Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Social Sciences 97
From Epidemiology to Brain Function
ACTA UNIVERSITATIS UPSALIENSIS
Dissertation for the Degree of Doctor of Philosophy in Psychology presented at Uppsala University in 2000
Furmark, T. 2000. Social Phobia. From Epidemiology to Brain Function. Acta Universitatis Upsaliensis.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Social Sciences 97. 72 pp. Uppsala. ISBN
Social phobia is a disabling anxiety disorder characterized by an excessive fear of negative evaluation in social
situations. The present thesis explored the epidemiology and neurobiology of the disorder. By means of a mailed
questionnaire, the point prevalence of social phobia in the Swedish general population was estimated at 15.6%.
However, prevalence rates varied between 1.9 and 20.4% across the different levels of distress and impairment used
to define cases. Thus, although social anxiety is widespread within the community, the precise diagnostic boundaries
for social phobia are difficult to determine. Social phobia was associated with female gender, low educational
attainment, psychoactive medication use, and lack of social support. A cluster analysis revealed that subtypes of
social phobia mainly differed dimensionally on a mild-moderate-severe continuum, with number of cases declining
with increasing severity. Public speaking was the most common social fear in all groups of social phobics and in the
population at large.
In the neurobiological studies, positron emission tomography was used to examine brain serotonin
metabolism and changes in the regional cerebral blood flow (rCBF) response to public speaking stress following
treatment with a selective serotonin reuptake inhibitor (SSRI) or cognitive-behavioral group therapy. Social phobics
exhibited lowered serotonin turnover, relative to non-phobics, mainly in the medial temporal cortex including the
bilateral rhinal and periamygdaloid regions. Symptom improvement with cognitive-behavioral- as well as SSRI-
treatment was accompanied by a reduced rCBF-response to public speaking in the amygdala, hippocampus and
adjacent temporal cortex, i.e. regions that serve important functions in anxiety. Thorough suppression of rCBF in
limbic brain regions was associated with favorable long-term treatment outcome. These results provide neuroimaging
evidence for a presynaptic serotonergic dysfunction in social phobia and for a common neural mechanism whereby
psychological and pharmacological anti-anxiety treatments act.
Key words: Anxiety, brain, epidemiology, fear, neuroimaging, neurotransmitters, positron emission tomography,
prevalence, serotonin, social phobia, subtypes, treatment.
Tomas Furmark, Department of Psychology, Uppsala University, Box 1225, SE-751 42 Uppsala, Sweden
Tomas Furmark 2000
Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2000
This thesis is based on the following papers, which will be referred to in the text by their Roman
I. Furmark, T., Tillfors, M., Everz, P.-O., Marteinsdottir, I., Gefvert, O. & Fredrikson, M.
(1999). Social phobia in the general population: prevalence and sociodemographic profile.
Social Psychiatry and Psychiatric Epidemiology, 34, 416-424.
II. Furmark, T., Tillfors, M., Stattin, H., Ekselius, L., & Fredrikson, M. (2000). Social phobia
subtypes in the general population revealed by cluster analysis. Psychological Medicine, 30,
III.Marteinsdottir, I., Furmark, T., Tillfors, M., Ågren, H., Hartvig, P., Fredrikson, M., Långström,
B., Fischer, H., Antoni, G., & Hagberg, G. (2000). Presynaptic serotonin imaging in social
phobia using [11C]-5-hydroxy-L-tryptophan and positron emission tomography (Manuscript).
IV.Furmark, T., Tillfors, M., Marteinsdottir, I., Fischer, H., Pissiota, A., Långström, B., &
Fredrikson, M. (2000). A common neural pathway for serotonergic drug therapy and cognitive-
behavioral treatment of social anxiety. (Submitted).
Reprints were made with permission from Steinkopff Verlag (study I) and Cambridge University
Press (study II).
‘What came over you?’ asked Falk. ‘Had you taken leave of
‘Yes, I think I had. I had worked at my speech for almost six
weeks and I knew exactly what I was going to say, but when
I got up there and saw all those eyes, everything went to
pieces. All my carefully constructed arguments broke down
like scaffolding; I felt the ground under my feet give way
and my thoughts whirled. Was it very crazy?’
- from August Strindberg’s “The Red Room”
(Dent: London, 1879/1967, p. 224)
TABLE OF CONTENTS
ABBREVIATIONS USED IN TEXT............................................................................................7
1. INTRODUCTION ......................................................................................................................8
1.1 About this thesis .....................................................................................................................8
1.2. The diagnosis of social phobia ..............................................................................................8
1.2.2. Historical perspectives on the diagnosis.........................................................................9
1.3 Characterizing psychopathology...........................................................................................10
1.3.1 Feared situations............................................................................................................10
1.3.3 Age of onset and natural course.....................................................................................12
1.3.4 Other associated features ...............................................................................................13
1.3.5 Diagnostic and conceptual issues ..................................................................................14
1.4 Etiology: Some factors related to the origins of social phobia.............................................15
1.4.1 Genetic factors...............................................................................................................15
1.4.2. Temperamental factors .................................................................................................16
1.4.3. Conditioning and ethological factors............................................................................16
1.4.4. Family factors...............................................................................................................17
1.4.5. Birth order.....................................................................................................................17
1.4.6. Peer-rejection and social isolation................................................................................17
1.4.7. A multifactorial approach.............................................................................................17
1.5 Treatment: Major Research findings ....................................................................................18
1.5.1 Pharmacological treatments...........................................................................................18
1.5.2 Psychological treatments ...............................................................................................19
1.5.3 Psychological treatments compared and combined with pharmacotherapy ..................19
1.5.4 How effective are “effective” treatments?.....................................................................20
2. BACKGROUND TO THE EMPIRICAL STUDIES ............................................................21
2.1 Background to study I and II.................................................................................................21
2.1.1 The epidemiology of social phobia: ..............................................................................21
2.1.2 The issue of social phobia subtypes...............................................................................25
2.2 Background to study III and IV ............................................................................................27
2.2.1 Neurobiological correlates to anxiety............................................................................27
2.2.2 Serotonin and anxiety ....................................................................................................31
2.2.3 Brain mechanisms in anti-anxiety treatments................................................................32
2.2.4 Neurobiological studies of social phobia.......................................................................34
3. THE EMPIRICAL STUDIES .................................................................................................35
3.1 Empirical studies on the epidemiology and subtypes of social phobia ................................35
3.1.1 Study I............................................................................................................................35
3.1.2 Study II ..........................................................................................................................38
3.2 Empirical studies on brain function in social phobia ...........................................................40
3.2.1. Study III ........................................................................................................................40
3.2.2 Study IV.........................................................................................................................42
3.3. Discussion of the individual studies....................................................................................45
3.3.1 The epidemiological studies ..........................................................................................45
3.3.2 The neurobiological studies...........................................................................................47
3.4 Overall discussion.................................................................................................................50
5. REFERENCES .........................................................................................................................53
ABBREVIATIONS USED IN TEXT
ANOVA Analysis of variance
APA American Psychiatric Association
APD Avoidant personality disorder
BA Brodmann area
11C Carbon-11 (radio isotope)
CBGT Cognitive-behavioral group therapy
CCK-4 Cholecystokinin tetrapeptide
CIDI the Composite International Diagnostic Interview
CRF Corticotropin-releasing factor
df Degrees of freedom
DIS the Diagnostic Interview Schedule
DIP-Q the DSM-IV and ICD-10 Personality Disorder Questionnaire
DSM-III the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition
DSM-III-R the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition revised
DSM-IV the Diagnostic and Statistical Manual of Mental Disorders, 4th edition
ECA the Epidemiologic Catchment Area research program
GAF Global assessment of functioning
H215O 15-oxygen radiolabeled water
5-HIAA 5-hydroxyindoleacetic acid
5-HT 5-hydroxytryptamine (serotonin)
ICD-10 International Classification of Diseases and Related Health Problems, 10th ed.
LSD Least significant difference
MAOIs Monoamine oxidase inhibitors
MBq mega Becquerel
NCS the National Comorbidity Survey
OCD Obsessive-compulsive disorder
PAG Periaqueductal gray
PCA Principal component analysis
PRCS the “Personal Report of Confidence as a Speaker” (questionnaire)
PET Positron emission tomography
rCBF Regional cerebral blood flow
ROI Region of interest
SD Standard deviation
SCID the Structural Clinical Interview for Psychiatric Disorders
SSRI Selective serotonin reuptake inhibitor
SIAS the “Social Interaction Anxiety Scale”
STAI-S Spielberger's State Anxiety Inventory
SPS the “Social Phobia Scale”
SPSQ the “Social Phobia Screening Questionnaire”
SVC Secondary visual cortex
WL Waiting-list control group
1.1 About this thesis
Anxiety is an unwelcome, agonizing, and disabling companion in life for 27.4 million people
each year in the USA (Greenberg et al., 1999). Anxiety is however not only a hindering barrier for
the individual, but also a significant problem for society at large. In 1990, the annual societal cost
of anxiety disorders in the US (e.g., in terms of psychiatric service use, mortality, lost
productivity, or other workplace costs) was estimated at $42.3 billion, equivalent to $63.1 billion
in 1998 dollars (Greenberg et al., 1999). Hence, it is difficult to overstate the importance of
research aimed at better understanding of the symptoms, causes, treatment, and prevention of
This thesis is about social phobia, which is arguably the most common of all anxiety
disorders (Jefferys, 1997), discerned by a profound fear of being observed or evaluated in various
social settings. The thesis is based on four empirical studies with two major themes. The first
theme deals with epidemiology, i.e. the commonness of social phobia and subtypes of the
disorder. The second theme concerns brain functioning with emphasis given to neurotransmitter
abnormalities and treatment effects on brain activity. The outline of the empirical studies is
preceded by an introductory section, which describes the diagnosis and characterizing
psychopathology of social phobia, its etiology and susceptibility to psychological and
1.2. The diagnosis of social phobia
In the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
social phobia (also listed as social anxiety disorder) is defined as a “marked and persistent fear of
one or more social or performance situations in which the person is exposed to unfamiliar people
or possible scrutiny by others” (American Psychiatric Association [APA], 1994, p. 416; see
Appendix A). Thus, the central feature of social phobia is an excessive fear of being observed or
scrutinized by unfamiliar persons. In particular, the individual finds agonizing the potential risk of
performing inadequately or showing overt signs of nervousness with resultant embarrassment or
humiliation. The social fears may be limited to specific settings such as formal public
appearances, or extend to a wider range of situations like social gatherings and casual
conversations. When exposed to phobic situations, or in anticipation thereof, the individual
typically reacts with anxiety symptoms such as palpitations, sweating, blushing, and catastrophic
thinking. Symptoms arise even though the person realizes that the reactions are exaggerated and
unreasonable. Consequently, the distressing situations are avoided or endured under intense
anxiety. In social phobia, symptoms interfere considerably with the person's daily routines, social
activities, relationships, occupational/academic functioning, or alternatively there is apparent
distress about having the phobia. If the individual is under age 18, the DSM-IV criteria require a
minimum duration of at least six months. Moreover, other medical conditions or mental disorders
must not better account for the social anxiety symptoms. DSM-IV also specifies a generalized
subtype of social phobia, which is the appropriate diagnosis when the fears extend to “most social
The operational criteria for social phobia in the current 10th revision of the International
Classification of Diseases and Related Health Problems (ICD-10; World Health Organization,
1993) have a few differences in comparison to DSM-IV. ICD-10 stipulates that the fear of
scrutiny involves small groups of people, rather than crowds, and gives emphasis to specific
stress-related physical symptoms such as blushing, hand tremor, nausea, and urgency of
1.2.2. Historical perspectives on the diagnosis
The term “phobia” has its origins in the Greek word φóβoς meaning terror or fear. In ancient
times the god Phobos was believed to call forth fear and terror in the enemies of the Greek
(Davey, 1997). Large numbers of fears have been named by adding “phobia” to a Latin or Greek
prefix. Some examples of relevance to social anxiety are scopophobia (fear of being observed),
xenophobia (fear of strangers), and antrophophobia (fear of people). The early concept formation
of social phobia has been described by several authors (e.g., Fahlén, 1995; Heckelman &
Schneier, 1995; Schneier, Johnson, Hornig, Liebowitz, & Weissman, 1992). Literary descriptions
of shyness and social anxiety can be traced back to Hippocrates 400 B.C. (Heckelman &
Schneier, 1995), but the first explicit reference to social phobia, or “phobie des situations
sociales”, was made in the early 1900’s by Janet (1903). In the 1930’s, Schilder used the term
“social neurosis” to describe extremely shy patients (Schilder, 1938, cited by Fahlén, 1995). In
the 1950’s, following Joseph Wolpe’s pioneering work on systematic desensitization, the interest
in behavioral therapy of phobias increased sharply. Working in this tradition, the British
psychiatrist Isaac Marks proposed in the 1960’s that social phobias could be thought of as a
distinct category (Marks, 1969; Marks & Gelder, 1966). Gradually this idea gained recognition by
the American Psychiatric Association, and in 1980 social phobia was officially included as a
psychiatric diagnosis in the third edition of the Diagnostic and Statistical Manual of Mental
Disorders - DSM-III (APA, 1980).
Closely resembling a specific (or simple) phobia, the DSM-III described social phobia as a
circumscribed fear of performance situations, with activities such as speaking, eating, or urinating
in front of others causing “significant distress”. This overlooked individuals exhibiting excessive
anxiety in numerous social settings, including informal conversations and interactional situations,
although these individuals could be diagnosed as having avoidant personality disorder - a
diagnosis on the axis II. Comorbidity between these two diagnoses was not allowed. The
diagnostic criteria were revised in the DSM-III-R (APA, 1987). “Significant distress” was
changed to “interference or marked distress”, comorbidity between social phobia and avoidant
personality disorder was now allowed, and the generalized subtype of social phobia was
introduced. In comparison to this substantial revision, the diagnostic criteria were only slightly
modified in going from DSM-III-R to the current fourth version of the DSM (APA, 1994).
Following the introduction of social phobia in DSM-III, research activity devoted to this
disorder was initially scant, which led some authorities to describe social phobia as “the neglected
anxiety disorder” (Liebowitz, Gorman, Fyer, & Klein, 1985). However, this picture has changed
altogether as social phobia has received massive attention in the past ten years resulting in an
enormous number of studies. It is noteworthy that a number of recent studies have preferred the
name “social anxiety disorder”, which is the alternative label given in DSM-IV. It is foreseeable
that this name will replace social phobia in future editions of the DSM because it is considered to
be better differentiated from specific phobia and may also convey the sense of pervasiveness and
impairment in a better way (Liebowitz, Heimberg, Fresco, & Stein, 2000).
1.3 Characterizing psychopathology
1.3.1 Feared situations
As stated in DSM-IV, individuals with social phobia fear and avoid situations in which they risk
negative evaluation, mainly by unfamiliar people. Virtually all situations in which the person is
being observed by others or gets in the focus of attention can become problematic. Public
speaking, however, is the most prevalent social fear (Kessler, Stein, & Berglund, 1998; Pollard &
Henderson, 1988; Stein, Walker, & Forde, 1994; Turner, Beidel, & Townsley, 1992). In the social
phobia literature, performance circumstances are commonly distinguished from interactional
situations. Public speaking involves a performance in front of other people, as do eating, drinking,
writing, acting, playing an instrument, and urinating in front of others. Fear arising in such
situations may thus be classified as performance fears (Hazen & Stein, 1995). Interactional fears,
on the other hand, may occur in settings such as parties, social gatherings, meetings, and face-to-
face conversations with strangers or authorities. Such fears may also arise in situations that
involve ambiguous or novel roles.
Three separate response systems are often used to analyze emotional behavior: the cognitive-
verbal, the behavioral-expressive, and the bodily-expressive system (Lang, 1985). Thus, it might
be fruitful to distinguish between cognitive, behavioral, and physiologic aspects of social phobia.
It should be noted that the characteristic symptoms of social phobia may be present in the phobic
situation, before the situation, and also after leaving it (Wells & Clark, 1997).
Virtually all cognitive models of social phobia (Beck, Emery, & Greenberg, 1985; Clark & Wells,
1995; Rapee & Heimberg, 1997) emphasize that social phobics are overly concerned with how
they are being perceived and evaluated by others. In the cognitive perspective, social anxiety may
emerge from an excess of negative thoughts, perceived personal shortcomings, excessively high
standards for one’s own performance, and/or unrealistic beliefs about the standards people
ordinarily use to evaluate others. According to the self-presentation theory, social anxiety occurs
when the individual is motivated to make particular impressions on others but distrusts his or her
own ability to successfully do so (Leary & Kowalski, 1995).
Prior to a problematic social situation, social phobics frequently review in detail what they
think might happen and how they can deal with the various difficulties arising. These ruminations
may sensitize the individual so that he or she enters the situation in a pre-activated self-focused
processing mode (Wells & Clark, 1997). During stressful situations, socially anxious individuals
typically report more negative and fewer positive thoughts than non-clinical or low anxious
subjects (Rapee, 1995; Stopa & Clark, 1993). The negative thoughts do not always stop
immediately on leaving a social situation. Rather, the negative ruminations tend to go on as the
phobic individual afterwards mentally reviews in detail what happened. Wells and Clark (1997)
use the term “post-mortem processing” to describe retrospective thinking about the phobic
situations. Post-mortem processing may be traced to a strongly felt need to repair self-esteem and
plan more effective strategies to deal with the situation in the future.
