Social Anxiety Disorder: Causes, Genetics, and Treatments

Subordination Stress Model

Primates depend on establishing social relationships, and like humans, they can be studied through laboratory assessments. Studies focusing on nonhuman primates in informal settings — specifically concerning dominance and subordination — targeted female cynomolgus monkeys. These studies established that subordinate animals dedicated more time living alone, scanning their social world with apparent fear. This behavior was directly opposite to that displayed by dominant animals. Biological analysis of subordinates further revealed hyperactive hypothalamic-pituitary-adrenal (HPA) axis activity, impaired dopaminergic neurotransmission, and disrupted serotonergic functions. A separate challenge study on socially subordinate animals registered HPA axis activation and hyper-secreted cortisol.

A challenge test using fenfluramine on housed cynomolgus macaques showed a low prolactin response, indicating a reduction in central serotonergic activity. These monkeys' social strata were associated with low social interactions and reduced body contact compared to those with high prolactin activity. A haloperidol test using a dopamine antagonist — which promotes prolactin secretion into the tuberoinfundibular pathways — exhibited prolactin reduction in subordinates (Shively, 1998). The implication of these results is a reduced postsynaptic dopamine receptor response in subordinates' pathways. Positron emission tomography studies registered reduced striatal dopamine D2 binding consistent with the neuroendocrine data, indicating abnormal neurotransmission in central dopaminergic circuits. These results parallel single-photon emission computerized tomography (SPECT) findings conducted on humans exhibiting anxiety disorder (Mathew, Coplan & Gorman, 2001, p. 1558).

Studies conducted on wild, socially subordinate baboons indicated neuroendocrine abnormalities similar to those found in depressed and anxious humans. Both hypercortisolemia and resistance to inhibitory feedback from dexamethasone were also registered. Subordinate male baboons were also found to contain lower insulin-like growth factor 1 levels than dominant males (Sapolsky & Spencer, 1997). These findings help explain the observed relationship between anxiety disorder and short stature (Mathew, Coplan & Gorman, 2001).

Variable-Foraging-Demand Model

The variable-foraging-demand model is also applicable in nonhuman primates. The model was developed by Paully and Rosenblum to produce non-assertiveness and social timidity by exposing nursing mothers to unpredictable foraging-demand situations, which subsequently invoked uneven attachment patterns in their infants (Rosenblum & Paully, 1984). Adult animals raised under demanding foraging conditions showed stable increases in social timidity compared to control subjects reared under predictable conditions. This was evident in behaviors such as reduced species-typical huddling, increased subordination, and avoidance of antagonistic encounters.

From a biological perspective, subjects in the variable-foraging-demand model displayed elevated levels of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Only those in the foraging model group showed significant correlations between CRF and both 5-HIAA and HVA levels, suggesting a functional connection between CRF status and both the serotonergic and dopaminergic systems. Additionally, elevated CRF levels in this group were closely correlated with reduced growth hormone development and a blunted response to the α2 adrenergic agonist clonidine. A further correlation was observed between anxiety reactivity and yohimbine, an α2 antagonist (Mathew, Coplan & Gorman, 2001).

A neurochemical analysis revealed significant relevance to social anxiety disorder through the associated alteration of dopaminergic CSF metabolites in primates housed under the foraging model. This aligns with various dopaminergic abnormalities found in human patients exhibiting social anxiety disorder. Behaviorally, young primates in variable-foraging-demand conditions exhibited pronounced behavioral inhibition, including elevated heart rates, raised stress levels, and increased salivary cortisol. Behavioral inhibition also correlated with elevated total norepinephrine activity. These findings suggest that affective environmental stress may shift both behavior and neurobiology in the direction of socially anxious characteristics (Mathew, Coplan & Gorman, 2001, p. 1559).

Animal Attachment Models

Historically, impaired attachment behavior has been closely linked with schizoid and autistic disorders. The key distinction between patients with those disorders and those with social anxiety disorder lies in their desire for social connection. Patients with social anxiety disorder desire attachments and connections but fear the associated interactions. In contrast, individuals with schizoid or autistic disorders lack interest in affiliative relationships entirely. Given these differences, attachment models offer limited direct contribution to understanding social anxiety disorder (Mathew, Coplan & Gorman, 2001).

Various studies have examined the role of neurotransmitter systems in affiliation and attachment among people with autism. Enhanced serotonergic activity was associated with increased affiliative characteristics in primates, while reduced serotonin levels led to social avoidance. In a related study, free-ranging primates with reduced CSF 5-HIAA levels demonstrated lower social competence and a greater tendency to leave their social groups at a young age, compared to those with higher CSF 5-HIAA levels (Mehlman et al., 1995).

