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Update on the efficacy of pharmacotherapy for

social anxiety disorder: A meta-analysis
ARTICLE in EXPERT OPINION ON PHARMACOTHERAPY OCTOBER 2014
Impact Factor: 3.53 DOI: 10.1517/14656566.2014.955472 Source: PubMed

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Original Research

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Update on the efficacy of

pharmacotherapy for social
anxiety disorder: a meta-analysis
1.

Introduction

2.

Method

3.

Results

4.

Discussion

5.

Expert opinion

Michelle L Davis, Jasper AJ Smits & Stefan G Hofmann

Boston University, Department of Psychological and Brain Sciences, Boston, MA, USA

Introduction: Social anxiety disorder (SAD) is a common mental health

problem that tends to be chronic in nature; fortunately, effective pharmacotherapy options exist. The current study provides an updated meta-analytic
review of their efficacy and potential guidelines for their application in SAD.
Methods: A comprehensive search of the current literature yielded 39 randomized, pill placebo-controlled trials of pharmacotherapy for adults diagnosed
with SAD. Data on potential moderators of treatment outcome were
collected, as well as data necessary to calculate effect sizes using Hedgess g.
Results: The overall effect size of pharmacotherapy for SAD is small to
medium (Hedgess g = 0.39). The most effective pharmacotherapy type was
phenelzine (Hedgess g = 1.14), followed by paroxetine (Hedgess g = 0.49),
venlafaxine ER (Hedgess g = 0.45) and moclobemide (Hedgess g = 0.23).
Conclusion: Effect sizes were not moderated by age, sex, length of treatment,
diagnostic subtype initial severity, maximum potential dose, or publication
year. It is concluded that pharmacotherapy is effective for treating SAD, but
there is considerable variation and room for further improvement. Future
directions may include pharmacological enhancement of psychological processes, such as d-cycloserine augmentation of exposure procedures.
Keywords: meta-analysis, pharmacotherapy, social anxiety disorder
Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Social anxiety disorder (SAD), one of the most common mental health problems, is
associated with numerous functional impairments, including comorbid alcohol use
disorder, sleep difficulties and overall impairments in well-being [1-4]. SAD tends to
be chronic if left untreated [5]. Both behavioral and pharmacological treatments have
shown promise, with cognitive behavioral therapy (CBT) and selective serotonin
reuptake inhibitors (SSRIs) currently recommended as first-line treatments [6].
However, pharmacological treatment options tend to be more widely utilized [6].
Accordingly, an updated analytic review of the current pharmacotherapy options,
along with an assessment of potential patient-specific moderating variables, is necessary both to inform practitioners of the most effective treatment options for
SAD and to guide future research regarding novel treatment options (e.g., treatment
combination or augmentation strategies and treatment matching).
Published placebo-controlled clinical trials of pharmacotherapy for SAD have
primarily focused on the efficacy of antidepressants, monoamine oxidase inhibitors
(MAOIs) and benzodiazepines. A brief overview of the most widely studied
pharmacotherapy treatment options and some current knowledge regarding their
efficacy is provided below.

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1.1

Antidepressants

SSRIs are the most widely studied treatment option and the
current treatment of choice for SAD [7]. They are considered
to be relatively safe and well tolerated [8], which tends to
make them preferable to earlier medications. Several metaanalyses have found them to be efficacious, with effect sizes
ranging from 0.65 in an analysis including only pill placebocontrolled trials [9] to 2.73 in an analysis including studies
with any type of control condition (e.g., waitlist, no treatment,
pill placebo or psychological placebo) [10]. Using Cohens [10]
convention of small (0.2), medium (0.5) and large (0.8)
effects, these effects correspond to a medium-to-large effect
size for SSRIs. Fewer studies have directly compared SNRIs,
a more recent class of antidepressants that inhibit both serotonin and norepinephrine reuptake, to SSRIs; however, venlafaxine, an SNRI, is considered to be one of the most efficacious
pharmacotherapies for SAD alongside other SSRIs [9].
Monoamine oxidase inhibitors
MAOIs are the second most widely studied pharmacotherapy
class for SAD and have been shown to be as effective as SSRIs.
In fact, a meta-analysis by Blanco and colleagues [9] generated
an effect size of 1.02 for phenelzine, a nonspecific MAOI,
which is thought to be more efficacious than moclobemide,
a selective inhibitor of monoamine oxidase A. Despite this,
MAOIs are infrequently utilized as a first-line treatment
option due to their higher rate of adverse events and dietary
constraints. Reversible monamine oxidase inhibitors (RIMAs)
tend to have fewer side effects and are generally safer. For
example, one such medication, a monoamine oxidase-A
inhibitor (MAO-A), brofaromine (ES = 0.66), was shown to
be as effective as SSRIs in the Blanco meta-analysis. Accordingly, it has been suggested that perhaps RIMAs are best
applied to those who do not respond to SSRI treatment [9].
1.2

