Social Anxiety Disorder

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Generalized social anxiety disorder: A still-neglected anxiety disorder 3 decades since Liebowitz’s review Toshihiko Nagata, MD, PhD,1* Futoshi Suzuki, MD, PhD2 and Alan R. Teo, MD, MS3 1Mental Health Clinic of Dr Nagata in Nanba, Osaka, 2Department of Child and Adolescent Psychiatry, Nagoya University Hospital, Aichi, and 3VA Portland Health Care System and Oregon Health & Science University, Oregon, USA

In the 3 decades since Liebowitz’s review of ‘a neglected anxiety disorder,’ controversy and chal- lenges have remained in the study of social anxiety disorder (SAD). This review examines evidence around the classification and subtyping of SAD, focusing on generalized SAD. Substantial discrepan- cies and variation in definition, epidemiology, assess- ment, and treatment of generalized SAD exist as the international literature on it has grown. In East Asian

cultures in particular, study of taijin kyofusho has been important to a broadened conceptualization of SAD into generalized SAD. Despite important progress with biological and other studies, many challenges in the understanding of generalized SAD will remain in the years to come.

Key words: generalized, social anxiety disorder, taijin kyofusho, under-recognition, undertreatment.

SOCIAL ANXIETY DISORDER (SAD) 1 is one of the

most common mental disorders, as shown by two recent general population surveys in the USA, which both found that almost one in 10 individuals suffers from SAD at some point in their lifetime.2,3

Onset typically occurs in childhood or early ado- lescence and takes a chronic course. SAD may cause significant distress and impairment in educational attainment, employment opportunities, the develop- ment of professional, peer and intimate relation- ships, and financial independence.4 The early onset and chronic course with rare spontaneous remission frequently causes secondary comorbidities, such as depression and alcohol-related problems.4

The conceptualization of SAD has rapidly altered and expanded during just the past few decades as progress has been made in SAD treatment strategies.

The disorder was initially considered as just a type of phobic reaction to a specific social situation akin to a specific phobia in DSM-III.5 With the advent of DSM- III-R,6 diagnostic criteria for the disorder underwent significant expansion. The specifier ‘generalized’ was introduced to the formal nosology in DSM-III-R6 to describe persons experiencing social fears in ‘most or all’ situations while allowing concurrent diagnosis of avoidant personality disorder. The label ‘social anxiety disorder’ was introduced in DSM-IV,7 and replaced ‘social phobia’ in DSM-5.1 Moreover, in the current version of DSM, typical fear and anxious situ- ations are defined as: (i) social interaction fears; (ii) observation fears; and (iii) performance anxiety (in criterion A). Thus fear of performance in public was deprioritized compared to social interaction in DSM-5.

This rapid expansion of concept was criticized as giving the diagnosis of SAD to individuals who have few social fears, overpathologizing the socially anxious8 and disease-mongering.9 Indeed, the distress of giving a speech in public is a normal reaction in

*Correspondence: Toshihiko Nagata, MD, PhD, Mental Health Clinic of Dr Nagata in Nanba, SAN-EI-Midosuji Bldg 3F, 3-5-8 Nanba, Chuo-Ku, Osaka 542-0076, Japan. Email: [email protected] Accepted 25 June 2015.

doi:10.1111/pcn.12327

mailto:[email protected]

human nature10 and psychosocial impairment from fear of public speech is much less than that from generalized SAD, which is characterized my multiple fears of social situations.11 On the other hand, SAD is still under-recognized even by mental health profes- sionals,12 and undertreatment of SAD, especially gen- eralized SAD, cannot be ignored.13

The ‘generalized’ specifier was removed in DSM-5 due to the dimensional nature of specific (just one or two public performances are feared), non- generalized (more than a few but less than half of social situations are feared) and generalized (more than half of social situations are feared) SAD.14

However, the concept of generalized SAD remains clinically useful. The categorical15 and prototype approach16 is essential in treating patients in real world settings, regardless of whether SAD psychopa- thology is scientifically dimensional or not.

This review focuses specifically on generalized SAD because it has received relatively little attention, con- tinues to be clinically important, and provides insight into related phenomena, such as taijin kyofusho (TKS).

CONCEPT OF GENERALIZED SAD

Emergence and evolution of the concept of generalized SAD

A group of researchers at Columbia University led the development of the concept of generalized SAD. After Marks and Gelder17 suggested that social phobia was different from other phobias, social phobia was offi- cially included in DSM-III.5 Social phobia in DSM-III was restricted to performance fears (fear of speaking, signing a check, or eating in public), although Marks’ original concept included more generalized forms of social anxiety (fears of initiating conversations or dating). At that time, patients with more generalized social anxiety were classified as having avoidant per- sonality disorder in DSM-III, because these patients were believed to need social skill training for person- ality disorder while ‘social phobics’ responded well to exposure therapy.18

Liebowitz et al.19 re-introduced social phobia as a neglected anxiety disorder except among behavior therapists, and suggested that DSM-III too restric- tively defined this disorder primarily as performance anxiety.5 They also showed that both psychopharma- cological and behavioral treatment intervention were effective in this population.

The social phobia section of DSM-III-R6 drastically shifted the paradigm to include broader social fears and reduced the diagnostic threshold such that avoid- ance of the fearful situation was not necessary anymore. Instead, the ‘generalized’ specifier (i.e., ‘the phobic situation includes most social situations’), first introduced into formal nosology the recommen- dation of consideration a concurrent diagnosis of avoidant personality disorder. No additional guide- line or criteria were provided, and the definition was criticized for ambiguity and arbitrariness afterward.14

This establishment of generalized SAD enhanced numerous investigations, including its high preva- lence rate within SAD, phenomenology of early onset, following a chronic and unremitting course, clinical trials of monoamine oxidase inhibitors (MAOI) and selective serotonin reuptake inhibitors (SSRI) and psychological interventions, such as cog- nitive behavioral therapy for this disorder.14

The label ‘social anxiety disorder’ was introduced in DSM-IV7 with quotation marks and in DSM-51

without quotation marks to mean a more pervasive and interfering condition than that implied by the label ‘social phobia’ and the limited DSM-III diag- nostic definition.

