Social anxiety disorder (SAD), one of the most common anxiety disorders, is characterized by an intense fear of social situations.
A new brain imaging study provides evidence that SAD is associated with an overactive serotonin system.
Key Takeaways:
- Using PET imaging, researchers found increased serotonin synthesis and reuptake in multiple brain regions in patients with SAD compared to healthy controls.
- The regions affected included the amygdala, raphe nuclei, striatum, thalamus, hippocampus, insula cortex and anterior cingulate cortex – areas involved in emotion processing and regulation.
- In SAD patients, serotonin synthesis in the amygdala correlated with severity of social anxiety symptoms, suggesting a link between serotonin and anxiety levels.
- The findings point to an overactive presynaptic serotonin system in SAD, contradicting theories that SAD is caused by low serotonin.
Source: JAMA Psychiatry
The Serotonin Hypothesis of Anxiety
The neurotransmitter serotonin has long been implicated in anxiety, but its exact role remains unclear.
Selective serotonin reuptake inhibitors (SSRIs), which increase serotonin levels, are effective in treating SAD – suggesting low serotonin may underlie this disorder.
However, SSRIs also temporarily increase anxiety when first administered, and animal research shows elevated serotonin can increase anxious behaviors.
This led researchers to hypothesize SAD may actually be associated with serotonin excess, rather than deficiency.
The brain’s serotonin system is complex, involving presynaptic synthesis and reuptake as well as postsynaptic receptors.
Imaging studies allow researchers to directly measure different aspects of this system in the living brain.
Measuring Brain Serotonin Synthesis and Reuptake
In this study, researchers used PET imaging with two radiolabeled tracers to compare serotonin synthesis and reuptake between SAD patients and healthy controls.
The tracer [11C]5-HTP allows measurement of the serotonin synthesis rate by tracking metabolism of the amino acid tryptophan into serotonin.
The tracer [11C]DASB binds to the serotonin transporter, allowing a quantification of serotonin reuptake.
44 SAD patients and 35 matched controls underwent PET scanning with one or both tracers.
Researchers analyzed the PET data to compare serotonin synthesis and reuptake between groups in regions involved in emotional processing.
High Serotonin Synthesis and Reuptake in SAD
The PET scans revealed increased [11C]5-HTP uptake and/or [11C]DASB binding in SAD patients compared to controls in the amygdala, raphe nuclei, striatum, thalamus, hippocampus, insula cortex and anterior cingulate cortex.
This suggests higher serotonin synthesis and reuptake rates – two markers of presynaptic serotonin activity – in these regions in SAD patients.
The raphe nuclei in the brainstem contain the cell bodies of serotonin neurons.
The striatum, thalamus, hippocampus, insula and anterior cingulate are areas innervated by serotonin projections from the raphe.
The amygdala, in particular, is densely innervated by serotonin fibers.
Notably, in the SAD group, serotonin synthesis rate in the amygdala positively correlated with patients’ scores on a scale measuring SAD severity.
This links elevated amygdalar serotonin to greater social anxiety symptoms.
Supporting Serotonin Excess in SAD
The findings add to evidence that SAD is characterized by excessive, rather than deficient serotonin signaling.
Previous studies found reduced serotonin 1A receptor binding in SAD patients, suggesting impaired serotonin inhibitory feedback.
1A receptors normally keep serotonin activity in check.
Downregulation of these inhibitory receptors could lead to overexpression of serotonin synthesis and reuptake, as well as greater serotonin release.
SSRIs may treat SAD by desensitizing these overly reactive serotonin pathways over time, rather than directly reversing a serotonin deficiency.
High Serotonin Levels: Presynaptic Synthesis in Anxiety Disorders
Similar patterns of high presynaptic serotonin have been reported in other anxiety disorders, including panic disorder and OCD.
This points to shared serotonergic abnormalities among these conditions.
In contrast, low serotonin synthesis and reuptake have been linked to depression.
This highlights differences in serotonin dysfunction between anxiety and mood disorders.
While the current study does not prove causation, the authors hypothesize that downregulated 1A autoreceptors lead to excessive serotonin neuronal firing.
This triggers compensatory increases in synthesis and reuptake.
However, the relationship between different aspects of serotonin neurotransmission is complex, and changes in one part of the system likely cause ripple effects across the others.
Study Limitations and Future Directions
A limitation is that serotonin synthesis and reuptake were measured in separate SAD cohorts, precluding analysis of how these measures directly correlate within individuals.
Some concerns also exist regarding the specificity of the [11C]5-HTP tracer for measuring serotonin synthesis.
However, evidence suggests it accurately reflects serotonin metabolism.
Future studies should investigate whether excessive serotonin activity normalizes in SAD patients showing symptom improvement with SSRI therapy.
This could help confirm if serotonin abnormalities play a causal role.
Research is also needed to further unravel interactions between the various components of the serotonin system in SAD and other anxiety disorders.
Serotonin Abnormalities in Social Anxiety Disorder
Using PET molecular imaging, this study demonstrated increased serotonin synthesis and reuptake in multiple emotion processing brain regions in patients with social anxiety disorder.
The findings point to systemic overactivity of the presynaptic serotonin system in this disorder.
They provide insight into the neurochemical underpinnings of social anxiety.
Uncovering the biological roots of anxiety disorders is key to developing more targeted, effective treatments for these often-debilitating conditions.
Research efforts should continue to map out serotonin abnormalities and other neural circuit dysfunctions underlying social anxiety and related disorders.
References
- Study: Serotonin synthesis and reuptake in social anxiety disorder: a positron emission tomography study
- Authors: Andreas Frick et al. (2015)