Benzodiazepines
Benzodiazepines are generally thought to be safe and effective for
short-term use. However, there are concerns about long-term use
of benzodiazepines due to their potentially addictive effects,
alongside persistent memory and cognitive effects after withdrawal [11]. The meta-analysis by Gould and colleagues [10]
yielded a medium-to-large effect size for benzodiazepines (ES =
0.72), similar to the more recent Blanco [9] analysis (ES =
0.97), both demonstrating equal efficacy between benzodiazepines and SSRIs.
The aims of the current review are to analyze extant randomized, placebo-controlled trials of pharmacotherapy for SAD to:
i) provide an updated estimate of the overall effect size for
pharmacotherapy for SAD; ii) determine whether there are
1.3

differences in efficacy between the most commonly researched

pharmacotherapy classes; iii) determine whether there are differences in efficacy between specific medications within the
most effective pharmacotherapy classes; and iv) determine
whether there are any potential moderating effects of individual or study characteristics on pharmacotherapy efficacy.
2.

Method

Search strategy
A comprehensive search was conducted in PsycINFO
(1840 to May 2014), MEDLINE (1966 to May 2014) and
Scopus (1869 to May 2014) databases for randomized
placebo-controlled pharmacotherapy trials for SAD. The following search terms were used to search keywords, title,
abstract and Medical Subject Headings: pharmacotherapy,
medication, or pharmacology; social anxiety, social anxiety disorder, SAD, or social phobia; and trial, or clinical
trial. We also examined citation maps and used cited by
search strategies to locate studies, which were then crossreferenced with references from reviews. Finally, we contacted
pharmacotherapy researchers for upcoming publications.
2.1

Inclusion/exclusion criteria
In order for studies to be included in the present analysis, they
must have included: i) pharmacotherapy for SAD including
more than two doses of medication; ii) a pill placebo control
condition; iii) adult participants meeting diagnostic criteria for
SAD; and iv) inclusion of specific measures of SAD treatment
outcome, including the Liebowitz Social Anxiety Scale (LSAS)
total score, the Clinical Global Impression of Severity Scale,
the Clinical Global Impression -- Social Phobia Scale, the Clinical Impression of Severity -- Social Phobia Scale or the Social
Phobia Disorders Severity and Change Form. The following
types of studies were excluded from the analysis: i) studies with
insufficient data to perform analyses (unless authors were able
to provide such data); ii) treatment studies utilizing only medication responders after a medication trial period; iii) reports of
single case studies; and iv) treatment conditions based on
augmentation or studies aimed at treating comorbid diagnoses.
2.2

Data collection and synthesis

We collected data on pharmacotherapy class, number of
participants, length of pharmacotherapy (in weeks), mean age,
percentage of male/female participants, pharmacotherapy dosage initial severity, and population subtype of SAD (generalized, nongeneralized or a mixed population of both subtypes).
We generated controlled effect sizes using Hedgess g using
the following formula when means and standard deviations
were available:
2.3

(1)
Hedgess g =

M Pharm M

3
Control
1
4 (nPharm + nControl 2) 1
(nPharm 1) SD 2 Pharm + (nControl 1) SD 2Control
nPharm + nControl 2
Expert Opin. Pharmacother. (2014) 15(16)

Update on the efficacy of pharmacotherapy for social anxiety disorder

Potentially relevant abstracts identified

and screened for retrieval (n = 2155)
Abstracts excluded due to lack of relevance to
the study (n = 2054)

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Relevant abstracts reviewed for more

detailed evaluation (n = 101)
Abstracts excluded due to not meeting
inclusion/exclusion criteria (n = 62):
No active control group (n = 23)
No DSM diagnosis of SAD (n = 11)
Necessary measures not included (n = 10)
Treatment responders only (n = 6)
Augmentation studies (n = 5)
Insufficient data (n = 3)
< 2 treatment doses (n = 2)
No pharmacotherapy (n = 2)
Studies included in the meta-analysis
(n = 39)

Figure 1. Consort diagram.

SAD: Social anxiety disorder.

where M refers to the mean, SD refers to the standard

deviation, n refers to the sample size, Pharm refers to the
pharmacotherapy condition and Control refers to the control
condition. Means and standard deviations were extracted
from post-treatment data. When means and standard deviations were not available, we converted significance tests (e.g.,
t, F) into Hedgess g [12]. We utilized random effects models,
which assume significant heterogeneity of the included
studies. All analyses were completed with Comprehensive
Meta-Analysis [13].
3.

