Duloxetine For The Treatment Of Generalized Social Anxiety - MBL ...

Original Research
Duloxetine for the Treatment of
Generalized Social Anxiety Disorder:
A Preliminary Randomized Trial of
Increased Dose to Optimize Response
Naomi M. Simon, MD, MSc, John J. Worthington, MD, Samantha J. Moshier, BA,
Elizabeth H. Marks, BA, Elizabeth A. Hoge, MD, Mina Brandes, MD,
Hannah Delong, BA, and Mark H. Pollack, MD
ABSTRACT
Objective: This is the first trial examining
duloxetine for generalized social anxiety disor-
der (GSAD) and the effect of increased dose for
those without early remission.
Methods: Individuals (n=39) with GSAD
received 6 weeks of open-label duloxetine 60
mg/day; those with a Liebowitz Social Anxiety
Disorder Scale (LSAS) score >30 at week 6 were
randomized in double-blind fashion to an addi-
tional 18 weeks of continued duloxetine 60 mg/
day or to duloxetine 120 mg/day.
Results: Duloxetine was associated with
a significant LSAS reduction at week 6 (91.3
[17.7] to 69.8 [28.5], paired t [df]=5.2 [38],
P

ciated with a moderate effect size (Cohen’s
d=.57), there was no significant difference at
week 24 endpoint in LSAS reduction (20.5 [26.0]
versus 7.3 [17.2], t [df]=1.6 [26], P=.13) nor remis-
sion (33% versus 8%) for duloxetine with dose
increased to 120 mg/day compared to duloxetine
continued at 60 mg/day. Overall, 44% (17/39) dis-
continued prior to week 24.
Conclusions: Though with limited power,
these data provide preliminary support for the
efficacy of duloxetine for GSAD, and suggest
continued improvement but limited remission
overall at 24 weeks for individuals remaining
symptomatic at week 6. These observations war-
rant further controlled study.
CNS Spectr. 2010;15(7):436-443.
BACKGROUND
Social anxiety disorder is common with a lifetime
prevalence of 12.1%. 1 An expanding body
of clinical experience and controlled trials has
demonstrated the efficacy of selective serotonin
reuptake inhibitors (SSRIs) and the serotonin
norepinephrine reuptake inhibitor (SNRI) venlafaxine
for the treatment of generalized social
anxiety disorder (GSAD). Paroxetine, sertraline,
and venlafaxine extended-release (XR) are
Food and Drug Administration approved for this
indication; nonetheless, many treated patients
do not achieve a robust response, 2-6 suggesting
additional pharmacotherapy strategies are
needed. Most studies examining the acute efficacy
of pharmacotherapy for GSAD, including
the SSRIs, have reported that approximately
one third to one half of patients do not meet
responder criteria, with an even lower proportion
achieving remission. 2,3,6
The newest SNRI, duloxetine, has been
shown to be effective at doses of 60 mg/day to
120 mg/day for anxiety associated with depression,
7 with possible greater efficacy for anxious
compared to non-anxious depression. 8 Three
large randomized controlled trials support the
efficacy and FDA approval of duloxetine for generalized
anxiety disorder (GAD). 9 While two case
reports provide initial suggestive evidence, 10,11
Original Research
there are, to our knowledge, no published data
systematically examining duloxetine for GSAD,
or the effect of increased dose for those who do
not remit with initial dosing.
Clinicians regularly face the question of when
to alter medication course for patients with
GSAD, yet there are no empirically derived data
available to guide practice. Although it often
takes a number of months for patients with
anxiety disorders to fully respond to pharmacotherapy,
clinicians frequently raise the dose of
medication early in the course of treatment. 12 It
remains unclear, however, whether such dose
escalation is warranted. Unnecessary dose elevations
may result in greater side-effect burden
and false expectations of truncated time
to response, resulting in premature medication
discontinuation for some patients. Because dose
response data from fixed dose studies are not
“stepped,” but random assignment, these and
flexible dose studies do not address the impact
of increasing dose for patients who remain
symptomatic at initial dose levels, compared to
those who continue at the same dose level. We
are not aware of studies to date in GSAD that
have addressed the relative benefit of increasing
dose versus “watchful waiting” in patients with
incomplete response to initial treatment.
To address the paucity of data specifically
regarding duloxetine for SAD, as well as the
impact of antidepressant dose escalation for
incomplete initial response, we initiated openlabel
duloxetine at 60 mg/day for 6 weeks, and
then randomized in double–blind fashion individuals
who had not achieved remission at week
6 to an additional 18 weeks of treatment with
either duloxetine at an increased dose of 120
mg/day or to duloxetine continued at 60 mg/
day with the addition of placebo. We selected 6
weeks as a time that a clinician in practice might
reasonably choose to increase an antidepressant
dose for a patient with GSAD who remained
symptomatic. We hypothesized that duloxetine
would be associated with a significant reduction
in GSAD symptoms overall. Further, we
hypothesized that those with persistent symptoms
after 6 weeks of duloxetine at 60 mg/day
would achieve greater response at week 24 endpoint
after 18 additional weeks of duloxetine at
an increased dose (to 120 mg/day) compared to
those randomized to continue on the same 60
mg/day (plus placebo) dose.
CNS Spectr 15:7 437
© MBL Communications Inc. July 2010

