Neurobiological Mechanisms of Social Anxiety Disorder

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1558 Am J Psychiatry 158:10, October 2001

Reviews and Overviews

Neurobiological Mechanisms of Social Anxiety Disorder

Sanjay J. Mathew, M.D.

Jeremy D. Coplan, M.D.

Jack M. Gorman, M.D.

Objective: The authors critically surveyed

several preclinical and clinical neurobio-

logical models of social anxiety disorder.

Method: The authors reviewed the recent

literature regarding three animal models

of particular relevance to social anxiety.

They then examined the recent literature

concerning clinical neurobiological aspects

of social anxiety disorder, including the de-

velopmental neurobiology of anxiety, the

genetics of fear and social anxiety, and

challenge and imaging studies.

Results: The available animal models are

useful paradigms for understanding the

features of social subordination stress, at-

tachment behavior, and environmental

rearing, but they incompletely account for

the known neurobiology of human social

anxiety disorder. The clinical neurobiology

literature surveyed implicates specific

neurotransmitter system abnormalities,most notably of the dopamine system, but

largely ignores neurodevelopmental pro-

cesses and the functional interactions be-

tween neurotransmitters. Both heritable

factors and environmental stress factors

appear to be responsible for the onset of

social anxiety disorder.

Conclusions: Social anxiety disorder

should be conceptualized as a chronic

neurodevelopmental illness that might

represent a fully compensated state in

adulthood. Future investigations from this

perspective are discussed.

(Am J Psychiatry 2001; 158:15581567)

Social anxiety disorder, also known as social phobia, isa common and disabling psychiatric illness that is charac-

terized by an excessive fear and/or avoidance of situations

in which an individual feels scrutinized by others and is

fearful of a negative evaluation by others. Although it is the

most common of the DSM-IV anxiety disorders, there is a

dearth of clinical neurobiological research on social anxi-

ety disorder and few preclinical models. This review fo-

cuses on the generalized subtype, which involves the fearof a wide range of social situations, with the goal of pro-

posing several neurobiological mechanisms that may ac-

count for the symptoms of this disorder. We begin with an

overview of three nonhuman primate models that are par-

ticularly relevant to social anxiety. Next, we review recent

literature in the clinical neurobiology of social anxiety dis-

order, focusing on important findings in developmental

neurobiology and genetics. Our findings suggest that so-

cial anxiety disorder should be reconceptualized as a

chronic neurodevelopmental illness instead of an epi-

sodic de novo adult disorder, a semantic distinction with

important treatment implications.

Models Relevant to Social Anxiety

Investigating social anxiety disorder with animal mod-

els is more problematic than investigating the condi-

tioned-fear paradigm in rodents, which we used to under-

stand panic disorder (1), largely because the interactional

nature of the disorder is less amenable to laboratory study.

Nevertheless, we review three nonhuman primate models

that seem particularly relevant.

Subordination Stress Model

Like man, primates are particularly dependent on social

relationships, and laboratory-based behavioral observa-

tions can be readily conducted. Shively (2) conducted in-

formative nonhuman primate studies in social subordina-

tion and dominance in laboratory-housed female

cynomolgus monkeys. Behavioral observations revealed

that subordinates spent more time alone, fearfully scan-

ning their social environment, than dominants. Biologicalstudies of these subordinates revealed evidence of hyper-

active hypothalamic-pituitary-adrenal (HPA) axis activity,

impaired serotonergic functioning, and impaired dopa-

minergic neurotransmission. In a challenge study with

ACTH, social subordinates hypersecreted cortisol, reflect-

ing HPA axis activation. When investigators carried out the

fenfluramine challenge test (which causes release of sero-

tonin), laboratory-housed cynomolgus macaques exhib-

ited a blunted prolactin response, which suggests reduced

central serotonergic activity. These monkeys were more

socially withdrawn and spent less time in passive body

contact than those who showed a high prolactin response

(3). When investigators carried out a haloperidol chal-

lenge test with a dopamine antagonist that enhances pro-

lactin secretion through tubero-infundibular dopamine

pathways, reduced prolactin responses were observed in

subordinates (2). This result suggested a lowering of the

sensitivity of postsynaptic dopamine receptors in this

pathway in the subordinates. Consistent with the neu-

roendocrine data, a positron emission tomography (PET)

study (4) of subordinates showed decreased striatal dopa-

mine D2 receptor binding, which suggests abnormal cen-


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NEUROBIOLOGY OF SOCIAL ANXIETY

anxiety disorder and the broad autism phenotype (defined

as milder aspects of autism, including social and commu-

nication deficits and stereotypical repetitive behaviors).