Results

Study selection
Our initial search yielded 2155 abstracts (see Figure 1), of
which 101 were deemed relevant to the current study after
review and evaluated for inclusion and exclusion criteria. Of
these, 62 did not meet inclusion criteria. The remaining 39
studies included pill placebo-controlled comparisons to SSRIs
(16 studies), MAOIs (6 studies), serotonin-norepinephrine
reuptake inhibitors (SNRIs) (3 studies), anticonvulsants (3
studies), MAO-As (1 study), antipsychotics (1 study), benzodiazepines (1 study), herbal supplements (1 study) and
noradrenergic and specific serotonin antidepressants (1 study).
Additionally, six studies included multiple pill placebocontrolled medication comparisons, including two studies
comparing an SNRI and an SSRI, one study comparing two
types of SSRIs, one study comparing two types of MAOIs,
one study comparing an SSRI and an NK1 receptor agonist
3.1

and one study comparing an MAOI and a beta-blocker. These

39 studies with a total sample size of 9905 individuals are
depicted in Table 1.
Publication bias
We calculated a fail-safe n
problem using the formula
3.2

[14,15]

to address the file drawer

(2)

X =

K ( K Z 2 706)
2 706

where K is the number of studies and Z is the mean Z

obtained from these studies. If the number of studies needed
to reduce the effect size to a nonsignificant level (i.e., the
fail-safe n) exceeds 5K + 10, the effect is considered robust [12].
The fail-safe n analysis of the 39 identified studies (i.e.,
5K + 10 = 205) suggested that it would require 3121 future
or unpublished studies with an effect size of zero for the
overall effect size to become nonsignificant. This implies
that our pooled effect size is robust. Using Begg and
Mazumdars rank correlation test [16], we found no evidence
of publication bias (Kendalls t = 0.13, z = 1.17, p = 0.24).
We then used the Trim and Fill method [17], which estimates
hypothetical studies that would lead to a symmetrical distribution around the mean effect size of all studies (these hypothetical effect sizes appear as black circles in the funnel plot of
standard errors depicted in Figure 2). When imputed, the six
additional hypothetical studies resulted in an adjusted overall
effect size of Hedgess g = 0.36 (95% CI: 0.27--0.44), which
appears as a black diamond in Figure 2.

Expert Opin. Pharmacother. (2014) 15(16)

M. L. Davis et al.

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Table 1. Studies included in the meta-analysis.

Study

Pharmacotherapy
type

Allgulander et al. (1999) [25]

Allgulander et al. (2004) [28]

Paroxetine
Paroxetine;
venlafaxine ER
Fluvoxamine
Paroxetine
Olanzapine
Phenelzine
Sertraline
Fluoxetine
Clonazepam
Fluoxetine
Citalopram;
GR205171
Phenelzine
Escitalopram
Sertraline
Fluoxetine
St. Johns Wort
Escitalopramz;
paroxetine
Paroxetine
Atenolol;
phenelzine
Paroxetinez
Sertraline
Paroxetine;
venlafaxine ER
Venlafaxine ER
Brofaromine
Moclobemide
Gabapentin
Pregabalin*
Venlafaxine ER
Moclobemide
Mirtazapine
Paroxetine
Fluvoxamine
Moclobemide
Venlafaxine ER*
Moclobemide*
Sertraline
Moclobemide;
phenelzine
Fluvoxamine
Levetiracetam

Asakura et al. (2007) [29]

Baldwin et al. (1999) [30]
Barnett et al. (2002) [31]
Blanco et al. (2010) [32]
Blomhoff et al. (2001) [33]
Clark et al. (2003) [34]
Davidson et al. (1993) [35]
Davidson et al. (2004) [36]
Furmark et al. (2005) [37]
Heimberg et al. (1998) [38]
Kasper et al. (2005) [39]
Katzelnick et al. (1995) [40]
Kobak et al. (2002) [41]
Kobak et al. (2005) [42]
Lader et al. (2004) [43]
Lepola et al. (2004) [44]
Liebowitz et al. (1992) [45]
Liebowitz et al. (2002) [46]
Liebowitz et al. (2003) [47]
Liebowitz et al. (2005a) [48]
Liebowitz et al. (2005b) [49]
Lott et al. (1997) [50]
Noyes et al. (1997) [51]
Pande et al. (1999) [52]
Pande et al. (2004) [53]
Rickels et al. (2004) [54]
Schneier et al. (1998) [55]
Schutters et al. (2010) [56]
Stein et al. (1998) [57]
Stein et al. (1999) [58]
Stein et al. (2002) [59]
Stein et al. (2005) [60]
TIMCTG, (1997) [61]
van Ameringen et al. (2001) [62]
Versiani et al. (1992) [63]
Westenberg et al. (2004) [64]
Zhang et al. (2005) [65]

