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Duloxetine in the treatment of

generalized anxiety disorder
Expert Rev. Neurother. 9(2), 155–165 (2009)

Susan G Kornstein†,
James M Russell,
Melissa E Spann,
Paul Crits-Christoph
and Susan G Ball
†
Author for correspondence
Department of Psychiatry,
Virginia Commonwealth
University, PO Box 980710,
Richmond, VA 23298-0710, USA
Tel.: +1 804 828 5637
Fax: +1 804 828 5644
skornste@vcu.edu
Generalized anxiety disorder (GAD) is a relatively prevalent and disabling condition. Duloxetine,
an inhibitor of both serotonin and norepinephrine, was approved by the US FDA in 2007 for
the treatment of GAD. Short-term efficacy of duloxetine in dosages of 60–120 mg/day has been
established in four double-blind, placebo-controlled trials of 9–10 weeks duration. Duloxetine
has also been found to meet rigorous criteria for noninferiority in comparison with venlafaxine
in GAD. Duloxetine has shown superiority on measures of functioning and quality of life and,
compared with placebo treatment, it reduces painful physical symptoms common in GAD
patients. Continuation treatment for acute treatment responders was found to prevent relapse
of GAD to a significantly greater degree than placebo. In all acute and long-term trials, duloxetine
was well-tolerated. This body of research suggests that duloxetine should be one of the options
considered as a first-line treatment for GAD.
Keywords : duloxetine • functioning • generalized anxiety disorder • pain • relapse

Generalized anxiety disorder (GAD) is char-
acterized by chronic symptoms of physical
and psychological anxiety, especially persist-
ent worry. Despite being often overlooked by
clinicians, GAD is relatively common and is
disabling. Epidemiological studies indicate that
there is a 12-month prevalence rate between
2 and 3%, and a lifetime prevalence rate of
approximately 5% for GAD [1–3] . Among
patients seen in primary care settings, approx-
imately 4–8% have GAD, but the correct
diagnosis is made less than half of the time
[4–6] . Only approximately 20% of patients with
GAD seen by primary care or other general
medical physicians receive an adequate course
of treatment [7] .
A wide range of functional impairments are
associated with GAD [8–10] . Moreover, the
disability associated with GAD is equal to,
or greater than, that observed with physical
disorders, such as heart disease and arthritis
[9,11] . In part, the considerable level of disabil-
ity seen with GAD is due to the high level
of comorbidity of GAD with other psychi-
atric and physical disorders [3,12] . However,
even among individuals diagnosed with pure
GAD (without any psychiatric comorbidities),
functional role impairment is similar to that
observed with major depressive disorder [13] .
Long-term follow-up studies of GAD patients
have indicated that full symptomatic recovery
occurs less than half of the time and relapse
rates are high [14,15] . Thus, GAD is considered
to be a chronic condition.
Successful treatment of GAD is clearly impor-
tant to reduce anxiety symptoms, and to improve
functioning and quality of life. Maintenance
treatment of GAD is often needed, not only
to prevent relapses of anxiety symptoms, but
also because GAD has been found to predict
the occurrence of episodes of major depressive
disorder up to 10 years following the diagnosis
of GAD [16] .
Pharmacologic treatment options
for GAD
Benzodiazepines and buspirone were the first
drugs approved by the US FDA for the treat-
ment of GAD. Although benzodiazepines
became the mainstay of short-term anxiolytic
treatment, they have been relegated by most
physicians to treat only acute anxiety symptoms
owing to rebound anxiety and presence of dis-
continuation symptoms [17,18] . Benzodiazepines
also carry a considerable risk of sedation, motor
and cognitive dysfunction, physical dependency
and withdrawal problems [19–22] .
Safety concerns regarding benzodiazepines
provided the impetus for the search for non-
benzodiazepine anxiolytics, such as the serot-
onin (5-hydroxytryptamine; 5-HT) receptor
5-HT1A partial agonists and antidepressants.

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 Drug Profile Kornstein, Russell, Spann, Crits-Christoph & Ball