Despite documented distinctions in severity between generalized and non-generalized SAD,4 the validity and clinical utility of the generalized and non-generalized specifiers have been the subject of criticism.14 Because subtype definitions have been inconsistently applied across studies, there is no par- ticular number of performance and interaction situ- ations required.20,21 There was no clear distinction, such as clear nonlinearity or point-of-rarity, between generalized and non-generalized even in interna- tional studies22 suggesting a continuum (or dimen- sional model).

Factor analysis in US and Canadian community samples23 as well as international community samples22 yielded a three-factor structure for SAD: (i) social interaction fears; (ii) observation fears; and (iii) public speaking fears.22 Thus, three and half decades since DSM-III,5 social interactional fear superseded public speaking fears as preeminent in SAD.

However, the ‘generalized’ specifier has been replaced with a ‘performance-only’ specifier identify- ing significant social anxiety occurring only in public performance situations in DSM-5.1 The performance- only specifier may instead be an indicator of mild or even sub-threshold SAD.

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Definition of generalized SAD

There is no consensus definition of generalized SAD. In early studies, subjects were classified into general- ized and non-generalized based on ‘reviewing each subjects’ files and classified’,24 or ‘reviewing SADS-LA (Schedule for Affective Disorders and Schizophrenia- Lifetime Anxiety version) narratives’.25

Later investigators operationally defined general- ized SAD with an indicated number of feared social situations. Hofmann et al.26 applied the ‘generalized’ subtype if the patients reported at least a moderate fear of situations from all four domains ([i] formal speaking/interaction; [ii] informal speaking/ interaction; [iii] observation by others; and [iv] assertion).

Also, the Structured Clinical Interview for DSM-IV was modified to classify generalized and non- generalized SAD. The modified version of the Struc- tured Clinical Interview for DSM-IV27 lists nine social interaction situations and eight performance situations. To diagnose generalized SAD, patients are required to exhibit fear and/or avoidance of at least four social situations and at least two of these had to involve interpersonal interactions.28,29

A total score of >60 on the Liebowitz Social Anxiety Scale (LSAS) was also used to define the generalized subtype,30 although LSAS was designed to assess the symptom severity, not act as a diagnos- tic tool.

Recent epidemiological studies operationalize gen- eralized SAD as consisting of individuals who fear >50% of all social situations assessed and non- generalized SAD as consisting of <50% of all social situations assessed.20 However, the number of social situations and performances (e.g. probes) varied by each assessment. For example, studies using the National Comorbidity Survey (NCS)2 assessed only six situations, whereas studies using the NCS Repli- cation (NCS-R)3 and the Canadian Community Health Survey Cycle 1.2 (CCHS 1.2)31 assessed 13 to 14 feared social situations.

To sum up, recent studies set the threshold of ‘gen- eralized’ as fearing more than half of the social and interaction situations that are listed in the assessment to eliminate ambiguity.31 To the best of our knowl- edge, no previous studies have set the threshold for ‘generalized’ to 80% or more of the listed social and interaction situations, although DSM-III-R and DSM-IV defined generalized as fear of most of the situations. Fears of social interaction, rather than

fears of performance in public or in observation are essential to be classified as generalized SAD.

EPIDEMIOLOGY

Epidemiology of SAD

After establishing the diagnostic criteria in formal nosology, numerous epidemiological studies were conducted.22 In particular, the World Health Organi- zation’s World Mental Health Survey Initiative pro- moted international epidemiological studies by standardizing assessment procedure after success of the NCS2 and the NCS Replication (NCS-R).3

Table 1 shows the 12-month prevalence by Composite International Diagnostic Interview (CIDI).2,3,32–49 At first, prevalence studies using earlier versions of CIDI and DSM-III-R look to be higher than ones by the latest version of CIDI and DSM-IV. This is probably due to the different number and content of probes of different versions of CIDI.

Before publication of these standardized epide- miological studies, people believed social phobia was more prevalent in Eastern countries than in Western countries because of norms in Eastern societies that highlight shame, as opposed to guilt in Western countries.50

However, the latest epidemiological studies suggest that SAD is typically more common in Western soci- eties and among female subjects and younger cohorts. The highest prevalence appears to be in North America and Oceania (New Zealand and Aus- tralia), followed by Latin America and South Africa, European countries, and lowest in Asia, as shown in Table 1.

Although it is not easy to deduce the factors con- tributing to varying prevalence rates of SAD in Table 1, one alternative explanation is how devel- oped a country is.22 Prevalence of social and interac- tional fears would be different among the countries depending on industrial activity, such as within the labor market (offering more opportunities for job interviewing) and presence of metropolitan environ- ments (offering more opportunities for social activi- ties, such as parties). This would imply that differences in SAD prevalence across countries are influenced by variable frequency of social situations more so than variable frequency of the associated fear itself. Indeed, the estimated lifetime prevalence of DSM-IV SAD is much higher in developed (6.1%) than developing (2.1%) countries.22 In addition, in

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developed countries, there are more significant sociodemographic predictors of SAD (being female, young, unmarried, low in education, low in income, and unemployed) than in developing countries (being low in education and low in income). However, this hypothesis cannot explain the low prevalence in Japan, a developed country. This issue will be discussed again below in the sociocultural section of this paper.