In the anxiety disorders, considerable research effort has been devoted to the issue of
information-processing biases toward threat-relevant cues, e.g. with regard to attention,
interpretation, and memory. Such biases have been reported in individuals with social phobia
(Lampe, 2000; Musa & Lépine, 2000). For instance, empirical studies using the Stroop paradigm,
dot probe test, and lexical decision tasks, generally support that social phobics show greater
vigilance to socially threatening information relative to physically threatening or neutral
information (Musa & Lépine, 2000). On the other hand, Wells and Clark (1997) review evidence
in support of their notion that hypervigilance to interoceptive threat cues lead social phobics to
avoid or direct attention away from external threat information in the social environment. Hence,
they argue that socially anxious individuals are cognitively characterized by self-focused attention
and poor encoding of environmental cues (Wells & Clark, 1997).
There is also support of an interpretation bias in social phobics. For instance, socially
anxious individuals have a tendency to rate their own performance far worse than do independent
judges (Rapee, 1995). Furthermore, it has been demonstrated that social phobics tend to interpret
ambiguous events as negative and overestimate the probability of negative social outcomes (Musa
& Lépine, 2000). Socially anxious individuals also exaggerate the extent to which observers can
notice that they feel distressed (Leary & Kowalski, 1995). Wells and Clark (1997) argue that the
socially phobic individual typically constructs a negative image of him/herself from an “observer
perspective”, i.e. the person often sees him/herself as if outside the body looking back at the self.
Cognitive studies have also explored whether social phobics show enhanced memory
retrieval of threat relevant information. The empirical support of such a memory bias has been
mixed and positive results may be contingent upon specific encoding conditions (Musa & Lépine,
2000). However, some studies do suggest that socially anxious individuals tend to remember
more negative data about themselves than do less distressed people (Breck & Smith, 1983;
O’Banion & Arkowitz, 1977).
According to the principles of operant conditioning (Skinner, 1974), phobias are thought to be
maintained by escape and avoidance behaviors. For example, when a spider phobic runs away
from the basement after seeing a spider crawling on the floor, the escape behavior is negatively
reinforced because it terminates aversive exposure. Future avoidance of entering the basement
similarly prevents potential aversive exposure. However, while these strategies reduce anxiety in
the short perspective, the phobic individual never gets a chance to learn more adequate and
nondistressing ways to deal with the phobic object. That is why exposure to feared events is an
essential feature in behavioral treatments of phobias. Escape and avoidance are prominent also in
social phobia, even though social situations are perhaps more difficult to avoid completely, and to
flee from, compared with phobogenic situations in specific phobia and agoraphobia. Running out
of the classroom when talking in class, going home early from a party, or hanging up the
telephone before the other party has been able to answer, are some examples of escape behaviors
in social phobia. Avoidance may be manifested in countless ways. Example cases here would be
when a talented student refrains from entering university because of fear of talking in class or
when a skillful employee turns down a promotion because the new position lays greater emphasis
on social contacts.
Wells and Clark (1997) argue that social phobia is maintained by subtle avoidance
maneuvers or “safety behaviors”, practiced by socially anxious individuals when phobic
situations are endured. Avoiding eye contact when talking in class, wearing cool clothes to avoid
sweating, and holding arms rigid to avoid shaking are some examples of such safety behaviors.
These are intended to reduce the risk of social failure, but in the process they prevent
disconfirmation of negative beliefs and preserve self-focused attention.
The issue of social skills should also be mentioned among the behavioral aspects of social
phobia. It could be suspected that social phobics lack the proper skills (verbal or non-verbal)
necessary to master social interactions or performance situations. However, research on this topic
has been inconsistent (Rapee, 1995). Even though social phobics appear to have inadequate
abilities in some studies, this might reflect inhibition rather than actual lack of skills. It is also
possible that such social abilities are inhibited only during states of high anxiety in phobic
situations (Rapee, 1995).
Social phobics exhibit basically the same somatic symptoms during (or in anticipation of)
anxiogenic exposure as observed in other anxiety disorders (Rapee, 1995), i.e. palpitations,
sweating, tremors, hot flushes, etc. These arousal symptoms stem from exaggerated activity in the
sympathetic division of the autonomic nervous system, and are characteristic features of the
“fight-or-flight” response (Cannon, 1927). Autonomic arousal is also accompanied by increased
blood pressure and increased secretion of stress hormones initiated by the hypothalamus-pituitary
gland-adrenocortical axis. However, facial blushing and somatic symptoms of embarrassment,
which are common in social phobia, might not be simply mediated by increased sympathetic
activity (Stein & Bouwer, 1997). For instance, blushing has sometimes been associated with
lowered heart rate and blood pressure and may stem from vasodilatation due to relaxation of
sympathetic tone, active cholinergic stimulation, or sympathetic arousal of beta-adrenergic
receptors (Stein & Bouwer, 1997). While the DSM-IV does not emphasize specific physical
symptoms beyond the appearance of a psychophysiological anxiety reaction, blushing, hand
tremor, nausea, and urgency of micturation are listed in the ICD-10 criteria for social phobia.
1.3.3 Age of onset and natural course
According to several retrospective studies, social phobia typically begins between early and late
adolescence (Amies, Gelder, & Shaw, 1983; Liebowitz et al., 1985; Mannuzza, Fyer, Liebowitz,
& Klein, 1990; Turner, Beidel, Dancu, & Keys, 1986). However, some reports suggest an even
earlier age of onset, and social phobia is not uncommon in anxiety-disorder clinics for children
(Last, Strauss, & Francis, 1987). From a developmental perspective it has been argued that
concerns about negative evaluation from other people or self-consciousness typically emerge
around 8 years of age. Consequently, social phobia should be rare in younger children (Hudson &
There is some empirical research suggesting that social phobia (Chartier, Hazen, & Stein,
1998; Reich, Goldenberg, Vasile, Goisman, & Keller, 1994; Solyom, Ledwidge, & Solyom,
1986) and shyness (Caspi, Elder, & Bem, 1988) remains fairly stable across the lifespan.
However, some epidemiological studies report a markedly higher prevalence using lifetime- as
compared to one-month estimates of prevalence (c.f. Kessler et al., 1994; Magee, Eaton,
Wittchen, McGonagle, & Kessler, 1996). This may argue against a chronic course, considering
that most phobics do not seek treatment (Magee et al., 1996; Weiller, Bisserbe, Boyer, Lepine, &
1.3.4 Other associated features
In the general population it has consistently been observed that women are more likely to have
social phobia - the women to men ratio being approximately 3:2 (Chapman, Mannuzza, & Fyer,
1995; Moutier & Stein, 1999). However, men seem to be somewhat more likely to seek
treatment, possibly because social phobic symptoms have more handicapping consequences for
men than for women (Weinstock, 1999).
Several epidemiological studies have reported that social phobia is over-represented among
unmarried individuals (Davidson, Hughes, George, & Blazer, 1993; Magee et al., 1996; Schneier
et al., 1992). In clinical samples it has also been observed that individuals with social phobia are
less likely to be married than individuals with other anxiety disorders (Sanderson, DiNardo,
Rapee, & Barlow, 1990). Similarly, studies of shyness have reported that shy males married and
had their first child at least 3 years later than the nonshy males (Caspi et al., 1988).
Age at assessment
Large-scale epidemiological studies have noted significant age-differences, such that the highest
lifetime prevalence rates of social phobia have been observed among the youngest individuals and
the lowest rates among the oldest individuals (Magee et al., 1996; Schneier et al., 1992).
Although this could reflect recall failure or poor reporting accuracy among the older subjects, or
greater exclusion from the sample of the more aged phobics, it is possible that social phobia is on
the rise in younger cohorts (Heimberg, Stein, Hiripi, & Kessler, 2000; see also 2.1.1).
Career factors and quality of life
Turner and colleagues (1986) found that the overwhelming majority of their studied group of
social phobics reported that their social anxiety led to significant occupational or academic
interference. Schneier et al. (1992) observed that social phobia was associated with lower levels
of educational attainment and income level. Social phobia is also associated with substantial
reductions in work productivity (Wittchen, Fuetsch, Sonntag, Müller, & Liebowitz, 2000).
Moreover, it has been noted that shy people are less likely than the nonshy to engage in career
promoting behaviors (Phillips & Bruch, 1988). Collectively, these data suggest that excessive
social anxiety may hamper career advancement. In addition, social phobia is associated with a
substantial decrease in the quality of life, impairing vital areas such as family functioning and
social and romantic relationships (Wittchen et al., 2000). Wittchen and colleagues (2000) also
observed considerable subjective suffering and negative life impact in subthreshold social phobia,
i.e. among individuals who met the all diagnostic criteria except the impairment/distress criterion
according to the diagnostic interview.
1.3.5 Diagnostic and conceptual issues
Subtypes of social phobia
As mentioned previously, the DSM-III-R introduced a generalized subtype of social phobia (when
the fear includes “most social situations”). Other forms of social phobia have often been referred
to as “nongeneralized”, but some authors have proposed more fine-grained subtyping schemes.
The issue of subtypes is further discussed elsewhere (see 2.1.2).
Social phobia is commonly accompanied by other psychiatric disorders. In the US National
Comorbidity Survey, other anxiety disorders such as simple phobia, agoraphobia, panic disorder,
and generalized anxiety showed the highest degree of comorbidity with social phobia (57%),
followed by affective disorders (41%) and substance abuse disorders (40%) (Magee et al., 1996).
Other studies suggest that the lifetime comorbidity rates are greater than 10% for specific phobia,
agoraphobia, major depressive disorder, obsessive-compulsive disorder, alcohol abuse, and drug
abuse (Moutier & Stein, 1999). Rates of comorbidity are highest in patients with the generalized
subtype (Moutier & Stein, 1999) and in most cases social phobia precedes the onset of comorbid
disorders (Schneier et al., 1992). The association between social phobia and alcohol abuse has
been noted by several investigators, suggesting that social phobics frequently self-medicate to
relieve their anxiety (Merikangas et al., 1998). It has also been reported that comorbid conditions
are associated with an increased risk of attempting suicide (Schneier et al., 1992). Even though
comorbid patients probably are the most impaired, empirical data suggest that “pure” and even
subthreshold social phobia can be very disabling (Wittchen et al., 2000).
Avoidant personality disorder
Several investigators have reported that social phobics show a high degree of comorbidity with
the axis II diagnosis avoidant personality disorder (APD), ranging from 25 to 89% (median
57.6%) for the generalized subtype and from 0-44% (median 17.5%) for the nongeneralized type
of social phobia (Heimberg, 1996; Herbert, Hope, & Bellack, 1992; Holt, Heimberg, & Hope,
1992; Schneier, Spitzer, Gibbon, Fyer, & Liebowitz, 1991; Turner et al., 1992). Because of the
substantial overlap, the discriminant validity of APD relative to social phobia has been much
debated. Given the considerable difficulties in distinguishing between APD and generalized
social phobia, it might be argued that having two diagnoses is redundant because in reality they
both define one and the same disorder. The DSM-IV task force recognized this problem but
eventually decided that both diagnoses should be retained awaiting further research (Heckelman
& Schneier, 1995). According to a dimensional view, both APD and social phobia, including its
subtypes, represent arbitrary cutoffs along a continuum of severity. APD has often been thought
of as a particularly severe form of social phobia (Holt et al., 1992). However, Heimberg (1996)
argued that the concept of APD does not serve a needed function alongside the more informative
diagnosis of social phobia, and other authors have also speculated that APD might be dropped in
future revisions of the DSM (Hazen & Stein, 1995).
Individuals with social phobia are usually well recognized by the content of their fears, but the
diagnostic distinction can sometimes be tricky. For example, panic disordered patients may
experience panic attacks in social or performance settings, individuals with generalized anxiety
disorder may worry about social situations, and depressed patients may exhibit social withdrawal
(Heckelman & Schneier, 1995).
Superficially, there are many similarities between social phobia and shyness. Individuals with
social phobia typically describe themselves as being shy, and the fear of negative evaluation from
others is central to both concepts. Unlike social phobia however, shyness is not a psychiatric
diagnosis with specific criteria - rather it is often defined by subjects’ self-attributions as being
either shy or nonshy (Heckelman & Schneier, 1995). Furthermore, the prevalence rates of shyness
in college students have been up to 40% in some studies (Cheek, Carpentieri, Smith, Rierdan, &
Koff, 1986) which are higher than for social phobia. Thus, while shyness and social phobia often
overlap, shyness is probably a broader and more heterogeneous category (Heckelman & Schneier,
1995). In a similar vein, socially anxious individuals could be described using a number of other
concepts that also lack specific criteria in a diagnostic sense, such as being introvert, neurotic,
inhibited, reserved, withdrawn, or isolated.
1.4 Etiology: Some factors related to the origins of social phobia
1.4.1 Genetic factors
A two- to three-fold increased risk of having social phobia has typically been observed among
first-degree relatives of social phobics in clinical samples (Bruch & Heimberg, 1994; Fyer,
Mannuzza, Chapman, Liebowitz, & Klein, 1993; Fyer, Mannuzza, Chapman, Martin, & Klein,
1995; Mannuza et al., 1995; Reich & Yates, 1988; Stemberger, Turner, Beidel, & Calhoun,
1995). Stein et al. (1998) noted that it is the relative risk for the generalized subtype that is
uniquely higher (approximately 10-fold in their study) among relatives of probands with
generalized social phobia. Moreover, a positive family history of excessive social anxiety has
been observed in social phobics in the general population (Lieb et al., 2000; Tillfors, Furmark,
Ekselius, & Fredrikson, in press) and community studies also suggest that the rate of social
phobia is raised among mothers of shy children (Cooper & Eke, 1999). Because social phobia and
other anxiety disorders tend to cluster in families, a genetic cause might be suspected. However,
in the etiologic perspective family studies cannot properly distinguish genetic from environmental
To disentangle the genetic contributions Kendler, Neale, Kessler, Heath, and Eaves (1992)
studied the concordance for social phobia in monozygotic and dizygotic twin-pairs, and observed
a significantly higher concordance rate in the former group. The heritability index was estimated
at approximately 30% suggesting that genetic factors explained one-third and nonshared
environmental factors two-thirds of the variability in familial transmission of social phobia
(Kendler et al., 1992). Genetic influences have also been noted on social fears defined in a
broader sense (Torgersen, 1983; Phillips, Fulker, & Rose, 1987) and on other variables of
relevance to social phobia such as behavioral inhibition (Kagan, Reznick, & Snidman, 1988; see
below), neuroticism, and introversion (Henderson, 1982). Taken together these data suggest that
genetic factors play at least a moderate role in the etiology of social phobia.
1.4.2. Temperamental factors
Temperament refers to inborn biases towards certain moods and emotional reaction styles
(Mussen, Conger, Kagan, & Huston, 1990). Jerome Kagan and coworkers have depicted two
temperamental styles of children called inhibited and uninhibited. Inhibited children are
characterized by withdrawal and increased autonomic arousal in situations of uncertainty, in
contrast to uninhibited children who tend to react with spontaneity and approach in these
situations (c.f. Kagan et al., 1988). About 10-15% of American (Caucasian) children belongs to
each category. Longitudinal studies suggest that children with a stable pattern of behavioral
inhibition have an increased risk for developing phobic disorders, particularly social phobia. An
increased risk of social phobia has also been observed in the parents of inhibited children
(Rosenbaum et al., 1991). Thus, it is possible that behavioral inhibition is a childhood precursor
to social phobia in adults. However, it is unclear whether behavioral inhibition is a risk factor for
later social phobia specifically or an anxiety proneness in general (Rosenbaum et al., 1991).
1.4.3. Conditioning and ethological factors
Classical conditioning models suggest that social phobia may emerge from aversive social
experiences through processes of associative learning (Mineka & Zinbarg, 1995). Making a
mistake or an unfavorable impression in social situations, e.g. when talking in class (becoming
the conditioned stimuli), might result in the individual being ridiculed, laughed at, or exposed to
hostility from others (the unconditioned stimuli). Thereby a social situation acquires the potential
to elicit fear or anxiety reactions (a conditioned response) in the future. There is evidence that
social phobics frequently attribute the onset of their phobia to such conditioning experiences. For
instance, Öst (1985) noted that conditioning was a likely etiologic pathway in 56.3% of the social
phobia patient sample whereas Stemberger et al. (1995) reported that 44% of their patient sample
had a history of traumatic conditioning. Hofmann and colleagues observed, however, that
although traumatic speaking events in the past were common among speech phobics, only 15%
reported such events at the same time as their phobia started and none of them reported traumatic
speaking events before their phobia onset (Hofmann, Ehlers, & Roth, 1995). Other authors have
noted that social phobia onset is gradual rather than abrupt (e.g., Fahlén, 1995). This could mean
that conditioning to contexts are more important than conditioning to specific fear cues. In the
brain, cue conditioning is thought to be served by the amygdala whereas contextual fear
conditioning requires longer times to be consolidated and is dependent on the hippocampus (Kim,
Rison, & Fanselow, 1993).
It is conceivable that social phobics acquire fear reactions with more ease and/or show a
higher resistance to extinction of learned fear compared with non-phobics. A related issue is the
notion of preparedness (Seligman, 1971). According to the preparedness theory, humans have an
evolutionarily formed predisposition to easily learn fear reactions to objects or situations that
were threatening to our early ancestors. In a series of studies on fear conditioning, Arne Öhman
and colleagues (Öhman, 1986) have demonstrated that angry faces belong to the class of
evolutionary fear-relevant stimuli, capable of eliciting conditioned fear reactions even when
presented below the threshold of conscious awareness. In the context of dominance hierarchies,
which have been evolutionarily important in the regulation of social life in animals and humans,
the angry face might signify an increased risk of dominance conflict and potentially harmful
assault. Social phobia in turn might be related to fearful and submissive behavior typically seen in
defeated animals taking a lower position in the hierarchy. Blushing and other symptoms of
embarrassment may constitute evolutionarily shaped appeasement displays that reduce the
likelihood that a dominant conspecific will attack (Stein & Bouwer, 1997).