Mean
age

%
Female

Tx
weeks

Outcome
measure

Diagnostic
Subtype

92
389

41.0
38.8

NR
53.4

12
12

LSAS
LSAS

Mixed
GSAD

265
290
12
96
277
60
75
117
36

32.4
36.1
NR
31.4
40.4
33.2
37.2
36.6
31.6

38.8
54.2
NR
40.6
60.5
52.0
42.7
47.4
52.8

10
12
8
12
24
16
10
14
6

LSAS
LSAS; CGI-S
LSAS
LSAS; CGI-S
CGI-SP
LSAS
LSAS; CGI-S
CGI-S
CGI-S

GSAD
Mixed
Mixed
Mixed
GSAD
GSAD
Mixed
GSAD
Mixed

81
358
12
60
40
820

34.9
37.5
42.6
39.5
37.5
36.9

49.6
45.5
33.3
58.0
52.5
47.2

12
12
10
14
12
24

SPDSC
LSAS
LSAS
LSAS
LSAS
LSAS; CGI-S

Mixed
GSAD
Mixed
GSAD
GSAD
GSAD

370
74

38.9
34.3

50.0
31.0

12
8

CGI-S
CGI-S

Mixed
Mixed

360
401
413

37.0
35.1
36.3

41.4
40.5
46.5

12
12
12

LSAS; CGI-S
LSAS; CGI-S
LSAS; CGI-S

GSAD
GSAD
GSAD

271
102
506
69
135
261
77
60
187
92
377
364
578
203
78

35.4
36.5
38.1
35.6
38.4
41.5
35.5
38.6
NR
39.4
34.4
36.9
36.4
35.7
NR

45.0
39.2
42.7
42.0
41.5
55.6
44.9
56.7
NR
35.9
47.0
41.7
43.0
44.4
NR

12
10
12
14
10
12
8
12
12
12
12
24
12
20
8

LSAS
LSAS
LSAS; CIS-SP
LSAS
CGI-S
LSAS; CGI-S
LSAS
LSAS
LSAS
LSAS
LSAS
LSAS
LSAS; CIS-SP
CGI-S
CGI-S

GSAD
Mixed
Mixed
Mixed
GSAD
GSAD
Mixed
GSAD
GSAD
Mixed
Mixed
GSAD
Mixed
GSAD
Mixed

294
16

38.0
37.5

52.0
53.0

12
7

LSAS; CGI-S
LSAS

GSAD
Mixed

*Study included two doses of the same medication.

z
Study included three doses of the same medication.

Study included five doses of the same medication.

CGI-S: Clinical global impression scale of severity of illness; CIS-SP: Clinical impression of severity -- social phobia scale; GSAD: Generalized social anxiety disorder;
LSAS: Liebowitz social anxiety scale; NR: Not reported.

Heterogeneity analysis
In order to test whether significant heterogeneity existed
between the 39 studies included in our study, we conducted
a heterogeneity analysis. The test was significant, Q(38) =
103.75, p < 0.001, suggesting that random effects analyses
were an appropriate choice for the current study.
3.3

Overall efficacy of pharmacotherapy for SAD

Overall, there was an advantage of pharmacotherapy over pill
placebo in an analysis of the 39 studies pooled across outcome
measures (Hedgess g = 0.39 [SE = 0.03, 95% CI: 0.32--0.45,
p < 0.001]). This effect was similar (c2 = 1.00, df = 2, p =
0.608) in an analysis of 30 studies with self-reported LSAS
3.4

Expert Opin. Pharmacother. (2014) 15(16)

Update on the efficacy of pharmacotherapy for social anxiety disorder

Funnel plot of standard error by Hedgess g

0.0

Standard error

0.1
0.2
0.3
0.4
0.5

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0.6
-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Hedgess g

Figure 2. Funnel plot of standard error by effect size.

