Efficacy of sertraline in a 12-week trial for generalized anxiety disorder

Article (PDF Available)inAmerican Journal of Psychiatry 161(9):1642-9 · October 2004with718 Reads
DOI: 10.1176/appi.ajp.161.9.1642 · Source: PubMed
Abstract
Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated. Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25). The primary outcome measure was baseline-to-endpoint change in the Hamilton anxiety scale total score. A secondary efficacy measure was the Clinical Global Impression (CGI) improvement score; response was defined as a score of 2 or less. Sertraline patients had significantly greater improvement than placebo patients on all efficacy measures at week 4. Analysis of covariance of the intent-to-treat group at endpoint (with the last observation carried forward) showed a significant difference in the decrease from baseline of the least-square mean total score on the Hamilton anxiety scale between sertraline (mean=11.7) and placebo (mean=8.0). Significantly greater endpoint improvement with sertraline than placebo was obtained for mean scores on the Hamilton anxiety scale psychic factor (6.7 versus 4.1) and somatic factor (5.0 versus 3.9). The rate of responders, based on CGI improvement and last observation carried forward, was significantly higher for sertraline (63%) than placebo (37%). Sertraline was well tolerated; 8% of patients versus 10% for placebo dropped out because of adverse events. Sertraline appears to be efficacious and well tolerated in the treatment of generalized anxiety disorder.
Article
1642 Am J Psychiatry 161:9, September 2004http://ajp.psychiatryonline.org
Efficacy of Sertraline in a 12-Week Trial
for Generalized Anxiety Disorder
Christer Allgulander, M.D.
Alv A. Dahl, M.D.
Carol Austin, M.D.
Philip L.P. Morris, M.D., Ph.D.
Jesper A. Sogaard, M.D.
Rana Fayyad, Ph.D.
Stan P. Kutcher, M.D.
Cathryn M. Clary, M.D.
Objective: Sertraline’s efficacy and toler-
ability in treating generalized anxiety dis-
order were evaluated.
Method: Adult outpatients with DSM-IV
generalized anxiety disorder and a total
score of 18 or higher on the Hamilton Anx-
iety Rating Scale were eligible. After a 1-
week single-blind placebo lead-in, patients
were randomly assigned to 12 weeks of
double-blind treatment with placebo (N=
188, mean baseline anxiety score=25) or
flexible doses (50–150 mg/day) of sertra-
line (N=182, mean anxiety score=25). The
primary outcome measure was baseline-
to-endpoint change in the Hamilton anxi-
ety scale total score. A secondary efficacy
measure was the Clinical Global Impres-
sion (CGI) improvement score; response
was defined as a score of 2 or less.
Results: Sertraline patients had signifi-
cantly greater improvement than placebo
patients on all efficacy measures at week
4. Analysis of covariance of the intent-to-
treat group at endpoint (with the last ob-
servation carried forward) showed a sig-
nificant difference in the decrease from
baseline of the least-square mean total
score on the Hamilton anxiety scale be-
tween sertraline (mean=11.7) and placebo
(mean=8.0). Significantly greater endpoint
improvement with sertraline than placebo
was obtained for mean scores on the
Hamilton anxiety scale psychic factor (6.7
versus 4.1) and somatic factor (5.0 versus
3.9). The rate of responders, based on CGI
improvement and last observation carried
forward, was significantly higher for sertra-
line (63%) than placebo (37%). Sertraline
was well tolerated; 8% of patients versus
10% for placebo dropped out because of
adverse events.
Conclusions: Sertraline appears to be ef-
ficacious and well tolerated in the treat-
ment of generalized anxiety disorder.
(Am J Psychiatry 2004; 161:1642–1649)
Over the past decade a series of more then 30 ran-
domized, placebo-controlled trials have established anti-
depressants targeting the serotonin transporter—selective
serotonin reuptake inhibitors (SSRIs) and clomipramine—
as first-line pharmacologic treatments for all major anxi-
ety disorders except specific phobias. It is now well docu-
mented that the anxiolytic efficacy of the SSRIs is not
secondary to their antidepressant effects. Instead, SSRI
anxiolytic efficacy appears to be independent of baseline
levels of depression, with improvement occurring concur-
rently with, and not mediated by, antecedent improve-
ment in depressive symptoms (1–3).
Two agents, extended-release venlafaxine (4, 5) and par-
oxetine (6), have demonstrated efficacy in generalized anx-
iety disorder. Both drugs significantly improve scores on
the psychic factor of the Hamilton Anxiety Rating Scale (7),
while neither has consistently demonstrated significant ef-
ficacy on the somatic factor. Previous research indicates
that buspirone (8, 9) and other antidepressants with sero-
tonergic activity, such as imipramine and trazodone (10),
also show greater improvement of psychic anxiety symp-
toms than somatic symptoms. In contrast, treatment of
generalized anxiety disorder with benzodiazepines is asso-
ciated with greater improvement in somatic than psychic
anxiety symptoms (8, 10). Although the DSM-IV criteria
emphasize the importance of psychic anxiety symptoms
for the purpose of diagnosis, somatic anxiety symptoms
contribute significantly to the clinical presentation and
distress associated with generalized anxiety disorder (11).
Sertraline has demonstrated efficacy across a broad
spectrum of anxiety disorders, such as obsessive-compul-
sive disorder (12, 13), panic disorder (14, 15), posttrau-
matic stress disorder (16), and social anxiety disorder (17,
18), but to our knowledge has not yet been tested for gener-
alized anxiety disorder in adults. A placebo-controlled pilot
study in children under age 18 years demonstrated signifi-
cant efficacy for sertraline in generalized anxiety disorder,
including effect sizes greater than 1 on both the psychic
and somatic factors of the Hamilton anxiety scale (19).