These studies point to a shared biology of attachment,

which makes the neurobiology of animal attachment po-tentially more relevant to social anxiety disorder than pre-

viously acknowledged.

Numerous neurotransmitter systems have been investi-

gated clinically in subjects with autism and preclinically in

primate models of attachment and affiliation. Raleigh and

colleagues (23) showed that enhancement of serotonergic

function resulted in improved social affiliativeness in pri-

mates, whereas low serotonin levels promoted avoidance.

In separate but related work, free-ranging primates with

low levels of CSF 5-HIAA showed less social competence

and were more likely to emigrate at a younger age from

their social groups than primates with higher levels of CSF5-HIAA (24).

The brain opioid system was the first neurochemical

system to be implicated as a regulator of attachment be-

haviors in primates and other species. In one study of

nonhuman primates (25), 10 juvenile macaques living in

a stable social group with their mothers and other group

companion subjects were administered naloxone, an opi-

ate antagonist. The primates receiving naloxone made

more grooming solicitations and received more grooming

and increased their proximity with their mothers. Kalin et

al. (26) studied reunions of nonhuman primate infants

after separations from their mothers and demonstrated

that both infants and mothers who were administered

morphine showed a significant reduction in clinging be-

haviors, whereas those given naltrexone increased their

clinging. Finally, there was evidence of complex interrela-

tionships between endogenous opioid activity and other

affiliative neurotransmitter systems, as it was suggested

that opiate activity was increased by oxytocin injections

in the rat (27). Clinically, there is some evidence that

opioid abusers have high rates of social avoidance and

anxiety (28).

The neurohormone oxytocin is well established in the

initiation but not the maintenance of maternal behavior

and pair bonding (29), as well as in social interactions in

nonhuman primates (30). Recent data from Insel and

Winslow (29) demonstrated that a genetically engineeredmouse lacking oxytocin emitted few isolation calls and

had reduced social interactions. They hypothesized that

the neural substrates of attachment are those pathways

which couple social recognition (olfactory, auditory, and

visual stimuli) to the neural pathways for reinforcement,

such as the [dopaminergic] mesolimbic projections from

the ventral tegmental area to the nucleus accumbens and

prefrontal cortex (p. 888). It is known that dopaminergic

neurotransmission is implicated in brain reward pathway

projections. Social anxiety disorder, as Stein (31) sug-

gested, might therefore be an illness characterized by

dysfunction within the system(s) that evaluate(s) the risksand benefits of social affiliation (p. 1280) by employment

of brain reward pathways. Anatomically, many of these

disparate attachment pathways traverse the anterior cin-

gulate, a region recently implicated by functional mag-

netic resonance imaging (fMRI) in an aspect of the human

maternal-infant bond: the response to infant cries (32). In

summary, animal attachment models implicate not only

oxytocin, but varied serotonergic, opioid, and dopaminer-

gic pathways.

Although they are incomplete in explaining the varied

cognitive misappraisals observed in patients with social

anxiety disorder, preclinical attachment models provide a

useful construct for understanding the aberrant social af-

filiativeness seen in subjects with social anxiety disorder

and provide guides for future investigations of the clinical

neurobiology of the disorder. Unfortunately, the amount

of replicated data in primate attachment neurobiology is

extremely sparse, particularly in neuroimaging. Thus, the

direct applicability of these animal models to social anxi-

ety disorder is necessarily limited at this time. (See Table 1

for a summary of preclinical models of social anxiety

disorder.)