1.4.4. Family factors
If parents themselves are socially anxious their children might acquire social fears and avoidance
through processes of modeling (Bandura, 1977). Öst (1985) reported that 15.6% of a studied
sample of social phobics attributed the acquisition of their phobia to modeling factors. Also,
families that are high in anxiety probably socialize less with other people, thereby restricting the
child’s exposure to social situations. Under such circumstances, an anxious child has less
opportunities to develop social skills and to learn that social situations are harmless (Hudson &
Rapee, 2000). Moreover, patients with social phobia tend to describe their parents as
overprotective (Bruch & Heimberg, 1994; Rapee & Melville, 1997). A controlling or
overprotecting parenting style may be associated with fearful and socially withdrawn behavior in
children, although this might be true not only for social phobics but for anxious individuals in
general (Hudson & Rapee, 2000).
1.4.5. Birth order
Sibling position might have an impact on social phobia because some studies have reported
increased rates of social anxiety or shyness among firstborn or only children relative to those born
later (Hudson & Rapee, 2000). Social anxiety may occur because of an increased pressure placed
on firstborn children to succeed or because these children lack the benefits of having older
siblings as social role models. However, other investigators have reported that first born children
show less trait anxiety than later-born siblings (Gates, Lineberger, Crockett, & Hubbard, 1988)
and that increasing adult fearfulness correlates with increasing birth order in the sibship (Croake,
Myers, & Singh, 1987). Thus, to date, reports on birth-order are inconclusive.
1.4.6. Peer-rejection and social isolation
Childhood experiences of peer-rejection and subsequent social isolation are not uncommon
among individuals with social phobia. Rapee and Melville (1997) noted that social phobics
retrospectively reported having fewer friends during middle childhood. Hudson and Rapee (2000)
review evidence supporting that “love shy” men often retrospectively report peer-rejection
experiences such as bullying, being picked last for sport teams, or never having close friends to
play with. It is possible that negative life experiences early in life sensitize the individual, e.g. so
that aversive stimuli of milder intensity may become capable of exciting fear circuits in the brain.
Thus, the likelihood increases that the person will react with anxiety when exposed to
psychosocial stressors in the future. In this case, social fears are acquired by non-associative
learning. Also, peer-rejection or neglect could lead to social isolation, which in turn might
hamper the development of social skills. Lack of social skills, in turn, probably further augment
social isolation (Hudson & Rapee, 2000).
1.4.7. A multifactorial approach
It is unlikely that any single factor underlies the etiology of social phobia. In a stress-diathesis
model both environmental and genetic factors are recognized as important. For instance, even
though various forms of environmental influences or learning can be significant, it is also
possible that socially anxious individuals learn fear reactions more easily than do non-anxious
persons due to genetic reasons. Thus, an inherited vulnerability might interact with environmental
stressors leading to the acquisition of a social fear. As mentioned previously, social phobia,
whether it is learned or innate, is likely to be maintained by avoidance/escape behaviors and
cognitive biases. Also, excessive social anxiety is probably mediated by overly reactive fear
circuits or dysfunctional neurotransmitter/receptor systems in the brain. This issue is further
discussed elsewhere in this thesis (2.2.1).
1.5 Treatment: Major Research findings
Following the huge increase in empirical studies on social phobia in the 1990’s, the effects of
various treatments also started to be evaluated extensively. To date, there is evidence for the
effectiveness of both pharmacological and psychological (i.e. cognitive-behavioral) treatments.
1.5.1 Pharmacological treatments
Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) were originally developed for the treatment of
depression, but clinicians soon observed that these agents also have anti-anxiety effects.
Fluoxetine appears to be the first SSRI used in social phobia, as reported by Sterbach (1990).
Since then, numerous open trials or naturalistic studies have demonstrated the effectiveness of
sertraline, paroxetine, and citalopram (c.f. Van Ameringen, Mancini, Oakman, & Farvolden,
1999). The beneficial effects of SSRIs in the treatment of social phobia have now also been
confirmed in several randomized placebo-controlled trials, e.g., on fluvoxamine (Stein, Fyer,
Davidson, Pollack, & Wiita, 1999b; Van Vliet, Den Boer, & Westenberg, 1994), sertraline
(Katzelnick et al., 1995), and paroxetine (Allgulander, 1999; Baldwin, Bobes, Stein,
Scharwachter, & Faure, 1999; Stein et al., 1998b; Stein et al., 1999a). Although other agents have
been equally beneficial in controlled studies, much of the current pharmacological research on
social phobia concerns the SSRIs. When issues such as safety, tolerability, drug dependency, and
effect on comorbid conditions are considered, the SSRIs have many advantages. In a recent
review, Van Ameringen et al. (1999) argued that the SSRIs are very likely to become the new
gold standard for the pharmacological treatment of social phobia.
Before the introduction of SSRIs, the monoamine oxidase inhibitors (MAOIs) were considered to
be the pharmacological treatment of choice in social phobia. Phenelzine in particular has been
proven effective in double-blind, placebo-controlled studies (Gelernter et al., 1991; Liebowitz et
al., 1992; Versiani et al., 1992; Heimberg et al., 1998). However, clinicians are somewhat
reluctant to use the classical MAOIs because of the potential risk for life-threatening hypertonic
reactions. Consequently, safe treatment requires strict dietary restrictions. Promising results have
been obtained with reversible inhibitors of monoamine-oxidase-A, such as brofaromine (Fahlén,
Nilsson, Borg, Humble, & Pauli, 1995; Lott et al., 1997; Van Vliet, Den Boer, & Westenberg,
1992) and moclobemide (the International Multicenter Clinical Trial Group on Moclobemide in
Social phobia, 1997; Noyes et al., 1997; Versiani et al., 1992; but poor outcome was reported by
Schneier et al., 1998).
High potency benzodiazepines such as clonazepam (Davidson et al., 1993c) and to a
lesser extent alprazolam (Gelernter et al., 1991) are also effective in social phobia, but the
potential risk of dependence and high comorbidity with substance abuse have dampened the
enthusiasm for these drugs. Other controlled trials in social phobia include the serotonin 5-HT1A
receptor agonist buspirone (Clark & Agras, 1991; Van Vliet, Den Boer, Westenberg, & Pian,
1997) and the serotonin 5-HT3 receptor antagonist ondansertron (c.f. Van Ameringen et al.,
1999), both of which appear to be only moderately effective. Controlled studies have failed to
demonstrate superior efficacy for β-blockers relative to placebo in generalized social phobia
(Liebowitz et al., 1992; Turner, Beidel, & Jacob, 1994). While β-blockers might mitigate
autonomic arousal on specific occasions, these drugs are probably ineffective in achieving stable
anxiolytic effects in the long-term.
1.5.2 Psychological treatments
Cognitive-behavioral group therapy
With regard to psychological treatments of social phobia, cognitive-behavioral group therapy
(CBGT) following principles developed by Heimberg and coworkers (c.f. Hope & Heimberg,
1993) is perhaps the most empirically validated method. Briefly, CBGT is a structured form of
psychotherapy, which incorporates simulated exposures to feared situations, cognitive
restructuring, and homework assignments for in vivo exposure. It is held in a group format,
ideally with 6-8 patients and two therapists. The standard treatment period runs for 12 weekly
sessions, each about three hours long. The effectiveness of CBGT has been demonstrated in
several controlled studies (c.f. Heimberg & Juster, 1995; Heimberg et al., 1998) and follow-up
assessments have shown that the beneficial effects are still evident five years after treatment
termination (Heimberg, Salzman, Holt, & Blendell, 1993b).
Based on their cognitive model of social phobia, Clark and Wells (1995) have also
developed a renowned treatment package that has many similarities with Heimberg’s CBGT,
although a greater emphasis is put on the identification and correction of safety behaviors
(described earlier) and the use of audio and video-feedback to correct distorted self-processing
(Wells & Clark, 1997). It is possible that these components add additional beneficial effects to
therapy (Morgan & Raffle, 1999).
Since the 1980’s four main types of psychological treatments for social phobia have been
evaluated: (1) social skills training, (2) exposure to feared events, (3) anxiety management (e.g.,
relaxation, distraction, brief cognitive procedures), and (4) cognitive therapy. As pointed out by
Butler and Wells (1995), all these methods have been effective, at least to some extent, although
their relative value is difficult to determine because of differences in study designs, outcome
measures, patient selection, comparisons made etc. Moreover, the basic treatment components are
frequently combined. In a meta-analysis of 42 cognitive-behavioral treatment studies on social
phobia, Taylor (1996) noted that all interventions reviewed, including placebo, had larger effect-
sizes than that of waiting-list controls, but only exposure in combination with cognitive
restructuring significantly surpassed placebo. Psychodynamic treatment has not been evaluated in
controlled studies. It should also be mentioned that although group treatment has many
advantages in social phobia, individual treatment has not been shown to be less effective.
1.5.3 Psychological treatments compared and combined with pharmacotherapy
Data on the relative effectiveness of psychotherapy and pharmacotherapy are very limited.
However, the effects of CBGT compare well to phenelzine (Gelernter et al., 1991) but might be
slightly less effective in the shorter perspective after 6 weeks and immediately after 12 weeks of
treatment (Heimberg et al., 1998). In a study of musicians with social phobia, cognitive-behavior
therapy was more effective than buspirone (Clark & Agras, 1991). In a meta-analysis Gould,
Buckminster, Pollack, Otto, and Yap (1997) noted that both cognitive-behavioral and
pharmacological treatments were significantly effective in social phobia, having effect sizes of
.74 and .62 respectively, but did not differ between themselves. Exposure based interventions,
either alone or combined with cognitive restructuring, were the most effective cognitive-
behavioral treatments, whereas the SSRIs and benzodiazepines yielded the highest effect sizes for
pharmacotherapy. CBGT was the most cost-effective intervention (Gould et al., 1997).
Psychological treatments might be more advantageous than pharmacotherapy in terms of number
of dropouts and long-term outcome, i.e. patients might relapse when medication is discontinued
(Stravinsky & Greenberg, 1998).
Studies examining the combination of psychological treatment and medication are scarce,
but on the whole such combinations have been disappointing as they have not exceeded the
effects of the treatment methods in isolation (Clark & Agras, 1991; Falloon, Lloyd, & Harpin,
1981; Gelernter et al., 1991; Turner et al., 1994). However, combinations of the most potent
psychological and pharmacological treatments have not yet been evaluated. This is an important
topic for future research, especially since recent studies have reported intriguing results from
combined treatments for panic disorder (Barlow, Gorman, Shear, & Woods, 2000) and depression
(Keller et al., 2000).
1.5.4 How effective are “effective” treatments?
Even though both psychological and pharmacological treatments may be very useful, it is also
apparent that a substantial number of patients with social phobia do not achieve a sufficiently
good treatment outcome. The proportion of responders in the most promising psychological and
pharmacological treatments are typically in the range of 70-80% (Heimberg et al., 1990a; 1998;
Van Ameringen et al., 1999). However, as Stravinsky and Greenberg (1998) point out, the
treatment results are often fairly modest and the number of patients who achieve full resolution of
social phobia is considerably lower than the above figures. In treatment studies, outcome is
typically reported in terms of statistically significant anxiety reduction. However, it is often
unclear whether patients truly change in a meaningful way, e.g. with regard to reduced avoidance
and improvements in family life, intimate relationships, activity rates, occupational and academic
functioning, etc. Thus, much work remains to be done before we can speak with confidence about
effective treatment for social phobia incorporating its consequences for general well-being. Also,
although most patients may benefit from treatment, outcome is generally poorer in more severe
forms of the disorder (e.g., in generalized as compared to nongeneralized social phobia), in the
presence of comorbid conditions (e.g., avoidant personality disorder and depression), and
possibly also in patients with earlier onset of the disorder (Lampe, 2000). Future treatment studies
should pay attention to these issues.
2. BACKGROUND TO THE EMPIRICAL STUDIES
2.1 Background to study I and II
2.1.1 The epidemiology of social phobia:
As presented in Table 1, numerous epidemiological studies have examined the prevalence of
social phobia in the general population since its official introduction in the DSM-III. Striking
between-study variability in prevalence rates can be noted. According to the first wave of studies,
e.g. the Epidemiologic Catchment Area (ECA) research project, DSM-III-defined social phobia
was a relatively rare disorder with an estimated lifetime prevalence of about 2-3% in the United
States (Bourdon et al., 1988; Davidson, Hughes, George, & Blazer, 1993; Eaton, Dryman, &
Weissman, 1991; Schneier et al., 1992). Roughly similar numbers were reported in New Zealand
(Wells, Bushnell, Hornblow, Joyce, & Oakley-Browne, 1989) and Europe (e.g., Lindal &
Stefanson, 1993; Wittchen, Ahmoi Essau, von Zerssen, Krieg, & Zaudig, 1992) whereas lower
counts (about 0.5%) were obtained in Korea (Lee et al.,1990a; 1990b) and Taiwan (Hwu, Yeh, &
Chang, 1989). However, it has been argued that these initial studies vastly underestimated the true
prevalence of social phobia (Walker & Stein, 1995) as later reports noted considerably higher
figures. For instance, a lifetime prevalence rate of 13.3% was observed in the National
Comorbidity Survey (NCS), making social phobia the third most common psychiatric disorder in
the United States, surpassed only by alcohol dependence and major depressive disorder (Kessler
et al., 1994).
It is likely that the higher prevalence rates of social phobia in more recent studies at least
partly reflect the difference in diagnostic criteria between DSM-III and DSM-III-R. Recall that in
DSM-III, social phobia was conceptualized primarily as a fear of circumscribed performance-
situations such as speaking or eating in front of others. Individuals with a broader range of fears,
including those with interactional anxiety, were excluded but could be diagnosed as having
avoidant personality disorder. The diagnostic criteria were broadened in the DSM-III-R, which
opened the door for individuals with interactional fears, as well as those with APD, to be
diagnosed as having social phobia. Sharp increases in prevalence rates in going from DSM-III to
more modern diagnostic criteria have been noted not only in the NCS but also in several other
studies. For instance, in Canada the point prevalence of DSM-IV social phobia was estimated at
roughly 10% by Stein, Walker, and Forde (1996), which can be compared to 2.9% reported by
Costello (1982) using DSM-III criteria. Similar trends have been noted, e.g. in New Zealand and
Switzerland (see Table 1).
There might also be other methodological explanations underlying the increases in
prevalence rates of later studies. Several limitations of the Diagnostic Interview Schedule (DIS)
(Robins, Helzer, Croughan, & Ratcliff, 1981), i.e. the assessment instrument used in the early
ECA-studies, have been noted. For instance, only three phobic situations were assessed by the
DIS (Chapman et al., 1995). The NCS (Kessler et al., 1994) used a somewhat more
comprehensive assessment tool, a modified version of the Composite International Diagnostic
Interview (CIDI; Robins et al., 1988), which asked about six social situations. This could have
increased the likelihood of identifying individuals with social phobia because assessment of many
situations is important to avoid missing cases (Heckelman & Schneier, 1995).
Another possibility is that the early ECA/DIS-studies focused only on severe cases of
social phobia by requiring a high level of psychosocial impairment (Stein et al., 1994). It has been
demonstrated that small modifications of the required level of distress and impairment used to
define cases can influence prevalence estimates dramatically. For example, Pollard and
Henderson (1988) noted that the point prevalence rates of social phobia varied between 2.0 and
22.6% when different levels of significant distress were applied. Stein and colleagues (1994)
reported that the rate of social anxiety syndrome in a Canadian community sample varied from
1.9 to 18.7% as the required level of psychosocial interference was altered. In another
epidemiological report, Stein et al. (1996) noted that about 10% of the respondents fulfilled the
DSM-IV criteria for social phobia, but this rate increased to 16% by adjusting the threshold for
inclusion from 6 to 5 on a seven-point impairment scale. Also, in a recent postal survey, 26.9% of
a large French sample admitted at least one strong fear in social situations with resultant
fear/avoidance most or some of the time, but successively narrowing the definition of social
phobia resulted in a one-month prevalence of 0.9% at the most stringent cut-off level (Pélissolo,
André, Moutard-Martin, Wittchen, & Lépine, 2000). Thus, it is likely that arbitrariness in the
choice of diagnostic threshold partly underlies the between-study variability in prevalence.
Yet another methodological concern is the choice of prevalence period. Rather small
variations between the lifetime, one-year, and one-month prevalence have been noted in many
studies, e.g. the ECA-reports, whereas other studies have reported striking differences. For
instance, while the lifetime prevalence of social phobia was 13.3% in the National Comorbidity
Survey, only 7.9% of the respondents fulfilled the criteria during the preceding 12-month period
(Kessler et al., 1994), and only 4.5% did so during the last thirty days (Magee et al., 1996).
Judging from these findings, a considerable proportion of individuals seems to recover from
social phobia, presumably either through treatment or “spontaneous remission”. However, this
interpretation is inconsistent with many reports describing social phobia as an undertreated
disorder (Magee et al., 1996; Weiller et al., 1996) that follows a rather chronic course (Chartier et
al., 1998; Reich et al., 1994; Solyom, et al., 1986). Alternatively, the variability across
prevalence-periods could be attributed to methodological flaws, such as unreliable assessment
instruments, or reporting biases. For instance, reporting biases associated with recall over longer
time periods is a well-recognized problem (e.g., Parker, 1987). However, the epidemiological
data suggest that the reporting bias among older subjects, if it exists, is manifested as an
exaggeration of social phobia early in life. This, in turn, implies that the higher lifetime
prevalence observed in younger as compared to older individuals (Magee et al., 1996; Schneier et
al., 1992) reflects a true cohort effect rather than a failure among older phobics to recall their
remitted social phobia.