The current study was undertaken to test the null hy-
pothesis that there is no significant difference in efficacy
between sertraline and placebo in the treatment of gener-
alized anxiety disorder when the Hamilton anxiety scale
total score is used as the primary efficacy measure. The
secondary null hypotheses were that sertraline would
show no significantly greater efficacy than placebo in im-
proving the following clinically important dimensions of
anxiety: 1) both psychic and somatic symptoms of gener-
alized anxiety disorder as measured by the two factors of
the Hamilton Anxiety Rating Scale (7), 2) quality of life and
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functioning as measured by the Quality of Life Enjoyment
and Satisfaction Questionnaire (20) and the Endicott Work
Productivity Scale (21), 3) perceptions of health as mea-
sured by a visual analogue scale, 4) subjective anxiety and
depressive symptoms as measured by the Hospital Anxiety
and Depression Scale (22), and 5) global severity and im-
provement as measured by the Clinical Global Impression
(CGI) severity and improvement scales (23).
Method
Study Design
This was a double-blind, placebo-controlled study comparing
the efficacy and tolerability of flexible doses of sertraline to pla-
cebo in the treatment of moderate to severe generalized anxiety
disorder. After completing a 1-week single-blind placebo lead-in
period, patients who met the eligibility criteria were randomly as-
signed to 12 weeks of double-blind treatment with either sertra-
line or placebo.
Sertraline treatment was initiated at 25 mg/day for the first
week, followed by 3 weeks of treatment with a dose of 50 mg daily.
From week 5 through week 6, flexible dosing was permitted in the
range of 50100 mg/day, increasing from week 7 through week 12
to a range of 50150 mg/day. At week 12 sertraline was blindly dis-
continued, abruptly for patients taking 1 capsule (50 mg) per day.
For patients taking a 100-mg dose, it was reduced to 50 mg for 7
days before discontinuation. For patients taking a 150-mg dose, it
was reduced to 100 mg for 3 days and then to 50 mg daily for 4
days before discontinuation.
The study was conducted at 21 investigational sites in Austra-
lia, Canada, Denmark, Norway, and Sweden. The protocol was
approved at each site by the appropriate institutional review
board, and written informed consent was obtained from each pa-
tient before enrollment.
Patient Selection
Patients were recruited from clinic referrals and from adver-
tisements in local media. Male or female outpatients were eligible
for entry if they were 18 years or older and had a primary diagno-
sis of DSM-IV-defined generalized anxiety disorder based on clin-
ical assessments and a structured interview (module P form of the
MINI-PLUS, version 5.0.0 [24]). Patients were also required to
have screening and baseline scores of 18 or higher on the Hamil-
ton Anxiety Rating Scale (7) and scores of 2 or higher (indicating
at least moderate severity) on Hamilton anxiety scale item 1 (anx-
ious mood) and item 2 (tension) at screening and at baseline.
Key exclusion criteria were 1) no current use of medically ac-
cepted contraception in fertile women, 2) current or past history
of bipolar, schizophrenic, psychotic, or obsessive-compulsive
disorder, 3) current history (past 6 months) of major depressive
disorder, dysthymia, social anxiety disorder, panic disorder (or
three or more reported panic attacks in the previous month),
posttraumatic stress disorder, body dysmorphic disorder, eating
disorder, or substance dependence and/or abuse, 4) a score of 16
or higher on the Montgomery-Åsberg Depression Rating Scale
(25), 5) concurrent psychotherapy specifically for generalized
anxiety disorder, 6) any clinically significant acute or unstable
medical condition, 7) positive result from a urine drug and sub-
stance screen (including benzodiazepines), 8) treatment with any
drug with psychotropic activity (other than infrequent use of
chloral hydrate, zolpidem, or zopiclone for insomnia) either con-
comitantly or within 2 weeks of random assignment (3 weeks for
monoamine oxidase inhibitors, 5 weeks for fluoxetine), 9) current
suicidal risk, and 10) previous failure to respond to an adequate
trial of antidepressant drug treatment (4 weeks at the minimum
effective daily dose) for generalized anxiety disorder.
The screening evaluation consisted of a psychiatric and medi-
cal history, including physical examination, electrocardiogram,
and standard laboratory testing. A urine benzodiazepine screen-
ing test was performed both at the baseline visit (in accordance
with the exclusion criteria) and after 2 weeks of double-blind
treatment (visit 2).
Efficacy Measures
The primary efficacy measure was the Hamilton Anxiety Rating
Scale (7). This assessment was performed at the screening and
baseline visits and at study weeks 1, 2, 4, 6, 8, and 12. The secondary
efficacy measures included the following investigator-rated scales:
1) the Montgomery-Åsberg Depression Rating Scale (25) and 2) the
CGI severity and improvement scales (23). The secondary efficacy
measures also included the following patient-rated scales: 1) the
Hospital Anxiety and Depression Scale (22), 2) the Quality of Life
Enjoyment and Satisfaction Questionnaire (20), 3) the Endicott
Work Productivity Scale (21), part I and part II (completed only by
patients currently employed or performing volunteer work), and 4)
a visual analogue scale measuring perceived state of health.