Although preclinical models are limited in their explanatory reach regarding social anxiety disorder, they do offer important constructs for understanding aberrant social behavior among those with anxiety disorders (Raleigh, Brammer & McGuire, 1983). They also provide a platform for advancing future neurobiological research. One significant limitation is the scarcity of data available for replication. At this time, the direct application of such animal models to social anxiety disorder research remains constrained (Mathew, Coplan & Gorman, 2001).

Genetic, Environmental, and Lifestyle Risk Factors

Genetic Factors

Low, Cui, and Merikangas (2008) conducted a study on 1,053 parents affected by social anxiety disorder (SAD), published in Biological Psychiatry. Their analysis revealed a heightened risk of acquiring SAD, particularly within the first five years of early adolescence. The research identified three parental groups believed to produce offspring at elevated risk of developing the disorder: parents with no history of mental disorders, parents with a history of mental illness but not social phobia, and parents with a complete SAD diagnosis (Sundaram, 2019).

Additional genetic studies examined risk factors associated with SAD (Lebowitz et al., 2016; Hitchcock, Chavira & Stein, 2009; Sundaram, 2019) and revealed the following: shyness in children correlates with shyness in biological mothers; children of SAD-affected parents may develop social anxiety disorders through observational learning; and the rate of SAD occurrence is higher in monozygotic (genetically identical) twins than in dizygotic (fraternal) twins, based on data from 2,163 female twins with documented anxiety (Sundaram, 2019).

Several specific genes have been identified as potential contributors to SAD development:

SLC6A4 gene: The SLC6A4 gene encodes the serotonin transporter (also known as SERT or 5-HTT). Research has demonstrated a strong association between this gene and SAD development, with SLC6A4 and its associated single nucleotide polymorphisms (SNPs) contributing significantly to SAD risk (University of Bonn, 2017). Defects in serotonin transport have been linked with social anxiety disorder (Frick et al., 2015). Because serotonin plays a crucial role in mood regulation, blockages in neurotransmitter release can cause serotonin imbalances that lead to anxiety disorders and conditions such as depression (Sundaram, 2019).

ADRB1 gene: Also known as the beta-1 adrenergic receptor (β1 adrenoreceptor), ADRB1 has been associated with the development of SAD, though scientific evidence directly confirming this association remains limited (Sundaram, 2019).

CRF receptor gene: Corticotropin-releasing factor (CRF) is a genetic component found within the CRHR2 CRF receptor. Genetic mutations in CRHR2 have been linked to social anxiety, as they inhibit the binding process between CRF and CRF2 receptors — a process critical to stress reduction (Reul & Holsboer, 2002). The gene encoding regulator of G protein signaling 2 (RGS2) is a quantitative trait gene that influences anxiety behavior in mice, making its human ortholog a compelling candidate gene for human anxiety phenotypes (Smoller et al., 2008). Some documentation has associated the RGS2 gene with SAD, though details remain limited (Sundaram, 2019).

Environmental Factors

SAD is associated with persistent fear of performing in social environments. These characteristics arise from both environmental conditions and the etiological features of the disorder.

Parenting factors: Evidence supports parent-child interactions as one of the predisposing factors for SAD. Research indicates that early-onset SAD is more closely tied to parenting factors than to other anxiety disorders. Parents can model negative social responses, exposing children to fears of negative judgment. Consistent with this view, SAD patients report that during their development, their parents placed strong emphasis on the appearance and opinions of others (Norton & Abbott, 2017; Khetrapal, 2019).

Parents who are overcontrolling and overprotective create restrictive environments that undermine children's social autonomy and self-efficacy, while also suppressing the development of social skills. This parenting style conveys to children that they are incapable of overcoming challenges without protection. Conversely, parents who encourage children to manage difficult situations independently foster a sense of social competence and significantly reduce SAD risk — an effect demonstrated in children as young as four years old (Majdandzic et al., 2014).

Negative and traumatic life experiences: SAD has also been linked to difficult or traumatic experiences. While SAD itself can lead to subsequent trauma, research indicates that prior exposure to adversity accelerates SAD-related risk, including the development of psychopathology (Smoller et al., 2008). SAD has been more strongly associated with childhood neglect and emotional abuse than with other forms of trauma such as physical or sexual abuse (Norton & Abbott, 2017).

Lifestyle Factors

People experiencing social anxiety express it differently, and symptoms do not necessarily manifest across all social situations. In familiar, friendly environments — such as those involving close friends, family members, or well-known colleagues — symptoms may not appear at all. When asked to speak publicly on a subject within their area of expertise, individuals with SAD may perform competently. However, in other contexts, the same individuals may experience significant anxiety and distress, even in situations that present no objective threat (Bridges to Recovery, n.d.).