Of all 5-HT1A partial agonists studied, only buspirone demon-
strated consistent anxiolytic properties [23] . However, buspirone
was found to have slower onset and a slightly weaker overall anti-
anxiety efficacy compared with various benzodiazepines [23,24]
and antidepressants [25] . Among tricyclic antidepressants, only
imipramine demonstrated clinical efficacy with GAD [26] .
In the past decade, selective serotonin reuptake inhibitors
(SSRIs) and serotonin–norepinephrine reuptake inhibitors
(SNRIs) were evaluated as treatments for GAD. Placebo-
controlled, randomized clinical trials were conducted, examin-
ing both short- and long-term efficacy and safety of sertraline
[27,28] , paroxetine [29–31] , escitalopram [32,33] and venlafaxine
[25,34–38] , in addition to duloxetine (studies reviewed herein).
Two SSRIs (paroxetine and escitalopram) and two SNRIs (ven-
lafaxine and duloxetine) received FDA approval for the treat-
ment of GAD. Since these agents can safely be used in the long
term, and because of their broad effectiveness across multiple
disorders that are often comorbid with GAD, these medica-
tions are now recommended as first-line pharmacotherapy for
GAD [39,40] , although clinical use of benzodiazepines for GAD
remains high [41] .
Background of duloxetine
Duloxetine hydrochloride is a selective inhibitor of the reuptake
of both serotonin and norepinephrine [42] . The elimination half-
life of duloxetine is approximately 12 h (range: 8–17 h). When
administered with food, the peak concentration of duloxetine
is delayed from 6 to 10 h after dosing. The pharmacokinetics
of duloxetine have been found to be dose proportional over the
therapeutic range [43] . Two cytochrome P450 isozymes, CYP2D6
and CYP1A2, are primarily responsible for the elimination of
duloxetine by hepatic metabolism [44] .
Duloxetine is now approved by the FDA for the treatment of
major depressive disorder, diabetic peripheral neuropathic pain,
fibromyalgia and GAD, and also in the EU for major depressive
disorder, diabetic peripheral neuropathic pain, GAD and stress
urinary incontinence. The primary contraindications for use of
duloxetine are: use of a monoamine oxidase inhibitor concomi-
tantly or in close temporal proximity; and use in patients with
narrow-angle glaucoma.
The potential anxiolytic effects of duloxetine were first
observed in animal studies using the mouse zero maze anxiety
model. In this research, duloxetine was found to have a sig-
nificant effect on all animal behaviors associated with anxiety
[45] . In humans, the effects of duloxetine on anxiety were first
observed in clinical trials of major depressive disorder. In these
studies, duloxetine was found to reduce the severity of anxiety
symptoms in addition to its efficacy with regard to depressive
symptoms [46] . GAD is thought to involve the disruption of
multiple neurotransmitters, including serotonin and norepine-
phrine [47] . Thus, there were several lines of evidence that are
supportive of the potential value of dual-action SNRI agents in
the treatment of GAD.
Short-term efficacy in GAD
Four 9–10-week multicenter, randomized, double-blind, pla-
cebo-controlled studies have investigated duloxetine in the
acute treatment of GAD (Table 1) . All studies involved adults
(aged 18 years or older) who had an American Psychiatric
Association Diagnostic and Statistical Manual of Mental
Disorders (DSM)-IV diagnosis of GAD. In addition, all stud-
ies had inclusion criteria designed to select only GAD patients
with moderate-to-severe symptoms. Specifically, patients needed
to have a Hospital Anxiety Depression Scale (HADS) [48] anxi-
ety subscale score of at least ten, a Covi Anxiety Scale [49] score
of at least nine, no item in the Raskin Depression Scale [50]
greater than three at the first study visit, and the Covi Anxiety
Scale score must have been greater than the Raskin Depression
Scale score at the first study visit (to ensure that anxiety rather
than depression was the primary symptomology). Furthermore,

Table 1. Studies of duloxetine in generalized anxiety disorder.

Study Dosing Treatments Design Results on primary Response rates (%) Ref.
efficacy measure*
DLX VEN PBO DLX VEN PBO
Koponen Fixed 60 or Yes Acute treatment DLX 60 mg > PBO; p < 0.001; 58 (60 mg); 31 [54]
et al. (2007) 120 mg 9 weeks DLX 120 mg > PBO; p < 0.001 56 (120 mg)
Rynn et al. Flexible 60–120 mg Yes Acute treatment DLX > PBO; p = 0.023 40 32 [55]
(2008) 10 weeks
Hartford Flexible 60–120 mg 75–225 mg Yes Acute treatment DLX > PBO; p = 0.007 47 54 37 [56]
et al. (2007) 10 weeks
Nicolini Flexible 60–120 mg 75–225 mg Yes Acute treatment DLX > PBO; p < 0.001 65 61 42 [57]
et al. (2008) 10 weeks
Davidson Flexible 60–120 mg Yes Relapse DLX > PBO; p < 0.001 79 (during [80]
et al. (2008) prevention open-label
26 weeks acute
treatment)
*
Primary efficacy measure on acute treatment studies was change in Hamilton Anxiety Rating Scale total score from baseline to end point. Primary efficacy measure
on relapse prevention study was time to relapse (≥2-point increase in Clinical Global Impressions – Severity ratings) or discontinuation owing to lack of efficacy.
DLX: Duloxetine; PBO: Placebo; VEN: Venlafaxine.