outcome scores (Hedgess g = 0.35 [SE = 0.02, 95% CI: 0.31

-- 0.40, p < 0.001]) and in an analysis of 20 studies with
7-point clinician-rated outcome scores (Hedgess g = 0.38
[SE = 0.04, 95% CI: 0.30 -- 0.47, p < 0.001]).
Efficacy of pharmacotherapy classes
Fail-safe n analyses were first conducted for each pharmacotherapy class and only those deemed robust (based on fail-safe n
analyses) were analyzed separately for comparisons of efficacy.
The classes deemed robust were SSRIs (20 studies; fail-safe
n = 898), MAOIs (8 studies; fail-safe n = 162) and SNRIs (5
studies; fail-safe n = 96). Pharmacotherapy classes that yielded
a significant advantage over pill placebo were SSRIs in an analysis of 20 studies involving 25 SSRI comparisons (Hedgess
g = 0.39 [SE = 0.03, 95% CI: 0.33--0.45, p < 0.001]), MAOIs
in an analysis of 8 studies involving 14 MAOI comparisons
(Hedgess g = 0.44 [SE = 0.10, 95% CI: 0.25 -- 0.63,
p < 0.001]) and SNRIs in an analysis of 5 studies involving
6 SNRI comparisons (Hedgess g = 0.45 [SE = 0.05, 95% CI:
0.35--0.55, p < 0.001]). A Cochrans Q test of heterogeneity,
utilized to examine potential differences between the three effective pharmacotherapy classes (i.e., SSRIs, MAOIs and SNRIs),
indicated no significant differences in effect size estimates based
on pharmacotherapy class (c2 =1.06, df = 2, p = 0.589).
3.5

Efficacy of specific medications

Among the SSRIs, only the effect size of paroxetine was robust
(with eight studies; fail-safe n = 286) and outperformed pill
placebo (Hedgess g = 0.49 [SE = 0.05, 95% CI: 0.40 to
0.58, p < 0.001]). Among the SNRIs, only the effect size of
venlafaxine ER was robust (with five studies; fail-safe n = 62)
and also outperformed pill placebo (Hedgess g = 0.45 [SE =
0.05, 95% CI: 0.35--0.55, p < 0.001]). Among the MAOIs,
both the effect sizes of phenelzine (with four studies; fail-safe
n = 59) and moclobemide (with five studies; fail-safe n = 41)
3.6

were robust. Both phenelzine (Hedgess g = 1.17 [SE = 0.33,

95% CI: 0.52--1.82, p = 0.001]) and moclobemide (Hedgess
g = 0.23 [SE = 0.06, 95% CI: 0.11--0.35, p < 0.001]) outperformed pill placebo. A mixed effects analysis indicated significant differences in efficacy among these four medication types
(c2 = 21.61, df = 3, p < 0.001). Phenelzine was significantly
more efficacious than venlafaxine ER (c2 = 4.55, df = 1,
p = 0.033), paroxetine (c2 = 4.09, df = 1, p = 0.043) and
moclobemide (c2 = 7.64, df = 1, p = 0.006). Paroxetine was
significantly more efficacious than moclobemide (c2 = 11.03,
df = 1, p = 0.001), but showed no differences in efficacy with
venlafaxine ER (c2 = 0.32, df = 1, p = 0.571). Finally, venlafaxine ER was also superior to moclobemide (c2 = 7.36, df = 1,
p =. 007). A summary of the effect sizes by medication type
and class is presented in Table 2.
Moderator analyses
Moderator analyses were completed using unrestricted maximum likelihood meta regressions. There was no significant relation between effect size and mean age (b = 0.01, p = 0.652), sex
(b = 0.00, p = 0.310), treatment duration (b = -0.01, p = 0.201),
initial severity (b = 0.00, p = 0.717), pharmacotherapy dosage
(b = 0.00, p = 0.316), or publication year (b = -0.01, p = 0.270).
Finally, we also found no significant difference in effect sizes
(c2 = 2.74, df = 1, p = 0.098) between the 20 studies utilizing
populations diagnosed with GSAD (Hedgess g = 0.36 [SE =
0.03, 95% CI: 0.31--0.41, p < 0.001]), and the 19 studies utilizing mixed populations of individuals diagnosed with either
GSAD and non-GSAD (Hedgess g = 0.48 [SE = 0.07, 95%
CI: 0.35--0.62, p < 0.001]).
3.7

4.

Discussion

Our analysis of 39 randomized, pill placebo-controlled trials

of pharmacotherapy for individuals diagnosed with SAD

Expert Opin. Pharmacother. (2014) 15(16)

M. L. Davis et al.

Table 2. Effect sizes by medication.

Medication
class

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Anticonvulsant

Medication

Gabapentin
Pregabalin (150 mg)
Pregabalin (600 mg)
Pooled pregabalin
Levetiracetam
Pooled anticonvulsant
Antipsychotic
Olanzapine
Benzodiapine
Clonazepam
b blocker
Atenolol
Herbal
St. Johns Wort
supplement
MAO-A
Brofaromine
MAOI
Phenelzine
Phenelzine
Phenelzine
Phenelzine
Pooled phenelzine
Moclobemide (75 mg)
Moclobemide (150 mg)
Moclobemide (300 mg)
Moclobemide (600 mg)
Moclobemide (900 mg)
Moclobemide
Moclobemide
Moclobemide (300 mg)
Moclobemide (600 mg)
Moclobemide
Pooled moclobemide
Pooled MAOI
NaSSA
Mirtazapine
NK1 receptor
GR205171
agonist
SNRI
Venlafaxine ER
Venlafaxine ER
Venlafaxine ER
Venlafaxine ER
Venlafaxine ER (75 mg)
Venlafaxine ER (150 mg)
Pooled velanfaxine ER
Pooled SNRI
SSRI
Citalopram
Escitalopram
Escitalopram (5 mg)
Escitalopram (10 mg)
Escitalopram (20 mg)
Pooled escitalopram
Fluoxetine
Fluoxetine
Fluoxetine
Pooled fluoxetine
Fluvoxamine
Fluvoxamine
Fluvoxamine
Pooled fluvoxamine
Paroxetine