Safety and Tolerability Measures
Spontaneously reported or observed adverse events were re-
corded, regardless of causality, in terms of time of onset, severity,
action taken, suspected causal relationship, and outcome. Use of
concomitant medications was recorded in terms of daily dose,
stop and start dates, and reason for use.
Statistical Analyses
A patient was included in the intent-to-treat analysis if he or
she had taken at least one dose of study medication during dou-
ble-blind conditions and had been assessed at baseline and at
least once after baseline for the primary efficacy measure. A pa-
tient was included in the safety analysis if he or she had taken at
least one dose of study medication.
It was expected that patients treated with sertraline would
show greater reductions in scores on the Hamilton anxiety scale
than would placebo patients and that the difference would be
statistically significant. Based on previously reported studies of
SSRIs in the treatment of generalized anxiety disorder (4), an in-
tent-to-treat group size of 185 per treatment was estimated, at an
experiment-wise alpha level of 0.05, in order to provide 85% sta-
tistical power to detect a mean difference in endpoint change
scores on the Hamilton anxiety scale of 2.6 with a standard devia-
tion of 8.1. This was based on the assumption that 10% of the ran-
domly assigned patients would not return for at least one post-
randomization visit and, therefore, would not qualify for the
intent-to-treat analysis.
Demographic and baseline characteristics were summarized
by using descriptive statistics for continuous variables and fre-
quency counts (and percentages) for discrete variables. Analyses
for comparing the homogeneity of continuous variables were
performed by using analysis of variance with treatment and site
as effects. Discrete variables were compared by using the Cochran-
Mantel-Haenszel chi-square procedure stratified by site.
The primary efficacy measure was the change from baseline to
endpoint (week 12 or the last observation carried forward) in the
total score on the Hamilton anxiety scale for the patients in the in-
tent-to-treat group. Secondary analysis of the Hamilton anxiety
scale and the remaining measures was conducted on the change
from baseline at each visit at which the scales were administered
(i.e., observed cases), as well as endpoint. For continuous efficacy
variables, analysis of covariance (ANCOVA) was performed on the
change from baseline. The ANCOVA model included terms for
site, baseline score, and treatment. Comparisons of the treatment
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groups on the categorical efficacy variables were made by using
the Cochran-Mantel-Haenszel row mean scores test with strati-
fication by site. Since the response levels might not be equally
spaced but would have a clear ordering, modified ridit scores
were used. In addition, the full model with the treatment-by-site
interaction was assessed by using logistic models, with cumula-
tive logits for ordered categorical responses.
Remission of generalized anxiety disorder was defined as an
endpoint total score on the Hamilton anxiety scale of 7 or less
(26). Effect sizes were calculated with endpoint change scores
(based on week 12 values or the last observation carried forward);
the difference between sertraline and placebo change scores was
divided by the square root of the pooled standard deviation of the
change scores.
Statistical analyses were performed by using the SAS statistical
package, version 6.12 (Cary, N.C., SAS Institute). Significance lev-
els were set at 0.05 and were two-sided.
Results
Patient Characteristics and Disposition
A total of 562 patients were screened, of whom 378 pa-
tients were randomly assigned to the study treatments at
the baseline visit (Figure 1). The majority of the patients
who did not pass the screening (142 of 184) did not meet
the study entry criteria. Thirteen patients (2% of the total
screened) were excluded because of a positive drug
screen. Of the 378 randomly assigned patients, 182 (99%)
of those who received sertraline and 188 (99%) of those
who received placebo had at least one postrandomization
assessment, thereby qualifying for inclusion in the intent-
to-treat analysis.
Baseline demographic and clinical characteristics are
summarized in Table 1. The only significant difference was
a lower age at the onset of symptoms of generalized anxi-
ety disorder among the patients treated with sertraline.
For the total study group (N=370), 51 patients (14%) re-
ported a previous diagnosis of depression, and 10 patients
(3%) reported a previous diagnosis of panic disorder.
Overall, 110 patients (30%) reported previous treatment
with a psychotropic medication.
A nonsignificantly higher proportion of patients as-
signed to sertraline than placebo completed all 12 weeks
of study treatment (80% versus 74%) (Figure 1).
Efficacy
Results for the primary outcome measure, the Hamilton
anxiety scale total score, and the secondary outcome mea-
sures are summarized in Table 2. Sertraline demonstrated
significantly greater efficacy than placebo at week 4 on all
primary and secondary symptom measures, including the
Hospital Anxiety and Depression Scale anxiety and de-
pression ratings (the Montgomery-Åsberg Depression
Rating Scale was not administered at this time point). The
time course of improvement in the total score on the
Hamilton anxiety scale is shown in Figure 2. The patients
ratings on the anxiety subscale of the Hospital Anxiety and
Depression Scale showed a similar time course of im-
provement (Table 2). Improvement in anxiety symptoms
for the sertraline group included significantly greater effi-
cacy than for the placebo group on both the psychic and
somatic factors of the Hamilton anxiety scale (Table 2).
Response was defined as a score of 2 or lower on the CGI
improvement scale. Treatment with sertraline was associ-
ated with significantly higher responder rates than was
placebo from week 4 through the end of study treatment
(Figure 3). The rate of remission, defined as a score of 7 or
less on the Hamilton anxiety scale, also was significantly
higher with sertraline than with placebo, both in an analy-
sis of completers at week 12 (37% versus 23%) (χ
2
=7.64, df=
1, p=0.006) and in an endpoint analysis with the last ob-
servation carried forward (31% versus 18%) (χ
2
=9.52, df=1,
p=0.002). In the endpoint analyses, the effect size for ser-
traline compared to placebo was 0.51 for the CGI improve-
ment scale and 0.44 for the Hamilton anxiety scale total
score, with an effect size of 0.54 for the psychic factor and
0.23 for the somatic factor of the Hamilton anxiety scale.
