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A randomized trial of sertraline, self- administered cognitive behavior therapy, and their combination for panic...
Article in Psychological Medicine · May 2010
DOI: 10.1017/S0033291710000930 · Source: PubMed
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A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder
D. Koszycki1,2*, M. Taljaard3,4, Z. Segal5 and J. Bradwejn2
1 Faculty of Education, University of Ottawa, ON, Canada 2 Department of Psychiatry, University of Ottawa, ON, Canada 3 Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada 4 Department of Epidemiology and Community Medicine, University of Ottawa, ON, Canada 5 Departments of Psychiatry and Psychology, University of Toronto and Centre for Addiction and Mental Health, Toronto, ON, Canada
Background. Self-administered cognitive behavior therapy (SCBT) has been shown to be an effective alternative to
therapist-delivered treatment for panic disorder (PD). However, it is unknown whether combining SCBT and
antidepressants can improve treatment. This trial evaluated the efficacy of SCBT and sertraline, alone or in
combination, in PD.
Method. Patients (n=251) were randomized to 12 weeks of either placebo drug, placebo drug plus SCBT, sertraline, or sertraline plus SCBT. Those who improved after 12 weeks of acute treatment received treatment for an additional
12 weeks. Outcome measures included core PD symptoms (panic attacks, anticipatory anxiety, agoraphobic
avoidance), dysfunctional cognitions (fear of bodily sensations, agoraphobic cognitions), disability, and clinical global
impression of severity and improvement. Efficacy data were analyzed using general and generalized linear mixed
models.
Results. Primary analyses of trends over time revealed that sertraline/SCBT produced a significantly greater rate of
decline in fear of bodily sensations compared to sertraline, placebo/SCBT and placebo. Trends in other outcomes
were not significantly different over time. Secondary analyses of mean scores at week 12 revealed that sertraline/
SCBT fared better on several outcomes than placebo, with improvement being maintained at the end of continuation
treatment. Outcome did not differ between placebo and either sertraline monotherapy or placebo/SCBT. Moreover,
few differences emerged between the active interventions.
Conclusion. This trial suggests that sertraline combined with SCBT may be an effective treatment for PD. The study
could not confirm the efficacy of sertraline monotherapy or SCBT without concomitant medication or therapist
assistance in the treatment of PD.
Received 13 May 2009; Revised 23 March 2010; Accepted 29 March 2010
Key words : Cognitive behavior therapy (CBT), combination treatment, panic disorder, self-help interventions, SSRI.
Introduction
Panic disorder (PD) is amenable to both pharma-
cotherapy and cognitive behavior therapy (CBT)
(Craske & Zucker, 2001; Bakker et al. 2005). Although
drug therapy and CBT are effective treatments for PD,
not all patients respond fully to monotherapy and
several studies have shown that combining these treat-
ments improves outcome. A recent systematic review
of randomized trials of combined antidepressant
and psychotherapy treatment for PD concluded that
combined treatment was superior to monotherapy
during acute and continuation treatment (Furukawa
et al. 2006). Despite the apparent benefits of an in-
tegrated approach, barriers to treatment accessibility
often prevent such an approach from being used.
Although antidepressants are easily obtained from
primary care physicians, access to trained CBT thera-
pists can be limited and the cost of CBT may be too
high for many individuals. These barriers can prevent
patients from receiving optimal treatment for their
PD (National Institutes of Health, 1991).
Various approaches have been developed to im-
prove access to CBT. For example, some approaches
reduce therapist–patient contact by delegating some
therapy tasks to computer-aided CBT (Marks et al.
2004). Others use self-help material that incorporate
* Address for correspondence: D. Koszycki. Ph.D., C.Psych.,
Faculty of Education, University of Ottawa, 145 Jean-Jacques Lussier,
Ottawa, Ontario, K1N 6N5, Canada.