156 Expert Rev. Neurother. 9(2), (2009)

 Duloxetine in the treatment of generalized anxiety disorder Drug Profile

patients were required to have a Clinical Global Impressions
(CGI) of Severity [51] score of four or higher (moderate) at the
screen visit and randomization visit.
An additional design feature of these studies is that the pri-
mary efficacy measure, the Hamilton Rating Scale for Anxiety
(HAM-A) [52] total score, was not used as part of the selection
criteria. Studies that use the primary efficacy measure as a sever-
ity selection criterion typically show a large decrease from base-
line to the first post-randomization visit, probably owing to an
upward bias in the baseline scores, so that patients reach the
severity eligibility score. In addition to the primary HAM-A
efficacy measure, secondary measures in all studies included the
HAM-A psychic and somatic anxiety factor scores, as well as
HAM-A response, remission and sustained improvement rates.
Response was defined as a change from baseline to end point
in the HAM-A total score of 50% or greater. Remission was
defined as a HAM-A total score of seven or less at end point.
Sustained improvement rates were defined as at least 30% reduc-
tion from baseline in HAM-A total score at a visit prior to end
point and sustained to end point. Other secondary efficacy meas-
ures included in all four studies were the HADS anxiety and
depression subscales, the CGI-Improvement (CGI-I) scale [51] ,
the Patient Global Impressions-Improvement (PGI-I) scale [50]
and Sheehan Disability Scale (SDS) [53] . Statistical significance
of all primary and secondary measures reported in the four acute-
phase studies are summarized in Table 2 . In all four studies, the
primary statistical ana­lysis was an ana­lysis of covariance examin-
ing the significance of treatment group differences on the mean
change from baseline to end point (last-­observation-carried-
forward) for the HAM-A total score during the double-blind,
acute-therapy phase, using all patients with at least one post-
baseline assessment. Additional mixed effect repeated measures
analyses were conducted incorporating all available data (these
analyses were consistent with the primary analyses and therefore
are not reviewed here). A summary of primary and secondary
results is presented later, followed by sections describing efficacy
results regarding key clinical issues (comparison with venlafax-
ine, time course of change, impact on functioning, impact on
pain, efficacy in special populations and relapse prevention) and
safety/tolerability findings.
The initial efficacy study was a 9-week trial that recruited
patients from 42 outpatient treatment facilities in five European
countries (Finland, France, Germany, Spain and Sweden), the
USA and South Africa [54] . A total of 513 patients (mean age:
43.8 years; 67.8% female) were randomized to receive treatment
with duloxetine 60 mg/day (n = 168), duloxetine 120 mg/day
(n = 170) or placebo (n = 175). The results indicated signifi-
cant differences between both duloxetine groups and placebo on
primary and all secondary efficacy measures (Table 2) . Response
rates were 58% for duloxetine 60 mg/day, 56% for duloxetine
120 mg/day and 31% for placebo (both duloxetine groups vs
placebo p ≤ 0.001).

Table 2. Statistical significance (p-values) for comparisons of duloxetine with placebo in four acute
treatment studies in generalized anxiety disorder.
Measure Koponen et al. (2007) [54] Rynn et al. Hartford et al. Nicolini et al. (2008) [57]
(2008) [55] (2007) [56]
DLX 60 mg DLX 120 mg DLX 20 mg DLX 60 mg
Primary measure
HAM-A total score ≤0.001 ≤0.001 0.023 ≤0.01 ≤0.01 ≤0.001
Secondary measures
HAM-A psychic factor ≤0.001 ≤0.001 <0.001 ≤0.001 ≤0.01 ≤0.001
HAM-A somatic factor ≤0.01 ≤0.001 NS NS NS ≤0.05
Response rate ≤0.001 ≤0.001 <0.05 NS ≤0.01 ≤0.001
Sustained response rate ≤0.001 ≤0.001 <0.05 ≤0.01 ≤0.05 *
≤0.05*
Remission rate ≤0.01 ≤0.001 NS NS ≤0.001 ≤0.001
Clinical Global Impressions-Improvement ≤0.001 ≤0.001 0.040 ≤0.01 ≤0.001 ≤0.001
Patient Global Impressions-Improvement ≤0.001 ≤0.001 0.046 ≤0.01 ≤0.001 ≤0.001
HADS anxiety subscale ≤0.001 ≤0.001 0.001 ≤0.001 ≤0.001 ≤0.001
HADS depression subscale ≤0.001 ≤0.001 NS ≤0.001 ≤0.001 ≤0.001
SDS global impairment ≤0.001 ≤0.001 <0.01 <0.01 ≤0.05 ≤0.01
SDS work ≤0.001 ≤0.001 <0.05 <0.001 ≤0.05* ≤0.01*
SDS social life ≤0.001 ≤0.001 <0.01 <0.01 ≤0.05 *
≤0.001*
SDS family/home ≤0.001 ≤0.001 <0.05 <0.05 ≤0.05* ≤0.01*
*
Eli Lilly, data on file (results not reported in [57]).
Significance of duloxetine compared with placebo in change from baseline to end point given.
DLX: Duloxetine; HADS: Hospital Anxiety Depression Scale; HAM-A: Hamilton Anxiety Rating Scale; NS: Not significant; SDS: Sheehan Disability Scale.