TABLE 1. Nonhuman Primate Models Relevant to the Study of Social Anxiety Disorder in Humans

Model Neurobiologic Alterations Brain Regions Clinical Correlations

Subordination stress Reduced serotonin act ivity Prefrontal cortex, raphe nuclei Blushing

Decreased striatal dopamine D2 binding Corpus striatum, nucleus accumbens,ventral tegmental area (midbrain)

Increased substance abuse

Hypothalamic-pituitary-adrenal axisactivation

Hippocampus, amygdala Anxiety and fear

Variable-foraging-demand

Increased CSF levels of corticotropin-releasing factor (CRF), homovanillicacid, and 5-hydroxyindoleacetic acid(5-HIAA); decreased cortisol levels

Hippocampus, amygdala, prefrontalcortex

Comorbid posttraumatic stressdisorder; behavioral inhibitionin children

Blunted growth hormone response toclonidine

Hypothalamic neurons of nucleusarcuatus, paraventricular CRF neurons

Other comorbid anxiety anddepressive symptoms

Attachment Lower 5-HIAA levels in CSF; increasedavoidant behaviors

Prefrontal cortex, raphe nuclei Social incompetence

Oxytocin system downregulation Diffusely in prefrontal cortex, limbicareas, postpituitary areas

Autistic or schizoid relationalpatterns; disruption of affiliation

Opiate system dysregulation; increasedendogenous opiates

Diffuse regions of prefrontal cortex andperiaqueductal gray matter

Increased social anxiety in opioidabusers


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Am J Psychiatry 158:10, October 2001 1561

MATHEW, COPLAN, AND GORMAN

Neurodevelopmental Issues

Neuroplasticity, Neurogenesis,

and Social Dominance

The explosion of research in neurodevelopment has af-

forded the opportunity of taking a specific animal model

of anxiety, such as one concerned with dominance or sub-

ordination stress, and investigating its neurobiological

correlates by means of in vivo neuroimaging or postmor-

tem tissue sampling. One of the more important findings

in human neurobiology in the past decade is accumulat-

ing evidence for the remarkable plasticity of the brain and

the development of neurogenesis in diverse brain regions,

such as the cortex, hippocampus, cerebellum, and olfac-

tory bulb (33). Gould et al. (34) demonstrated altered neu-

roplasticity in tree shrews in an enduring dominant-sub-

ordinate relationship derived from a social dominance

paradigm (35). Specifically, her group showed a rapid de-

crease in the number of new cells produced in the dentate

gyrus of subordinate tree shrews compared to those who

remained unexposed to a stressful experience (34). Thisfinding was more recently replicated in marmoset mon-

keys by using a resident intruder paradigm, a psychosocial

stress model similar to that of the dominant-subordinate

model for the tree shrews (36). At this time, we do not

know the nature of neuroplastic changes in the brains of

human infants with early signs and symptoms of social

anxiety; thus, the translational implications of stress-in-

duced decreases in granule cell production in animal

models is unknown. However, a recent study has shown

that granule neurons are potentially involved in hippo-

campal-dependent learning tasks (37) and that conse-

quent decreases in the number of granule neurons are

likely to alter adult hippocampal formation (37). Stressfulexperiences, which increase levels of circulating glucocor-

ticoids and stimulate hippocampal glutamate release (38),

might thus inhibit granule cell neurogenesis. In adult so-

cial anxiety, we hypothesize that excessive glutamatergic

transmission in hippocampal and cortical regions might

be a key component of the dysfunctional circuitry, and

successful treatments might serve to prevent the inhibi-

tion of neurogenesis while modifying glutamatergic neu-

rotransmission.

Although most animal studies have focused on hippo-

ampal formation, there is evidence that stressors affect

cortical neurons as well (39). Neuroplastic changes are

also dependent on levels of neurotrophins, such as nerve

growth factor, which is known to be differentially modu-

lated by experience (40). In fact, drugs such as the selective

serotonin reuptake inhibitors (SSRIs), useful in treating

social anxiety, are known to increase expression of brain-

derived neurotrophic factor in the hippocampus (41, 42).