Furthermore, cross-cultural studies that at least superficially use an identical methodology
also report significant differences in prevalence rates (Table 1). One extreme example is the use
of the CIDI in Udmurtia, Russia which for social phobia yielded a DSM-III-R lifetime prevalence
of 52.7% (Pakriev, Vasar, Aluoja, & Shlik, 2000) as compared to 13.3% in the US (Kessler et al.,
1994) and 7.8% in the Netherlands (Bijl, Ravelli, & Van Zessen, 1998). Although this could
reflect true cultural variations, other explanations exist. It is possible that there are differences
across countries and research groups in the way the diagnostic instruments are administered and
translated. There might also be differences among cultures in attitudes about revealing
information to interviewers, and variations in the cultural relevance of the questions asked
(Chapman et al., 1995). Random sampling errors are also possible, but perhaps not likely given
the large samples used (Chapman et al., 1995).
To recapitulate, epidemiological studies on social phobia have reported highly varying
prevalence estimates (range 0-52.7% in Table 1). Among the numerous methodological
explanations that might underlie this variability, it should be mentioned that different studies have
used different diagnostic criteria, assessment methods, prevalence periods, and required levels of
severity/impairment to define cases. Future epidemiological research should be planned with
these issues in mind. Using ICD-criteria might yield a lower prevalence compared with DSM-
definitions (Pakriev et al., 2000; Wacker et al., 1992). Also, only a small number of studies
reports on the prevalence of isolated social fears. Nonetheless, judging from existing data it is
likely that public speaking is the most frequently endorsed situational fear in the general
community (Kessler et al., 1998; Pollard & Henderson, 1988; Stein et al., 1994).
Table 1. The prevalence of social phobia in adult non-clinical samples (ECA=Epidemiologic Catchment Area
program, NCS=National Comorbidity Survey; DIS=Diagnostic Interview Schedule, CIDI=Composite International
Diagnostic Interview, PSE=Present State Examination).
Country/study Male Female Total Prevalence
ECA, weighted 1.06
Bourdon et al. (1988)
Boyd et al. (1990)
Eaton et al. (1991)
ECA, four sites:
Myers et al. (1984)
George et al. (1986)
Davidson et al. (1993)
Schneier et al. (1992)
St Louis 2.0 Point DSM-III Structured
500 Pollard &
11.5 Lifetime DSM-III Structured
2163cKendler et al. (1992)
NCS - multistage
area (48 states)
Magee et al. (1996)
Kessler et al. (1994)
Vega et al. (1998)
Puerto Rico 1.1
DSM-III DIS 1513 Canino et al. (1987)
Dick et al. (1994)
Bland et al. (1988)
Offord et al. (1996)
Stein et al. (1994)
Stein et al. (1996)
Lifetime DSM-III DIS 3134
Lee et al. (1990a)
Lee et al. (1990b)
Lifetime DSM-III DIS 5005
Hwu et al. (1989)
930eWells et al. (1989)
Feehan et al. (1994)
Table 1. (continued)
Country/study Male Female Total Prevalence
Degonda & Angst (1993)
Wacker et al. (1992)
Arillo et al. (1998)h
Roca et al. (1999)
Lépine & Lellouch (1995)
Pélissolo & Lepine (2000)
Faravelli et al. (1989)
Faravelli et al. (2000)
Carta & Rudas (1998)h
The Netherlands 2.8
DSM-III-R CIDI 7076 Bijl et al. (1998)
DSM-III DIS 483 Wittchen et al. (1992)
ICD-10 CIDI 855 Pakriev et al. (2000)
Lindal & Stefanson (1993)
Arnarson et al. (1998)
Point DSM-IV Postal survey 621
aurban; e18-year-olds only i0.9% with a more narrow definition
brural fpure social phobia j1.9% with a more narrow definition
cfemale-female twin pairs gsocial phobia with agoraphobia kundivided simple and social phobia
dMexican Americans hcited in Lecrubier et al. (2000) l52.7% with DSM-III-R criteria
2.1.2 The issue of social phobia subtypes
With emphasis given to performance-oriented fears, the DSM-III definition of social phobia
overlooked individuals exhibiting excessive anxiety in numerous social settings, including face-
to-face conversations and interactional situations. As previously outlined, the diagnostic criteria
were revised in DSM-III-R and a generalized subtype, described as fear of “most social
situations”, was then introduced. Although not formally listed in the DSM-nomenclature, the
remainder of social phobia has by exclusion often been referred to as “nongeneralized” (Hazen &
Stein, 1995; Heimberg, Holt, Schneier, Spitzer, & Liebowitz, 1993a).
However, the subtype organization in DSM-III-R has been subject to substantial criticism.
First, the phrase “most social situations” was not fully operationalized. Second, using the quantity
rather than the quality of social situations for a categorical distinction (generalized vs.
nongeneralized social phobia) might have questionable face validity (Heckelman & Schneier,
1995). Third, the implicit two-part subtype structure in DSM-III-R may be reorganized into a
more fine-grained tripartite system. Heimberg and coworkers (Heimberg et al., 1993a; Herbert et
al., 1992; Holt et al., 1992) have proposed that, while the term generalized social phobia can be
used as a description of severely affected phobics, those who fear only one or two distinct
situations form a separate subgroup referred to as “discrete” (or circumscribed) social phobia.
Arguably, an intermediate category of social phobics are constituted of individuals who fear a
number of social situations even though they are functioning quite well in broad social contexts.
The term “nongeneralized” has also been utilized specifically for this group of social phobics
(Heimberg et al., 1993a; Herbert et al., 1992; Holt et al., 1992). Fourth, underscoring qualitative
features some investigators have suggested that the type of social fear, i.e. the distinction between
performance and interactional fears, could be used to distinguish subtypes (e.g., Mannuzza et al.,
1995; Turner et al., 1992). Hence, in the social phobia literature “performance” and “limited
interactional” subtypes have been discussed (Heimberg et al., 1993a). On the other hand, the
relevance of categorical subtypes has been challenged because individuals with social phobia may
differ mainly in degree of severity rather than in a qualitative sense (Hazen & Stein, 1995;
Heckelman & Schneier, 1995).
Given the conceptual problems, social phobia subtyping still remains matter of dispute. In
the absence of empirical evidence, the social phobia task force refrained from including other
subtypes than generalized social phobia in the development of the fourth edition of the DSM
(Hazen & Stein, 1995). Thus, the DSM-III-R system was kept intact in DSM-IV. As a
consequence of the diagnostic difficulties, little is known about the prevalence of social phobia
subtypes in the general population. By applying latent-class analysis on the National Comorbidity
Survey data, Kessler and colleagues (1998) identified two broad classes of social phobics, those
with speaking fears and those who endorsed at least one other social fear, superficially resembling
the nongeneralized and generalized subtypes. US lifetime prevalence estimates were 4.8% and
8.5%, respectively. Recently, Wittchen, Stein, and Kessler (1999) observed that the lifetime
prevalence of DSM-IV social phobia in German adolescents was 9.5% in females and 4.9% in
men and about one-third was classified as having generalized social phobia. However, more
epidemiological research is clearly needed, and future research efforts should give careful
attention to the definition of social phobia subtypes. To obtain empirically derived and fine-
grained subtypes, future research could benefit from abandoning a priori definitions that are
based on theoretical speculation, and instead adopt data-driven classification methods such as
Further research on social phobia subtypes is also motivated because preliminary evidence
suggests that subtypes may differ with regard to a number of variables that could have
implications both for preventive strategies and the choice of treatment, such as age of onset
(Brown, Heimberg, & Juster, 1995; Mannuzza et al., 1995), history of traumatic conditioning
experiences (Stemberger et al., 1995), social skills (Tran & Chambless, 1995),
psychophysiological stress responses (Heimberg et al., 1990b; Levin et al., 1993), and level of
impairment after therapy (Hope, Herbert & White, 1995; Brown, Heimberg, & Juster, 1995).
2.2 Background to study III and IV
2.2.1 Neurobiological correlates to anxiety
In the 1930’s, following previous pioneering work by William James (1884/1969) and Walter
Cannon (1927), the American anatomist James Papez proposed an early model of the
neuroanatomical circuitry underlying emotions (Papez, 1937). Although it was principally based
on theoretical speculation, the model outlined by Papez became very influential. Since then, there
have been great advances in our knowledge of the emotional brain (see review by LeDoux, 1996),
particularly in the field of fear and anxiety. Our understanding of the neural circuitry underlying
anxiety mainly stems from several decades of experimental research in animals utilizing lesion,
electrical stimulation, pharmacological, and single cell recording techniques. During more recent
years, functional neuroimaging methods have been applied to study emotions in humans.
Together, these streams of research have been of profound importance in the development of
affective neuroscience as a scientific discipline in its own right (Davidson & Sutton, 1995). We
may now, enlightened by extensive empirical research (in contrast to Papez), delineate a model of
the neuroanatomy of fear and anxiety.
Neuroanatomy of anxiety: An integrated model
In an attempt to unify animal and human research findings on anxiety into an integrated
neuroanatomical model (see Figure 1), Charney and colleagues (Charney & Deutch, 1996;
Charney, Grillon, & Bremner, 1998) firstly suggested that such a model should distinguish
between afferent and efferent systems as well as an intermediate stimulus processing chain. Fear
or anxiety (concepts that are often used synonymously although distinctions can be made) can be
thought of as the organism’s response to exteroceptive or interoceptive stimuli that signify threat.
The afferent arm of the anxiety circuit includes the sensory systems (visual, auditory,
somatosensory), which pass on the information in the anxiety-inducing stimulus from peripheral
receptor cells to the dorsal thalamus. The thalamus in turn relays sensory information to primary
sensory areas in the cortex and the stimulus is further processed in neighboring cortical
association regions. The association areas then project to widespread parts of the brain including
the amygdala, rhinal, cingulate, and orbitofrontal cortices. The amygdala, which also receives
crude sensory information directly from the thalamus, is the most widely studied and probably the
most crucial structure for the interpretation and expression of fear/anxiety. It has been called “the
hub in the wheel of fear” (LeDoux, 1996). The amygdala is interconnected with the hippocampus,
which in turn participates in contextual analyses, as well as the consolidation and retrieval of
fearful memories. The hippocampus receives inputs from all sensory systems via transition areas
consisting of the entorhinal, perirhinal, and parahippocampal cortices. The amygdala projects to
the efferent fear system, e.g., the locus coeruleus, periaqueductal gray, hypothalamus, and
striatum, subserving many executive aspects of anxiety including autonomic, endocrine, and
skeletal-motor responses (Charney & Deutch, 1996; Charney et al., 1998).
It is beyond the scope of the present thesis to give a detailed review of each structure in
the neuroanatomical anxiety model (Figure 1), and other regions not included may be considered
important as well. However, because of the enormous interest devoted to the amygdala and
hippocampus in affective and cognitive neuroscience, a more thorough description of the
functional role of these subcortical structures in anxiety is presented below.
sympathetic and para-
sympathetic nervous system
hormonal stress response
sensory or memory stimuli
fight or flight responses
PERIRHINAL, PARAHIPPOCAMPAL CORTEX
Figure 1. Brain regions mediating fear and anxiety. The figure is a modified version of a model previously presented
by Charney and Deutch (1996).
With regard to animal studies, Heinrich Klüver and Paul Bucy reported in 1937 that lesions to the
temporal lobe in rhesus monkeys yielded sedative effects such as exaggerated tameness and
willingness to approach normally fear provoking stimuli (Klüver & Bucy, 1937). It was later
demonstrated that the change in emotional behavior following such lesions could be attributed
specifically to the defective amygdala (Weiskrantz, 1956). Several other lines of evidence also
support that the amygdala plays a crucial role in fear and anxiety in animals. For instance,
electrical stimulation of the amygdala can evoke fearful or defensive behavior as well as rage
attacks (Kling & Brothers, 1992). Single-cell recordings indicate that neurons in the amygdala are
sensitive to frightening and emotionally salient stimuli (Jacobs & McGinty, 1972; O’Keefe &
Bouma, 1969). Moreover, fear conditioning paradigms have frequently been used to study the
neural basis of emotional information processing. It is well documented that the amygdala is an
important site for the mechanisms underlying increased startle reflex in the presence of a cue
previously paired with an electric shock or aversive stimuli (Davis, 1992). Neuronal firing in the
amygdala can also be altered when a neutral stimulus is paired with aversive stimulation
(Applegate, Frysinger, Kapp, & Gallagher, 1982; Pascoe & Kapp, 1985; Umemoto & Olds, 1975)
and studies have shown that injections of anxiolytic drugs into the amygdala affect behavioral
correlates of conditioned anxiety (Scheel-Krüger & Petersen, 1982; Shibata, Kataoka, Gomita, &
Ueki, 1982; Shibata, Yamashita, Yamamoto, Ozaki, & Ueki, 1989). LeDoux and coworkers
(LeDoux, Romanski, & Xagoraris, 1989; LeDoux, Ruggiero, & Reis, 1985) have demonstrated
that auditory and visual fear conditioning occurs in rats with lesions to the auditory and visual
cortex, respectively. It has been suggested that the emotional learning process is mediated by
direct projections from the thalamus to the amygdala, bypassing cortical circuits. Interruption of
the thalamo-amygdala connection as well as lesions of the amygdala itself have been reported to
interfere with fear conditioning (Kim & Davis, 1993; LeDoux, 1996).
Also in humans there are many sources of evidence supporting that the amygdala is
involved in fear or anxiety. In human patients with damage to the amygdaloid complex,
impairments have been noted with regard to: fear conditioning (Bechara et al., 1995; LaBar,
LeDoux, Spencer, & Phelps, 1995), startle reflex potentiation by aversive emotive stimuli
(Angrilli et al., 1996); declarative memory for emotional material (Adolphs, Cahill, Schul, &
Babinsky, 1997; Cahill, Babinsky, Markowitsch, & McGaugh, 1995; Markowitsch et al., 1994) as
well as the recognition of fear in facial expressions (Adolphs, Tranel, Damasio, & Damasio,
1994; 1995; Adolphs et al., 1999; Broks et al., 1998; Calder et al., 1996; Sprengelmeyer et al.,
1999; Young et al., 1995), verbatim material (Scott et al., 1997; Sprengelmeyer et al. 1999), and
body postures (Sprengelmeyer et al., 1999). Evidence from sedative psychosurgery suggests that
damage to the amygdaloid complex results in at least some loss or change of negative affect
(Aggleton, 1992). Electrical stimulation of the amygdaloid complex in man has been reported to
elicit symptoms of fear (Halgren, 1982). Similarly, fear seems to be the most common affect
produced by temporal lobe epileptic discharge, which is associated with abnormal electrical
activity in the amygdala (Gloor, 1992).
Neuroimaging is another source of evidence for amygdalar participation in fear. In the
initial wave of brain mapping studies, amygdalar involvement was generally not observed during
symptom provocation in patients with anxiety disorders (see reviews by Dager et al., 1996; Rauch
& Shin, 1997). A number of recent studies, however, have noted amygdalar activation, e.g., in
patients with posttraumatic stress disorder scanned during conditions that involved trauma
reminders (Rauch et al., 1996; Shin et al., 1997) or perception of threat-related stimuli (Rauch et
al., 2000). Provocative stimulation has also been reported to activate the amygdala in patients
with obsessive-compulsive disorder (Breiter et al., 1996b). Furthermore, in brain mapping studies
of healthy volunteers, amygdalar activation has been noted during anxiety induced by drugs such
as cholecystokinin tetrapeptide [CCK-4] (Benkelfat et al., 1995) and procaine (Ketter et al., 1996;
Servan-Schreiber, Perlstein, Cohen, & Mintun, 1998). Other emotionally relevant neuroimaging
studies have shown that the amygdala is engaged in the perceptual processing of fearful facial
expressions (Breiter et al., 1996a; Morris et al., 1996; 1998; Phillips et al. 1997; Whalen et al.,
1998b), linguistic threat cues (Isenberg et al., 1999), aversive pictures (Irwin et al., 1996; Lane et
al., 1997; Paradiso et al., 1999), aversive odor (Birbaumer et al., 1998; Zald & Pardo, 1997), and
aversive gustatory (Zald, Lee, Fluegel, & Pardo, 1998) stimulation. Finally, consistent with the
vast animal literature, a number of recent imaging studies suggest that the amygdala is involved
in fear conditioning processes also in humans (Büchel, Dolan, Armony, & Friston, 1999; Büchel,
Morris, Dolan & Friston, 1998; Furmark, Fischer, Wik, Larsson, & Fredrikson, 1997; LaBar,
Gatenby, Gore, LeDoux & Phelps, 1998; Morris, Öhman, & Dolan, 1998; Schneider et al., 1999).
In summary, substantial evidence supports that the amygdala is fundamentally involved in
fear and anxiety, both in animals and in humans. However, despite the huge body of research
there is still some uncertainty about wether the amygdaloid complex truly is necessary for the
production of negative emotions, as some lesion studies suggest that patients with amygdala
damage exhibit normal reactions to affectively provocative stimulation and several neuroimaging
studies report that emotionally alerting stimuli fail to activate the amygdala (Cahill, 1999).