Study

Pande et al. (1999) [52]

Pande et al. (2004) [53]
Pande et al. (2004) [53]
Zhang et al. (2005) [65]
Barnett et al. (2002) [31]
Davidson et al. (1993) [35]
Liebowitz et al. (1992) [45]
Kobak et al. (2005) [42]
Lott et al. (1997) [50]
Blanco et al. (2010) [32]
Heimberg et al. (1998) [38]
Liebowitz et al. (1992) [45]
Versiani et al. (1992) [63]
Noyes et al. (1997) [51]
Noyes et al. (1997) [51]
Noyes et al. (1997) [51]
Noyes et al. (1997) [51]
Noyes et al. (1997) [51]
Schneier et al. (1998) [55]
Stein et al. (2002) [59]
TIMCTG, (1997) [61]
TIMCTG, (1997) [61]
Versiani et al. (1992) [63]

Schutters et al. (2010) [56]

Furmark et al. (2005) [37]
Allgulander et al. (2004) [28]
Liebowitz et al. (2005a) [48]
Liebowitz et al. (2005b) [49]
Rickels et al. (2004) [54]
Stein et al. (2005) [60]
Stein et al. (2005) [60]

Furmark et al. (2005) [37]

Kasper et al. (2005) [39]
Lader et al. (2004) [43]
Lader et al. (2004) [43]
Lader et al. (2004) [43]
Clark et al. (2003) [34]
Davidson et al. (2004) [36]
Kobak et al. (2002) [41]
Asakura et al. (2007) [29]
Stein et al. (1999) [58]
Westenberg et al. (2004) [64]
Allgulander et al. (1999) [25]

Hedgess g

SE

95%
CI low

95% CI
high

0.53
-0.09
0.17
0.05
0.39
0.20
0.72
0.97
0.04
-0.07

0.24
0.21
0.21
0.15
0.48
0.14
0.56
0.24
0.28
0.31

0.05
-0.50
-0.23
-0.24
-0.55
-0.08
-0.38
0.49
-0.52
-0.68

1.00
0.33
0.58
0.33
1.34
0.48
1.82
1.44
0.59
0.54

2.18
-0.42
0.84
0.30
0.82
1.40
1.29
4.00
0.13
-0.22

0.03
0.67
0.40
0.76
0.41
0.16
0.20
0.00
0.90
0.82

0.36
0.49
1.18
0.95
2.16
1.17
0.01
0.17
0.12
0.13
0.19
0.20
0.26
0.37
0.19
1.22
0.23
0.44
0.13
0.46

0.20
0.26
0.29
0.29
0.35
0.33
0.15
0.15
0.15
0.15
0.15
0.23
0.10
0.10
0.10
0.30
0.06
0.10
0.26
0.40

-0.03
-0.02
0.61
0.38
1.48
0.52
-0.29
-0.13
-0.18
-0.17
-0.12
-0.25
0.06
0.17
-0.01
0.64
0.11
0.25
-0.37
-0.33

0.75
0.99
1.76
1.52
2.84
1.82
0.31
0.47
0.42
0.43
0.49
0.65
0.47
0.57
0.39
1.81
0.35
0.63
0.63
1.24

1.81
1.90
4.02
3.27
6.25
3.51
0.08
1.10
0.78
0.84
1.21
0.89
2.56
3.64
1.84
4.10
3.76
4.47
0.51
1.14

0.07
0.06
0.00
0.00
0.00
0.00
0.93
0.27
0.44
0.40
0.23
0.37
0.01
0.00
0.07
0.00
0.00
0.00
0.61
0.25

0.62
0.40
0.48
0.37
0.42
0.42
0.45
0.45
0.32
0.25
0.28
0.25
0.37
0.29
0.11
0.56
-0.03
0.25
0.30
0.67
0.27
0.35
0.84

0.13
0.12
0.12
0.12
0.13
0.13
0.05
0.05
0.40
0.11
0.11
0.11
0.11
0.05
0.31
0.19
0.25
0.20
0.13
0.22
0.12
0.10
0.22