(Email: dkoszyck@uottawa.ca)
Psychological Medicine, Page 1 of 11. f Cambridge University Press 2010 doi:10.1017/S0033291710000930
ORIGINAL ARTICLE
standard CBT techniques designed to reduce panic
attacks, anticipatory anxiety and phobic avoidance
(Gould & Clum, 1995). Research on self-administered
CBT (SCBT) is limited but available data suggest that
this may be a successful and low-cost method of deliv-
ering CBT to PD patients (Gould et al. 1993; Gould &
Clum, 1995; Carlbring et al. 2003), with some studies
reporting equivalence of self- to therapist-directed
CBT (Lidren et al. 1994; Park et al. 2001; Carlbring et al.
2005; Kiropoulos et al. 2008). SCBT may be included in
the treatment armamentarium of primary care phys-
icians, who treat the majority of PD patients, and can
be introduced as an initial intervention in the treat-
ment process or as a compliment to pharmacotherapy.
However, before SCBT is widely prescribed, large
controlled clinical trials are needed to demonstrate its
clinical value when used alone or in combination with
medication. This randomized controlled study evalu-
ated the efficacy of acute and extension treatment of
PD with SCBT and the serotonin-reuptake inhibitor
sertraline, alone or in combination.
Method
Subjects
Out-patients were recruited from 15 academic health
centers through media advertisements and self- or
practitioner referrals. The ethics committee at each
hospital approved the study and patients provided
written informed consent. Patients were eligible for
the study if they met DSM-IV criteria for PD with or
without agoraphobia (AG) based on both a psychiatric
interview and a Structured Clinical Interview for
DSM-IV (SCID; First et al. 1997). To minimize placebo
response and select patients with at least moderately
severe PD, participants had to have a minimum of
six full panic attacks in the 4-week period prior to
the screen visit, and two full panic attacks a week in
the 2-week lead-in period before the baseline visit.
Co-morbid depression, generalized anxiety disorder,
social phobia, somatization disorder and specific
phobia were allowed as long as these conditions were
secondary to and not clinically more prominent than
the PD¡AG. To prevent the inclusion of severely
depressed patients, subjects were eligible if their score
on the 21-item Hamilton Depression Rating Scale
was f17 (Hamilton, 1960). Patients were excluded if they had other Axis I
psychiatric disorders; electroconvulsive therapy in the
past 6 months; a history of psychosurgery; significant
medical conditions; abnormal laboratory findings;
a hypersensitivity to serotonergic agents; a history of
non-response to sertraline; lactose intolerance; sig-
nificant suicide risk; and use of any psychotropics
within 14 days of the baseline visit (6 weeks
for fluoxetine) or treatment with CBT in the past
12 months. Oxazepam was allowed during the study if
needed, with a maximum daily dose of 15 mg and
a weekly total dose of 60 mg. Women who were
pregnant, lactating or not using reliable contraception
were excluded.
Study design
The study used a factorial randomized design with
Drug (sertraline or placebo drug) and Self-Help (SCBT
or no SCBT) as factors. Factorial trials are an efficient
way to evaluate two or more interventions and allow
for the evaluation of separate effects of each inter-
vention and possible additive effects of combined
treatments (McAlister et al. 2003). Patients were ran-
domly allocated to one of four groups by a computer-
generated randomization code: placebo drug alone
(PBO), placebo drug plus SCBT (PBO/SCBT), sertra-
line alone (SERT), or sertraline plus SCBT (SERT/
SCBT). Placebo and sertraline were provided as
matching capsules and administered double-blind.
Investigators at each site were provided with a sealed
envelope that contained the identification of the study
drug being administered to the patient. In a medical
emergency, the investigator was authorized to break
the code for that subject only. Outcome assessments
were made by investigators who were blind to allo-
cation of the drug and who were not told whether the
patient was assigned to SCBT. Patients were instructed
not to divulge their SCBT assignment to the in-
vestigators.
Procedures
After completing the screening evaluations, patients
entered a 14-day lead-in period in which they
prospectively recorded their panic attacks and, if
necessary, underwent a wash-out from a disallowed
medication. If, at the end of the lead-in period, the
frequency of panic attacks had fallen to below the en-
trance criteria, the lead-in period was extended by an
additional 2 weeks. If panic attack frequency remained
below the entrance criteria, the patient was excluded.