Recently, it has been argued that the amygdala is involved in threat detection, but mainly in
ambiguous situations (Whalen, 1998). Also, the exact role of the amygdala and its subnuclei in
aversive memory formation is not clear. The amygdala may serve only time-limited modulatory
functions in memory storage and may not be necessary for all types of fear acquisition (Cahill,
1999). Moreover, amygdalar functioning is probably not limited to the domain of emotions or to
negative emotions only (Hamann, Ely, Grafton, & Kilts, 1999; Rolls, 1999).
At least since the 1950’s, the hippocampus has been of prime interest for studies of memory and
cognition following the initial observations of H.M. - a well-studied patient who became severely
amnesic after surgical removal of the hippocampal regions (Scoville & Milner, 1957). H.M. also
appeared to have lost at least some capacity for anxiety (Gray & McNaughton, 1996). However,
in the neuroscientific literature, cognitive functions such as episodic memory encoding and spatial
analysis have generally been attributed to the hippocampus whereas emotive functions are often
overlooked. Questioning the sharp distinction between cognition and emotion, Jeffrey Gray and
colleagues have argued that the septo-hippocampal region is crucial for the behavioral inhibition
system, which in turn mediates the condition of anxiety (Gray & McNaughton, 1996). The
behavioral inhibition system is activated at times of risk assessment when the organism stops
ongoing behavior and becomes attentive while bodily resources are mobilized in preparation for a
quick behavioral response such as fight or flight. Anxiety may thus be thought of as excessive
activity in the septo-hippocampal behavioral inhibition system. This notion receives support from
animal studies suggesting that the behavioral changes caused by anxiolytic drugs are paralleled by
patterns seen after lesions to this system (Gray & McNaughton, 1996).
Moreover, fear conditioning studies in animals have shown that the hippocampus
(together with the rhinal cortex) participates in conditioning to fear contexts, but probably not in
conditioning to specific fear cues (LeDoux, 1996). Phobic avoidance develops from learning
which settings are dangerous, presumably involving contextual analyses at the hippocampal level
(Gorman, Kent, Sullivan, & Coplan, 2000). Furthermore, when a fear or anxiety-inducing sensory
stimulus is passed on through the thalamus into the temporal cortex, the hippocampus, and the
amygdala, it is likely that appurtenant memory traces of anxious experiences are stimulated
(Charney et al., 1998). Thus, the hippocampus is probably involved in the consolidation and
retrieval of fearful memories, or at least certain aspects of such memories.
Also in neuroimaging studies of patients with anxiety disorders, the hippocampal and
parahippocampal regions have been of fundamental interest ever since the pioneering imaging
report on panic disorder by Reiman, Raichle, Butler, Herscovitch, and Robins (1984). In a recent
positron emission tomography (PET) study, patients with panic disorder showed an increase in
resting-state glucose metabolism in the left hippocampus and parahippocampal area, relative to
healthy controls (Bisaga et al., 1998). A trait abnormality in this brain territory could be
associated with vulnerability for misprocessing anxiety-provoking stimuli (Bisaga et al., 1998).
In summation, the hippocampus appears to play an important role in traumatic memory
consolidation and retrieval, context-specific processing of anxiogenic information, behavioral
inhibition, and the fluctuation of approach-avoidance behaviors during threat evaluation. The
hippocampus projects to the amygdala and receives convergated inputs from sensory systems
through projections from the “transition” cortex, i.e. the entorhinal, perirhinal, and
parahippocampal cortical regions (LeDoux, 1996). It has been proposed that the hippocampal
region, together with the amygdala and transition cortex, serve as an alarm center, cautioning the
individual to threatening exteroceptive stimulation (Reiman, 1997).
2.2.2 Serotonin and anxiety
In the brain, serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter synthesized from L-
tryptophan, which is an amino acid that primarily comes from the diet. The synthesis involves
several steps. First, tryptophan is transformed to the serotonin precursor 5-hydroxytrypthophan
(5-HTP) by means of the enzyme tryptophan hydroxylase. Another enzyme, 5-HTP-
decarboxylase, then converts 5-HTP to 5-HT, i.e., to serotonin. Serotonin is eventually broken
down into its synaptically inactive metabolite 5-hydroxyindoleacetic acid (5-HIAA). This process
is catalyzed by yet another enzyme - monoamine oxidase. The cellbodies of serotonergic neurons
are found in the brainstem raphe region, and there are two principal serotonergic pathways: (a)
descending projections from the caudal raphe into the spinal cord and (b) ascending projections
from the medial and dorsal raphe nuclei, which reach widespread areas of the central nervous
system. Interestingly, the serotonergic innervation is particularly dense in medial temporal lobe
regions including the amygdala and hippocampus (Jacobs & Azmitia, 1992). SSRIs block the
reuptake of serotonin into the presynaptic nerve terminal, thereby increasing the concentration of
serotonin in the synaptic cleft.
Although it is highly unlikely that complex emotional reactions like anxiety can be
explained by deficiencies in just one neurotransmitter, there is substantial evidence that serotonin
plays a pivotal role in the regulation of anxiety. This opinion is supported by numerous animal
studies which have evaluated the effects of serotonergic drugs on various behavioral correlates to
aversive emotional states (Handley, 1995). Also, initial clinical observations in human patients
suggested anxiolytic effects of drugs acting upon serotonergic transmission in the brain, and this
has now been demonstrated in controlled studies (c.f. Gorman & Kent, 1999). In the
pharmacotherapy of anxiety disorders such as social phobia, the SSRIs have rapidly become the
drug treatment of choice (Van Ameringen et al., 1999). It has also been speculated that behavioral
therapy of anxiety disorders is effective due to a direct effect on the serotonergic system (Baer,
However, the specific functions of serotonin in anxiety regulation still remain to be
clarified. For instance, it is not agreed whether serotonin increases or decreases anxiety.
According to the classical theory, excessive 5-HT induces anxiety (while decreases are associated
with impulsiveness and aggressiveness). This notion is mainly supported by earlier experimental
studies in animals evaluating the effect of serotonergic drugs on punished behavior or
approach/avoidance conflict situations, but these studies sometimes used anxiety models of
questionable ecological validity (Graeff, Viana & Mora, 1997). While other studies conversely
suggested an anxiolytic effect of 5-HT, the classic view was mainly challenged by the
introduction of SSRIs, which are antidepressant and anti-anxiety medications that are widely held
to enhance 5-HT neurotransmission (Graeff, Guimaraes, De Andrade, & Deakin, 1996). To
reconcile the conflicting evidence regarding increases and decreases, Deakin and Graeff (1991)
have suggested a dual role of 5-HT such that the ascending 5-HT pathway from the dorsal raphe
to the amygdala and frontal cortex elevates conditioned fear, whereas 5-HT inhibits innate anxiety
reactions in the periaqueductal gray region. Further exploration is needed to clear up this issue.
2.2.3 Brain mechanisms in anti-anxiety treatments
The neural effects of SSRIs
Given the uncertainties with regard to the way serotonin influences anxiety, the neural
mechanisms underlying effective SSRI-treatment of anxiety are incompletely understood. In
SSRI-treatment, there also appears to be some heterogeneity among clinical groups. For instance,
SSRI-treatment of depression, panic disorder, and obsessive-compulsive disorder can vary in dose
requirement, initial anxiogenic effects, response latency, and principal action on presynaptic or
postsynaptic processes (Nutt et al., 1999). Gorman et al. (2000) argued that the conflicting results
in research on 5-HT and anxiety could be better understood after a more refined analysis of the
pathways participating in serotonergic neurotransmission. First, projections of 5-HT neurons to
the locus coeruleus are inhibitory, such that increased activation of the serotonergic neurons in the
raphe attenuate noradrenergic neurons in the locus coeruleus, with resultant decreases in
cardiovascular or autonomic symptoms of anxiety. Second, as previously noted by Deakin and
Graeff (1991), defensive or escape reactions are mitigated by inhibitory projections of the raphe
neurons to the periaqueductal gray region. Third, increasing levels of serotonin may diminish the
hormonal stress response by preventing the hypothalamic release of corticotropin-releasing factor
(CRF). Thus, SSRIs may act by diminishing arousal at the locus coeruleus level, defense/escape
behaviors at the periaqueductal gray level, and concentrations of anxiety provoking CRF at the
hypothalamic level (Gorman et al., 2000). Also, some preliminary evidence suggests that
increasing levels of serotonin may inhibit cortical and thalamic inputs from activating the
amygdala itself (Gorman et al., 2000).
Different or common brain mechanisms in pharmacotherapy versus psychotherapy?
Because it is poorly understood how successful treatment of anxiety disorders relates to
concomitant changes in brain activity in the first place, it is not known whether efficacious drug
treatment and psychotherapy engage similar or different neurofunctional networks. In an early
article, Gorman, Liebowitz, Fyer, and Stein (1989) hypothesized that anti-panic medications work
“bottom-up” through stabilization of unstable brain stem nuclei, and that cognitive-behavioral
therapy works “top-down” through modification of dysfunctional cognitions, presumably
involving the prefrontal cortex. However, the rationale for behavioral treatment of anxiety is
based largely on classical fear conditioning theories (Craske & Rowe, 1997). Recall that
numerous animal studies indicate that fear conditioning processes are crucially dependent on
subcortical structures such as the amygdala and hippocampus (LeDoux, 1996). It has also been
observed in animals that anxiolytic effects can be achieved by injections of benzodiazepines
directly into the amygdaloid complex (Scheel-Krüger & Petersen, 1982; Shibata et al., 1982;
1989) and that the effects of anxiolytic drug administration are paralleled by lesions to the
hippocampus (c.f. Gray & McNaughton, 1996). The amygdala and hippocampus may be
important targets not only for traditional anxiolytic drugs but possibly also for successful
psychological treatments and second-generation (e.g., SSRI) pharmacotherapy.
Revising their early theory, Gorman and colleagues (2000) recently suggested that SSRI-
medications may reduce anxiety by attenuating the activity of the amygdala, thereby disrupting its
potential to stimulate projection sites downstream, e.g. in hypothalamic and brain stem regions.
Psychotherapies might exert their effects upstream from the amygdala. Cognitive biases and
abnormal emotional reactions may be modified by enhancing the capacity of the medial prefrontal
cortex to inhibit the amygdala. Reduction of avoidance behaviors may stem from
“deconditioning” of fear originally learned at the level of the hippocampus, as suggested by
studies of contextual fear conditioning in animals. (Gorman et al., 2000). Gray and McNaughton
(1996) have suggested that behavior therapy is beneficial because it allows systematic habituation
of the septo-hippocampal response to anxiety-provoking stimuli. Also, it can probably not be
excluded that cognitive-behavior therapy has a direct action in the amygdala. Alternatively, while
it is possible that anti-anxiety treatments intervene directly in abnormally functioning brain
regions (e.g., the amygdala), it is equally possible that they compensate for abnormality by
influencing other areas in the brain (Reiman, 1997).
Various underlying mechanisms have previously been discussed in the psychotherapy
literature. For instance, cognitive theories of anxiety reduction have stressed the importance of
processes such as improved self-efficacy (Bandura, 1977) or increased accuracy of fear
estimations (Rachman, 1994). Presumably the cognitive mechanisms engage frontal or more
wide-spread parts of the neocortex that participate in conscious awareness. Behavioral theories of
anxiety reduction have, in addition, suggested that therapy may act by habituation, extinction, or
other emotional processing mechanisms (Craske & Rowe, 1997), which probably rely more on
subcortical structures like the amygdala. Conceivably, the different components in treatment
packages, such as exposure and cognitive restructuring, could differ with regard to principal sites
of action in the afferent arm, in the intermediate stimulus processing chain, or in the efferent arm
of the anxiety model outlined in Figure 1.
Also, with regard SSRI-treatment it has been suggested that, in addition to the direct drug
effect, SSRIs could work indirectly through “psychological” processes (Hayward & Wardle,
1997). Neurochemical changes caused by the drug might modify the individual's experience of
anxiety. Exposure to anxiogenic situations is then increasingly tolerated and the individual may
habituate, or alternatively, learn new approach behaviors and form success-memories that
compete with fear reactions as suggested by the extinction and emotional processing theories
(Hayward & Wardle, 1997). At the time of market introduction, it was proposed that the SSRIs
acted by “toughening” the individual, making him/her less sensitive to stressful events (Kramer,
1993). Presumably, this corresponds to less sensitive fear circuits in the brain, which could in
theory be equally achieved by psychological treatments.
While there are informed speculations about brain mechanisms in anti-anxiety treatments, as
outlined above, modern neuroimaging techniques provide the means to put these speculations
under scientific scrutiny. Not only could neuroimaging, employed before and after treatment, be
very helpful in unraveling the mechanisms underlying anxiety reduction. Such studies could also
identify prognostic and prescriptive factors associated with different therapies. Ultimately,
imaging studies could facilitate the development of treatment components that are directly
tailored to intervene with the underlying pathophysiology.
Despite their potential, brain imaging tools have quite seldom been used in psychiatric
treatment studies. However, in a landmark PET-study, Baxter et al. (1992) reported that both
behavior therapy and fluoxetine reduced resting glucose metabolism in the right caudate nucleus
in patients with obsessive-compulsive disorder (OCD). The behavioral therapy results were later
replicated by Schwartz, Stoessel, Baxter, Martin, and Phelps (1996), and treatment response
could also be predicted from initial metabolism in the orbitofrontal cortex (Brody et al., 1998).
Neural changes following pharmacotherapy of OCD have been investigated by several other
groups (e.g., Baxter et al., 1987; Hoehn-Saric, Perlson, Harris, Machlin, & Camargo, 1991;
Molina et al., 1995; Perani et al., 1995; Rubin, Ananth, Villanueva-Meyer, Trajmar, & Mena,
1995; Rubin et al., 1995; Swedo et al., 1992). Imaging reports on treatment for other anxiety
disorders are surprisingly few and methodologically heterogeneous, but include studies of
benzodiazepines in generalized anxiety (Buchsbaum et al., 1987; Mathew & Wilson, 1991; Wu et
al., 1991) and specific phobia (Fredrikson, Wik, Annas, Ericson, & Stone-Elander, 1995),
tricyclic antidepressants in panic disorder (Nordahl et al., 1998), and eye movement
desensitization in posttraumatic stress disorder (Levin, Lazrove, & van der Kolk, 1999). A
consistent pattern of brain regions mediating anxiety reduction does not emerge because findings
are mixed and sometimes negative. Also in depression, some studies report that treatment
normalizes abnormal resting-state glucose hypometabolism, often initially seen in the prefrontal
cortex, while others suggest that metabolic hypoactivity persists after successful therapy, thus
constituting a trait rather than a state marker (Kumar, 1997; Trivedi & Husain, 1997). It should be
noted that nearly all neuroimaging treatment studies on negative affect have evaluated changes in
the resting-state only. While such studies are informative, activation studies exploring the effects
of treatment on provoked anxiety conditions also need to be performed.
2.2.4 Neurobiological studies of social phobia
Serotonin and social phobia
As mentioned, social phobics respond favorably to medications that act upon serotonergic
neurotransmission in the brain (Van Ameringen et al., 1999) and some data also imply that SSRIs
may increase sociability in normal healthy volunteers (Knutson et al., 1998). Moreover, it has
been observed that, relative to controls, social phobics have a greater cortisol response to the
serotonin-releasing compound fenfluramine, possibly indicating supersensitivity of the post-
synaptic 5-HT receptors (Tancer, 1993). Also, serotonin drugs may facilitate the achievement of
social dominance in vervet monkeys (Raleigh, McGuire, Brammer, Pollack, & Yuwiler, 1991).
Taken together, these data suggest that serotonin is somehow involved in the pathophysiology of
social phobia. However, the complexity of this issue is illustrated by the fact that social phobics
may respond with increasing anxiety to fenfluramine or meta-chlorophenylpiperazine challenges,
which increase serotonin concentration (Nutt, Bell, & Malizia, 1998), whereas decreasing levels
of public speaking anxiety following oral fenfluramine administration have been observed in
healthy volunteers (Graeff et al., 1996). Thus, the exact role of the serotonin system in social
phobia (and other anxiety disorders) remains to be elucidated.
Neuroimaging: Studies of social anxiety provocation
Functional neuroimaging techniques such as PET have only recently been applied to study states
of social anxiety. Using 15O-water PET, Reiman (1997) studied social phobics singing the
alphabet song either alone or under observed conditions. Evaluative anxiety was associated with
significantly increased regional cerebral blood flow (rCBF) in the thalamus, midbrain, and the
lateral prefrontal, midcingulate, sensorimotor, and anterior temporal cortices. Trends for
significance were observed in the amygdala, hippocampus, hypothalamus, and cerebellum as well
as in the medial prefrontal and anterior cingulate cortices. In other PET-studies, social anxiety has
been associated with rCBF-redistribution in the right dorsolateral prefrontal and the left parietal
areas (Bell, Malizia, & Nutt, 1999) and also in the visual and medial frontal cortices (van
Ameringen et al., 1998). It should be emphasized that all these studies (Reiman, 1997; Bell et al.,
1999; van Ameringen et al., 1998) report preliminary data only. In a recently completed PET-
study (Tillfors et al., submitted) our group observed that the neural response (indexed by rCBF) to
public speaking, relative to speaking alone, differed between social phobics and healthy controls.
Relative to controls, neuronal activity was more elevated in phobics in the amygdaloid complex,
while rCBF increased less in the retrosplenial, parietal, and secondary visual cortices and
decreased more in the orbitofrontal, insular, and temporal pole cortical areas.
Neuroimaging: Treatment studies
Previous studies exploring treatment effects on provoked social anxiety states are lacking.
However, Van der Linden et al. (2000) recently reported results from single photon emission
computed tomography assessments before and after eight weeks of SSRI (citalopram) treatment.