www.expert-reviews.com 157
 Drug Profile Kornstein, Russell, Spann, Crits-Christoph & Ball
The second duloxetine GAD study was a 10-week flexible-dose
trial [55] . In this study, a total of 327 patients were randomized
to duloxetine dosed from 60 to 120 mg/day or placebo. The
majority of the sample was female (61.7%), and the mean age
was 41.6 years. The mean baseline HAM-A was approximately
23 points, indicating moderately severe GAD. On the primary
efficacy measure (HAM-A total score), duloxetine was statisti-
cally superior to placebo, with a mean decrease of 8.1 points in
the HAM-A total score for duloxetine and 5.9 points for placebo
(p = 0.02). On secondary efficacy measures, duloxetine, compared
with placebo, showed a significantly higher response rate, sus-
tained response rate, and significantly greater improvement on the
CGI-I, PGI-I and HADS anxiety subscale (Table 2) . The response
rate was 40% for duloxetine and 32% for placebo (p < 0.05).
The third study was a 10-week trial that included three treat-
ment groups: duloxetine (flexibly dosed from 60 to 120 mg/day;
n = 162), placebo (n = 161) and venlafaxine extended-release
(XR) (flexibly dosed from 75 to 225 mg/day; n = 164) [56] . The
venlafaxine group was included as part of a noninferiority objec-
tive to be assessed based on data from this study combined with
a subsequent study of similar design (described in the next sec-
tion). Similar to the other studies, 62.6% of patients were female
and the average age was 40.8 years. Results showed significantly
greater improvement from baseline to end point on the HAM-A
total score for duloxetine compared with placebo. Response rates
were 47% for duloxetine and 37% for placebo (this difference did
not reach significance). Significant differences between duloxet-
ine and placebo were evident on the CGI-I, PGI-I, HADS anxi-
ety subscale, HADS depression subscale and sustained response
rates (Table 2) .
The fourth study was also a 10-week trial and included duloxe-
tine (60–120 mg/day; n = 158), venlafaxine XR (75–225 once
daily; n = 169) and placebo (n = 170) groups [57] . There was also
a duloxetine 20 mg group included in the design, with half the
number of patients as the other treatment arms randomized to
this group (n = 84). Patients were adult outpatients with a mean
age of 42.8 years; 57.1% were women. Both duloxetine groups
had significantly greater improvements on HAM-A total score
from baseline to end point compared with placebo. Significant
differences for both duloxetine groups in comparison to pla-
cebo were evident for the CGI-I, PGI-I, HADS anxiety subscale
and HADS depression subscale. There were also significantly
higher response and remission rates for duloxetine compared
with placebo (Table 2) .
Analyses pooling data across all four acute treatment studies has
recently been completed [Eli Lilly, Data on File] . In this pooled data-
set, the overall response rate for duloxetine (combined patients
randomized to 60, 120 and 60–120 mg) was 53% compared
with 35% for placebo (p < 0.001). Remission rates were 33% for
duloxetine and 20% for placebo (p < 0.001).
In summary, these four trials clearly established the efficacy
of duloxetine relative to placebo in the treatment of GAD, with
significant differences between drug and placebo evident in
all four trials on the primary efficacy measure, and significant
differences in response rates in three of the four studies. The
158
difference in response rates between duloxetine and placebo in
the pooled database was 18%, and the difference in remission
rates was 13%.
Only one study examined both duloxetine 60 and 120 mg,
and this study showed 120 mg was effective; however, there was
no evidence that 120 mg is superior to or provides additional
benefit over 60 mg [54] . Thus, 60 mg/day is the dosage approved
by the FDA.
Noninferiority comparison of duloxetine &
venlafaxine XR
As mentioned, two of the four trials included venlafaxine XR
treatment groups for the purpose of a noninferiority comparison
to be conducted by pooling data from the two trials [58] . The
objective of a noninferiority comparison is to examine whether
one medication is not worse than the other by more than a pre-
specified amount. Such studies are often conducted to compare a
newer medication to an already approved medication with estab-
lished efficacy. To accomplish the objective of such studies, the
investigators must specify in advance a noninferiority margin –
that is, the amount of difference between treatment groups that
would be the largest clinically acceptable difference.
A consensus panel of expert leaders in the field of GAD convened
in 2005 to provide guidelines for defining noninferiority in GAD
trials [59] . This consensus meeting was supported by Eli Lilly with
an unrestricted educational grant, but no Lilly personnel were
present at the meeting or involved in the panel’s recommenda-
tion. The task of the panel was to set a noninferiority margin
for the HAM-A total score in GAD trials. Their recommenda-
tion was for a noninferiority margin of 1.5 HAM-A points with
a one-sided 97.5% confidence interval. This would mean that, in
the comparison of duloxetine with venlafaxine XR, if the lower
bound of the one-sided 97.5% confidence interval of the differ-
ence between venlafaxine XR and duloxetine mean changes from
baseline exceeded (i.e., closer to zero or above zero) 1.5 HAM-A
points, duloxetine would be declared as noninferior to venlafaxine
XR on this criterion. In addition to setting this margin, the panel
provided six additional statistical and clinical criteria to establish
conclusive noninferiority in the treatment of GAD [59] . These six
additional criteria for establishing noninferiority were as follows:
• The existence of at least one three-group, double-blind com-
parison trial for the test intervention with an active comparator
and placebo;
• The treatment response rate should be at least ten percentage
points higher for the test and active comparator groups com-
pared with the placebo group;
• The response rate of the test intervention is no more than five
percentage points lower than the response rate in the active
comparator group;
• Both the test intervention and the active comparator must be
superior to placebo by a clinically meaningful difference in
HAM-A total score (set by the panel to be at least a two-point
improvement);
Expert Rev. Neurother. 9(2), (2009)
 Duloxetine in the treatment of generalized anxiety disorder
• The differences between the active intervention and placebo,
and test intervention and placebo, need to be statistically