There is some evidence of increasing prevalence of SAD. Initially this was suspected to be a cohort effect. Heimberg et al.51 reported the significant cohort effect of SAD in an analysis of data from the US NCS. Interestingly, SAD with exclusive fears of speaking did not increase, while SAD with other fears increased. The increase was most pronounced among people with social and economic advantage (i.e.,

white, married, well-educated). Recent epidemiologi- cal updates in Australia41 and Japan44 suggest more solid evidence for increasing prevalence, although NCS2 and NCS-R3 showed similar prevalence rates. On a descriptive level, Crome et al.41 reported an almost twofold increase from 2.3% to 4.2% of the prevalence of 12-month SAD between 1997 and 2007 in Australia. Kawakami et al.44 also reported a threefold increase from 0.7% to 2.3% of the preva- lence of 12-month SAD between the first World Mental Health Japan Survey (WMH-J, 2002–2006) and the second WMH-J (2013), although the number of subjects in the second WMH-J is too small (N = 525 for preliminary results) to be conclusive. In addition, sales of newer antidepressants in Japan pla- teaued in 200752 and Japan’s use ranks lowest among East Asian countries,53 which has led to significant

Table 1. Epidemiological studies of SAD using the CIDI with DSM-III-R and DSM-IV

Region/country Study Year N Assessment 12-month prevalence

DSM-III-R USA Kessler2 1994 8098 CIDI Revised/DSM-III-R 7.9 Brazil Vorcaro32 2004 1037 CIDI/DSM-III-R 9.1 Chile Vicente33 2006 2978 CIDI 1.0 & 1.1/DSM-III-R 6.4 Netherlands Bijl34 1998 7076 CIDI/DSM-III-R 4.8

DSM-IV North and Latin America

USA Ruscio3 2008 9282 CIDI 3.0/DSM-IV 7.1 USA Grant35 2005 43093 AUDADIS-IV/ DSM-IV 2.8 Mexico Medina-Mora36 2005 5826 CIDI/DSM-IV 1.7

Europe Europe Alonso37 2004 21425 CIDI/DSM-IV 1.2 Romania Florescu38 2009 2357 CIDI/DSM-IV 1.0 Ukraine Bromet39 2005 4725 CIDI/DSM-IV 1.5

Asia–Pacific Australia Lampe40 2003 10641 CIDI-auto/DSM-IV 2.3 Australia Crome41 2014 8841 CIDI 3.0/DSM-IV 4.2 New Zealand Wells42 2006 12992 CIDI 3.0/DSM-IV 5.1 Japan Kawakami43 2005 1663 CIDI/DSM-IV 0.8 Japan Kawakami44 2014 525 CIDI3.0/DSM-IV 2.3 China (Beijing and Shanghai) Shen45 2006 5201 CIDI3.0/DSM-IV 0.2 Korea Cho46 2007 6275 CIDI 2.1/DSM-IV 0.2

Africa South Africa Williams47 2008 4351 CIDI3.0/DSM-IV 1.9 Nigeria Gureje48 2006 4984 WMH-CIDI/DSM-IV 0.3

Middle-East Lebanon Karam49 2006 2857 CIDI3.0/DSM-IV 1.1

AUDADIS-IV, Alcohol Use Disorder and Associated Disabilities Interview Schedule, DSM-IV Version; CIDI, Composite International Diagnostic Interview; CIDI-auto, computerized version of the CIDI; WMH, World Mental Health Survey.

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criticism.9 It could be that undertreatment of SAD in Japan is contributing to a rise in prevalence, but the precise causes for the increase in SAD remain unknown.

Epidemiology of generalized SAD

General population surveys suggest that the general- ized type of SAD predominates, with performance- only SAD comparatively rare (Table 2).3,21,31,35,41,54

Stein et al.21 reported that that among individuals with SAD in the community, the percentage that were generalized and speaking fear only (public speaking and/or speaking in small groups) in community was 26.8% and 2.9%, respectively. Grant et al.35 reported that the percentage of generalized type (more than 7 of 14 feared situations) and speaking fear only were 53.6% and 3.5%, respectively. More recently, two studies using the same assessment (CIDI 3.0) reported similar percentages of the generalized type of SAD in the USA (71%)3 and Canada (77.1%).31

The most recent epidemiological study (appearing after publication of DSM-5) showed a prevalence of just 0.3% for the performance-only subtype of SAD.41

The prevalence of generalized SAD among adoles- cents in the community might be somewhat lower than in the adult population,54 although most treatment-seeking adolescents have generalized SAD.55 In addition, generalized SAD is often associ-

ated with comorbid major depression, comorbid anxiety disorders, and suicidal ideation.20 Recent studies suggest the possibility that generalized SAD is linked with sociodemographic factors rather than comorbidity.31 The extremely low prevalence of a ‘performance-only’ SAD subgroup among adolescent samples54,55 calls into question the usefulness of this specification for either research or clinical practice.

