Serotonin Synthesis and Reuptake in Social Anxiety Disorder

Abstract

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.

Serotonin States and Social Anxiety

“…Thus, it is not at first clear why anxiety would result when increased serotonin synthesis is accompanied by increased SERT availability (Figure, B). Frick et al 5 speculate that potentiated serotonergic neuronal activity (ie, firing rates) and concomitantly increased extracellular serotonin levels might constitute the key underpinnings. How, then, to reconcile the findings of increased SERT availability reported by Frick et al 5 with findings of mice and rats with geneticallyengineereddeficienciesinSERTassimilarlycontributingtoheightened anxiety-related states?…”

“…An answer is to focus on the outcome for, arguably, the most important aspect of the serotonin system: extracellular serotonin signaling levels. Frick and coauthors 5 hypothesize that extraneuronal serotonin levels are increased in individuals with social anxiety disorder as a result of potentiated serotonin synthesis and, furthermore, that increased SERT binding is a neuroadaptive response to higher extracellular serotonin levels. Mice having a primary defect in SERT expression similarly exhibit increased extracellular serotonin levels; however, in this case, increased extracellular serotonin levels were derived directly from a lack of reuptake.…”

“…This fact, in concert with the observation that social anxiety disorder is a frequent precursor to major depressive episodes and is the most common comorbid disorder in patients with anxious depression, has motivated interest in identifying a serotonergic basis for social anxiety disorder. In a study reported in this issue, Frick et al 5 use positron emission tomography to measure what they consider to be indices of serotonin synthesis and serotonin transporter density. They find that both measures are increased in patients with social anxiety disorder.…”

“…Serotonin neurons number fewer than 300 000 in humans (0.0003% of brain neurons) and are clustered in 9 brainstem groups called the raphe nuclei. The 3 most rostral clusters project forward to anterior brain structures, including the amygdala, striatum, hippocampus, thalamus, insula, and anterior cingulate cortex studied by Frick et al 5 These authors administered a radioactive serotonin precursor with a short half-life ([ higher in individuals with social anxiety disorder (Figure, B). Two processes control serotonin neurotransmission.…”

“…Reuptake, which largely occurs by serotonin transporters (SERT), further controls extracellular serotonin levels. In the study by Frick et al, 5 SERT density was estimated from [ 11 C]DASB binding potential and was higher in patients with social anxiety disorder than in healthy controls (Figure, B).…”