significant on the primary outcome measure;
• The noninferiority margin between the test intervention and
the active comparator needs to be less than 50% of the differ-
ence between active comparator and placebo, and the difference
between the test intervention and the active comparator is not
clinically meaningful.
The recommendations of the consensus panel were then used
for a noninferiority comparison of venlafaxine XR and duloxetine
in the treatment of GAD. Based on an a priori plan, data from the
two 10-week, acute treatment trials of duloxetine, venlafaxine XR
and placebo for GAD were pooled [56,57] . Noninferiority studies
typically require larger sample sizes, thus the planned pooling
of two studies provided adequate statistical power for the non-
inferiority comparison. Following recommended guidelines for
noninferiority ana­lysis [60] , the primary ana­lysis was specified to
be conducted on data from the per-protocol patients who were
treated with duloxetine (n = 239) or venlafaxine XR (n = 262).
The per-protocol sample was defined as patients who had com-
pleted at least 4 weeks of treatment, had baseline and post-baseline
HAM-A ratings after at least 4 weeks of treatment, and did not
have any protocol violations that were judged to potentially have
an impact on the ana­lysis or conclusions.
The results were that duloxetine 60–120 mg/day met all of the
statistical and clinical criteria for noninferiority. The mean differ-
ence in HAM-A total score improvements between the duloxetine
group and the placebo group was 3.8; this difference between the
venlafaxine XR and placebo groups was 3.6 points. Subtracting
these two drug–placebo mean differences yields a point estimate
of 0.20 HAM-A total score points in favor of duloxetine. The
lower bound of the one-sided 97.5% confidence interval for this
point estimate was 1.28 in the per-protocol sample. Because this
lower bound of 1.28 was within the prespecified 1.5 margin, this
criterion for noninferiority was met. Response rates for duloxetine,
venlafaxine XR and placebo were 56, 58 and 40%, respectively.
Based on this rigorous testing procedure with multiple clinical
and statistical criteria, it can be concluded that the efficacy of
duloxetine was noninferior to the efficacy of venlafaxine XR in
the treatment of GAD.
Time course of change
The time course of symptom relief is of clinical interest in the treat-
ment of chronic disorders such as GAD. Early symptomatic improve-
ment can be an indicator of eventual clinical response. In addition,
many clinicians believe that faster onset of action can help maintain
treatment compliance. The time course of change was evaluated in
each of the four acute treatment trials. In two of the studies [56,57] ,
statistically significant differences between duloxetine (regardless of
dosage group) and placebo were evident as early as week 1 (p ≤ 0.05)
and remained significant (p ≤ 0.01) at all subsequent visits. In the
other two studies [54,55] , differences between duloxetine and placebo
were statistically significant (p ≤ 0.001) at week 2 and remained
significant (p ≤ 0.001) at all subsequent visits.
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Drug Profile
When a patient with GAD demonstrates an early response to
duloxetine, there is a high likelihood that the patient will meet
response and remission criteria by the end of acute treatment.
This was demonstrated in a recent study using pooled data from
three of the four duloxetine GAD studies [61] . Specifically, it was
reported that at week 2, 79% of the duloxetine-treated patients
who achieved a HAM-A total score improvement in the range
of 40–59% were HAM-A responders at end point. In addition,
approximately half of duloxetine-treated patients who demon-
strated HAM-A total score improvement in the range of 40–59%
were classified as having remitted in terms of their functional
impairment (defined as an SDS global functional improvement
score ≤ 5 at end point) at acute treatment end point. Similar
results were apparent using week 4 data to predict end point
response and remission status.
Impact on functioning
Improvement in functioning and quality of life is of key impor-
tance in GAD because of the overall level of impairment in vari-
ous aspects of daily functioning typically seen in those with GAD.
To evaluate the impact of duloxetine on functioning in GAD
patients, an ana­lysis of data from three of the acute treatment
duloxetine studies has been reported [62] . This report included
results from the 9-week fixed-dose study [54] and two of the
10-week flexible-dose studies [55,56] . Measures of functioning and
quality of life outcomes included the SDS, the Quality of Life
Enjoyment and Satisfaction Questionnaire Short Form [63] and
the European Quality of Life Five Dimensions [64] . Significantly
greater improvement in functioning from baseline to end point for
duloxetine, compared with placebo, was found in all three studies
for all facets of functioning (SDS global functioning scale, SDS
work scale, SDS social life scale and SDS family/home responsi-
bility scale scores) and in two of the three studies for quality of
life (Quality of Life Enjoyment and Satisfaction Questionnaire
Short Form). Using pooled study data, a further article explored
the extent to which duloxetine treatment improved function-
ing into the normative range [65] . On the European Quality of
Life Five Dimensions (administered in two of the studies), it was
found that 58.0% of the duloxetine-treated patients scored within
the normative range at end point, compared with 38.9% of the
placebo-treated patients (p ≤ 0.001). The results of these two
articles indicate that, across independent studies, patients taking
duloxetine consistently improved in impairments in functioning
associated with GAD and had an enhanced quality of life relative
to patients taking placebo.
An additional ana­lysis has revealed that improvements in
functional impairment with duloxetine treatment of GAD are
primarily a function of improvement in the psychic symptoms
of anxiety [66] . Using data from two of the duloxetine acute treat-
ment trials, it was shown that change from baseline to end point
in psychic anxiety accounted for 47% of the total treatment effect
(duloxetine vs placebo) on improvement of functional impair-
ment. Improvements in somatic anxiety accounted for 7%, while
improvements in overall pain accounted for 9%, of the treatment
effect of duloxetine on functional impairment.
159
 Drug Profile Kornstein, Russell, Spann, Crits-Christoph & Ball
Impact on pain in GAD