UNDER-RECOGNITION OF GENERALIZED SAD Given the nature of generalized SAD having an early onset and chronic course with little spontaneous remission and risks of secondary mood and sub- stance use disorder,4 treatment intervention as early as possible may prevent the personal suffering and lost opportunity associated with this chronic mental disorder. However, the low proportion of people seeking treatment for SAD is a key concern. Even in the USA, only about one-third of individuals with a lifetime history of SAD reported ever receiving treat- ment specifically for SAD.3 Despite the degree of impairment associated with generalized SAD, it is notable that less than one-fifth of these youth have ever contacted a professional concerning their social fears.54

Even when patients with SAD are receiving evalu- ation and treatment for mental health problems, SAD

Table 2. Subtypes of SAD in clinical and community population studies

Study Area N Assessment Generalized type Performance- only type

Stein (2000)21 USA 1 956 CIDI 2.1/DSM-IV 26.8% (≥7/12)† 2.9%‡

Grant (2005)35 USA 43 093 AUDADIS-IV/ DSM-IV 53.8% (≥7/14)§ 3.5%¶

Ruscio (2006)3 USA 9 282 CIDI 3.0/DSM-IV 71% (≥8/14)††

Chartrand (2011)31 Canada 36 984 WMH-CIDI 77.1% (≥7/13) Crome (2014)41 Australia 8 841 CIDI 3.0/DSM-IV 0.3% Burstein (2011)54 Adolescent USA‡‡ 10 123 WHO-CIDI3.0 55.8% (≥7/12) 0.7%§§

†Original six probes of CIDI 2.1 with 6 additional social phobic situational probes (for total of 12). ‡Either (or both) of speaking in public or speaking in a meeting in absence of other fears. §Generalized SAD phobia by reporting 3 or more fears among 14 fears. ¶Pure speaking fear. ††Generalized SAD by reporting 8 or more fears among 14 fears. ‡‡Aged 13–18 years old. §§Exclusive fear of ‘acting, performing, or giving a talk in front of a group of people’. ADIS-C/P, Anxiety Disorders Interview Schedule for Children and Parents for DSM-IV; SAD, social anxiety disorder; WHO-CIDI3.0: World Health Organization Composite International Diagnostic Interview Version 3.0.

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does not appear to be detected by clinicians. For instance, among patients with generalized SAD in a managed care organization, an estimated 8.2% had the condition, but just 0.5% had a diagnosis of SAD in their medical record in the last year.13 In the same study, 31.4% of individuals with SAD had a mental health specialty visit, 34.3% had filled at least one antidepressant prescription, and 44.1% had either a mental health specialty visit or an antidepressant pre- scription in the past year. Other studies corroborate these problems: SAD is often not recognized by primary care and delays in referral for SAD are much longer compared with other anxiety disorders.56

Moreover, even mental health professionals do not recognize comorbid SAD among outpatients with depression. Zimmerman and Chelminski12 reported that only 2.1% of outpatients were diagnosed with SAD by usual clinical interview in initial assessment, although the semi-structured interview revealed that 32.7% had SAD. This discrepancy was much higher than for panic disorder among this population (8.1% by clinical interview and 15.7% by semi-structured interview). After being given the diagnosis of SAD, 73.5% of subjects desired treatment for SAD.

Why are very few SAD patients recognized and why do they not seek treatment? Owing to the early onset and chronicity of SAD, many individuals may also believe that these symptoms are part of their person- ality and therefore cannot be changed. Another hypothesis by Dalrymple and Zimmerman57 is that historically SAD has received less media attention compared with depression or other anxiety disorders.

The low proportion of people seeking treatment for SAD as a primary concern highlights that clini- cians could increase SAD treatment rates by explicitly screening for social anxiety as routine practice when people present with other mental disorders.4

SOCIOCULTURAL CONSIDERATIONS OF GENERALIZED SAD AND TKS Our review of the epidemiological literature suggests a wide range of lifetime prevalence rates of SAD, with Asian samples having some of the lowest rates and American samples having some of the highest. One frequently used explanation for the discrepancy is differences between East and West, especially TKS in Japan and other East Asian countries.58

Long before Marks and Gelder’s report,17 TKS was considered a prototype of ‘Neurose’ in Japan (since the 1930s) by Morita,59 Kasahara et al.,60 and Yamashita.61 There are two subtypes of TKS: ‘tension’ and ‘offensive’ subtypes (Table 3).61–63 Although the tension subtype with ‘fear of being noticed’ resembles SAD, early Japanese investigators concentrated on describing severe clinical pictures and contrasting it with the favorable outcome of the offensive subtype of TKS in the literature.60,61 Along these lines, Takahashi64 introduced TKS to the West as ‘an indi- vidual’s intense fear that his or her body, its parts or functions, displease, embarrass, or are offensive to other people in appearance, odor, facial expressions, or movements’. Meanwhile, the ‘tension’ subtype of TKS remained unknown to those in the West. SAD

Table 3. Diagnostic criteria for taijin kyofusho

A. At least one of the following features: (i) Fear of blushing in the presence of others (ii) Fear of stiffening of facial expression, of trembling of the head, hands, feet, or voice, of sweating while facing others (iii) Fear of physical deformities being noticed (iv) Fear of emitting body odors (v) Fear of line-of-sight becoming uncontrollable (vi) ear of uncontrollable flatus in the presence of others

B. Either of the following two, because of the above fear(s) (i) Tension subtype: Fear of being looked at (noticed) by others (ii) Offensive subtype: Fear of offending or embarrassing others

C. At most points during the course of the disorder, the person recognizes that the fear is excessive or unreasonable. D. The fear(s) interferes significantly with the person’s normal routine, occupational (academic) functioning, or social

activities or relationships, or there is marked distress about having the fear(s) E. The symptoms must have been present for at least 1 year. In individuals under age 18 years, the duration should have

been at least 6 months.

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involves a fear of humiliating oneself, whereas in TKS (specifically, the offensive subtype of TKS), the focus of fear is offending others or making them uncomfort- able by a personal flaw or shortcoming (e.g., emitting an unpleasant body odor). Under the DSM diagnos- tic system, psychiatrists in Western countries have traditionally thought that TKS is classified into obsessive–compulsive disorder, body dysmorphic disorder, delusional disorder somatic type, or para- noid or schizotypal personality disorders.65

TKS had been considered specific to Japanese culture, but this may not be so. It is listed as one of the culturally bound syndromes in the DSM-IV,7 con- sequently drawing little attention from Western audi- ences. However, recent studies66,67 reveal that SAD patients even in Western countries admit to TKS symptoms when asked. Accordingly, DSM-568 has broadened feared consequences from humiliation and embarrassment to now include fear of rejection or offending others.