Improvement in symptom measures was associated
with significantly greater improvement in quality of life
and functional outcomes for sertraline than for placebo,
as measured by the Quality of Life Enjoyment and Satis-
FIGURE 1. Disposition of Patients Screened for Study of
Sertraline Treatment for Generalized Anxiety Disorder
Completed study
(N=147, 80%)
Completed study
(N=139, 74%)
Discontinued prematurely
(N=37, 20%):
Adverse events (N=15)
Lack of efficacy (N=3)
Withdrew consent (N=9)
Lost to follow-up (N=4)
Other/
administrative (N=6)
Discontinued prematurely
(N=50, 27%):
Adverse events (N=19)
Lack of efficacy (N=4)
Withdrew consent (N=21)
Lost to follow-up (N=2)
Other/
administrative (N=4)
Not randomly assigned (N=184):
Did not meet entry
criteria (N=142)
Withdrew consent (N=25)
Lost to follow-up (N=4)
Other/administrative (N=13)
Did not receive study
medication (N=4)
Did not receive study
medication (N=1)
Randomly assigned
to sertraline (N=188)
Included in random
assignment (N=378)
Screened (N=562)
Randomly assigned
to placebo (N=190)
Received treatment (N=184) Received treatment (N=189)
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faction Questionnaire and Endicott Work Productivity
Scale (Table 2).
Tolerability and Safety
The mean endpoint dose of sertraline was 95.1 mg/day
(SD=45.5). Sertraline was generally well tolerated. Discon-
tinuations due to adverse events were 8% for sertraline and
10% for placebo (Figure 1, n.s.). Treatment-emergent ad-
verse events are shown in Table 3. Most of the adverse events
were reported to be mild to moderate in severity. The inci-
dence of severe adverse events was 3% or higher with sertra-
line for the following: sweating (3.8% versus 0.0% for pla-
cebo), headache (3.3% versus 4.8%), nausea (4.3% versus
1.6%), insomnia (4.3% versus 3.7%), anxiety (3.3% versus
4.2%), and decreased libido in women (4.6% versus 0.0%).
The mean change from baseline in weight was 0.0 kg
(SD=2.3) for sertraline and 0.4 kg (SD=2.4) for placebo; the
difference was not significant. Weight gain of 7% or more
over baseline was observed in five patients (3%) taking
sertraline compared to nine patients (5%) taking placebo.
There were no clinically significant changes in vital signs
(blood pressure, heart rate, or respiratory rate).
Discussion
This 12-week double-blind trial showed that sertraline, in
daily doses of 50150 mg, has significantly greater efficacy
than placebo in the treatment of generalized anxiety disor-
der. The anxiolytic response to sertraline was achieved by
week 4 and was notable for its efficacy across all primary
and secondary outcome measures, including the psychic
and somatic anxiety factors of the Hamilton anxiety scale
(Table 2).
The significantly greater efficacy of sertraline, com-
pared to placebo, in improving scores on the psychic fac-
tor of the Hamilton anxiety scale is consistent with pub-
lished reports for paroxetine (6) and extended-release
venlafaxine (4, 5, 27) in generalized anxiety disorder.
SSRIs, and most other drugs that act by modulating sero-
tonergic neurotransmission (e.g., buspirone, trazodone,
imipramine) (811), have consistently demonstrated
greater short-term efficacy for improving psychic symp-
toms of anxiety than for somatic symptoms. This is espe-
cially evident from a meta-analysis of the item-by-item ef-
ficacy of extended-release venlafaxine (28), although the
greater efficacy of paroxetine for short-term psychic anxi-
ety demonstrates the same pattern (6). In contrast, the
published literature suggests that benzodiazepines have
greater efficacy for improving somatic symptoms of anxi-
ety than for psychic symptoms (811). It is interesting that
psychotherapy, especially cognitive behavior therapy, has
also been shown in controlled trials to be effective in treat-
ing generalized anxiety disorder, with comparable im-
provement in both psychic and somatic symptoms (29).
The finding in the current study that sertraline has sig-
nificantly greater short-term efficacy than placebo in the
treatment of somatic anxiety, as measured by the somatic
anxiety factor of the Hamilton anxiety scale, is consistent
with similar data from a double-blind, placebo-controlled
TABLE 1. Baseline Clinical and Demographic Characteristics of Patients With Generalized Anxiety Disorder Who Were
Randomly Assigned to Treatment With Sertraline or Placebo
Characteristic Sertraline (N=184)
a
Placebo (N=189)
a
Analysis
N % N % Chi-Square
b
df p
Sex 2.51 1 0.12
Female 109 59 97 51
Male 75 41 92 49
Race 0.89 1 0.35
White 179 98 182 97
Other 3 2 6 3
Highest educational level 3.92 2 0.15
Partial or full high school 80 44 73 40
Some college or bachelor’s degree 95 52 97 53
Some or full graduate or professional school 6 3 14 8
Current marital status 0.65 2 0.73
Married or cohabiting 119 65 122 65
Divorced, separated, or widowed 26 14 32 17
Single 38 21 35 19
Current employment status
c
——
Full-time work (including in home) 118 64 116 61
Part-time work 36 20 32 17
Student 1910168
Unemployed, retired, or other 25 14 37 20
Mean SD Mean SD F df p
Age (years) 40.3 11.1 42.4 11.5 3.19 1, 354 0.08
Age at onset of symptoms of generalized anxiety disorder (years) 22.9 11.9 25.6 12.9 4.68 1, 354 0.04
a
Data on some variables were missing for some patients. The percents are based on the number of patients with available data.
b
Cochran-Mantel-Haenszel test.
c
Some students also had full- or part-time work.