METHODS
Subjects
Treatment-seeking outpatients >18 years of
age with a primary diagnosis of GSAD were
recruited by media advertisement. All study
procedures were approved by the Institutional
Review Board at Massachusetts General Hospital
(MGH), and all study participants signed written
informed consent with a physician investigator
prior to participation. Psychiatric screening
was completed by study physicians, utilizing the
Structured Clinical Interview for the Diagnostic
and Statistical Manual of Mental Disorders,
Fourth Edition. 13 Medical screening included
medical history, physical exam, and laboratory
testing, including complete blood count, chemistry
screen, thyroid screening, urine toxicology,
and pregnancy tests (for women).
Eligible were adults >18 years of age with a primary
current diagnosis of GSAD and a Liebowitz
Social Anxiety Scale (LSAS) score >50. Exclusion
criteria included concurrent use of other psychotropic
medications (with β-blockers and anticonvulsants
allowed if being used for a medical
indication and if at a stable dose for >1 month);
prior lack of response or intolerance of duloxetine;
non-response to more than two prior pharmacotherapy
trials at minimally adequate dose
and duration; significant suicidal ideation (defined
as a Montgomery Asberg Depression Rating Scale
[MADRS] item 10 score >3), or suicidal behaviors
within 6 months prior to intake. Diagnosis of any
of the following DSM-IV mental disorders was
exclusionary: a lifetime history of schizophrenia or
any other psychosis, mental retardation, organic
medical disorders or bipolar disorder; eating disorders
in the past 6 months; alcohol or substance
abuse in the past 3 months; or alcohol/substance
dependence within the past 6 months. Entry of
patients with major depressive disorder (MDD),
dysthymia, panic disorder, GAD, posttraumatic
stress disorder, or obsessive-compulsive disorder
was permitted if GSAD was judged to be the predominant
disorder, in order to increase accrual of
a clinically relevant sample. Also excluded were
pregnant or lactating women and women of childbearing
potential not using medically accepted
forms of contraception. Additional exclusion criteria
included: medical instability, a history of narrow-angle
glaucoma; or seizure disorders with
the exception of a history of childhood febrile seizures
as well as active liver disease. Concurrent
Original Research
psychotherapy initiated within 2 months of baseline,
and ongoing psychotherapy of any duration
directed specifically toward GSAD (eg, cognitivebehavioral
therapy or psychodynamic therapy
focused on exploring specific, dynamic causes of
the phobic symptomatology and providing skills
for their management) were prohibited.
Procedures
Eligible participants entered Phase 1, which
consisted of 6 weeks of open-label duloxetine initiated
at 60 mg/day. Study clinicians were allowed
to decrease the duloxetine to 30 mg/day over the
first 2 weeks only if necessary to minimize any
treatment emergent side effects, so long as 60 mg/
day dosing was reached by week 3. Those who
did not achieve remission (defined as a week 6
LSAS score