The etiology of TKS has also been understood by cultural differences. American culture engenders an independent self-identity governed by personal abili- ties, desires, and autonomy, whereas East Asian cul- tures focus on interdependent self-identity and emphasize the importance of relationships, agree- ableness, conformity, and modesty.69 Some evi- dence70 suggests that collectivistic countries are more accepting toward socially reticent and withdrawn behaviors than individualistic countries, and collec- tivistic countries also report greater levels of social anxiety and more fear of blushing than individualis- tic countries. TKS can also be partially explained by Japanese culture being pseudo-sociophobic, meaning that a well-adapted individual will show a submissive and self-defeating attitude even if the person has inner strength and confidence.71 With this tendency in mind, it may come as no surprise that ‘shy- inhibited’ students in Shanghai were highly evaluated for leadership by teachers and had higher grades compared to ‘average’ students.72 These results suggest the possibility that an individual might delib- erately act as ‘a shy person’ in a pseudo-sociophobic culture. Increased rates of SAD in Japan44 might be explained by the more recent introduction of Ameri- can cultural tendencies.

We must also discuss the notable differences in treatment between social phobia as described in DSM-III and TKS as conceived by Morita.59 DSM is a phenomenological diagnostic system. Conversely, Morita considered TKS through the perspective of

sensitive and obsessional temperament and obses- sional preoccupation with physical symptoms (hot flushes or palpitations). In Morita therapy, patients with TKS had to stay at a treatment dormitory with Morita and his wife, in an effort to create a family-like atmosphere. He encouraged the patients to accept the symptoms rather than fight them, a strategy resem- bling mindfulness, radical acceptance, and validation in modern acceptance and commitment therapy or dialectical behavior therapy. He excluded ‘hysterical’ patients (cluster B personality disorders in current DSM diagnostic system), probably because such patients do not adapt well to the paternal treatment atmosphere. In support of the value of creating a family-like atmosphere, Nagata et al.73 found that those with the offensive subtype of SAD place signifi- cantly higher social value on the importance of parent–child relationships compared with those with usual SAD.

COMPARISONS BETWEEN GENERALIZED AND NON-GENERALIZED SAD

Descriptive comparisons between generalized and non-generalized SAD

Non-generalized SAD is defined as the fear of a limited number of social situations,11 and appears to have relatively distinct symptoms and etiological roots. The onset for generalized SAD is typically before the age of 10,4 whereas individuals with non- generalized SAD have a later onset at about age 16.25

Individuals with non-generalized SAD may have more traumatic social experiences in childhood than those with generalized SAD,74 although people with generalized SAD have also described their parents as more socially restrictive and less emotionally sup- portive than individuals with non-generalized SAD.75

These findings suggest that the development of non- generalized SAD may be associated with condition- ing experiences. Conversely, generalized SAD seems to be more like personality disorders, characterized by early onset and childhood shyness74 and behav- ioral inhibition.76

Despite these apparent distinctions between gener- alized and non-generalized SAD, population studies have suggested that SAD is on a single continuum with greater number of feared situations associated with greater clinical severity. A culmination of these results has been the removal of the generalized speci-

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fier in DSM-5. There were no specific number of fears to classify generalized and non-generalized SAD in the NCS-R.3 Instead, the number of social fears exhib- ited by an individual with SAD showed a linear dose– response relationship with psychiatric comorbidity, role impairment, and treatment-seeking.3,20 In an international study, the number of fears was also significantly related to some types of role impairment even after controlling for types of fears, with no evi- dence of meaningful nonlinearity that would support the distinction between generalized and non- generalized SAD.22 There was also not a specific number of performance fears or number of interac- tional fears that significantly predicted role impair- ment. In addition, mean age of onset was inversely related to number of social fears in both developed and developing countries. No sharp inflection point in the association was found that might be used to justify a distinction between generalized and non- generalized SAD.

Biological differences in physiological responses

Marked physiological responses of patients with spe- cific SAD (just one or two feared social situations) during role-plays of social situations has been consis- tently found in several studies.24,77–79 Heimberg et al.24

reported that participants with specific SAD had marked heart rate increases in the first minute of a social role-play and their heart rate never returned to baseline, although participants with generalized SAD did not show this physiological response. Other studies also showed similar results for individuals with specific SAD when doing a speech task com- pared to a generalized SAD group.77–79 These acute physiological reactions associated with specific SAD appear to resemble situation-bound panic attacks experienced by individuals with specific phobias.80

Generalized SAD is associated with heightened physiological response to a broader range of stimuli, including performance and interactional social stimuli as well as physical threat and neutral stimuli. In contrast, performance anxiety is associated with heightened startle reflex specific to performance-fear- related stimuli.81

Heredity

Family studies suggest the heredity of generalized SAD. Mannuzza et al.25 reported that the relatives of

generalized SAD probands were more likely to have a diagnosis of SAD than relatives of non-generalized SAD probands. Similarly, Stein et al.82 found that the prevalence of generalized SAD was significantly higher among first-degree relatives of people with generalized SAD (25%) than among relatives of com- parison subjects without SAD (5%), whereas the per- centage of first-degree relatives who had non- generalized SAD (mostly fear of public speaking) did not differ significantly between the groups. Tillfors et al.83 reported that the relatives of those with avoid- ant personality disorder or SAD are at risk for having SAD, and that the pattern of family aggregation sug- gests that avoidant personality disorder and SAD are not separate disorders.