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TABLE 2. Scores on Outcome Measures of Patients With Generalized Anxiety Disorder Who Were Treated With Sertraline or
Placebo
Sertraline Placebo
Score Score Analysis
a
Efficacy Measure N Mean
b
SD or SE
b
NMean
b
SD or SE
b
Fdf p
Hamilton Anxiety Rating Scale
Total
Baseline 182 24.6 4.6 188 25.0 4.9
Change at week 4 171 7.7 0.5 179 5.2 0.5 15.52 1, 330
<0.0001
Change at week 12 150 13.8 0.6 146 10.1 0.6 21.93 1, 276
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 182 11.7 0.6 188 8.0 0.6 19.43 1, 350
<0.0001
Psychic factor
Baseline 182 13.5 2.8 188 13.8 2.8
Change at week 4 171 4.3 0.3 179 2.6 0.3 17.96 1, 330
<0.0001
Change at week 12 150 8.0 0.4 146 5.3 0.4 34.02 1, 276
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 182 6.7 0.4 188 4.1 0.4 30.39 1, 350
<0.0001
Somatic factor
Baseline 182 11.0 3.3 188 11.2 3.2
Change at week 4 171 3.5 0.2 179 2.6 0.2 8.11 1, 330 0.005
Change at week 12 150 5.9 0.3 146 4.8 0.3 6.77 1, 276 0.01
Change at endpoint (week 12 or last observation carried
forward) 182 5.0 0.3 188 3.9 0.3 6.29 1, 350 0.02
Hospital Anxiety and Depression Scale
Anxiety
Baseline 181 12.8 3.5 188 13.0 3.3
Change at week 4 169 3.0 0.3 179 2.2 0.3 5.57 1, 328 0.02
Change at week 12 150 5.3 0.3 146 3.2 0.3 28.23 1, 276
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 181 4.5 0.3 188 2.6 0.3 21.73 1, 349
<0.0001
Depression
Baseline 181 7.1 3.8 188 6.9 3.7
Change at week 4 169 0.8 0.2 179 0.0 0.2 4.94 1, 328 0.03
Change at week 12 150 2.7 0.3 146 0.7 0.3 28.62 1, 276
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 181 2.1 0.3 188 0.3 0.3 21.41 1, 349
<0.0001
Montgomery-Åsberg Depression Rating Scale
Baseline 166 10.8 2.9 172 10.8 3.2
Change at week 12 150 5.4 0.4 147 2.0 0.4 39.35 1, 277
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 166 4.8 0.4 172 1.1 0.4 42.27 1, 318
<0.0001
CGI
Severity
Baseline 182 4.25 0.58 188 4.35 0.61
Change at week 4 171 0.83 0.06 178 0.45 0.06 19.08 1, 329
<0.0001
Change at week 12 150 1.89 0.10 146 1.20 0.10 26.58 1, 276
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 182 1.56 0.10 188 0.90 0.09 26.14 1, 350
<0.0001
Improvement
Week 4 171 2.88 0.08 179 3.37 0.08 18.20 1, 331
<0.0001
Week 12 150 1.94 0.10 146 32.66 0.10 29.91 1, 277
<0.0001
Endpoint (week 12 or last observation carried forward) 182 2.30 0.10 188 3.00 0.10 26.17 1, 351
<0.0001
Quality of Life Enjoyment and Satisfaction Questionnaire
total (%)
Baseline 169 62.6 11.5 171 62.6 10.1
Change at week 6 157 5.4 0.8 159 2.5 0.8 6.98 1, 296 0.009
Change at week 12 151 9.9 1.0 144 4.3 1.0 17.82 1, 275
<0.0001
Change at endpoint (week 12 or last observation carried
forward) 169 9.0 1.0 171 2.4 0.9 25.66 1, 320
<0.0001
Endicott Work Productivity Scale
Baseline 109 28.8 14.6 108 30.7 14.2
Change at week 12 101 10.1 1.3 94 3.9 1.4 14.68 1, 175 0.0002
Change at endpoint (week 12 or last observation carried
forward) 109 9.2 1.3 108 2.5 1.4 16.77 1, 197
<0.0001
a
Analysis of covariance of the change from baseline, with terms for site, baseline score, and treatment.
b
For baseline values, raw mean and standard deviation. For visits during treatment, least-square mean and standard error of the mean
change score.
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trial of sertraline in children and adolescents with general-
ized anxiety disorder (19). It should be noted that the inci-
dence of treatment-emergent somatic symptoms (e.g.,
nausea, diarrhea, sweating), while relatively modest, none-
theless appears to have reduced the magnitude of the av-
erage improvement in the somatic anxiety score. This is
similar to what is observed in depression studies, in which
the magnitude of state-dependent improvement with
SSRIs in sleep and sexual dysfunction, as shown by group
mean change scores at endpoint, is also reduced by treat-
ment-emergent adverse events in a minority of patients.