Course and Neural Circuitry of Precursors

Given the remarkable developmental plasticity of key

neural structures, there is considerable interest in delin-

eating the fear and anxiety circuitry across the stages of

development (43, 44). Longitudinally, recent work has

confirmed that a significant number of children classified

as inhibited will develop generalized social anxiety by

young adulthood (45, 46). Kagan (47) noted that 4-month-

old infants who had a low threshold for becoming dis-

tressed and motorically aroused to unfamiliar stimuli

were likely to become fearful and subdued in early child-

hood. Similarly, children identified as behaviorally inhib-

ited at 21 months who remained inhibited at subsequent

follow-up visits at ages 4, 5.5, and 7.5 years, showed higher

rates of anxiety disorders than children who were not be-

haviorally inhibited (48), although the findings were not

specific for social anxiety. However, a more recent pro-

spective study by Pine et al. (43) has suggested a more spe-

cific association between childhood and adult social pho-

bia, a finding consistent with those of family studies

among adults (49).

The identification of neurobiological correlates to adult

social anxiety disorder in children helps validate clinical

and epidemiological observations linking behaviorally in-hibited children with adult patients (50). The most notable

neurobiological correlates of clinical observations have

been the brain laterality studies performed in high-reac-

tive and inhibited children (51, 52) and in animals (53).

Davidson (52, 54) demonstrated in infants and adults that

withdrawal-related emotions, such as anxiety, were asso-

ciated with activation of the right frontal region, whereas

left prefrontal cortex activation was related to approach-

related emotions. Adult patients with social anxiety disor-

der showed a large increase in activations in right anterior

temporal and lateral prefrontal scalp regions when antici-

pating making a speech in relation to comparison subjects

(52, 55). In related preclinical work, EEG recordings infearful rhesus macaques demonstrated relatively higher

right frontal lobe activity, elevated cortisol and CSF CRF

concentrations, and more intense defensive responses

(53, 56). Although these findings are interesting, they

might be relatively disorder nonspecific, in that Rauch et

al. (57) demonstrated increased activation in the right in-

ferior frontal cortex, among other regions, across three

anxiety diagnoses (obsessive-compulsive disorder [OCD],

PTSD, and simple phobia) in a PET symptom-provocation

paradigm. Thus, although the epidemiological links be-

tween behavioral inhibition and adult social anxiety disor-

der appear to be validated by common regional alterations

in brain activity, the biological associations might be dis-

order nonspecific.

Genetics of Social Anxiety Disorder

Although there is increasing evidence that social anxiety

disorder and its childhood variants, including behavioral

inhibition and shyness, have a strong familial basis, the

genetics of the disorder have not been adequately studied.

Several early studies (58, 59) established a familial link, but


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only for the generalized subtype (59). It was reported that

if a proband has a diagnosis of social anxiety disorder, the

percentage of first-degree relatives with the illness was

15%, which was greater than the 10% finding in subjects

with agoraphobia and less than the 31% seen in subjects

with simple phobia (49). Subsequently, a larger study (60)

showed that the generalized subtype was markedly in-

creased in frequency (approximately 10 times greater)

among first-degree relatives of generalized social phobic

probands. Another study (61) demonstrated that the chil-

dren of patients with social anxiety disorder were at an in-

creased risk of developing this disorder and other anxiety

disorders.

The low genetic concordance rates for social anxiety

disorder in monozygotic twins (62) have suggested that

genetics plays a limited role in its development. As we sug-

gested for panic disorder (1), what appears to be inherited

is a susceptibility to social anxiety, not the disorder itself.

Although no systematic genetic linkage studies employing

a genomic scan or search among candidate genes have

been conducted for social anxiety disorder so far, suchstudies are underway for panic disorder (63) and OCD

(64). Likewise, molecular genetic studies of candidate

genes for the several neurotransmitter systems implicated

in social anxiety, notably the serotonin transporter and

dopamine receptor and their various subtypes, have al-

lowed for associations between specific genes and behav-

ioral traits, such as harm avoidance and novelty seeking

(65, 66)characteristics relevant to the social anxiety dis-

order phenotype. Thus, genetic and family studies in so-

cial anxiety disorder are still in their infancy but support

longitudinal clinical data that are suggestive of links be-

tween childhood and adult variants of the disorder.