Patients meeting entry criteria at both screening and
baseline visits were randomized. Safety and efficacy
were measured at baseline and at weeks 1, 2, 3, 4, 6, 8,
10 and 12, and toxicology screening was repeated at
weeks 6 and 12. Patients who completed the acute
treatment were eligible to enter 12 weeks of extension
treatment if they showed an adequate response (i.e.
Clinical Global Impression of Improvement score of 1,
2 or 3) and good tolerance to the study treatments.
Outcome was assessed at weeks 16, 20 and 24.
2 D. Koszycki et al.
Treatment was discontinued at week 24 and patients
were followed monthly for an additional 6-month
period to assess relapse. The results of the discon-
tinuation phase will be published separately.
Treatments
Sertraline and placebo were provided within the con-
text of clinical management sessions as described by
Fawcett et al. (1987). Study drugs were initiated at
25 mg/day and increased to 50 mg/day after 1 week.
In the presence of dose-limiting side-effects, patients
were maintained at 25 mg/day for an additional week.
If side-effects persisted and the dose could not be in-
creased, the patient was withdrawn from the study.
The dose was maintained at 50 mg/day until week 4.
Thereafter, the dose was increased by 50 mg every
2 weeks or more until maximum improvement on
the Clinical Global Impression scale (Guy, 1976) was
obtained. The targeted maximal dose for acute treat-
ment was 200 mg/day. During extension treatment,
patients were maintained at the dose achieved by
week 12. However, if side-effects occurred at any time,
the dose was decreased to the next lower level. Com-
pliance with study medication was monitored by pill
count. A returned capsule count for trial medication
was recorded at each visit to monitor compliance.
SCBT consisted of 12 audiotapes and a workbook
that contained monitoring forms for homework. The
tapes and workbook were developed for this study by
psychologists with expertise in CBT (D.K. and Z.S.).
Each tape described the principles of treatment and
provided detailed instructions and homework.
Treatment components included extensive psycho-
education about anxiety and the cognitive model of
PD, breathing retraining and relaxation skills, cogni-
tive restructuring that addressed misappraisal of
panic symptoms, interoceptive and situational ex-
posure, and relapse prevention. Tapes were dis-
tributed weekly during acute treatment by a research
coordinator and a standard format was adopted for
instructions to be given to patients. Compliance was
assessed at each visit by asking patients how much
time they spent listening to the tape, whether they at-
tempted the suggested homework and whether they
recorded their homework in the workbook. Patients
who entered the 12-week extension phase were given
the CBT package to use at their own discretion and no
particular instructions were given.
Assessments
Multiple outcome measures were selected as key
measures in PD research (Shear & Maser, 1994): for
core PD symptoms, a panic diary was used to assess
frequency of panic attacks and frequency of anticipat-
ory anxiety, and the avoidance-alone subscale of
the Mobility Inventory for Agoraphobia (MI-AAL;
Chambless et al. 1985) was used to assess agoraphobic
avoidance. The study investigator recorded the fre-
quency of panic attacks and anticipatory anxiety after
reviewing the patient’s daily diary with the patient.
Dysfunctional cognitions were assessed with the Body
Sensations Questionnaire (BSQ), which measures fear
of arousal-related bodily sensations (Chambless et al.
1984), and the Agoraphobic Cognitions Questionnaire
(ACQ), which measures panic-related cognitions
(Chambless et al. 1984). Disability due to PD was as-
sessed with the Sheehan Disability Scale (SDS), which
measures impairment in the areas of work, social
life, and family life (Sheehan et al. 1996). Finally, the
Clinical Global Impression (CGI; Guy, 1976) was used
to provide an overall evaluation of symptom severity
(CGI-S) and improvement (CGI-I). The study was
powered to detect moderate effect sizes for the quan-
titative outcomes.
Data analyses
Continuous outcomes were analyzed using linear
mixed-effects regression models, implemented in SAS
version 9.1 (SAS Institute Inc., USA), with time (in
weeks since baseline) coded as a continuous variable.