Whether sertraline offers an advantage in effectively
treating somatic anxiety symptoms needs to be confirmed
by additional studies. Regardless, it is important to note
that the somatic cluster of anxiety symptoms contributes
significantly to the clinical presentation of generalized anx-
iety disorder and to the distress and disability associated
with this diagnosis, even though these symptoms may have
less utility as diagnostic criteria (11, DSM-IV-TR). This was
illustrated in the current study by the fact that somatic
symptoms contributed more than 40% to the total symp-
tom burden, as reflected in the Hamilton anxiety scale total
score at baseline. This somatic contribution to generalized
anxiety disorder is consistent with data from other studies
of the treatment of generalized anxiety disorder (46, 8, 27).
In the current study, the magnitude of the improvement
in the Hamilton anxiety scale total score at week 12 (or last
observation carried forward) with sertraline relative to
placebo (approximately 12 versus 8 points) is comparable
to what has been reported in the two studies of extended-
release venlafaxine with week 12 data (4, 5). The two pub-
lished studies of paroxetine (6, 30) are difficult to compare
because they were 8 weeks in duration and because the
placebo response rates were relatively high in both studies
(45% and 47% according to analyses with the last observa-
tion carried forward and with the response criterion based
on the CGI improvement scale score). In the current study,
the placebo response rate at endpoint (week 12 or the last
observation carried forward) for placebo was 37%, accord-
ing to the CGI improvement scale criterion, compared to
63% for sertraline. It is interesting that applying an illness-
specific criterion (i.e., 50% reduction in Hamilton anxiety
scale total score) to the response at endpoint yielded a
more conservative estimate of treatment effect (56%
versus 29%) (Cochran-Mantel-Haenszel χ
2
=26.74, df=1,
p<0.001) but one with a higher odds ratio in favor of sertra-
line over placebo.
The rate of remission at endpoint (with the last observa-
tion carried forward) was 31% for sertraline (versus 18%
for placebo), while the remission rate among completers
was 37% (versus 23% for placebo). The results achieved af-
ter short-term sertraline treatment are notable given the
baseline severity (mean Hamilton anxiety scale score, 25)
and chronicity (1520 years) of generalized anxiety disor-
der in the current study group. Obtaining these remission
rates for sertraline within 3 months is notable, in compar-
ison to a naturalistic follow-up study of patients with gen-
FIGURE 2. Change in Anxiety Score Across 12 Weeks of
Treatment With Sertraline or Placebo for Patients With
Generalized Anxiety Disorder
a
a
Differences between groups were analyzed with analysis of covari-
ance for the subjects included in the intent-to-treat group, with the
last observation carried forward. The model included terms for site,
baseline score, and treatment.
*p
<0.01. **p<0.0001.
Mean Change From Baseline in Total
Score on Hamilton Anxiety Rating Scale
Time (weeks)
0
–2
–4
–6
–8
–10
–12
–14
Base-
line
12 4 6 8 12
Last Observation
Carried Forward
Sertraline (N=182)
Placebo (N=188)
**
*
**
**
**
FIGURE 3. Rates of Response to Sertraline and Placebo
Among Patients With Generalized Anxiety Disorder
a
a
Differences between groups were analyzed with the Cochran-Man-
tel-Haenszel row mean scores test with stratification by site.
*p
<0.001.
Patients With Score of 2 on
Improvement Scale of Clinical Global Impression
Week 4 Week 8 Endpoint
(week 12 or last
observation
carried forward)
80
Sertraline
Placebo
60
40
20
0
N=171 179 157 155 182 188
*
*
*
1648 Am J Psychiatry 161:9, September 2004
SERTRALINE AND GENERALIZED ANXIETY
http://ajp.psychiatryonline.org
eralized anxiety disorder treated in a psychiatric setting, in
whom remission occurred in 38%, even after 5 years (31).
The sertraline remission rates may be cautiously placed
within the context of short-term remission results from
two previously published flexible-dose studies of extended-
release venlafaxine (32) and paroxetine (6). In both studies
the baseline Hamilton anxiety scale scores and illness du-
rations were similar to those in the current study. The rate
of remission at endpoint in the trial of extended-release
venlafaxine (week 8 or the last observation carried for-
ward) was 32% (versus 15% for placebo), while the rate of
remission at endpoint in the paroxetine study was 36%
(versus 23% for placebo). The sertraline versus placebo ef-
fect size for remission in the current study was similar to
what was reported for both extended-release venlafaxine
and paroxetine.
Improvement with sertraline in the symptoms of gener-
alized anxiety disorder was associated with parallel im-
provement in scores on the secondary anxiety and de-
pression measures, such as the Hospital Anxiety and
Depression Scale and the Montgomery-Åsberg Depres-
sion Rating Scale (Table 2). It is of interest that the patient-
rated Hospital Anxiety and Depression Scale anxiety and
depression subscales, respectively, were as sensitive to
the anxiolytic and antidepressant effects of sertraline as
the investigator-rated Hamilton anxiety scale and Mont-
gomery-Åsberg Depression Rating Scale.
Symptom reduction after short-term treatment with
sertraline rapidly resulted in significant improvement in
both quality of life and work productivity (Table 2). The
baseline score of 63% on the Quality of Life Enjoyment and
Satisfaction Questionnaire in the current study suggests
that these patients with generalized anxiety disorder had a
degree of impairment in quality of life that is equivalent to
what has been reported in similar treatment groups with
major depression and greater than in patients with social
anxiety and panic disorder (33, 34).