Twin studies have also found heritability rates of SAD ranging from 20 to 50%,84,85 although these researchers have acknowledged that genetic factors do not play an ‘overwhelming’ role in the etiology of phobic disorders. Other twin studies have been unable to support heritability for specific anxiety dis- orders.86 By contrast, the study of environmental factors associated with SAD has produced fairly con- sistent results, showing support for various factors, such as parental overprotection and rejection.87

To summarize, results from family and twin studies suggest familial transmission that may be specific to SAD, whereas the mixed findings from the twin studies suggest a predisposition toward anxiety more generally rather than to specific anxiety disorders. Hudson and Rapee88 concluded that given the greater specificity obtained in family studies (which measure both genetic and environmental factors) compared with twin studies, the family environment likely plays a more instrumental role in the transmission of SAD. Therefore, although genetic factors may play a part, current evidence suggests that its role as an etio- logical factor is largely dependent upon more proxi- mal environmental factors.

Neuroimaging studies

A full review of significant advances in neuroimaging studies of SAD is beyond the scope of current review (see recent reviews, such as Fouche et al.89 or Bruhl et al.90). However, in general, findings of functional imaging have been fairly consistent. Individuals with SAD demonstrate increased activation of the amyg- dala and connecting frontal–striatal cortices when exposed to negative or threatening facial expres- sions.89,90 Furthermore, treatment studies indicate

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that both pharmacotherapy and psychotherapy of SAD normalize abnormal activation in the amygdala or related structures.89,90 In addition, some studies of brain structure and functional connectivity in indi- viduals with SAD reported decreased white matter connectivity between the amygdala and orbitofrontal cortex and increased connectivity in the medial pre- frontal cortex.89,90 Neuroimaging studies have paid little attention to been subtyping SAD or examining differences between generalized and non-generalized SAD.

TREATMENT PERSPECTIVE In clinical settings, patients with specific SAD tend to visit behavioral therapists. However, as men- tioned in the undertreatment section, very few patients with generalized SAD self-initiate visits with mental health professionals. What further compli- cates matters is that in research settings, individuals with generalized SAD tend to be recruited in ran- domized trials. As a consequence, the evidence basis for pharmacotherapy for SAD is largely that of the evidence basis for generalized SAD. These factors underscore the importance of mental health profes- sionals assessing all patients for generalized SAD. Patients with chronic generalized SAD will fre- quently visit physicians because of other acute dis- orders, such as major depression or substance- related and addictive disorders.

In evaluating and treating SAD, careful attention needs to be paid to both the differential diagnosis and co-occurring disorders. The following highlights some of the key considerations.

Neurodevelopmental disorders

Autism spectrum disorders have been of heightened concern in recent years. Persistent impairment in reciprocal social communication and social interac- tion (Criterion A) and restricted, repetitive patterns of behavior, interests, or activities (Criterion B) are their essential features.1 Initial interview with individuals who have generalized SAD frequently cannot cor- rectly assess social communication capacity because of patients’ anxiety in the appointment. However, careful observation in future appointments and addi- tional assessment will reveal adequate reciprocal social communication and social interaction with familiar or intimate partners.

Panic disorder and agoraphobia

Before diagnosing specific SAD, it is especially impor- tant to exclude the possibility of panic disorder. Liebowitz91 pointed out that ‘a person with social anxiety disorder may feel panicked on a subway car only if other people are looking at him, but would be perfectly comfortable alone in the same subway car.’ Panic attacks in panic disorder are unexpected and sudden, while panic attacks in specific SAD are trig- gered by the target-specific phobic situation.

Depressive disorders

Generalized SAD is linked more with depressive dis- orders than performance fears in community studies.92 Generalized SAD, with its characteristic early onset and chronic course, leads to elevated risk of development of major depressive disorder, as lon- gitudinal studies have shown.93 SAD should not be diagnosed if social avoidance is limited to periods of depression. Careful assessment of the chronology of generalized SAD and depressive disorders will lead to the appropriate treatment.

Substance-related and addictive disorders

Individuals with generalized SAD are prone to sub- stance misuse as a form of self-medication,94 and patients with generalized SAD may misuse alcohol as a form of repeated relief from the heavy tension of various ‘social interactions,’ as opposed to less fre- quent use if their anxiety were limited to few social gatherings or public speaking. Popular group treat- ment modalities, such as Alcoholics Anonymous, are frequently difficult for patients with generalized SAD to engage in because of difficultly with social interac- tions and speaking in the group.

Personality disorders

Because generalized SAD usually begins in childhood and persists into and through adulthood with a chronic course, generalized SAD can resemble a per- sonality disorder. A person with schizoid personality disorder enjoys being alone and does not wish to socialize, whereas individuals with generalized SAD desire to keep company with surrounding people. Avoidant personality disorder is another consider- ation, and has been retained in DSM-5 after consid- erable debate.14 General population studies report

732 T. Nagata et al. Psychiatry and Clinical Neurosciences 2015; 69: 724–740

that 36.4% of cases of generalized SAD in the National Epidemiologic Survey on Alcohol and Related Conditions of the United States95 and 35.8% of cases of SAD in the Australian National Survey of Mental Health and Well-Being40 were also diagnosed with avoidant personality disorder. Both of these studies suggested increased comorbidity of affective disorders, such as major depression impairment in quality of life, and disability for these individuals.96

Hikikomori

A form of severe social withdrawal lasting more than 6 months, hikikomori is estimated to have a preva- lence of 1.2% among adults under the age of 40 in Japan.97 Careful assessment of these individuals may reveal the presence of generalized SAD.98

Schizophrenia

As with schizoid personality disorder, the social avoidance of schizophrenia should be distinguished from the social fear of SAD. However, due to the chronic course of generalized SAD, it can be associ- ated with schizophrenia,99 though predictors have not been found.