To account for correlation among the repeated mea-
sures over time, the intercept and time were specified
as random effects and an unstructured covariance
matrix was specified for the random effects par-
ameters. The mixed model methodology, as opposed
to conventional repeated-measures ANOVA, allows
all available observations on each patient to be used
without having to use an imputation procedure such
as last-observation carried forward. The mixed models
were estimated by means of Restricted Maximum
Likelihood (REML), and degrees of freedom were
computed using the Kenward–Roger approach (Littell
et al. 2006). Categorical outcomes were analyzed using
generalized linear models with the log link function
and Poisson variance function specified for count
variables, and the logit link function and binomial
variance function specified for dichotomous variables.
The generalized estimating equations (GEE) approach
was used to account for correlation among repeated
measures over time using an AR(1) working corre-
lation structure and robust (sandwich) covariance es-
timators for the regression coefficients. Predictors
included in each model were: drug (sertraline,
placebo); SCBT (SCBT, no SCBT); interaction between
drug and SCBT; time; two-way interactions between
time and drug, and time and SCBT; time-squared (t2)
to allow for possible quadratic trends over time;
Self-administered CBT and sertraline for panic disorder 3
two-way interactions between t2 and drug, and t2 and
SCBT; and three-way interactions between time, drug
and SCBT, in addition to t2, drug and SCBT. In this
longitudinal randomized trial, our interest was fo-
cused on the trends over time among the groups and
the main coefficients of interest in the analyses were
therefore the two-way and three-way interactions
with time. Likelihood-ratio tests were used to compare
the models including quadratic effects of time, with
the reduced models involving linear effects of time
only: if the likelihood-ratio tests were significant, the
results are presented for the quadratic trend models;
otherwise, the results are presented for the linear trend
models. To maintain the family-wise error rate associ-
ated with testing multiple outcomes, we used the
Bonferroni adjustment (Proschan & Waclawiw, 2000);
that is, we required the p value for any effect in our
regression models to be f0.05 divided by the number of related scales representing each construct (i.e.
0.05/3=0.016 for the three core PD symptoms, 0.05/2=0.025 for dysfunctional thoughts, 0.05/3= 0.016 for patient-rated disability and 0.05/2=0.025 for clinical global impression). If the main or inter-
action effects with time were significant at the
Bonferroni-adjusted significance levels, we then
constructed tests of hypotheses comparing the trends
among the four arms using single and multiple degree
of freedom contrasts. We first tested whether there
was a significant linear (or quadratic) trend in each
treatment group; we then constructed simultaneous
tests concerning the equality of the regression slopes
among the four arms. Finally, we compared the least
squares means among the arms at week 12, using the
Tukey–Kramer adjustment for multiple comparisons.
We fitted similar models to the data from patients
advancing to the extension treatment, this time
comparing least square mean differences among the
treatment groups at weeks 16, 20 and 24 using the
Tukey–Kramer adjustment for multiple comparisons.
Results
Subject characteristics
A total of 289 participants were screened or went
through the formal screening lead-in period. Of these,
251 met study criteria at baseline and were random-
ized to one of the four treatment groups (see Fig. 1).