Treatment with sertraline was well tolerated, with a pat-
tern of adverse events that was similar to what has previ-
ously been reported in studies of sertraline for the treatment
of depression and anxiety disorders. Six adverse events were
rated as severe by more 3% of the patients. Confirming ser-
tralines tolerability was the similarity in the rates of dis-
continuations due to adverse events for sertraline (8%) and
placebo (10%).
The main limitation of the current study, which is shared
by most recent placebo-controlled trials for anxiety disor-
ders, is the exclusion of patients with comorbid major de-
pressive disorder. This is perhaps of less concern with ser-
traline, given its established efficacy in major depressive
disorder, as well as recent evidence for efficacy in comor-
bid major depressive disorder and panic disorder (35).
In conclusion, the results of this 12-week treatment
study demonstrate that sertraline is an effective and well-
tolerated treatment of generalized anxiety disorder. This
anxiolytic benefit extends to both psychic and somatic
anxiety symptoms. Furthermore, symptomatic improve-
ment is associated with parallel improvement in quality of
life and occupational functioning.
Acknowledgments
In Australia the principal investigators were David Barton, M.D.,
Melbourne, Victoria; Phillip Boyce, M.D., Penrith, New South
Wales; Philip L.P. Morris, M.D., Ph.D., Southport, Queensland; and
John Tiller, M.D., Melbourne, Victoria. In Canada the principal
investigators were Richard Bergeron, M.D., Hull, Quebec; Yves
Chaput, M.D., Saint-Jean-Sur-Le-Richelieu, Quebec; Stan P.
Kutcher, M.D., Halifax, Nova Scotia; Arumuga Ravindran, M.D.,
Ottawa, Ontario; and Meir Steiner, M.D., Hamilton, Ontario. In
Denmark the principal investigators were Kirsten Behnke, M.D.,
Frederiksberg; Flemming Bjorndal, M.D., Greve; Peter Oster-
gaard, M.D., Middelfart; and Jesper A. Sogaard, M.D., Kalundborg.
In Norway the principal investigators were Marit Bjartveit-Krüger,
M.D., Levanger; Alv A. Dahl, M.D., Oslo; Ingrid Østby-Deglum,
M.D., Ottestad; and Torbjørn Sigurdson, M.D., Trondheim. In Swe-
den the principal investigators were Christer Allgulander, M.D.,
Huddinge; Goran Björling, M.D., Trollhattan; Anna Loewenstein,
M.D., Göteborg; and Ingemar Sjodin, M.D., Linkoping.
Presented in part at the 41st annual meeting of the American Col-
lege of Neuropsychopharmacology, San Juan, Puerto Rico, Dec. 8–12,
2002, and at the 23rd annual conference of the Anxiety Disorders As-
sociation of America, March 27–30, 2003, Toronto. Received May 28,
2003; revision received Sept. 24, 2003; accepted Nov. 20, 2003. From
the Neurotec Department, Section of Psychiatry, Karolinska Insti-
tutet, Stockholm; the Department of Psychiatry, Aker University Hos-
pital, University of Oslo; Pfizer, Inc., New York; the Department of
Psychiatry, University of Queensland, Brisbane, Queensland, Austra-
lia; and the Department of Psychiatry, Dalhousie University/Capital
Health, Halifax, Nova Scotia, Canada. Dr. Sogaard is in private prac-
tice in Kalundborg, Denmark. Address reprint requests to Dr. Allgu-
lander, Karolinska Institutet, Neurotec Department, Section of Psy-
chiatry at Huddinge, University Hospital, 141 86 Huddinge, Sweden;
Christer.Allgulander@neurotec.ki.se (e-mail).
TABLE 3. Treatment-Emergent Adverse Events
a
in Patients
With Generalized Anxiety Disorder in a 12-Week Comparison
of Sertraline and Placebo
Patients With Event (%)
Fishers
p
Sertraline
(N=184)
Placebo
N=189)
Adverse Event
a
N%
b
N%
b
Nausea 52 28 25 13 <0.001
Insomnia 37 20 28 15
<0.05
Sweating 35 19 8 4
<0.001
Decreased libido in men 13 17 5 5
<0.05
Dizziness 201117 9n.s.
Diarrhea 21 11 9 5
<0.05
Anxiety 19101810n.s.
Fatigue 19 10 9 5
<0.05
Decreased libido in women 11 10 1 1
<0.01
Dyspepsia 16 9 11 6 n.s.
Ejaculation disorder in men 7 9 0 0
<0.01
Influenza-like symptoms 13 7 10 5 n.s.
Loose stools 10 5 2 1
<0.05
Anorexia 10542n.s.
a
Not included unless the incidence was higher for patients taking
sertraline than for those taking placebo or was the same in both
groups.
b
Gender-specific adverse events are calculated on the basis of the
appropriate number of subjects; the sertraline group contained 75
men and 109 women, and the placebo group contained 92 men
and 97 women.
Am J Psychiatry 161:9, September 2004 1649
ALLGULANDER, DAHL, AUSTIN, ET AL.
http://ajp.psychiatryonline.org
The clinical trial was sponsored by Pfizer, Inc.
The authors thank Hana Kosar, B.S.N., and Michelle Hosten of
Pfizer and the other principal investigators for their contribution to
the generation and collection of data.