0.37
0.16
0.23
0.12
0.17
0.17
0.35
0.35
-0.46
0.04
0.07
0.03
0.15
0.18
-0.50
0.19
-0.53
-0.13
0.05
0.24
0.04
0.16
0.42

0.87
0.63
0.72
0.61
0.68
0.68
0.55
0.55
1.10
0.46
0.50
0.47
0.59
0.39
0.72
0.92
0.47
0.64
0.56
1.10
0.50
0.54
1.27

4.92
3.29
3.87
2.94
3.29
3.29
8.82
8.82
0.81
2.34
2.58
2.27
3.29
5.23
0.35
2.96
-0.11
1.28
2.33
3.04
2.31
3.63
3.90

0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.42
0.02
0.01
0.02
0.00
0.00
0.72
0.00
0.91
0.20
0.02
0.00
0.02
0.00
0.00

Both the phenelzine and moclobemide arms of the Versiani et al. (1992) study evidenced larger effect sizes compared to other trials with similar doses (see
Table 2). Analyses were re-run without the Versiani study for estimated effect sizes of overall efficacy across pharmacotherapy (Hedgess g = 0.36 [SE = 0.03,
95% CI: 0.31 to 0.42, p < .001]), phenelzine efficacy (Hedgess g = 0.85 [SE = 0.21, 95% CI: 0.44 to 1.27, p < .001]), and moclobemide efficacy
(Hedgess g = 0.21 [SE = 0.04, 95% CI: 0.12 to 0.30, p < .001]).

Expert Opin. Pharmacother. (2014) 15(16)

Update on the efficacy of pharmacotherapy for social anxiety disorder

Table 2. Effect sizes by medication (continued).

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Medication
class

Medication
Paroxetine
Paroxetine
Paroxetine
Paroxetine
Paroxetine
Paroxetine (20 mg)
Paroxetine (40 mg)
Paroxetine (60 mg)
Paroxetine
Pooled paroxetine
Sertraline
Sertraline
Sertraline
Sertraline

Hedgess g

Study
Allgulander et al. (2004) [28]
Baldwin et al. (1999) [30]
Lader et al. (2004) [43]
Lepola et al. (2004) [44]
Liebowitz et al. (2005a) [48]
Liebowitz et al. (2002) [46]
Liebowitz et al. (2002) [46]
Liebowitz et al. (2002) [46]
Stein et al. (1998) [57]
Blomhoff et al. (2001) [33]
Katzelnick et al. (1995) [40]
Liebowitz et al. (2003) [46]
van Ameringen et al.
(2001) [62]

Pooled sertraline
Pooled SSRI
Pooled overall

SE

95%
CI low

95% CI
high

0.59
0.50
0.32
0.64
0.40
0.47
0.36
0.33
0.62
0.49
0.27
0.80
0.33
0.38

0.13
0.12
0.11
0.11
0.12
0.15
0.15
0.15
0.15
0.05
0.15
0.56
0.10
0.15

0.34
0.26
0.11
0.43
0.16
0.18
0.06
0.04
0.33
0.40
-0.02
-0.30
0.14
0.09

0.83
0.73
0.54
0.85
0.64
0.77
0.65
0.62
0.91
0.58
0.56
1.89
0.53
0.68

4.64
4.18
2.94
6.02
3.29
3.14
2.38
2.20
4.17
10.56
1.83
1.43
3.31
2.58

0.00
0.00
0.00
0.00
0.00
0.00
0.02
0.03
0.00
0.00
0.07
0.15
0.00
0.01

0.34
0.39
0.39

0.07
0.03
0.03

0.20
0.33
0.32

0.48
0.45
0.45

4.69
12.43
12.12

0.00
0.00
0.00

Both the phenelzine and moclobemide arms of the Versiani et al. (1992) study evidenced larger effect sizes compared to other trials with similar doses (see
Table 2). Analyses were re-run without the Versiani study for estimated effect sizes of overall efficacy across pharmacotherapy (Hedgess g = 0.36 [SE = 0.03,
95% CI: 0.31 to 0.42, p < .001]), phenelzine efficacy (Hedgess g = 0.85 [SE = 0.21, 95% CI: 0.44 to 1.27, p < .001]), and moclobemide efficacy
(Hedgess g = 0.21 [SE = 0.04, 95% CI: 0.12 to 0.30, p < .001]).