Clinical Neurobiology of Social Phobia

The two primary tools for the neurobiologist investigat-

ing social anxiety disorder have been pharmacological

probes and, more recently, neuroimaging. In examining

the clinical neurobiological literature, we attempt to high-

light data that replicate preclinical experiments, if possi-

ble, although few such studies have been performed.

Pharmacological Probes

Challenge studies have shown abnormalities in mono-

amine (dopamine, norepinephrine) and indoleamine (se-

rotonin) neurotransmission. Of the serotonergic studies,

Tancer et al. (10) reported an augmented cortisol response

to fenfluramine in patients with social anxiety relative to

comparison subjects, a finding similar to that observed in

subjects with panic disorder. Hollander et al. (67) reported

increased anxiety responses to the serotonergic probem-

CPP, but there were no notable neuroendocrine alter-

ations. In studying dopamine function, Tancers group

(10) did not find any abnormality of dopaminergic func-

tion when usingL-dopa as the pharmacological probe (see

Appendix 1 for a summary of dopaminergic abnormalities

observed in social anxiety disorder [6872]). Other probes

commonly used in studies of panic disorder, such as CO2,

lactate, pentagastrin, and epinephrine, generally have

produced an intermediate response, between those of pa-

tients with panic disorder and comparison subjects, in pa-

tients with social anxiety disorder (73, 74). A recent report

by Pine et al. (75) revealed a lack of association between

CO2 sensitivity and childhood social phobia, which is

consistent with studies finding no association between

childhood social phobia and adult panic disorder (76). We

conclude from these limited studies that there exists an

overlapping but distinct neurobiology of social anxiety

disorder and panic disorder.

Norepinephrine in Social Phobia

Since autonomic hyperarousal (manifested by flushing,

tachycardia, and tremulousness) is a common symptom

of patients with panic anxiety and social anxiety in perfor-

mance situations, understanding autonomic nervous sys-

tem function in these patients might shed light on the dys-functional circuitry involved in social anxiety disorder.

Stein et al. (77) performed an orthostatic challenge test in

patients with social anxiety disorder, panic disorder, and

healthy comparison subjects and found that the first

group had higher plasma levels of norepinephrine before

and after the challenge. This finding was not replicated in

a subsequent study comparing subjects with social phobia

with normal comparison subjects, and in fact there was a

suggestion of impaired parasympathetic (not sympa-

thetic) activity in the group with generalized social anxiety

disorder in relation to comparison subjects (78).

Limited data have suggested that the 2 adrenergicantagonist yohimbine increases social anxiety in patients

wi th soci al an xi et y di so rder an d is as soci at ed wi th

increased plasma 3-methoxy-4-hydroxyphenylglycol

concentrations (79). In contrast, Papp et al. (80) infused

intravenous epinephrine in patients with social anxiety

disorder and observed that only one out of 11 patients ex-

perienced observable anxiety, which suggests that an in-

crease in plasma epinephrine levels alone is inadequate

to cause social anxiety. Notably, Tancer et al. (81) ob-

served a reduced GH response to intravenous, but not

oral, clonidine, an 2 adrenergic agonist. The blunted GH

response to clonidine is also observed in subjects with

panic disorder, major depressive disorder, and general-

ized anxiety disorder and is thought to possibly reflect re-

duced postsynaptic adrenergic-2 receptor functioning

owing to norepinephrine overactivity. Alternatively, Co-

plan et al. (16) hypothesized that the blunted GH re-

sponse to clonidine or other GH secretagogues may re-

flect an increased central activity of the fear-inducing

neuropeptide CRF. In summary, although there are lim-

ited data on the role of autonomic nervous system dys-

function in social anxiety, the autonomic hyperarousal


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cessfully treated patients with early intervention and

successfully treated patients who were managed only in

adulthood would be of interest, as would analyses of treat-

ment responsivity across comorbid subgroups. Such sec-

ondary prevention studies might be the natural extension

of longitudinal studies of behaviorally inhibited children.