62 PBO 65 PBO/SCBT 63 SERT 61 SERT/SCBT
62 included in ITT 64 included in ITT 62 included in ITT 59 included in ITT
43 completed 12 weeks AT 19 dropped at of AT • 9 lack of efficacy • 6 adverse events • 2 withdrew consent • 2 protect violation
44 completed 12 weeks AT 20 dropped out of AT • 5 lack of efficacy • 3 adverse events • 5 withdrew consent • 1 protocol violation • 2 lost to follow-up • 4 other
46 completed 12 weeks AT 16 dropped out of AT • 5 lack of efficacy • 5 adverse events • 1 withdrew consent • 3 protocol violation • 1 lost to follow-up • 1 other
43 completed 12 weeks AT 16 dropped out of AT • 2 lack of efficacy • 7 adverse events • 2 withdrew consent • 2 lost to follow-up • 3 other
30 entered 12 weeks ET 13 did not enter ET • 7 lack of efficacy • 2 adverse events • 3 withdrew consent • 1 other
34 entered 12 weeks ET 10 did not enter ET • 5 lack of efficacy • 1 adverse events • 4 withdrew consent
35 entered 12 weeks ET 11 did not enter ET • 6 lack of efficacy • 2 adverse events • 2 withdrew consent • 1 protocol violation
36 entered 12 weeks ET 7 did not enter ET • 2 lack of efficacy • 2 withdrew consent • 2 protocol violation • 1 other
28 competed ET 2 dropped out of ET • 2 lack of efficacy
27 completed ET 7 dropped out of ET • 2 lack of efficacy • 1 adverse event • 1 withdrew consent • 1 protocol violation • 1 lost to follow-up • 1 other
31 completed ET 4 dropped out of ET • 1 lack of efficacy • 2 lost to follow-up • 1 other
33 completed ET 3 dropped out of ET • 1 lack of efficacy • 1 withdrew consent • 1 lost to follow-up
289 SCREENED
251 RANDOMIZED
Fig. 1. Flow of participants during the trial. ITT, intent-to-treat; AT, acute treatment; ET, extension treatment.
4 D. Koszycki et al.
Four participants had no post-baseline assessments
and were excluded from the intent-to-treat (ITT)
analyses. Table 1 presents the demographic and base-
line characteristics of the ITT sample. Differences
among the treatment groups were not statistically
significant.
Attrition
Seventy-one patients (28.7%) discontinued acute
treatment prematurely. Of the 176 patients who
completed 12-week acute treatment, 135 advanced to
12-week extension treatment. Of these, 16 (11.8%)
discontinued treatment prematurely. Attrition was
similar across treatment groups. The reasons for
discontinuing acute and extension treatment are de-
scribed in Fig. 1.
Study drug, concomitant anxiolytic use, and safety
The dose (mean¡S.D.) of the study drug was
138.3¡59.5 mg/day for PBO, 126.9¡62.1 mg/day
for PBO/SCBT, 116.1¡59.6 mg/day for SERT and
95.8¡57.6 mg/day for SERT/SCBT. Oxazepam was
used at least once by 55.9% of participants (n=138) and the mean weekly dose ranged from 24.8¡30.9 mg
to 33.7¡18.0 mg. The groups did not differ in use or
dose of oxazapam. The mean dose of the study drug
was similar for patients who advanced to extension
treatment. There were no clinically relevant changes in
vital signs or weight during the trial. The majority of
patients reported at least one adverse event during
acute or extension treatment, with 28.9% (n=72) reporting a severe adverse event. The frequency of
adverse events overall and severe adverse events were
similar across treatment groups. There were no serious
adverse events as defined by US Food and Drug
Administration regulations (Ott & Yingling, 2006).
Compliance with SCBT
Compliance with the SCBT program during acute
treatment was good. The percentage of participants
who listened to at least 80% of the tapes was 81.2% for
PBO/SCBT and 91.5% for SERT/SCBT. In both treat-
ment groups, 64% of patients completed at least 80%
of the assigned homework.