over time in GSAD. Secondary efficacy measures
included the MADRS as a measure of depressive
symptoms, and three patient rated measures
of quality of life and disability: the three-item
Sheehan Disability Scale, 16 the 16-item Quality of
Life Enjoyment and Satisfaction Questionnaire
(Q-LES-Q), 17,18 and the GSAD specific 11-item
Liebowitz Self-Rated Disability Scale. 19
Safety monitoring included psychiatric
assessments, side-effect query, and vital signs at
each visit, as well as liver function tests at weeks
0, 6, 12, and 24. Study drop points for safety
were clinical worsening defined as an increase
in Clinical Global Impression of Severity ratings
(CGI-S) over baseline of >2 points, any liver function
test >3 times the upper limit of normal at
any assessment, or lack of compliance defined
as missing >4 consecutive days of study drug.
At the end of their study participation, subjects
received $30/visit for completing the assessments,
and were offered 3 months of follow up
clinical visits with a psychopharmacologist at
the end of the trial at no charge.
Data Analyses
All analyses were performed for a modified
ITT sample, as defined a priori, consisting of
subjects who had at least one assessment on
medication in Phase 1 or 2, respectively. After
confirmation that the primary outcome measure
was normally distributed, analyses examining
overall treatment effect consisted of paired ttests
for within subject change in Phase 1, Phase
2, and overall for the full 24 weeks. Primary analyses
comparing randomized dosing in Phase 2
consisted of between-subjects two-sided t-tests.
Binary indicators of clinical response (CGI-I=1
or 2) and remission (LSAS

Only one participant in the trial continued in a
prior psychotherapy, which was supportive in
nature and not directed at GSAD.
Phase 1 Outcomes
In Phase 1 with 6 weeks of open-label duloxetine
at 60 mg/day, there was a significant reduction in
LSAS score (21.5 points, P

nificantly differ between treatment arms (20.5
points for 120-mg group versus 7.3 points for
the 60-mg group; Table 2), although increased
duloxetine dose was associated with greater
LSAS reduction consistent with a moderate
effect size (Cohen’s d= .57). Similarly, reduction
in CGI-S scores did not significantly differ
(Table 2). There was also no significant difference
in response or remission by dose group
(FET P each >.15). Of the 15 subjects randomized
to duloxetine120 mg/day, response status was
achieved for nine (60%) and remission status for
five (33%) subjects by endpoint. In comparison,
there were four (31%) responders and one (8%)
remitter amongst the 13 subjects randomized to
remain on duloxetine 60 mg/day plus placebo.
We also performed a follow-up longitudinal
regression analysis to examine whether there
Original Research
was a difference in the slope of symptomatic
change over time as measured by LSAS scores
at each visit, adjusting for severity (LSAS score)
at week 6 randomization. While there was a significant
reduction in the LSAS over time overall
during Phase 2 (β(SE)=-1.05(0.29), P