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    • "Our findings demonstrated the SRT treatment alone and in combination with NR (100 mg/ kg) reduced the anxiety-like behavior induced by DOX treatment. The results of SRT in our study are corroborated by previous reports of clinical trials in the patients with general anxiety disorder [58]. Similarly, protective effects of NR and SRT alone and in combination were observed in the depressive-like behavior, CORT, and monoamines level. "
    [Show abstract] [Hide abstract] ABSTRACT: The present study was designed to investigate the neuroprotective effect of naringin (NR) alone as well as its combination with sertraline (SRT) against doxorubicin (DOX)-induced neurobehavioral and neurochemical anomalies. DOX (15 mg/kg; i.p.) administration caused behavioral alterations, oxidative stress, neuroinflammation, mitochondrial dysfunction and monoamines alteration in male Wistar rats. NR (50 and 100 mg/kg; i.p.) and SRT (5 mg/kg; i.p.) treatment significantly attenuated DOX-induced anxiety and depressive-like behavior as evident from elevated plus maze (EPM) and modified forced swimming test (mFST), respectively. NR treatment significantly attenuated DOX-induced raised plasma corticosterone (CORT), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) levels in the hippocampus (HC). Furthermore, we found that combination of NR and SRT regimen ameliorated DOX-induced behavioral anomalies through modulation of the 5-HT level and mitochondrial complexes protection pathway along with alleviation of oxidative stress in the HC region. Therefore, NR treatment alone or in combination with SRT could be beneficial against DOX-induced neurotoxicity.
    Full-text · Article · May 2016
    • "Sertraline, along with the SSRIs escitalopram and paroxetine, is a first-line pharmacologic treatment for GAD (Baldwin and Polkinghorn, 2005). Randomised, placebo controlled trials have found Sertraline efficacious for GAD in adults (Allgulander et al., 2004; Brawman-Mintzer et al., 2006), children and adolescents (Rynn et al., 2001; Walkup et al., 2008) over 9 to 12 weeks, and Sertraline Internet Interventions 1 (2014) 169–174 ⁎ Corresponding author at: Black Dog Institute, Hospital Road, Prince of Wales Hospital, Randwick, NSW 2031, Australia. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Generalised Anxiety Disorder (GAD) is a high prevalence, chronic disorder that can be treated effectively through a number of web-based programs. However, online web programs for GAD have not been compared to standard pharmacological treatment. The present study compares an Internet Intervention (Active Website) for GAD and a selective serotonin re-uptake inhibitor (SSRI) (Sertraline), with an online attention placebo condition (Control Website). Objective: To evaluate the effectiveness of a web-based intervention for GAD in comparison to standard antidepressant medication and an online attention placebo condition over a 10 week period, and with a follow-up at 6 and at 12 months. Methods: The study was part of a larger scale prevention program. 152 people aged 18–30 years who met the criteria for GAD on the MINI received referrals to the treatment sub-study. The primary outcome was anxiety symptoms measured by the Generalised Anxiety Disorder 7-item Scale (GAD-7), and the secondary outcome was depression measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Results: There was very poor uptake to the trial (around 14% of those referred). However, even in this small sample, Sertraline compared to the Control Website was significant at post-test and 6 months, and the Internet Intervention was significant at post-test. Relative to the Control Website condition at post-test, for the GAD-7 and CES-D respectively, the between group effect sizes were d = 2.43 and d = 0.68 for the Active Website condition, and 3.00 and 0.20 for the Sertraline condition. The within group effect size for the Control Website from baseline to post-test was −0.04 for the GAD-7 and 0.31 for CES-D respectively. Conclusions: The findings will need to be extended and confirmed in a larger trial. However, they do suggest that both standard pharmacological treatment and online interventions for GAD are effective in samples with a diagnosis of GAD recruited via online methods. The low rate of engagement for face-to-face treatment by those who opt first for a web program suggests that treatment preferences are important in help-seeking.
    Full-text · Article · Oct 2014
    • "However, the Psychopharmacology (2011) 215:1–11difference was not statistically significant in the intentionto-treat analysis. The other two head-to-head trials compared paroxetine and venlafaxine (Allgulander et al. 2004a; Liebowitz et al. 2005a). Mean doses of the substances were comparable in both trials, and no statistically significant differences in the reduction of LSAS scores were reported between venlafaxine and paroxetine. "
    [Show abstract] [Hide abstract] ABSTRACT: A growing number of controlled clinical trials suggest that different second-generation antidepressants (SGA) may be effective in the treatment of social anxiety disorder (SAD). The aim of the present study is to evaluate the effectiveness of SGA in SAD and to investigate possible differences in their efficacy. We performed a systematic review and meta-analysis of all double-blind, randomized, controlled clinical trials involving second-generation antidepressants in adult patients with SAD published on PubMed/MEDLINE, PsycINFO, and Current Controlled Trials databases until July 2009. Our analyses were based on changes in Liebowitz Social Anxiety Scale (LSAS), Clinical Global Impression (CGI), and standardized mean difference (SMD). Twenty-seven controlled clinical trials, comprising ten different SGA, were selected. When comparing the reduction of LSAS scores, the group receiving active drugs showed a significantly greater reduction compared to those observed in the placebo group [pooled weighted mean -11.9 (IC 95% -14.5 to -9.4)]. The combined relative risk (RR) for the different drugs revealed a 62% increase in treatment response (final CGI ≤2) for those using SGAs, compared to those receiving placebo [RR 1.62 (95% CI 1.44-1.81)]. The combined SMD for the SGAs was -0.43 (IC 95% -0.49 to -0.37). Second-generation antidepressants are efficacious treatment for patients with SAD. However, our results do not suggest differences of efficacy among different drugs.
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