‘Dark side’

There is a ‘dark side’ to SAD that involves character- ological dysfunction. Kashdan et al.100 reported that a significant percentage of individuals with SAD show high novelty-seeking or risk-prone behaviors. More- over, 10.6% of individuals with SAD in the general population also have antisocial personality disor- der.101 We have known for years that around half of inpatients with borderline personality disorder have SAD.102 Obviously, these individuals with comorbid SAD and high impulsivity cannot be treated in the same way as prototypical SAD with features of shyness, submission, inhibition, and risk aversion. No mechanism had been found for the relationship between SAD and impulsivity. These individuals with ‘impulsive SAD’ should be treated as having a cluster B personality disorder if impulsivity is primary,103

rather than SAD.

Pharmacotherapy

Numerous pharmacological trials for SAD have been undertaken. Recent investigations tend to concen-

trate on generalized SAD rather than including both generalized and non-generalized SAD. The medication–placebo difference appears to be greater in the severe subgroup than in the moderate sub- group.104 MAOI were the first medications that were widely tested in placebo-controlled trials. Even now, MAOI, especially phenelzine, are believed to be highly effective in treating SAD. However, patients must strictly keep a low-tyramine diet to avoid the risk of hypertensive crisis. As a result, MAOI are not recommended as first-line. SSRI (e.g., fluvoxamine, sertraline, paroxetine, and escitalopram) and serotonin-noradrenaline reuptake inhibitors (SNRI, e.g., venlafaxine) have the most evidence of efficacy. Thus, SSRI are now first-line pharmacological treat- ment for SAD.105 Two studies106,107 showed the effi- cacy of SSRI and SNRI for children and youth with SAD without significant risk of suicide attempts or increased impulsivity. Other medications have not consistently shown favorable evidence for efficacy in SAD, including generalized SAD, as shown in Table 4.28,107–133

Response rates for pharmacotherapy range between 43% and 71% at 12 weeks as presented in Table 4. These data suggest that around half to one- third of patients with SAD do not improve with an adequate dose and duration of an SSRI. Duration of treatment was the only statistically significant predic- tor of treatment response.134 Another issue is how long patients with SAD should continue to take medication. There are few studies to help answer this question, although best estimates, especially for gen- eralized SAD, are at least 6 months, and a year if possible.135

Another issue is what the second choice of medi- cation is if the first medication is not effective. Recently, Pollack et al.136 reported that addition of a high-potency long-acting benzodiazepine (clonazepam) tended to be more effective than addi- tion of a placebo to SSRI (27% vs 17%) among non- responders to an SSRI alone. However, Silberman137

pointed out that generalized SAD patients cannot be ‘cured ’ with a benzodiazepine even if it looks to be effective in the short-term. Alternatively, a benzodi- azepine might be administered to avoid drop-out and should be tapered after a few months as suggested by Seedat and Stein.138

In real-world clinical practice, if the first medica- tion is not effective for a patient with generalized SAD, we suggest that the clinician consider add-on or switching to psychotherapy.

Psychiatry and Clinical Neurosciences 2015; 69: 724–740 Generalized social anxiety disorder 733

Table 4. Double-blind studies including selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors for GSAD

Medication/Publication N GSAD

Dose (mg, average or range)

Response rate†

Drug Placebo

Clonazepam Davidson et al. 1993108 75 2.4 78% 20%

Phenelzine Heimberg et al. 1998109 64 59.6 65% 33% Blanco et al. 2010110 62 65.9 54% 33%

Fluvoxamine van Vliet et al. 1994111 30 150 46% 7% Stein et al. 1999112 92 202 43% 23% Asakura et al. 2006113 265 GSAD 150, 300 45% 30%

Sertraline Katzelnick et al. 1995114 10 134 50% 9% Van Amerigen et al. 2001115 204 GSAD 147 53% 29%

Paroxetine Stein et al. 199828 183 GSAD 20–50 55% 24% Baldwin et al. 1999116 290 20–50 66% 33% Allgulander 1999117 92 GSAD 20–50 70% 8% Wagner et al. 2004107 322‡ 10–50 78%‡ 38%

Escitalopram Lader et al. 2004118 166 GSAD 5, 10, 20 71%§ 50% Kasper et al. 2005119 358 GSAD 10–20 54% 39%

Venlafaxine ER¶

Allgulander et al. 2004120 434 GSAD 75–225 69% 36% Rickels et al. 2004121 272 GSAD 75–225 50% 34% Liebowitz et al. 2005122 440 GSAD 201.7 58.6% 36.1% Liebowitz et al. 2005123 271 GSAD 75–225 44% 30% Stein et al. 2005124 364 GSAD 75, 150–225 58% 33% March et al. 2007106 293‡ GSAD 37–225 56%‡ 37%

Mirtazapine Muehlbacher et al. 2005125 66 30 Decrease of LSAS††

Schutters et al. 2010126 60 GSAD 30–45 13% 13% Gabapentin

Pande et al. 1999127 69 GSAD 900–3600 38% 17% Pregabalin

Pande et al. 2004128 135 GSAD 150 or 600 43%‡‡ 22% Levetiracetam

Zhang et al. 2005129 16 GSAD 500–3000 22%§§ 14% Stein et al. 2010130 148 GSAD 1180 41% 47%

Olanzapine Barnett et al. 2002131 12 5–20 Decrease of BSPS¶¶

Quetiapine Vaishnavi et al. 2007132 15 −400 40%††† 0%

Atomoxetine Ravindran et al. 2009133 27 GSAD 40–100 21%‡‡‡ 33%

†Response rate at 12 weeks (otherwise individually indicated). ‡Children and adolescents (8–17 years of age) and 16 weeks. §20 mg and at 12 weeks, 88% for 20 mg at 24 weeks. ¶Venlafaxine extended release. ††Decreased LSAS in Medication group at 10 weeks. ‡‡600 mg at 14 weeks. §§At 7 weeks. ¶¶Decreased BSPS in medication group at 8 weeks. †††At 8 weeks. ‡‡‡At 10 weeks. BSPS, Brief Social Phobia Scale; GSAD, generalized social anxiety disorder; LSAS, Liebowitz Social Anxiety Scale.

