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Neuroscience and Psychiatry |

Serotonin States and Social Anxiety

Murray B. Stein, MD, MPH1,2,3; Anne M. Andrews, PhD4,5,6
[+] Author Affiliations
1Department of Psychiatry, University of California–San Diego, La Jolla
2Department of Family Medicine and Public Health, University of California–San Diego, La Jolla
3Veterans Affairs San Diego Healthcare System, San Diego, California
4Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, Los Angeles, California
5Department of Chemistry and Biochemistry, Hatos Center for Neuropharmacology, Los Angeles, California
6Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
JAMA Psychiatry. 2015;72(8):845-847. doi:10.1001/jamapsychiatry.2015.0486.
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This Neuroscience and Psychiatry article discusses the role in social anxiety of a novel disrupted regulatory sequence in serotonin neurochemistry resulting from overactive serotonin signaling.

Social anxiety disorder is characterized by fear and avoidance of situations in which an individual believes he or she may be subject to scrutiny and at risk for embarrassment or humiliation. It is the most common of the anxiety disorders, affecting more than 5% of the general population, with an early age at onset that is frequently associated with high rates of depressive comorbidity.1 Social anxiety disorder is frequently treated pharmacologically with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors, several of which are approved by the US Food and Drug Administration for this indication. Nonetheless, only 30% to 40% of patients have full and satisfactory responses to these agents.2 Attempts have been made to enable genetic prediction of response to SSRIs in patients with social anxiety disorder,3 but such efforts are still in the early stages and have, to our knowledge, yet to be replicated.

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Serotonin States Associated With Social Anxiety

A, Serotonin (5-HT) is synthesized from l-tryptophan by the rate-limiting enzyme tryptophan hydroxylase (TPH) to produce 5-hydroxytryptophan (5-HTP) followed by amino acid decarboxylase (AADC). After sequestration by vesicle monoamine transporters (VMAT), serotonin is released in response to neuronal firing. Extracellular serotonin interacts with receptors (eg, 5-HT1A receptors, which function as heteroreceptors and autoreceptors, the latter providing negative feedback in raphe networks). Serotonin transporters (SERT) remove serotonin for vesicular repackaging or catabolism by monoamine oxidase (MAO) into 5-hydroxyindoleacetic acid (5-HIAA). B, Using positron emission tomography, Frick et al5 find that [11C]5-HTP influx is increased, which is interpreted as an indicator of increased serotonin synthesis. Moreover, [11C]DASB binding potential is increased, suggesting greater numbers of plasma membrane SERT in social anxiety disorder. C, By contrast, mice with constitutively reduced SERT show increased anxiety-related behavior and are characterized by increased serotonin synthesis, decreased intracellular (vesicular) serotonin levels, higher extracellular serotonin levels, and desensitized 5-HT1A autoreceptor function. LNAAT indicates large neutral amino acid transporter.

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