Second, a better understanding of the developmental

neurobiology of the brain regions important in social anx-

iety, such as the amygdala and striatum, and their interac-

tions with the cortex, ascending monoaminergic systems,

and hippocampus, clearly is necessary. Related to this ob-

jective neurodevelopmental genetic research, we should

attempt to target susceptibility genes for the broad social

anxiety phenotype. We have a limited understanding of

the interaction between genetic vulnerability and stress

exposure in socially anxious individuals. Cross-fostering

paradigms in which primates raised under the variable-

foraging-demand condition are randomly assigned to the

offspring of either socially withdrawn or socially compe-

tent mothers might help answer the question of whether

stress exposure has a more pernicious effect on geneticallysusceptible individuals.

Third, MRS imaging can be used to study neurotrans-

mitter systems that have not received extensive attention

in social anxiety, such as the glutamatergic system. Pre-

clinical rodent models contend that prefrontal cortical

efferents, either directly or by means of thalamic nuclei ef-

ferents, use the glutamatergic system as a primary source

of neuronal stimulation of the fear neurocircuitry, which

originates from the central nucleus of the amygdala and

bed nucleus of the stria terminalis (93, 94). Stressful situa-

tions faced by a person with social anxiety disorder might

stimulate glutamate release in hippocampal (38) and

other brain regions. In this light, agents that attenuateglutamatergic neurotransmission should reduce anxiety

levels, as well as the concomitant biochemical alterations

associated with stress. Clinical investigations of gluta-

matergic antagonists might be warranted, since the SSRIs

have been only partially successful in the treatment of this

disorder. MRS also allows investigators to explore neu-

rotransmitter interactions in vivo, such as the interaction

between serotonin and glutamate, elegantly recently ex-

plored by Rosenberg et al. (95) in pediatric OCD.

Finally, an important limitation of our understanding of

the neurobiology of social anxiety is the difficulty in dis-

criminating what findings are a response to anxiety or

stress and what are true risk factors for the development of

anxiety. It is of importance that the clinical neuroendocri-

nology of social anxiety suggests a fully compensated state

in adulthood, in that no peripheral (i.e., HPA axis) pathol-

ogy is evident. In this light it would be of interest to study

patients with a recent onset of social anxiety disorder ver-

sus patients with distant onset in order to gauge which

neuroendocrine findings persist and which ones change

over the course of the illness. Another important contrast

would be to study patients with active social anxiety disor-

der versus patients in remission. A more refined under-

standing of this compensatory phenomenon might offer

valuable insights not only into social anxiety disorder but

into other psychiatric disorders with prominent neuroen-

docrine abnormalities as well.

Received July 13, 2000; revision received Jan. 10, 2001; accepted

Jan. 18, 2001. From the New York State Psychiatric Institute, the De-

partments of Psychiatry and Clinical Psychobiology, College of Physi-

cians and Surgeons, Columbia University. Address reprint requests to

Dr. Mathew, Department of Psychiatry, College of Physicians and Sur-

geons, Columbia University, 1051 Riverside Dr., Box 84, New York, NY

10032; [email protected] (e-mail).

Funded in part by NIH grant MH-00416 and Center for the Neural

Systems of Fear and Anxiety grants MH-58911 and MH-00416 (to Dr.

Gorman), a Scientist Development Awards for Clinicians grant MH-

01039 (to Dr. Coplan), and a National Alliance for Research on Schizo-

phrenia and Depression Young Investigator Award and a Psychiatric

Institute Research Support grant (to Dr. Mathew).

The authors thank Marc Laruelle, M.D., for his contributions.

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APPENDIX 1. Preclinical and Clinical Evidence for Dopa-minergic Dysregulation in Social Anxiety

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Neurobiological Mechanisms of Social Anxiety Disorder

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