Results suggested that pharmacotherapy reduced resting-state neuronal activity in the left-sided
temporal, mid frontal and cingulate cortices whereas increases were noted in occipital regions
bilaterally, but the findings did not survive correction for multiple comparisons.
Neuroimaging: Other studies
To date, neuroimaging research in social phobia also encompass studies of brain structural
volume (Potts, Davidson, Krishnan, & Doraiswamy, 1994), dopaminergic function (Schneier et
al., 2000; Tiihonen et al., 1997), resting metabolic activity (Davidson et al., 1993b; Stein &
Leslie, 1996; Tupler et al., 1997), electroencephalograms during anticipatory anxiety (Davidson,
Marshall, Tomarken, & Henriques, 2000), and brain perfusion during unpleasant emotional
perception (Birbaumer et al., 1998) and aversive conditioning processes (Schneider et al., 1999).
This type of research has only begun and more studies are needed to delineate brain dysfunctions
that are specific for social phobia.
Outside the field of neuroimaging, neurobiologically oriented studies of social phobia include
examinations of psychoactive drug effects, genetic contributions, neuroendocrine imbalances as
well as psychophysiological, biochemical, and behavioral responses to various stressful
challenges (see reviews by Bell et al., 1999; Miner & Davidson, 1995; Nickell & Uhde, 1995;
Nutt et al., 1998; Potts, Book & Davidson, 1996; Stein, 1998). While many of the findings are
intriguing, much work remains to be done before a clear and consistent picture of specific
neurobiological abnormalities in social phobia emerges.
3. THE EMPIRICAL STUDIES
3.1 Empirical studies on the epidemiology and subtypes of social phobia
3.1.1 Study I
Social phobia in the general population: prevalence and sociodemographic profile
Aim and background
The first study sought to determine the point prevalence and demographic characteristics of social
phobia in the Swedish general population. A mailed questionnaire assessing anxiety in multiple
performance and interactional situations was used to identify cases of social phobia, reveal
demographic features, and to yield frequency estimates of social fears in the general community.
The study was motivated for several reasons. Prevalence estimates of social phobia are important
in the planning of mental health interventions, and Scandinavian studies on this topic are lacking.
The majority of epidemiological studies have used out-dated (i.e. DSM-III) diagnostic criteria
whereas studies using modern DSM-IV definitions of social phobia are rare. Also, previous
studies have generally used few situational probes, which inflates the risk of missing cases. Some
demographic/descriptive characteristics have shown inconsistent results across studies whereas
other variables such as urbanicity, immigration, birth order, and social support are understudied.
Finally, data on the distribution of social fears in the normal population are scarce.
A questionnaire hereafter referred to as “the Social Phobia Screening Questionnaire” (SPSQ) was
constructed by the authors in a consensus process and then mailed to a large general population
sample. The SPSQ assessed the level of social distress in 14 potentially phobic situations. Each
situation was rated on a 0-4 (min-max) distress scale yielding a total distress score of 0-56 for
each individual. The situational questions served partly to yield prevalence estimates of social
fears independent of social phobia, and partly to determine whether “marked distress” as defined
in the DSM-IV criteria was a fulfilled condition. Presence of social phobia was further
determined by means of diagnostic true/false questions covering criteria A-D in DSM-IV. Each
question/criterion was formulated as a statement, e.g. “in the following situation(s) I always
become very nervous”, which was followed by the list of the 14 situations. Subjects could tick a
box corresponding to a social situation or choose “none of the above situations”. The question
covering the E-criterion concerned impairment in three different life domains
(occupational/academic, leisure time, or social activities). Thus, the level of impairment endorsed
by the individual could vary between 0-3 (min-max).
The a priori definition used to define cases of social phobia was as follows: (a) distress
rating of ≥ 3 on at least one of the 14 potentially phobic situations, (b) this situation had to be
consistently endorsed in the subsequent diagnostic questions assessing criteria A-D, and (c) the
subject had to admit impairment or marked distress due to social anxiety in at least one of the
three life domains assessed by the E-criterion question. Prevalence of social phobia was also
estimated across different cut-off levels, i.e. varying degrees of distress and impairment used in
conjunction with the diagnostic questions. Point prevalence was chosen over other estimates in
order to avoid reliability problems associated with recall over longer time periods. The SPSQ also
included a section assessing demographic characteristics and family history of excessive social
anxiety. A final section assessed avoidant personality disorder with diagnostic questions
extracted, with permission, from the DSM-IV and ICD-10 Personality Disorder Questionnaire;
DIP-Q (Ottosson et al., 1998).
In a preliminary psychometric evaluation, the SPSQ correctly classified all 35 cases and
19 of 20 non-cases in a reference sample interviewed with the structured clinical interview for
axis I disorders (SCID; First et al., 1998). The alpha coefficient for the 14-item social distress
scale was 0.90 and it correlated highly with the Social Phobia Scale (r = 0.77, p<0.0001) and the
Social Interaction Anxiety Scale (r = 0.79, p<0.0001), which are established clinical measures
(Mattick & Clarke, 1998). This indicated that the measures of sensitivity (100%), specificity
(95%), homogeneity, and concurrent validity were satisfactory.
The SPSQ was mailed to 2000 adults (1000 male/female, aged 18-70) randomly selected
from a population based registry (Enator). Subjects were selected from the greater Stockholm area
or the island of Gotland in equal proportion (1000/each). These regions were chosen in order to
evaluate urban-rural differences. The Gotland sample was also selected from three different
urban-rural regions. Questionnaires were filled out anonymously. After reminders, interpretable
questionnaires were obtained from 1202 respondents, i.e. 60.1% (541 men, 661 women; mean
age= 41.8, SD=14.1; 621 from Stockholm and 581 from Gotland).
Table 2. The prevalence of social phobia assessed with diagnostic (DSM-IV) questions
and varying levels of social distress and functional impairment. No. 4 was the a priori
chosen cut-off level.
Cut-off level Prevalence
1) Diagnostic questions; impairment ≥ 1 domain
2) Diagnostic questions; impairment ≥ 2 domains
3) Diagnostic questions; impairment = 3 domains
4) Diagnostic questions; distress rating
5) Diagnostic questions; distress rating ≥ 3; impairment ≥ 2 domains
6) Diagnostic questions; distress rating ≥ 3; impairment = 3 domains
7) Diagnostic questions; distress rating = 4; impairment ≥ 1 domain
8) Diagnostic questions; distress rating = 4; impairment ≥ 2 domains
9) Diagnostic questions; distress rating = 4; impairment = 3 domains
The point prevalence of social phobia was estimated at 15.6% (95% confidence interval: 13.5-
17.6%) using the a priori definition, but prevalence rates varied between 1.9-20.4% across the
different levels of distress and impairment used to define cases (see Table 2). Eighty-eight
(14.2%) individuals in the Stockholm sample and 100 (17.2%) Gotlanders met the criteria for
social phobia. There were no significant differences in prevalence rates between the Stockholm
and Gotland samples (χ2 = 2.1, df = 1, n.s.), nor between different Gotland urban/rural regions (χ2
= 4.6, df = 2, n.s.). Public speaking was the most common social fear both in social phobics
(77.1%) and in the entire sample (24.0%) - see Table 3. In comparison with non-phobic
individuals, social phobia was associated with female gender (χ2 = 8.8, df = 1, p<0.005), low
educational attainment (χ2 = 11.3, df = 2, p<0.005), psychotropic medication use (χ2 = 20.1, df =
1, p<0.0001), lack of social support (χ2 = 29.2, df = 1, p<0.0001), and younger age (χ2 = 7.7, df =
2, p<0.05), although the latter finding did not survive Bonferroni-correction. An attrition analysis
based on telephone interviews revealed that 12 of 80 (12.5%) contacted nonresponders met the
impairment criterion, which was significantly fewer than among questionnaire responders (χ2 =
9.1, df = 1, p<0.005).
It was observed that social phobia was a highly common disorder, with an estimated point
prevalence of 15.6% although this estimate was highly sensitive to variations in the diagnostic
cut-off level used. The results are consistent with previous studies showing that: (a) the use of
modern diagnostic criteria (DSM-III-R or DSM-IV) usually yields considerably higher prevalence
rates than the older DSM-III studies, (b) prevalence rates may vary dramatically across different
diagnostic thresholds, e.g., the required level of impairment and distress, (c) public speaking is by
far the most prevalent social fear, and (d) in the general population social phobia is more common
in women than in men and also in those with lower educational levels, whereas urbanicity appears
to have relatively little impact. It can be concluded that social anxiety is a distressing problem for
a substantial proportion of the general population although the exact diagnostic boundaries for
social phobia are difficult to determine.
Table 3. The prevalence of social fears, i.e. the proportion of individuals that rated the potentially
phobic situation as ≥ 3 on a 0-4 social distress scale.
Prevalence n (%)
1. Speaking (or performing) in front of a group of people
2. Being addressed in a group of people
3. Maintaining a conversation with someone unfamiliar
4. Writing in front of others
5. Expressing opinions in front of others
6. Eating/drinking in public
7. Being alone with someone unfamiliar
8. Making a phone call to someone unfamiliar
9. Using public lavatories
10. Attending a party (or a social gathering)
11. Entering a room in which unfamiliar people are seated
12. Initiating a conversation with someone unfamiliar
13. Dealing with authority figures (e.g. a boss or a teacher)
14. Interacting with colleagues during coffee- or lunchbreaks
3.1.2 Study II
Social phobia subtypes in the general population revealed by cluster analysis
Aim and background
The aim of the second study was to explore the point prevalence and descriptive characteristics of
empirically derived social phobia subgroups in the general population. A fundamental problem
with earlier studies on social phobia subtypes is that these tend to use a priori definitions based
on subjective clinical observations or theoretical speculation. Studies examining subtypes could
benefit from using data-driven and exploratory classification methods, such as cluster analysis, to
delineate subtype formations empirically. Empirical definitions of social phobia subtypes are
needed to improve diagnostics. Moreover, partly reflecting the diagnostic uncertainties, little is
known about the prevalence of social phobia subgroups in the general population. Accurate
determinations of subtypes could have implications for the therapy and prevention of social
phobia as subtypes may differ with regard to treatment outcome and etiology.
The epidemiological method was the same as in study I. Briefly, the SPSQ was used to identify
cases of social phobia in the Swedish general community. To reveal subtypes, symptomatology
data were extracted from the 188 identified social phobics and entered into a hierarchical cluster
analysis. This is a multivariate data-reduction technique that groups individuals based on the
characteristics they possess (Hair, Anderson, Tatham, & Black, 1995). The cluster analysis was
based on Ward’s method and squared Euclidean distances (Hair et al., 1995). The cluster variate
consisted of the following four variables: (a) distress ratings of the 14 phobic situations (range 0-
56), (b) number of phobic situations rated as ≥3 on the distress scale (range 0-14), (c) level of
functional impairment, i.e. the number of impaired life domains endorsed on the E-criterion
question (range 0-3), and (d) number of criteria fulfilled for avoidant personality disorder (range
0-7), assessed with questions extracted from the DIP-Q (Ottosson et al., 1998). Subtypes have
previously been suggested to differ on these characteristics (c.f. Rapee, 1995). Standardization in
Z-scores was performed prior to cluster analysis.
To establish initial clusters, the percentage change in agglomeration coefficients was
evaluated for solutions of two to ten clusters and a scree plot was used to detect a point of
inflection (Hair et al., 1995). To decide the optimal number of clusters, the initial results were
evaluated against criteria suggested by Bergman (1998), e.g., the accepted solution must be
meaningful, theoretically interpretable, and the explained error sum of squares must be
satisfactory. Criterion validity was evaluated by comparing clusters on the Social Phobia Scale
(SPS) and the Social Interaction Anxiety Scale (SIAS) (Mattick & Clarke, 1998). Finally, profile
analyses were performed in which clusters were compared on a set of sociodemographic and
Three clusters emerged, consisting of social phobics scoring either high, intermediate, or low on
all variables (see Figure 2). In accordance with terminology previously used in the social phobia
literature these clusters were labeled generalized, nongeneralized, and discrete social phobia.
However, clusters also conformed to a severe, moderate, and mild subtype. Point prevalence rates
were 2.0%, 5.9%, and 7.7% respectively. The explained error sum of squares in the three-cluster
solution was 69.4%. This was above the level of 67% suggested to reflect homogenous clusters
(Bergman, 1998). In addition, the hierarchical three-cluster solution was compared to an iterative,
nonhierarchical cluster analysis (k-means clustering, Hair et al., 1995) with three clusters
specified in the analysis. This yielded a kappa of 0.79 and an 87.2% agreement between the two
methods, suggesting that clusters were robust. All subtypes were differentiated both on the SPS
and the SIAS, indicating satisfactory criterion validity. The profile analyses revealed that
generalized or severe social phobia tended to be overrepresented among individuals with low
levels of educational attainment and social support. Public speaking was the most common fear in
By and large, the obtained cluster solution matched the categorical three-part subtype
organization previously proposed by Heimberg and coworkers (c.f. Heimberg et al., 1993a)
consisting of generalized, nongeneralized, and discrete social phobia. The discrete subtype, which
was dominated by public speaking phobics, was the most prevalent (7.7%), followed by the
nongeneralized (5.9%), and generalized (2.0%) social phobia. However, although categorical
definitions could be used, the most parsimonious interpretation of the results is that social phobia
subtypes in the general population mainly differ dimensionally along a mild-moderate-severe
continuum, and that the number of cases declines with increasing severity.
Distress Situations Impairment APD
Cluster 1 (n = 24)
Cluster 2 (n = 71)
Cluster 3 (n = 93)
Figure 2. Cluster profiles revealed by a hierarchical cluster analysis. Three
clusters , i.e. subtypes of social phobia, were obtained either with high (top
line), intermediate (middle line), or low Z-scores (bottom line) on four variables
assessed. These were: social distress ratings, number of feared situations,
level of functional impairment, and number of criteria fulfilled for avoidant
personality disorder (APD).
3.2 Empirical studies on brain function in social phobia
3.2.1. Study III
Presynaptic serotonin imaging in social phobia using
positron emission tomography
Aim and background
Although fenfluramine challenge studies, as well as the reported efficacy of serotonin uptake
blockers indicate that serotonin is involved in the regulation of social anxiety, detailed knowledge
of how serotonergic imbalances contribute to the pathophysiology of social phobia and other
anxiety disorders is lacking. Parallel advances in radiochemistry and neuroimaging
methodologies have made it possible to study brain serotonin metabolism in human subjects.
Thus, the aim of the third study was to examine cerebral radioactivity uptake derived from
radiolabeled 5-hydroxytryptophan (5-HTP), i.e. the precursor to serotonin synthesis, in social
phobics compared with healthy controls using PET.
Eighteen (10 male/8 female, mean age = 35.2, range = 23-46 years) previously untreated patients
with DSM-IV social phobia and an equal number healthy controls, similar in gender and age,
were recruited by means of newspapers advertisements. Following a brief telephone interview,
subsequent screening included self-report questionnaires, structured clinical (SCID) interviews
(First et al., 1998), and a public speaking test. Criteria for exclusion were: current psychiatric
disorder (other than social phobia) or organic brain disorder, somatic disease, chronic use of
prescribed medication, abuse of alcohol/narcotics, left-handedness, and pregnancy.
All subjects underwent PET-assessments using the radiotracer [β-11C]-5-HTP. In rats, this
tracer has by 75% been converted to 11C-5-HIAA, the metabolite of serotonin, 40 minutes after
administration (Lindner et al., 1997). Patients and controls were matched with regard to local
time during scanning. All subjects refrained from tobacco, alcohol, and caffeine 12 hours, and
from food (but not water) 5 hours before scanning. PET-scans were performed with a GEMS
PC2048-15B eight-ring scanner with a 10 cm axial field of view and an axial/transaxial resolution
of approximately 6 mm. An average [β-11C]-5-HTP image, consisting of the time frames from
15-60 minutes, was made. The image from the [β-11C]-5-HTP scan was automatically aligned to
a H215O scan. This was performed in addition to the [β-11C]-5-HTP scan to obtain a scan with full
axial coverage of the brain to be used for stereotactical normalization. All individual [β-11C]-5-
HTP images were anatomically normalized in the standard Greitz brain atlas (Greitz, Bohm,
Holte, & Eriksson, 1991).
PET-data were filtered with a 12 mm Gaussian filter and then analyzed using a blocked
ANOVA design implemented as a multiple linear regression (Friston et al., 1995). Changes in
regional normalized [β-11C]-5-HTP derived uptake between patients and controls were evaluated
using the spatial extent of connected clusters of voxels with a Z-score above 1.96 (p<0.05)
(Friston, Worsley, Frackowiak, Mazziotta, & Evans, 1994). In addition, data on [β-11C]-5-HTP
derived uptake were also evaluated using principal component analysis (PCA) (c.f. Andersson et
The pixel-wise linear regression analysis revealed region specific group differences (omnibus
p<0.000001) between social phobics and healthy controls with regard to [β-11C]-5-HTP derived
uptake. Patients exhibited significantly (p<0.05) lower uptake relative to controls bilaterally in the
medial temporal cortex including the periamygdaloid, entorhinal, and perirhinal regions
(Brodmann areas [BA] 34/36) as well as the left inferior temporal gyrus (BA 21). Borderline
significant trends (p=0.057-0.068) for lowered uptake among social phobics were noted in the left
anterior cingulate cortex (BA 25/33), right insula (BA 13/14), and the inferior frontal cortex (BA
47) bilaterally. Social phobics showed elevated uptake, compared to controls, in the bilateral
cerebellum. In the PCA, principal components one [F(1,34) = 7.2; p<0.05] and three [F(1,34) =
4.2; p<0.05] suggested social phobia-related processes (negative loadings being associated with
social phobia) which explained 18.0% and 8.0% of the variance respectively. The neural
networks revealed by the PCA suggested lowered [β-11C]-5-HTP derived uptake in social phobics
in regions overlapping with those implicated by the subtractive analysis but also in the basal
ganglia, periaqueductal gray and more widespread areas of the neocortex.