Efficacy evaluation
Core panic disorder symptoms
The results of the mixed model analyses for frequency
of anticipatory anxiety, frequency of panic attacks
and agoraphobic avoidance (MI-AAL) are summar-
ized in Table 2. For anticipatory anxiety, the p value
for the drugrtime effect was 0.0353, which was non- significant after adjustment for multiplicity, indicating
no statistically significant main effect of the drug
treatment; the SCBTrtime effect was also non- significant (p=0.1980), as was the test for additive
Table 1. Demographic and clinical characteristics at baseline for the ITT population
Variable SERT+SCBT PBO PBO+SCBT SERT
Age (years) 36.22¡10.9 35.24¡9.9 36.80¡12.2 36.40¡10.0
Female gender 44 (74.6) 37 (57.7) 47 (73.4) 33 (53.2)
Primary diagnosis
Panic disorder 15 (24.2) 20 (31.2) 15 (24.2) 21 (35.6)
Panic disorder with agoraphobia 47 (75.8) 44 (68.7) 47 (75.8) 38 (64.4)
Secondary diagnosis 23 (37.1) 25 (39.1) 30 (48.4) 27 (45.8)
Major depression 5 (8.1) 4 (6.2) 4 (6.4) 4 (6.8)
Dysthymia – – 1 (1.5) 2 (3.4)
Generalized anxiety disorder 6 (9.6) 9 (14.1) 2 (3.2) 7 (11.9)
Social anxiety disorder 7 (11.3) 6 (9.4) 15 (24.2) 6 (10.2)
Specific phobia 4 (6.4) 5 (7.8) 5 (8.1) 4 (6.8)
Anxiety disorder NOS – – 1 (1.6) –
Othera 1 (1.6) 1 (1.6) 2 (3.2) 4 (6.8)
Duration of PD (years) 9.74¡10.5 10.33¡10.9 8.95¡8.0 10.63¡9.5
Number of panic attacks in 2 weeks 11.06¡13.4 8.27¡7.5 8.97¡7.4 12.34¡19.2
ITT, intent-to-treat; SERT, sertraline; SCBT, self-administered cognitive behavior therapy; PBO, placebo; NOS, not otherwise
specified; PD, panic disorder.
Values are given as n (%) or mean¡standard deviation. a Other secondary diagnosis included hypochondriasis, learning disability, eating disorder and avoidant personality disorder.
Self-administered CBT and sertraline for panic disorder 5
interaction of the two treatments over time (p=0.7506). The predicted linear trends in the four treatment
groups are displayed in Fig. 2a. There were significant
rates of decline in the mean frequency of anticipatory
anxiety over time in all four groups, with estimated
weekly reductions of 1.6, 1.3, 1.1 and 0.6% in the
SERT/SCBT, SERT, PBO/SCBT and PBO groups re-
spectively. At week 12, the predicted mean frequency
of anxiety was 8.9, 11.7, 13.6 and 14.5% in the SERT/
SCBT, SERT, PBO/SCBT and PBO groups respect-
ively, but none of the pairwise comparisons were
significantly different; moreover, among patients en-
tering the continuation phase, none of the pairwise
comparisons at weeks 16, 20 and 24 were significant.
For panic attack frequency, the drugrtime and SCBTrtime effects were non-significant (p=0.5289 and 0.1234 respectively), and the test for the additive
interaction of the two treatments over time was also
non-significant (p=0.4550). Thus, there were no stat- istically significant effects on panic attack frequency
over time associated with any of the treatments. The
predicted trends for the four groups are displayed
in Fig. 2b. There were significant reductions in the risk
of panic attacks over time in all four groups with esti-
mated weekly relative risk reductions of 4.3, 5.9, 4.5
and 2.9% in the SERT/SCBT, SERT, PBO/SCBT and
PBO groups respectively. At week 12, the predicted
mean frequency of panic attacks was 11.4, 8.3, 6.8 and
12.1 times per week in the SERT/SCBT, SERT, PBO/
SCBT and PBO groups respectively, but none of the
pairwise differences were statistically significant. The
absence of effects persisted into the extension phase,
with no significant differences observed in the fre-
quency of panic attacks at weeks 16, 20 or 24.
For the MI-AAL there were no significant linear or
quadratic drug by time or SCBT by time effects, and
the tests for additive interaction effects over time were
also not significant. The predicted quadratic trends for
the four groups are displayed in Fig. 2c. There were
significant quadratic rates of decline in all four groups.
The mean scores at week 12 were 1.5, 1.9, 1.8 and 2.0 in
the SERT/SCBT, SERT, PBO/SCBT and PBO groups
respectively, with the Tukey–Kramer adjusted pair-
wise comparison between SERT/SCBT and PBO
significant [adjusted (adj) p=0.0155]. For patients en- tering the continuation phase, the mean scores at week
24 were significantly lower in SERT/SCBT than in
PBO (adj p=0.0331) and significantly lower in SERT/ SCBT than in PBO/SCBT (adj p=0.0455).