734 T. Nagata et al. Psychiatry and Clinical Neurosciences 2015; 69: 724–740

Psychotherapy

Acarturk et al.139 conducted a meta-analysis of psy- chotherapy studies for SAD published up until January 2007. Twenty-nine randomized studies were included and results showed that psychotherapy for adults with SAD was effective. However, patients with generalized SAD were chosen as subjects in only five of the 29 studies. Moreover, few studies were placebo-controlled trials.

As Hoffman140 pointed out, the placebo-controlled effect size of cognitive behavioral therapy for SAD is in the moderate range. As a result, a newer generation of cognitive-behavioral therapies are being devel- oped, including social mishap exposures, attention retraining, identifying and eliminating safety behav- iors, and modifying post-event processing. Recently, two studies141,142 showed that psychodynamic therapy had comparable efficacy compared with cog- nitive behavioral therapy, although cost-effectiveness should be considered. Two recent studies143,144 exam- ined the effect of administration of D-cycloserine before exposures in the context of cognitive behav- ioral therapy. Both studies found that D-cycloserine was superior to placebo as an adjunct to cognitive behavioral therapy.

Combination of pharmacotherapy and psycho- therapy is another choice if monotherapy is not effec- tive. However, results have failed to show clear efficacy of combination treatment. Davidson et al.145

reported that response rates were 50.9% in a fluoxetine group, 51.7% in a cognitive behavioral group therapy group, 54.2% in a cognitive behavioral group therapy and fluoxetine group, 50.8% in a cog- nitive behavioral group therapy and placebo group, and 31.7% in a placebo group. All active treatments were significantly better than placebo, and combina- tion treatment was not better than one for general- ized SAD. In contrast, Blanco et al.110 reported that response rate for a combination of phenelzine and cognitive behavioral group treatment was better (71.9%) than placebo (33.3%), cognitive behavioral group treatment alone (47.1%), and phenelzine alone (54.3%), although subjects were not limited to those with generalized SAD.

CONCLUSION As expansion of the conceptualization of SAD has occurred, the heterogeneity of this disorder has also

grown. We discuss here two areas of ongoing chal- lenge in the field.

First, debate persists as to whether the current diag- nostic threshold is appropriate. Usually, psychothera- peutic approaches are believed to be effective for the patients with the ‘performance-only’ subtype of SAD (in DSM-5) and generalized SAD (not in DSM-5). However, evidence for pharmacotherapy, especially SSRI, is strong for generalized SAD but weak for ‘per- formance only’ and non-generalized SAD. Although Robins and Guze’s criteria for diagnostic validity of psychiatric disorders does not include treatment availability,146 nowadays the availability of valid and safe treatment approaches is essential to recommend people visit their doctor. Moreover, the threshold between normal shyness and ‘performance only’ appears arbitrary, and the latter may not be clinically significant. For example, Narrow et al.147 reported that past-year prevalence rate of SAD in the NCS study decreased from 7.4% to 3.7% after applying a clinical significance criterion. The ‘performance-only’ specifier for SAD may merely be an indicator of very mild severity, often in the sub-threshold level. Taken together, this suggests that clinical significance requires careful examination in cases of SAD, with generalized SAD having the strongest basis for meeting a valid diagnostic threshold.

Another lingering issue is the role of tempera- ment in SAD. As mentioned earlier, the concept of TKS considers the combination of both symptoms and temperament. Fear of interaction situations is associated with higher behavioral inhibition,76 while impulsivity and novelty-seeking is also seen in a segment of individuals with SAD. Whether tempera- ment is inhibited or impulsive is important in consideration of the type of medication and psycho- therapy. Thus, the categorical15 and prototype16

(high in both fear of interaction and behavioral inhibition) approach is especially suitable in treat- ment decisions, even if the degree of psychopathol- ogy in SAD is dimensional from a scientific point of view.

Just 3 decades ago, patients with generalized SAD had been conceptualized as having avoidant person- ality disorder and were thought to need long-term social skills training. While evidence for the effective- ness of other treatment approaches for generalized SAD has accumulated since then, lack of recognition and undertreatment of generalized SAD persists. More biological and psychopathological studies are needed to clarify the clinical significance of general-

Psychiatry and Clinical Neurosciences 2015; 69: 724–740 Generalized social anxiety disorder 735

ized SAD in comparison with ‘performance-only’ or specific SAD. Many challenges in our understanding and education of others about SAD remain.

ACKNOWLEDGMENTS T.N. has received honoraria for lectures, manuscripts, and/or consultancy from Eli Lilly Japan K.K., Dainippon Sumitomo Pharma Co., Ltd, GlaxoSmithKline K.K., Co., Ltd, Mitsubishi Tanabe Pharma Co., Ono Pharma Co., Ltd, and Yoshitomi- yakuhin within the last 3 years. F.S. has received honoraria for lectures from AbbVie, Eli Lilly Japan K.K., and Meiji Seika Pharma within the last 3 years.

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