Social phobics, as compared to healthy individuals, were mainly characterized by attenuated
[β-11C]-5-HTP derived uptake in limbic/paralimbic brain regions, including the periamygdaloid
and rhinal cortices, suggesting suppressed serotonergic synthesis rate in neural pathways that are
involved in the regulation of fear/anxiety. These findings are consistent with the hypothesis that
serotonergic imbalances make substantial contributions to the pathophysiology of social phobia.
3.2.2 Study IV
A common neural pathway for serotonergic drug therapy and cognitive-behavioral treatment of
Aim and background
The neurofunctional networks mediating anxiety reduction are incompletely understood, as brain
mapping studies on anti-anxiety treatments are few. While a small number of resting-state studies
have been performed, activation studies evaluating treatment effects on provoked anxiety
conditions have been neglected in neuroimaging. Also, systematic comparisons of
pharmacological and psychological treatments are lacking. Hence, it is unknown whether
effective psychotherapy and pharmacotherapy of excessive anxiety engage common or different
neural pathways. Also, it is not known whether changes in brain activity can predict long-term
treatment outcome. The fourth study sought to address these issues by examining the effects of
cognitive-behavioral therapy and SSRI-treatment on regional cerebral blood flow, measured with
PET, during provoked anxiety in patients with social phobia.
Eighteen (10 male/8 female, mean age = 35.2, range = 23-46 years) previously untreated DSM-IV
social phobics with marked publics speaking fears were recruited by means of newspaper
advertisements. Screening included self-report questionnaires, structured clinical (SCID)
interviews (First et al., 1998), and a public speaking test. Informed consent was obtained. By the
use of PET and 15O-labeled water, rCBF was first measured at pretreatment while patients
performed a 2.5 minute speech (about a travel experience or vacation) in the presence of a silently
observing audience of 6-8 persons. To heighten observational anxiety the speech was recorded
from a close distance with a portable videocamera. Patients were matched for severity, sex, and
age in triplets, and then randomized to nine weeks of SSRI-medication, cognitive-behavioral
group therapy (CBGT), or a waiting list (WL) control group with six patients in each study group.
There were three generalized and three nongeneralized social phobics in each group. The SSRI-
group was treated with citalopram with a 40 mg (SD=9.8) daily mean dosage. Patients came for
check-ups at week two, four, and seven. CBGT incorporated simulated exposures to feared
situations (with a focus on public speaking), cognitive restructuring, and homework assignments
following principles developed by Heimberg and coworkers (c.f. Hope & Heimberg, 1993). All
patients were scanned again after the nine-week treatment/waiting period. WL-subjects were
thereafter treated with citalopram.
Treatment outcome was evaluated by use of public speaking state anxiety measures, i.e.
the patient’s subjective ratings of fear and distress on a 0-100 (min-max) scale and the
Spielberger state-anxiety inventory (STAI-S) administered immediately after each scanned
speech. Heart rate in beats per minute was also recorded during scans. In addition, patients
completed a standard battery of social anxiety questionnaires (the SPS, SIAS, SPSQ, PRCS and
GAF-scales; see study I, Bodlund, Kullgren, Ekselius, Lindström, & von Knorring, 1994; Clark et
al., 1997) before, after, and one year after treatment. Patients improving ≥1SD from the
pretreatment mean value on 7-9 outcome variables were labeled “much improved”, 4-6 variables
“moderately improved”, and 0-3 variables “unimproved”. Patients that were at least moderately
improved were considered to be responders.
PET-data were obtained by means of previously validated methods. An eight-ring brain
PET scanner (GEMS PC2048-15B) with a 10 cm axial field of view and an axial/transaxial
resolution of approximately 6 mm was used. Tracer injections, 700-1300 MBq of H215O dissolved
in 3-4 ml of water, i.e. approximately 15 MBq/kg body weight, were performed at twelve-minute
intervals. PET-data were collected in fifteen 10-sec frames during 150 sec. PET-data were
normalized for global flow using linear scaling. Individual rCBF-images were anatomically
normalized in the standard Greitz brain atlas (Greitz et al., 1991). To improve signal-to-noise
ratio patients spoke twice in front of the audience and image data were averaged across the two
scans into mean images to be compatible with a random-effect model. Blocked ANOVAs, based
on general linear regression (Friston et al., 1995), were used for statistical analyses. Local
changes were evaluated using the spatial extent of connected clusters of voxels with a Z-score
above 2.6 (Friston et al., 1994). Mean voxel values for each subject and condition were also
extracted for ROI (region of interest) analyses, with ROIs being anatomically predefined in the
computerized brain atlas (Greitz et al., 1991).
There were no significant multivariate or univariate differences between groups with regard to
outcome measures before treatment. Paired t-tests revealed that both the SSRI and CBGT-groups
improved significantly [t(5) 2.2-5.9, p = 0.002-0.04] from pre to post treatment on most outcome
variables whereas WL-subjects did not change on any measure [t(5) = 0.1-2.0; p = 0.10-0.89].
Separate ANOVAs also indicated that treated subjects improved more than controls as significant
[F(1,16)= 4.9-6.9, p<0.05] group × time interactions were noted on three social anxiety
questionnaires (the SPS, PRCS, and GAF-scales), and follow-up Fisher’s LSD-tests showed that
the treated subjects (merged group) improved significantly (p≤0.01) more than controls. In
addition, borderline significant [F(1,16)=3.7-4.1, p = 0.06-0.07] group × time interactions were
obtained on the STAI-S and distress measures and treated subjects were again more improved
(p≤0.05; Fisher’s LSD) than waiting-list subjects on both these measures at posttreatment. There
were two much improved and two moderately improved patients each (67% responder rate) in the
SSRI- and CBGT-groups, suggesting that the two interventions were about equally beneficial.
One WL-patient was also classified as moderately improved, possibly due to habituation effects.
All nine responders confirmed symptom improvement in individual posttreatment interviews.
In CBGT- and SSRI-treated patients, symptom improvement was accompanied by a
significantly reduced rCBF-response to public speaking bilaterally in the amygdala, hippocampus,
and anterior/medial temporal cortex including the entorhinal, perirhinal, parahippocampal, and
periamygdaloid areas. Responders (n=9), regardless of treatment approach, also decreased their
neural response to public speaking in the same temporal lobe regions. Changes in rCBF were not
observed in waiting-list controls. Interaction contrasts revealed that the rCBF-response to public
speaking decreased significantly more in both treated groups relative to controls in the previously
implicated temporal lobe regions, albeit mainly in the right hemisphere. Consistently, the rCBF-
response also decreased more in responders relative to nonresponders in the right amygdala and
hippocampus as well as cortically in the right rhinal/periamygdaloid areas (see Figure 3).
Altered rCBF was also noted in a few regions outside the temporal lobe. In the CBGT-
group, rCBF decreased in the periaqueductal gray area while increases were noted in the right
cerebellum and secondary visual cortex (BA 19). In the SSRI-group, rCBF decreased in the left
thalamus and left inferior frontal cortex (BA 10/47). Responders showed rCBF-decreases in the
bilateral anterior cingulate (BA 25/32) inferior frontal (BA 47) and dorsolateral prefrontal (BA 9)
cortices. In the between-group comparisons, rCBF decreased more in responders than
nonresponders in the bilateral anterior cingulate (BA 24/33) and right dorsolateral prefrontal (BA
9) cortices. The SSRI- and CBGT-groups differed only with regard to perfusion in the right
thalamus, which increased more with SSRI- than cognitive-behavioral treatment.
Based on the social anxiety questionnaire results, 7 of the 12 treated patients were
considered to be “much improved” and 5 patients “less improved” at the one-year follow up. A
stepwise discriminant analysis was performed to evaluate whether the attenuation of rCBF in the
implicated subcortical regions immediately following treatment could predict level of
improvement one year later. The periaqueductal gray (p=0.005), left thalamus (p=0.006), right
(p=0.02), and left amygdala (p=0.06) combined to yield a significant discrimination (Wilk’s
Lambda=0.16, F=9.4, p<0.006) that was 100% accurate in predicting the two levels of
improvement. Favorable outcome at one-year follow-up was associated with a greater initial
attenuation of the subcortical rCBF-response to public speaking.
CBGT SSRI Responders
CBGT-WL SSRI-WL Resp-Nonresp
Figure 3. (A) PET-images showing significant decreases in the rCBF-response to an anxiogenic public speaking
task after as compared to before treatment. Images display rCBF-decreases for social phobics treated with
cognitive-behavioral group therapy (CBGT; left), a selective serotonin reuptake inhibitor (SSRI; middle), and for
responders regardless of treatment approach (right). Points of neural convergence were observed in the amygdala,
hippocampus, and surrounding temporal cortical regions. (B) Corresponding between-group differences in the
amount of rCBF-change with treatment. Images show a greater reduction in the neural response to public speaking
in CBGT- relative to waiting list (WL) subjects (left), SSRI- relative to WL-subjects (middle) and in responders
relative to nonresponders (right).
Both SSRI- and cognitive-behavioral treatments were significantly and about equally effective in
improving social phobia symptomatology. Neural points of convergence for the two types of
treatment were observed in the amygdala, hippocampus, and neighboring cortical areas which are
regions previously shown to serve important functions in anxiety. Suppression of amygdalo-
hippocampal-temporal cortex neurons may thus be a common neural mechanism whereby
successful anti-anxiety treatments act. The degree of response diminution to public speaking in
the amygdala, in conjunction with the PAG and left thalamus, predicted clinical status a year
later. Amygdalar attenuation in particular may thus be a prerequisite for immediate and long-term
3.3. Discussion of the individual studies
3.3.1 The epidemiological studies
At 15.6% the prevalence of social phobia appears to be higher in Sweden than in most other
countries, although this figure is in the vicinity of the 13.3% lifetime prevalence noted in USA
(Kessler et al., 1994) and 16% in Switzerland (Wacker, Müllejans, Klein, & Battegay, 1992).
Compared with other Nordic countries the Swedish estimate is higher than the six-month
prevalence rate of 4% noted in Iceland (Arnarson, Gudmundsdottir, & Boyle, 1998). Even though
both studies used postal surveys, comparisons are complicated because of dissimilarities in
questionnaire design. In general, it is also difficult to decide whether differences in prevalence
rates, in comparison to other studies, should be attributed to a true cultural divergence or
The study draws attention to several methodological concerns in epidemiological studies
of social phobia. Most notably, the finding that prevalence figures varied markedly (range 1.9-
20.4%) across the different levels of distress and impairment used to define cases is consistent
with several other reports (Pélissolo et al., 2000; Pollard & Henderson, 1988, Stein et al., 1994;
1996). The DSM-III-R and DSM-IV do not specify the required level of impairment or distress,
and in the absence of a gold standard for validation, the choice of diagnostic thresholds becomes
arbitrary. This, in turn, may at least partly explain why the prevalence rates across studies vary to
such a large extent.
Public speaking was by far the most common social fear consistent with previous reports
(Kessler et al., 1998; Pollard & Hendersson, 1998; Stein et al., 1994). Also congruent with other
studies (e.g., Canino et al., 1987; George, Hughes, & Blazer, 1986; Hwu et al., 1989; Lee et al.,
1990b; Magee et al., 1996; Vega et al., 1998) urbanicity did not influence the prevalence of social
phobia. Morevover, the sociodemographic results are consistent with previous studies noting that
social phobia is associated with female gender (c.f. Weinstock, 1999) low educational attainment
(Magee et al., 1996; Schneier et al., 1992), and low social support (Magee et al., 1996). However,
in the light of earlier reports (c.f. Chapman et al., 1995), the negative findings with regard to
marital and occupational status and to some extent also birth-order, were unexpected. About 13%
of the identified individuals with social phobia admitted that they were currently using
psychoactive drugs. Nonetheless, very few of these subjects stated that social anxiety was their
main problem, which fits the common description of social phobia as being an undertreated
disorder (Weiller et al., 1996).
Among the limitations of the study the concerns associated with different diagnostic cut-
off levels have already been mentioned. Furthermore, it was not possible to determine the extent
to which comorbid psychiatric conditions affected the prevalence figures. Moreover, one
interpretation of the attrition analysis is that social phobia was more common among responders
than nonresponders, which could have exaggerated the prevalence estimates. However, other
investigators have noted that the prevalence of a disorder is higher among nonresponders
(Allgulander, 1989; Kessler et al., 1994). The generalizability of the study might be limited to the
geographical areas selected, i.e. Stockholm and Gotland, although there is no apparent reason to
suspect that the samples differ systematically from the Swedish general population. It could also
be argued that the postal survey methodology has drawbacks, particularly in comparison to
structured diagnostic interviews. However, several limitations of the most common interviews
used in epidemiological research have been discussed in the social phobia literature (c.f. Stein et
al. 1994). Also, the psychometric evaluation suggested that the SPSQ was a satisfactory
assessment tool. To the extent that the prevalence of 15.6% included subsyndromal cases, it is
plausible that this primarily reflects the lack of stringency in the diagnostic (DSM-IV) criteria and
general difficulties associated with making a precise demarcation of the disorder.
To summarize, study I suggests that, while there are considerable obstacles in setting the
accurate diagnostic boundaries for social phobia, it is evident that social anxiety is a distressing
problem for a remarkably large number of individuals in the general community.
By the use of cluster analysis three homogenous groups of social phobics were identified which,
by and large, matched the categorical tripartite subtype system previously proposed by Heimberg
and coworkers (Heimberg et al. 1993a; Herbert et al. 1992; Holt et al. 1992), consisting of
generalized, nongeneralized, and discrete social phobia. In contrast to clinical samples where the
generalized subtype dominates (c.f. Turner et al., 1986) discrete social phobia was the most
common in the general population (point prevalence 7.7%), followed by the nongeneralized
(5.9%) and generalized (2.0%) subtypes. None of the prevalence rates differed as a function of
urbanicity. Compared with the other subtypes, generalized social phobia tended to be over-
represented among those who were poorly educated and lacked social support. Public speaking
was the most common fear in all groups, acknowledged by nearly 80% of all social phobics. The
discrete type was dominated by public speaking fear and 3.2% of the respondents in the entire
sample fulfilled the criteria for social phobia with public speaking as their only fear. This is
consistent with other studies in which about 3-5% of the general population has reported public
speaking phobia in isolation (Stein et al. 1994; 1996).
In general, results are difficult to compare with other studies on social phobia subtypes
because exploratory classification techniques have been neglected. However, as mentioned
previously, Kessler et al. (1998) estimated the prevalence of empirically derived subtypes by the
use of latent-class analysis, noting a US lifetime prevalence of 4.8% for phobics with speaking
fears (one of two classes identified) and 8.5% for those who endorsed at least one other fear (the
second main class). However, the subtype classification in the Kessler et al. (1998) study was
restricted because only six situations were assessed and only one of these concerned interactional
Other epidemiological data on subtypes are scarce. Wittchen et al. (1999) noted that about
one third of the social phobics in a German adolescent sample were of the generalized subtype,
i.e. roughly 3% of the women and 1.5% of the men. In the Epidemiological Catchment Area
project, Schneier et al. (1992) observed that the majority (79.5%) of subjects with social phobia
feared only one of three assessed categories of fear whereas 17.2% feared two categories and
3.3% feared all three categories. In a Canadian telephone survey Stein et al. (1994) observed that
68.6% of those reporting social anxiety acknowledged difficulty with more than one social
situation, 39.7% with more than two, and 8.7% with more than four of seven situations. These
findings suggest that the generalized (or severe) subtype is in minority relative to other forms of
social phobia in the general community.
Although the three subtypes in study II may be described categorically as generalized,
nongeneralized, and discrete types, they mainly conformed to a severe, moderate, and milder form
of social phobia. The DSM-IV encourages the use of mild-moderate-severe diagnostic specifiers,
and this dimensional terminology might be the most appropriate for social phobia. The use of
negations, as in “nongeneralized”, is awkward because this subtype can also be described, e.g. as
“nondiscrete”. Also, the meaning of “nongeneralized” has varied across studies. Many other
subtype labels have been discussed in the literature, such as “specific”, “circumscribed”,
“performance”, and “limited interactional”, but a sensible and empirically sound rationale for
categorical subtype designations remains to be established. In comparison, the severe-moderate-
mild terminology appears conceptually clear and empirically supported.
Several limitations apply to study II. General concerns associated with the survey method,
attrition, and difficulties in setting diagnostic thresholds have been discussed in conjunction with
study I. Self-report measures as opposed to clinical interviews were relied upon to identify cases
of social phobia. Also, cluster analysis does not estimate the variate empirically. Instead it is
specified by the researcher, which makes the definition of the variate crucially important. The
choice of variables to define clusters was motivated by previous research. Social phobia subtypes
should by definition differ in number of feared situations, and they have previously been reported
to differ in distress ratings, level of functional impairment, and comorbidity with avoidant
personality disorder (Heimberg et al. 1990b; Herbert et al. 1992; Holt et al. 1992; Hope et al.