revealed a pooled effect size of Hedgess g = 0.39, which corresponds to a small-to-medium overall effect of pharmacotherapy for SAD. We found no significant differences in
efficacy among the three most widely researched pharmacotherapy classes (SSRIs, SNRIs and MAOIs). Of the specific
pharmacotherapy types, only paroxetine (an SSRI), venlafaxine ER (an SNRI), and phenelzine and moclobemide
(MAOIs) had robust enough effect sizes to perform comparisons. Phenelzine (Hedgess g = 1.17) significantly outperformed all of the other three medications, with paroxetine
(Hedgess g = 0.49) and venlafaxine ER (Hedgess g = 0.45)
demonstrating no differences in efficacy, and both outperforming moclobemide (Hedgess g = 0.23). We found no
differences in pharmacotherapy efficacy based on mean age,
percentage of females, number of treatment weeks, SAD
population type initial severity, pharmacotherapy dosage or
publication year.
Compared to a previous study with similar inclusion
criteria [9], our overall effect size was somewhat smaller (i.e.,
0.39 compared to their 0.65), perhaps due to differences in outcome measures (the previous analysis utilized categorical
responder data) and year of publication. Overall, however, our
findings are similar to those in previous meta-analyses, suggesting that SSRIs, SNRIs (venlafaxine ER, specifically) and
MAOIs (particularly phenelzine) are all moderately effective
in the treatment of SAD. Phenelzine was associated with the
largest effects, significantly outperforming the other drug classes. These findings combined with the brief overview of the
pharmacotherapy profiles above, point to some prescription
considerations, which have been previously alluded to. First,

the greater efficacy of MAOIs needs to be weighed against the

relatively less advantageous side effect profile. Additionally,
though not examined in this analysis, for patients with comorbid depression and SAD, antidepressant medications may be
particularly advantageous, while practitioners might be wary
of prescribing benzodiazepines to patients with comorbid alcohol use disorders and SAD.
While our publication bias calculations indicated that our
effect size was relatively robust against hypothetical unpublished null or negative results, we must still acknowledge our
lack of inclusion of unpublished studies as a limitation of
this analysis.
Our analysis did not provide any insight into individual or
study characteristics that might be associated with increased
efficacy of pharmacotherapy. However, uncovering characteristics associated with either increased or decreased treatment
response is an important area for future research.
5.

Expert opinion

The effect sizes derived in meta-analyses using pill placebocontrolled trials are in the small-to-medium range, suggesting
that the placebo effect may be of significant concern.
Additionally, the effect sizes reported in this analysis reflect
post-treatment improvement; it is likely that when pharmacotherapy is withdrawn, many patients experience relapse if no
other coping strategies are in place. This points to a need
for studies examining the mechanism of these interventions,
which might lead to novel and improved treatment strategies.
For example, we may see benefit from either combining or

Expert Opin. Pharmacother. (2014) 15(16)

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by 64.20.179.190 on 10/06/14

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M. L. Davis et al.

augmenting behavioral treatments, such as CBT, with pharmacotherapy strategies, both in an attempt to enhance the
efficacy of CBT and perhaps to reduce the amount of sessions
necessary to derive benefit from CBT, making it more disseminable and cost-effective. Recent studies have demonstrated
that CBT, though similar in efficacy to pharmacotherapy
with an effect size of 0.62 in a meta-analysis of 5 RCTs
[18]), may have longer-lasting effects [19,20]. However, this
treatment modality is less often utilized, perhaps due to
limited availability of CBT practitioners or ease of dissemination [6]. A meta-analysis examining CBT and pharmacotherapy combination strategies indicated that it might be useful
to combine these approaches at least in the short term. However, combination strategies showed no benefit over standalone treatment in the long term [21]. Accordingly, rather
than combining approaches that may have similar mechanisms of action, current research has focused on attempting
to use medications that augment mechanisms that may be
specific to CBT, such as extinction learning. One such medication, d-cycloserine (DCS), has shown promise in the treatment of SAD in recent trials, such that those who receive
DCS prior to exposure sessions evidence better treatment outcomes than those receiving placebo [22-25]. DCS is a partial
NMDA receptor agonist that is implicated in extinction
learning and memory. DCS seems to work particularly well
when combined with abbreviated exposure-based CBT protocols, perhaps by accelerating treatment gains, lending to its
potential as a strategy for decreasing patient cost and burden
with CBT. Though the DCS evidence base is currently mixed
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This study was funded by grants R01AT007257
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Affiliation
Michelle L Davis1, Jasper AJ Smits1 &
Stefan G Hofmann2

Author for correspondence

1
The University of Texas, Department of
Psychology and Institute for Mental Health
Research, 305 E 23rd St, Stop E9000, Austin,
TX 78712, USA
2
Boston University, Department of Psychological
and Brain Sciences, 648 Beacon Street, 6th floor,
Boston, MA 02215, USA
E-mail: shofmann@bu.edu

Expert Opin. Pharmacother. (2014) 15(16)

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