable only in subjects who were homozygous for the long allele of the 5-HTTLPR or the G variant of the TPH2 G-703T polymorphism, and not in carriers of short or T alleles. Moreover, the TPH2 polymorphism was a significant predictor of clinical placebo response, homozygosity for the G allele being associated with greater improvement in anxiety symptoms. Path analysis supported that the genetic effect on symptomatic improvement with placebo is mediated by its effect on amygdala activity. Hence, our study shows, for the first time, evidence of a link between genetically controlled serotonergic modulation of amygdala activity and placebo-induced anxiety relief.
IMPORTANCE Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively. OBJECTIVE To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([ 11 C]5-HTP) and 11 C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [ 11 C]DASB. DESIGN, SETTING, AND PARTICIPANTS We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex-and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [ 11 C]5-HTP PET imaging. We acquired [ 11 C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex-and age-matched healthy controls. Participants were recruited through newspaper advertisements.
A random sample of 1000 subjects (20-65 years of age) received a postal questionnaire regarding sick building syndrome (SBS), including the three-dimensional model of demand-control-support (DCS). The response rate was 70% (n = 695), and 532 were occupationally active. Female gender and atopy were the main predictors of symptoms. Eye symptoms were more common at low social support combined with strained work situation [odds ratio (OR) 2.37], and at high social support combined with active work situation (OR 3.00). Throat symptoms were more common at low social support combined with either passive (OR 1.86) or strained situation (OR 2.42). Tiredness was more common at low social support combined with either passive (OR 2.41), strained (OR 2.25), or active situation (OR 1.87), and at high social support combined with active work situation (OR 1.83). Low social support combined with either passive (P = 0.01) or strained job situation (P = 0.01) was associated with a higher symptom score (SC). The lowest SC was found at a relaxed work situation, irrespective of social support. In conclusion, female gender, low age, asthma, atopy and psychosocial work environment are associated with symptoms. The three-dimensional model can predict symptoms compatible with SBS, but in a more complex way than earlier research indicated. Practical Implications A multi-disciplinary approach, including psychosocial stress factors as well as personal factors such as gender, age, atopy and asthma, and indoor exposures, should be applied in studies on symptoms compatible with sick building syndrome (SBS). Males and females perceive psychosocial work conditions differently, and may react differently to job stressors. The psychosocial work environment can be as important as gender and atopy as a predictor of SBS symptoms.
The amygdala is a key structure in the pathophysiology of anxiety disorders, and a putative target for anxiolytic treatments. Selective serotonin reuptake inhibitors (SSRIs) and placebo seem to induce anxiolytic effects by attenuating amygdala responsiveness. However, conflicting amygdala findings have also been reported. Moreover, the neural profile of responders and nonresponders is insufficiently characterized and it remains unknown whether SSRIs and placebo engage common or distinct amygdala subregions or different modulatory cortical areas. We examined similarities and differences in the neural response to SSRIs and placebo in patients with social anxiety disorder (SAD). Positron emission tomography (PET) with oxygen-15-labeled water was used to assess regional cerebral blood flow (rCBF) in 72 patients with SAD during an anxiogenic public speaking task, before and after 6-8 weeks of treatment under doubleblind conditions. Response rate was determined by the Clinical Global Impression-Improvement scale. Conjunction analysis revealed a common rCBF-attenuation from pre-to post-treatment in responders to SSRIs and placebo in the left basomedial/basolateral and right ventrolateral amygdala. This rCBF pattern correlated with behavioral measures of reduced anxiety and differentiated responders from nonresponders. However, nonanxiolytic treatment effects were also observed in the amygdala. All subgroups, including nonresponders, showed deactivation of the left lateral part of the amygdala. No rCBF differences were found between SSRI responders and placebo responders. This study provides new insights into the brain dynamics underlying anxiety relief by demonstrating common amygdala targets for pharmacologically and psychologically induced anxiety reduction, and by showing that the amygdala is functionally heterogeneous in anxiolysis.
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