1995; Schneier et al. 1991; Turner et al. 1992). Lastly it should be noted that with social phobia
lying on a continuum, any subtyping scheme is arbitrary, and that cluster formations along a
severity continuum were not unexpected since the variables used to define clusters correlated
To conclude, in the Swedish general population three homogenous groups of social
phobia were identified by cluster analysis. Although these roughly matched the categorical
generalized, nongeneralized, and discrete subtypes described by Heimberg and colleagues
(Heimberg et al., 1993a), the three empirically derived subtypes could most parsimoniously be
described dimensionally as a severe, moderate, and milder form of social phobia with number of
cases decreasing with increasing severity.
3.3.2 The neurobiological studies
Results showed that patients with social phobia were characterized by lower [β-11C]-5-HTP
derived uptake relative to controls, suggesting suppressed serotonin synthesis rate, mainly in the
temporal periamygdaloid, entorhinal, and perirhinal cortices bilaterally, but also in the left
anterior cingulate, the right insula, and the inferior frontal cortex in both hemispheres. Results
from the principal component analysis generally supported the obtained pattern of lowered
regional [β-11C]-5-HTP derived uptake in social phobia as compared to healthy individuals. Two
functional networks related to social phobia were revealed by the first and third principal
components. The first component was composed of the same brain territories as implicated in the
subtraction analysis, but also included the basal ganglia, periaqueductal gray, and more widely
distributed areas of the neocortex. The third principal component revealed a second network
encompassing the mid cingulate and temporal cortices, including the perirhinal region, both of
which are commonly noted in studies of negative emotion (Charney & Deutch, 1996). The results
are consistent with Handley’s (1995) hypothesis of low cerebral serotonin concentration
contributing to anxiety. This notion is supported by reports on the anxiolytic effects of SSRIs
suggesting that anxiety relief can be attributed to serotonin enhancement.
The implicated regions with altered uptake may reflect serotonergic neural networks that
are compromised in social phobia. The temporo-limbic cortex, including the
periamygdaloid/rhinal regions, probably participates in the chain of events when exteroceptive
stimulation is modulated by emotional significance (LeDoux, 1996). These cortical areas are
probably functionally integrated with the deeper amygdalo-hippocampal structures, which in turn
subserve anxiety responses or bodily defense reactions to threatening stimulation (Gray &
McNaughton, 1996; Reiman, 1997). The anterior cingulate cortex could be engaged in the
attentional and behavioral response to threatening stimulation and/or in the conscious experience
of anxiety (Reiman, 1997). Lowered uptake was noted in the “affective division” of the cingulate,
i.e. the rostral-ventral proportion including the subgenual cortex, which has been consistently
implicated in neuroimaging reports on emotional manipulation (Whalen et al., 1998a). The
inferior frontal gyrus might participate in affective working memory and emotional perception
(Kosslyn et al., 1996; Sprengelmeyer, Rausch, Eysel, & Przuntek, 1998) and presumably
facilitates behavioral integration of emotionally relevant exteroceptive information. The anterior
insula has been suggested to form an interoceptive alarm system evaluating cognitions,
interoceptive sensory stimuli, and body sensations that signals potential internal danger (Reiman,
Social phobia was characterized by significantly elevated uptake in the cerebellum only.
The cerebellum is functionally involved in motor behavior but also in attention (Allen, Buxton,
Wong & Courchesne, 1997) and other sensory/cognitive processes (Barinaga, 1996) which could
be influenced by excessive social anxiety. The dorsal bounds of the cerebellar cluster extended
into the superior temporal regions of the right hemisphere but because of the large axial distance
from the maximum voxel in the lower regions, this finding is probably too uncertain for further
neurofunctional interpretation. A trend for elevated uptake in social phobics was also observed in
a pons area that was anatomically consistent with the midbrain raphe nuclei, although these
structures were not delineated explicitly by the brain atlas used (Greitz et al., 1991). The
functional relevance of this finding remains to be determined.
The use of the radiotracer [β-11C]5-HTP is in its infancy, and this tracer needs to be
further validated before unequivocal conclusions can drawn from studies using it. Thus the
present findings should be regarded as preliminary. Further studies are necessary to determine
whether the presynaptic serotonergic dysfunction observed truly is a reproducible feature of the
patophysiology of social phobia. Future studies could also investigate whether the SSRIs and
other serotonin agents enhance serotonergic neurotransmission in the brain areas implicated in
The outcome analyses showed that patients with social phobia improved significantly and about
equally with nine weeks of CBGT- or SSRI-treatment whereas waiting-list controls did not
change. In both treatment methods the anxiolytic effects were associated with a decreased
cerebral blood flow response to anxiety provocation (public speaking) in the amygdala,
hippocampus, and the adjacent entorhinal, perirhinal, parahippocampal, and periamygdaloid
cortices. This effect was very robust. In the within-group contrasts both the SSRI- and CBGT-
groups showed this pattern of neural change from pre- to posttreatment, whereas the unimproved
waiting-list control group did not. Additionally, responders regardless of treatment modality also
exhibited an analogous change in rCBF. Moreover, between-group contrasts showed that the
rCBF-response decreased significantly more in the above regions in both the SSRI- and CBGT-
groups relative to waiting-list controls. Finally, the neural response to public speaking also
decreased significantly more in responders as compared to nonresponders in the same temporal
lobe regions. Because both CBGT- and SSRI-treated subjects improved while waiting-list
controls did not, it is unlikely that the beneficial effects can be attributed to repeated testing,
subject maturation, statistical regression, or other potentially confounding factors. Integration of
the results with previous imaging studies on anti-anxiety treatments is difficult because these are
methodologically heterogeneous and have generally assessed resting states only (e.g., Baxter et
al., 1992; Schwartz et al., 1996; Van der Linden et al., 2000), used anxiolytics of the older
generation (e.g., Mathew & Wilson, 1991), or reported negative findings (Fredrikson et al., 1995).
The discriminant analysis revealed that initial response decrement in the amygdala, in
conjunction with the periaqueductal gray and left thalamus, could accurately discriminate much
from less improved patients a year later. Thus, significant response diminution in temporo-limbic
territories could be imperative both for immediate and long-term anxiety reduction. In social
phobics, the amygdala and hippocampus have previously been implicated in the processing of
conditioned aversive stimuli, as well as facial and unpleasant odor stimulation (Birbaumer et al.,
1998; Schneider et al., 1999). Preliminary neuroimaging evidence also suggests that neuronal
activity in these regions may mediate the untreated social anxiety reaction (Reiman, 1997; Tillfors
et al., submitted). The amygdaloid-hippocampal region has been suggested to constitute an alarm
system alerting the individual when activated by threatening stimulation (Reiman, 1997).
Conceivably, the rhinal, parahippocampal, and periamygdaloid cortices transit sensory and/or
memory information into this system (LeDoux, 1996). Anxiety disordered patients probably
suffer from easily triggered alarm reactions, and suppression of amygdalo-hippocampal neurons
could thus be a common neural mechanism whereby both pharmacological and psychological
therapies exert their anxiolytic effect.
The amygdala and hippocampus have previously been demonstrated to have a role in
neural habituation to emotionally salient stimuli (Fischer, Furmark, Wik, & Fredrikson, 2000;
Fischer et al., 2000). Thus, as proposed by Gray and colleagues (Gray & McNaughton, 1996) it is
possible that cognitive-behavior therapy works by permitting systematic habituation of neuronal
activity directly in these brain structures. Although some of the rCBF-changes are compatible
with cognitive mechanisms of treatment, these may be more prominent in anticipation of rather
than during phobic exposure. Thus, cognitive influences on anxiety could be of general
importance albeit not prominent during the scanned time frame. SSRIs may yield comparable
neural effects to those of behavior therapy, e.g. by correcting for a medial raphe nucleus
malfunction with resultant decreased firing of cortical and amygdaloid-hippocampal neurons
(Grove, Coplan, & Hollander, 1997). An increase of serotonin may inhibit thalamic and cortical
inputs from activating the amygdala (Gorman et al., 2000).
Altered perfusion with treatment was seen only in a few regions outside the temporal lobe.
Decreased flow in the periaqueductal gray region (CBGT-group) probably reflects attenuated
defensive reactions as this region is involved in fight-flight and freezing reactions (Behbehani,
1995). Neuronal response decrement in the left thalamus (SSRI-group), occipitotemporal junction
(CBGT/SSRI-groups), and the inferior frontal and anterior cingulate cortices (responders) could
correspond to a downgraded evaluative function, e.g. a lessened assignment of affective value to
exteroceptive or facial stimuli following treatment. Prefrontal rCBF-diminution (responders) may
influence the experiential component of anxiety, signifying a less intense conscious experience of
emotion (Reiman, 1997) or a reduction of catastrophic cognitions (Grove et al., 1997). All these
rCBF-decreases might be secondary to the inhibition of the amygdala (LeDoux, 1996). Increased
flow in the secondary visual cortex (SVC) in CBGT-subjects could be associated with restored
external attention and lessened self-focus (Wells & Clark, 1997). Similarly, the cerebellar
activation (GBGT-group) may support external attention (Allen et al., 1997), or it could reflect
altered motor, sensory or cognitive activity (Barinaga, 1996). CBGT and SSRI-treatments were
only distinguished by perfusion in the right thalamus, which increased less with psychotherapy
than citalopram. Speculatively, thalamic activation may relate to an active inhibition of later
stages in the sensory stimulus processing chain (Fischer et al., 2000).
The between-group comparisons suggested that the rCBF-response diminution was more
pronounced in the right hemisphere, consistent with theories of right-hemispheric domination in
negative emotion (Davidson, 1995). However, evaluation of the Z-score maps indicted that the
left amygdalo-hippocampal regions were also significantly involved, although the left
deactivations did not survive Bonferroni-correction. Because statistical power is lost in the
between-group contrasts, the absence of significant left-sided temporal deactivations, when
corrected for multiple comparisons, may reflect type-II errors (false negatives) rather than true
lateralization effects. Among the limitations it should thus be noted that the sample size was
rather small, contributing to restricted statistical power and enhanced risk of type-II errors,
particularly in the between-group analyses. Also, even though the inclusion of a waiting-list
control group was a methodological improvement compared with most other imaging studies on
anti-anxiety treatments, other relevant comparison-groups are lacking. For instance, to evaluate
the specific components of the psychological and pharmacological treatments, it would have been
ideal to compare the treated groups to attentional (e.g., educational-supportive) psychotherapy
and pill placebo. Furthermore, the direct physiological effects of the SSRI could have been
studied by administering citalopram to a group of healthy volunteers. However, Bonne et al.
(1999) recently showed that long-term administration of the SSRI fluoxetine did not change
rCBF, or global flow, in healthy volunteers. Finally, it would have been interesting to examine
whether the combination of CBGT and citalopram enhances the therapeutic effect on brain
function. This is a topic for future research.
3.4 Overall discussion
Taken together, study I and II suggest that social anxiety can be thought of as a normally
distributed variable where people are arranged from low levels of anxiety at one end of the
distribution to increasingly higher levels of normal social anxiety (the majority), passing through
a gray zone (e.g., shyness, introversion), then somewhere crossing the border to pathological
conditions (social phobia) which then in turn could be subdivided into mild, moderate, and more
severe forms of social anxiety pathology at the other end of the distribution. Thus, the more
stringent diagnostic cut-off levels in study I, using higher levels of distress and impairment to
define cases, may identify moderate- and severe forms of the disorder (nongeneralized and
generalized subtypes) but neglect the milder (or discrete) subtype. Similarly, the most liberal cut-
off level, resulting in a point-prevalence of 20.4%, probably includes not only the milder forms of
social phobia but also subsyndromal cases. However, it is possible that this dimensional view is
too simplified because clinical observations suggest that some individuals may describe
themselves as outgoing and nonshy even though they experience marked distress in circumscribed
settings such as public speaking situations. This would suggest that social phobia and shyness
(and possibly introversion, neuroticism etc.) are multivariate conditions that do not necessarily lie
on the same continuum. Also, isolated public speaking phobia shows close resemblance to a
specific phobia. These diagnostic topics are complex and related to the several ongoing debates in
psychiatry, such as the validity and practical utility of categories versus dimensions in psychiatric
diagnostics, and the relation between psychopathology and underlying personality or
The neurobiological studies in this thesis also leave several intriguing questions
unanswered. For instance, does the serotonin synthesis rate change as a function of treatment with
SSRIs and/or CBGT? To answer this question [β-11C]-5-HTP images obtained before and after
therapy need to be compared, which is underway in our laboratory. Meanwhile, areas that showed
both reduced pretreatment [β-11C]-5-HTP derived uptake (suppressed serotonin synthesis) and
changes in brain perfusion as a function of treatment were observed mainly in the medial
temporal lobe (the rhinal/periamygdaloid cortices). It is possible that the reduced blood flow here
following therapy corresponds to a serotonergically mediated inhibition of these areas because
treatment has increased the levels of synthesized serotonin. In a similar vein, enhanced
pretreatment serotonin turnover and increased posttreatment flow in cerebellar regions (noted in
CBGT-patients) could mean that therapy produces disinhibition of the cerebellum, possibly
resulting in less inhibited bodily expressions.
There are also other unanswered questions. Could measures of serotonin metabolism be
used to predict short- and long-term treatment outcome? Are there sex differences with regard to
brain perfusion and presynaptic serotonin function? Do subtypes of social phobia that are
classified on the basis of other pathology variables differ in brain perfusion and/or serotonergic
function? Alternatively, could neural measures such as rCBF and cerebral serotonin metabolism
be used to delineate subtypes of social phobics that differ meaningfully with regard to other
descriptive characteristics? These important topics are currently being investigated, or should I
say scrutinized, in our laboratory.
The tentative conclusions of this thesis can be summarized as follows:
•While social anxieties, particularly in public speaking circumstances, are remarkably
widespread within the Swedish general community, the exact diagnostic boundaries for social
phobia are difficult to set. This is illustrated by the point prevalence of social phobia, which
was estimated at 15.6%, but varied between 1.9 and 20.4% across the different levels of
distress and impairment used to define cases.
•Subtypes of social phobia can most parsimoniously be described dimensionally, i.e. as
representing different levels on a mild-moderate-severe continuum, with number of cases
decreasing with increasing severity.
•Social phobia is characterized by a presynaptic serotonergic dysfunction, i.e. a suppressed
serotonin synthesis rate indexed by a lowered uptake derived from [β-11C]-5-HTP, mainly in
the periamygdaloid/rhinal cortices of the temporal lobe, but also in the inferior frontal, insular,
and anterior cingulate cortical regions.
•Serotonergic (SSRI) drug therapy and cognitive-behavioral treatment of social phobia exert
their anxiolytic effects by attenuating activity in a common neural pathway encompassing the
amygdala, hippocampus, and adjacent temporal cortex - i.e. the “alarm system” of the brain.
Satisfactory long-term treatment outcome may require therapies that thoroughly suppress
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Here, at last, I would like to express my sincere gratitude to the following good people:
My supervisor Mats Fredrikson for incredible support over the years and for showing that it is
possible to be an outstanding scientist and a genuinely nice guy at the same time (how do you do
My co-author and friend Maria Tillfors for pleasant collaboration over the years and for tolerating
half a decade of schlager singing.
My colleague Håkan Fischer for introducing me to the world of PET in a most patient and
My colleague Ina Marteinsdottir, Bengt and their three cats for good work, good food, and good
My colleagues Anna Pissiota and Örjan Frans for friendship and rewarding discussions.
To Lars Bäckman for valuable comments on a preliminary version of this thesis.
To the skillful personnel of the Department of Psychology and Uppsala PET-centre, Uppsala
University, for providing stimulating working environments.
To my parents Esteri and Hans, and my sisters Lena and Anneli with families, for love,
encouragement and good company.
To Kristina for reminding me that there is more to life than science.
To the participating patients for strengthening my impression that individuals with social phobia
often are unusually sympathetic and likable characters.
Illustration on page 4 made by Anneli Furmark.
For financial support I thank the Swedish Council for Research in Humanities and Social
Sciences and the Non-graduated Researchers Fund, Uppsala University.
The DSM-IV criteria for social phobia (American Psychiatric Association, 1994, p. 416):
A. A marked and persistent fear of one or more social or performance situations in which the
person is exposed to unfamiliar people or to possible scrutiny by others. The individual fears
that he or she will act in a way (or show anxiety symptoms) that will be humiliating or
embarrassing. Note: In children, there must be evidence of the capacity for age-appropriate
social relationships with familiar people and the anxiety must occur in peer settings, not just in
interactions with adults.
B. Exposure to the feared social situation almost invariably provokes anxiety, which may take the
form of a situationally bound or situationally predisposed panic attack. Note: In children, the
anxiety may be expressed by crying, tantrums, freezing, or shrinking from social situations
with unfamiliar people.
C. The person recognizes that the fear is excessive or unreasonable: Note: In children, this feature
may be absent.
D. The feared social or performance situations are avoided or are endured with intense anxiety or
E. The avoidance, anxious anticipation, or distress in the feared social or performance situation(s)
interferes significantly with the persons normal routine, occupational (academic) functioning,
or social activities or relationships, or there is marked distress about having the phobia.
F. In individuals under age 18, duration is at least 6 months.
G. The fear or avoidance is not due to the direct physiological effects of a substance (e.g., a drug
of abuse, medication) or a general medical condition, and is not better accounted for by
another mental disorder (e.g., panic disorder with or without agoraphobia, separation anxiety
disorder, body dysmorphic disorder, a pervasive developmental disorder, or schizoid
H. If a general medical condition or another mental disorder is present, the fear in criterion A is
unrelated to it: e.g., the fear is not of stuttering, trembling in Parkinson’s disease, or exhibiting
abnormal eating behavior in anorexia nervosa or bulimia nervosa.
Specify if Generalized: if the fears include most social situations (also consider the additional
diagnosis of avoidant personality disorder).