Another clinical concern in the treatment of both anxiety disorders
and depressive disorders is the role of painful physical symptoms.
Within primary care settings, where many GAD patients seek treat-
ment, the most common presenting complaints of GAD patients
are somatic symptoms (48%) and pain (35%) [6] . Common painful
physical symptoms in GAD include both nonspecific pain (lower
back and unexplained causes) and also specific pain conditions,
such as migraine and arthritis [12,67] . The presence of pain in GAD
patients has been found to be associated with higher healthcare
costs in comparison with GAD without pain [68] . Successful treat-
ment of pain symptoms associated with GAD is likely to improve
compliance as well as reduce healthcare utilization and costs, in
addition to positively impacting on patient functioning.
There has been increasing interest in the role of dual-action
serotonin and norepinephrine reuptake inhibitors in the treatment
of pain [69] . This interest has emerged out of knowledge about the
role of descending serotonergic and noradrenergic neural pathways
in chronic inflammatory pain [70] , together with evidence that
these same serotonergic and noradrenergic pathways also send
ascending signals to areas of the brain implicated in both depres-
sion and anxiety [71] . Consistent with this hypothesized connec-
tion, duloxetine has demonstrated efficacy in the treatment of
painful symptoms associated with major depressive disorder [72,73] ,
and in the treatment of two pain syndromes, fibromyalgia and
diabetic peripheral neuropathy [74–77] .
A recent article examined the efficacy of duloxetine in the treat-
ment of specific pain symptoms co-occurring with a diagnosis of
GAD using pooled data from two of the duloxetine GAD acute
treatment trials [78] . In these two studies, pain during the past
week was assessed with a widely used self-report visual analogue
scale (VAS) [54,55] . Separate ratings were obtained for overall pain,
headache, backache, shoulder pain, proportion of day while awake
with pain and daily interference due to pain. At baseline, 61.3% of
840 patients randomized to either duloxetine or placebo had ratings
indicative of clinically significant pain on at least one of the pain
scales, again highlighting the close association of pain and GAD.
Among those GAD patients with painful symptoms at baseline,
duloxetine resulted in significantly greater change from baseline to
end point on the HAM-A total score, HADS anxiety scale, HADS
depression scale, HAM-A psychic factor and SDS global improve-
ment score, compared with placebo (all p values < 0.001, except
HAM-A total score: p = 0.002). With regard to painful physi-
cal symptoms, duloxetine demonstrated statistically significantly
greater reductions from baseline to post-baseline assessments of pain
on all six VAS pain scales compared with placebo. In percentage
terms, the mean change baseline to end point ranged from 40.1
to 45.2% across the six VAS scales for duloxetine, compared with
22.0 to 26.3% for placebo. Thus, among GAD patients with pain,
duloxetine both improves anxiety symptoms and reduces painful
physical symptoms, relative to placebo.
Efficacy in special populations
The efficacy of duloxetine for GAD in special populations
has been examined in secondary analyses of the data from the
160
acute treatment studies. These analyses have included evalu-
ation of duloxetine efficacy in the elderly and also separately
by gender.
A report providing analyses of the efficacy of duloxetine in
elderly patients with GAD targeted the subset of patients who
were aged 65 years or older within the four acute treatment tri-
als. Across the four trials, there were 73 patients (duloxetine
n = 45; placebo n = 28) who were aged 65 years or older (4.9%
of the 1491 randomized patients in these trials) [79] . Despite the
limited sample size, duloxetine-treated patients showed signifi-
cantly greater change from baseline to end point on the primary
efficacy measure (HAM-A total), as well as the HAM-A psy-
chic anxiety factor, HADS anxiety scale and HADS depression
scale, compared with placebo-treated patients. No significant
difference between duloxetine and placebo was evident for the
HAM-A somatic anxiety factor. However, caution should be
used in interpreting these results given that the analyses were
conducted post hoc with a limited sample size and reduced power
to detect treatment differences.
Efficacy of duloxetine for men and women has also been exam-
ined by pooling data across the four acute treatment trials [Eli
Lilly, Data on File] . For both men and women, highly significant
(all p values < 0.001) differences between duloxetine and placebo
were evident on change in the HAM-A total from baseline to end
point, response and remission rates, HADS anxiety and SDS
global functioning score.
These secondary analyses indicate that duloxetine is broadly
efficacious for both men and women, and the elderly. No studies
have been conducted with duloxetine in children or adolescents
with GAD.
Long-term efficacy: relapse prevention
One study has examined the long-term efficacy of duloxetine
to prevent relapse in GAD [80] . In this study (Table 1) , adult
patients with GAD (n = 887; mean age = 43.3 years; 61.0%
female) were first treated with flexible dosed open-label duloxe-
tine (60–120 mg/day) for 26 weeks. Responders (≥50% reduc-
tion in HAM-A total score to ≤11 and CGI–I of ‘much/very
much improved’ ratings for the last two visits of open-label
phase) were then randomly assigned to receive duloxetine or
placebo for a 26-week, double-blind, relapse-prevention phase.
The primary efficacy measure during the double-blind phase
was time to relapse, with relapse defined as at least a two-point
increase in CGI-Severity ratings or discontinuation owing to
lack of efficacy. During the open-label phase, 78.8% of patients
met responder criteria and were eligible for randomization to
the relapse prevention phase. A significantly longer time to
relapse was found for duloxetine compared with placebo dur-
ing the relapse prevention phase. Relapse rates were 41.8%
for placebo-treated patients and 13.7% for duloxetine-treated
patients. In addition, placebo-treated patients significantly
worsened on each efficacy measure (HAM-A total, HAM-A
somatic, HAM-A psychic, CGI-I, PGI-I, HADS anxiety and
HADS depression) relative to duloxetine-treated patients over
the course of the relapse-prevention phase. Thus, continuation
Expert Rev. Neurother. 9(2), (2009)
 Duloxetine in the treatment of generalized anxiety disorder Drug Profile