it is worth noting that the mean MADRS score was
relatively low at baseline for this primary GSAD
sample (mean=11.2 points). Duloxetine treatment
did result in significant improvement in all
three quality of life measures in the 24-week trial
(Sheehan Disability Scale [SDS], Q-LES-Q, and
Liebowitz Self-Rated Disability Scale [LSRDS], each
P30 points, with approximately half
of this score reduction occurring after week 6,
supporting the notion advanced in other studies
that the benefits of pharmacologic treatment for
GSAD symptoms may accrue gradually over time.
For example, post-hoc analyses from a 20-week
randomized trial of sertraline for GSAD 2 found
that only 30% of patients responded by 10 weeks,
while an additional 44% of initial non-responders
met response criteria by week 20; remission rates
were lower, though moved in the same direction,
with only 8% at week 10, with 29% of initial
non-remitters going on to achieve remission by
week 20 (Van Ameringen, written communication,
April 2009). In a 6-month, randomized controlled
trial of venlafaxine XR for GSAD, while
overall mean LSAS score change on venlafaxine
XR was 38 points, the week 6 to 28 drop was only
~10 points. 5 Thus, additional research is needed
to understand how long an “optimal” medication
trial is in GSAD, although available evidence supports
continued gains through at least 6 months.
Contrary to our hypothesis, non-remitters
after 6 weeks did not experience a significantly
greater drop in LSAS score, or rates of response
or remission by increasing the dose of duloxetine
to 120 mg/day relative to continuing duloxetine
at 60 mg/day for an additional 18 weeks.
There are a number of possible explanations
for our study’s findings. First, conclusions from
Phase 2 of this study are limited by its small
sample size and pilot nature, and we cannot rule
out a type 2 error due to limited power. Further,
there was by chance a higher rate of mood or
anxiety comorbidity and more women in the
60 mg dose group (Table 1). We did, nonetheless,
find a greater numeric reduction in LSAS
score of 20.5 compared to 7.3 points for 120 mg
compared to 60 mg/day, respectively, consistent
with a moderate effect size. It is also possible
that 6 weeks was too early to make a decision
about a change in dosing in GSAD, as some participants
continued to improve beyond 6 weeks
without a dose change, though our trial was not
designed to determine the optimal timing of a
CNS Spectr 15:7 442
© MBL Communications Inc. July 2010

dose change. It is worth noting that a large multicenter
randomized controlled study of duloxetine
in adults with MDD similarly reported no
advantage of increasing the dose to 120 mg/day
compared to continued 60 mg/day for an additional
8 weeks in subjects who did not achieve
remission after 6 weeks. 21
Importantly, there are also likely finer measures
of change clinicians may employ than the
binary assessment of remission status we used
in this trial when deciding whether to maintain
or change a specific medication and dose at a
given time. For example, while Phase 1 reduction
in LSAS was minimally associated with
Phase 2 LSAS reduction, slope of change in a
variety of variables such as mood, level of function,
and GSAD symptoms may be important in
predicting who may respond best to an increase
in dose. Further, some individuals with the
greatest reduction in LSAS who achieved remission
by week 6 were not randomized into Phase
2, and thus the possible range for week 6 LSAS
improvement examined as a predictor of Phase
2 LSAS change was truncated by design. This
may in part explain the lack of significant association
of Phase 1 change with Phase 2 change.
Our power was too limited to examine the moderating
effect of these clinical features on differential
response, but would be of interest in
future study. Further, conclusions from this trial
are limited to a sample of treatment-seeking
patients with primary, generally chronic, GSAD.
Another limitation is the relatively high overall
drop-out rate, at 44%. However, this is comparable
to other 6-month trials of pharmacotherapy for
GSAD, including a trial with venlafaxine in which
57% did not complete the full 28 weeks. 5 The overall
study discontinuation due to adverse events of
21% (8/39) with duloxetine in the current trial was
also comparable to the 21% rate in the 6-month
venlafaxine trial with higher doses (venlafaxine
XR 150–225 mg/day), 5 and comparable to the 15%
rate reported in the combined large, randomized
controlled trials of duloxetine for GAD. 22 Notably,
there was no difference in rates of discontinuation
between the two randomized duloxetine dose
level treatment arms. Our experience with initiation
side effects with 60 mg/day in this trial suggests
it may be best to initiate duloxetine at 30
mg/day and titrate the dose gradually for individuals
with GSAD, consistent with general clinical
experience with other antidepressants in the treatment
of anxiety disorders.
Original Research
CONCLUSION
Although power was limited and larger, and
randomized placebo-controlled trials are needed,
these data provide preliminary support for the
potential efficacy of duloxetine for GSAD, and suggest
continued improvement at 24 weeks for individuals
who are symptomatic at week 6. Increasing
the dose to 120 mg/day at 6 weeks versus continuing
60 mg/day did not result in a significantly
greater improvement, but was suggestive of
greater efficacy at the level of a moderate effect
size. Tolerability results suggest that initiation at
lower doses (ie, 30 mg) and slower dose titration
may be beneficial in this population. CNS
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