treatment with duloxetine for 6 months is effective at preventing

Table 3. Treatment-emergent adverse events*.
relapses and other deteriorations in symptoms and functioning
in GAD patients. Adverse event % with % with p-value
duloxetine placebo
Tolerability & safety (n = 910) (n = 665)
Table 3 presents pooled data on adverse events from all four acute Nausea 33.8 10.2 <0.001
treatment duloxetine GAD studies [Eli Lilly, Data on File] . Overall, Headache 16.3 17.9 0.41
the types of adverse events evident for duloxetine in the treatment
Dizziness 13.5 7.5 <0.001
of GAD were similar to those arising in the treatment of other
indications for duloxetine. The most common adverse events were Dry mouth 11.6 3.6 <0.001
nausea, headache, dizziness, dry mouth and fatigue (Table 3) . Rate Fatigue 10.7 3.5 <0.001
of discontinuation owing to adverse events was 14.1% for duloxet- Constipation 9.7 3.5 <0.001
ine and 5.4% for placebo in the pooled study database. Among the
Diarrhea 7.9 5.6 0.025
elderly (65 years or older), 22.2% of 45 duloxetine-treated patients
discontinued treatment owing to an adverse event, compared with Insomnia 7.6 3.6 0.002
0% of 28 placebo-treated patients. Somnolence 7.8 1.8 <0.001
Further analyses combining data from all four acute treat- Hyperhidrosis 7.4 2.0 <0.001
ment studies have examined safety in regard to a variety of
All events occurring in 5% or more of duloxetine-treated patients.
*

additional parameters, including pulse, blood pressure, weight,
blood chemistry and hematology assessments [Eli Lilly, Data
on File] . Statistically significant differences between duloxetine
and placebo in change from baseline to end point were evident
for pulse, systolic blood pressure, diastolic blood pressure and
weight, although the magnitudes of the changes were small.
For duloxetine and placebo, respectively, the mean changes
from baseline to end point were: pulse: 1.98 and -0.15 beats
per minute; systolic blood pressure: 0.52 and -1.08 mmHg;
diastolic blood pressure: 0.86 and -0.51 mmHg; weight: -0.37
and 0.35 kg. Few patients (<1%) showed sustained elevation in
blood pressure, and there were no significant differences between
duloxetine and placebo in the rates of sustained elevations in
blood pressure. Across a wide range of blood chemistry and
hematology laboratory tests, there were no significant differ-
ences in the rates of treatment-emergent potentially clinically
significant values.
The relapse prevention study examined heart rate and blood
pressure changes over the course of both the 26-week open-­label
phase and the 26-week double-blind phase of the study [80] .
During the open-label phase, duloxetine showed small but sta-
tistically significant within-treatment increases in both heart rate
and diastolic blood pressure. However, no significant differences
between duloxetine and placebo on change in heart rate or blood
pressure over the course of the 26-week relapse prevention phase
were evident.
In summary, the tolerability data on duloxetine in the treatment
of GAD was consistent with its known tolerability profile in other
indications. No safety concerns were apparent with either short- or
long-term treatment with duloxetine.
Expert commentary
Although often overlooked in primary care and other set-
tings, there has been increasing recognition of the prevalence
of GAD, as well as the high level of comorbidity of GAD with
other psychiatric and physical disorders, and the considerable
impact that GAD has on functioning and quality of life. These
Data are pooled from four acute treatment studies [54–57].
considerations suggest that careful thought needs to be given to
the choice of treatments for individuals with GAD in order to
improve functioning and address associated symptoms, such as
painful physical symptoms. The potential for relapse and recur-
rence of symptoms in GAD is high and also needs to be taken
into account in treatment planning.
The acute treatment and relapse prevention studies conducted
on duloxetine for GAD support the inclusion of this medication
as one of several in the group of SSRIs/SNRIs recommended as
first-line treatment of this disorder [39,40] . The documented effi-
cacy of duloxetine in improving patients’ overall functioning, in
addition to reducing anxiety symptoms, adds to the consideration
of duloxetine as an option in the treatment of GAD. Also of note
are the data that document the effectiveness of duloxetine with
regard to painful physical symptoms that often accompany GAD.
Since such pain symptoms further impact functioning and qual-
ity of life, and potentially reduce compliance if not addressed,
clinicians should be aware of duloxetine’s role in treating such
painful physical symptoms.
In addition to statistical significance, the data from the
duloxetine trials suggest that clinically meaningful changes
are evident with this agent. Clinical significance can be evalu-
ated in a number of ways. One way is in terms of response
rates. On this criterion, there were 53% of duloxetine-treated
patients (in the pooled study database) that demonstrated a
clinical response, and this rate of response was superior to pla-
cebo by a clinically meaningful degree (35% of placebo-treated
patients showed a clinical response). A second way to index
clinical significance is to focus on how many patients return
to normal levels of functioning. For duloxetine, 47% of the
duloxetine-treated patients scored within the normative range
of a measure of functioning at treatment end point, compared
with 28% for placebo. A third way to evaluate the ‘mean-
ingfulness’ of treatment differences is through calculation of
effect sizes (standardized mean drug–placebo differences) for

www.expert-reviews.com 161
 Drug Profile Kornstein, Russell, Spann, Crits-Christoph & Ball

different agents. Within the two studies that included both
duloxetine and venlafaxine, both medications showed moder-
ate effect sizes for change in the HAM-A total score relative
to placebo: 0.360 for duloxetine and 0.358 for venlafaxine.
In the treatment of depression, Turner et al. have shown that,
for positive studies that contribute to successful submissions
(i.e., demonstrating a clinically relevant difference between
active drug and placebo) across 74 FDA-registered studies of
12 approved antidepressants, the average effect size was 0.33;
across all studies (­positive or negative) the average effect size
was 0.31 [81] . Thus, the size of the drug–placebo difference
seen for duloxetine in the treatment of GAD is comparable to
that observed in positive studies used by the FDA to approve
antidepressants in the treatment of depression.
The rigorous noninferiority tests on duloxetine compared with
venlafaxine provide an additional point of clarity that is not often
available to clinicians during the process of evaluating and select-
ing treatment alternatives. Without such noninferiority testing,
questions about the relative effectiveness of different medications
linger because standard statistical comparisons (superiority test-
ing) of active medications typically leave the issue unresolved
(i.e., such trials conclude no significant difference between active
medications, but cannot conclude that two medications have
similar efficacy within a certain margin). When trials designed
to directly test noninferiority are not available, researchers are
prone to resort to indirect comparative inferences that are based
on results of one drug in one set of studies being compared
with results for a different drug in a different set of studies.
These indirect inferences can be highly problematic owing to
differences in study design and patient populations across studies
[82] . However, with duloxetine and venlafaxine, there is strong
evidence that duloxetine is noninferior to venlafaxine in the
treatment of GAD.
Some limitations of the duloxetine GAD trials should be
mentioned to put the findings in context. Since GAD is often
a chronic condition, long-term treatment is typically needed.
Further long-term studies, beyond the one relapse prevention
trial, will be important to ascertain the duration of treatment
that is needed to effectively prevent relapses and recurrences.
Another limitation relates to the issue of comorbidity. Patients
with significant comorbidities (e.g., major depressive disorder
and substance dependence) were excluded from the duloxetine
trials, as they typically are from GAD studies. Further research
is needed to identify efficacious treatments for such comorbid
populations. A final limitation is that all of the duloxetine studies
were sponsored by the company that markets this medication
(Eli Lilly), with company employees as coauthors. Additional
studies sponsored by independent agencies (e.g., the NIH) would
be welcome.
Five-year view
It will be important for additional active comparator studies to be
conducted over the next 5 years to inform decision-making regard-
ing the range of medications available in the treatment of GAD. In
the treatment of major depressive disorder, it has been suggested that
SNRIs may have an advantage over SSRIs [83] . With GAD, only
one small, nonblinded comparison of venlafaxine to paroxetine has
been published [84] , so this question requires further examination.
Active comparator studies of SSRI versus SNRI, with noninferiority
testing, will probably sort this out in the years to come.
The pharmacological treatment of GAD could also be influ-
enced by any reconceptualization of the GAD syndrome poten-
tially incorporated into the American Psychiatric Association’s
DSM-V, due out in 2012. Studies have already explored the
impact of changes to the DSM criteria, such as eliminating the
6-month duration, excessive worry and three associated symptoms
criteria [85] . When these changes to the GAD criteria are made,
the prevalence of GAD more than doubles [85] . If such changes are
made to the diagnostic criteria, new studies of a range of treatment
options will be needed to inform clinical practice.
Future research will also attempt to improve on the response
and remission rates that are observed in the treatment of GAD.
Clinicians need to know what to do when the first-line acute
treatment of GAD fails. For patients who have failed to respond,
the relative benefits of continuing the same treatment, increasing
the dose of the same treatment, switching to another treatment,
or augmenting treatment with another pharmacological agent
or with evidence-based psychotherapy, will need to be explored.
Through such developments, clinical treatment of GAD will
move closer to the ideal treatment goal of remission of symptoms
and restoration of functioning.
Financial & competing interests disclosure
Funding for this research was received from Eli Lilly and Company and
Boehringer Ingelheim GmbH. The authors have no other relevant affiliations
or financial involvement with any organization or entity with a financial
interest in or financial conflict with the subject matter or materials discussed
in the manuscript apart from those disclosed.
Writing assistance was utilized in the production of this manuscript and
was provided by Paul Crits-Cristoph, who assisted S Kornstein with drafting
of the manuscript. All of the research supporting the studies was provided by
Lilly and BI.

Key issues
• Duloxetine is a relatively balanced inhibitor of the reuptake of both serotonin and norepinephrine.
• Short-term efficacy of duloxetine in generalized anxiety disorder (GAD) has been established in four 9–10-week trials.
• Duloxetine has demonstrated noninferiority to venlafaxine in the treatment of GAD.
• Duloxetine, relative to placebo, is effective at improving functioning and reducing painful physical symptoms in patients with GAD.
• Duloxetine is effective in preventing relapse of GAD among those who initially respond to treatment.
• Adverse events seen with duloxetine in the treatment of GAD are similar to those seen with other indications.

162 Expert Rev. Neurother. 9(2), (2009)

 Duloxetine in the treatment of generalized anxiety disorder
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Department of Psychiatry, Virginia
Commonwealth University,
PO Box 980710, Richmond,
VA 23298-0710, USA
Tel.: +1 804 828 5637
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Eli Lilly and Company, Lilly Corporate
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