Dysfunctional thoughts
The results of the mixed model analysis for scores on
the BSQ and ACQ are summarized in Table 2. There
were no significant linear or quadratic drug by timeT a b le
2 . R es u lt s of
m ix ed
m od el an al y se s
V a ri a b le
A n ti ci p a to ry
P a n ic
fr e q u e n cy
M I- A A L
B S Q
A C Q
C G I- S
C G I- I
S D S W
o rk
L if e
S D S S o ci a l
L if e
S D S F a m il y
L if e
In te rc e p t
2 2 .0 ** * (2 .8 1 )
2 .8 5 ** * (0 .1 3 )
2 .3 1 ** * (0 .1 2 )
4 6 .5 ** * (1 .4 7 )
3 1 .2 ** * (1 .0 6 )
4 .4 6 ** * (0 .1 1 )
x 3 .8 1 ** * (0 .0 2 )
5 .3 6 ** * (0 .3 3 )
5 .4 9 ** * (0 .3 2 )
1 .4 2 ** * (0 .1 1 )
D ru g
5 .6 5 (3 .9 7 )
x 0 .2 1 (0 .1 7 )
x 0 .0 2 (0 .1 7 )
x 3 .6 9 (2 .0 7 )
x 2 .0 2 (1 .5 0 )
x 0 .1 3 (0 .1 5 )
0 .3 6 (1 .4 3 )
0 .0 4 (0 .4 7 )
0 .2 2 (0 .4 6 )
0 .0 2 (0 .1 6 )
S C B T
4 .2 3 (3 .9 3 )
x 0 .2 0 (0 .1 7 )
x 0 .0 4 (0 .1 7 )
x 3 .0 0 (2 .0 5 )
x 0 .7 6 (1 .4 9 )
x 0 .1 0 (0 .1 5 )
0 .8 8 (2 .4 2 )
x 0 .5 7 (0 .4 7 )
x 0 .3 5 (0 .4 5 )
0 .1 6 (0 .1 6 )
D ru g r S C B T
x 3 .7 0 (5 .6 3 )
0 .5 4 **
(0 .2 6 )
0 .0 6 (0 .2 5 )
7 .0 0 **
(2 .9 4 )
1 .9 6 (2 .1 3 )
0 .2 1 (0 .2 1 )
x 0 .7 2 (0 .4 8 )
0 .2 2 (0 .6 7 )
0 .7 2 (0 .6 5 )
0 .0 7 (0 .2 3 )
T im
e x 0 .6 2 ** * (0 .2 4 )
x 0 .0 3 **
(0 .0 1 )
x 0 .0 7 **
(0 .0 2 )
x 3 .0 4 ** * (0 .3 6 )
x 1 .5 9 ** * (0 .2 4 )
x 0 .1 3 ** * (0 .0 2 )
0 .7 4 ** * (2 .1 0 )
x 0 .1 0 ** * (0 .0 3 )
x 0 .3 2 (0 .0 8 )
x 0 .0 6 * (0 .0 3 )
D ru g r ti m e
x 0 .7 0 * (0 .3 3 )
x 0 .0 1 (0 .0 2 )
0 .0 1 (0 .0 3 )
0 .5 0 (0 .5 1 )
0 .0 8 (0 .3 3 )
x 0 .0 3 (0 .0 2 )
0 .0 9 (1 .1 0 )
– x 0 .1 0 (0 .1 1 )
0 .0 0 6 (0 .0 4 )
S C B T r ti m e
x 0 .4 3 (0 .3 3 )
x 0 .0 3 (0 .0 2 )
0 .0 0 5 (0 .0 3 )
0 .3 7 (0 .5 0 )
0 .1 3 (0 .3 3 )
x 0 .0 2 (0 .0 2 )
x 0 .0 9 (0 .9 2 )
x 0 .0 3 (0 .0 4 )
x 0 .0 5 (0 .1 1 )
x 0 .0 2 (0 .0 4 )
D ru g r S C B T
r ti m e
0 .1 5 (0 .4 7 )
0 .0 3 (0 .0 4 )
x 0 .0 8 (0 .0 5 )
x 1 .9 5 **
(0 .7 3 )
x 0 .7 4 (0 .4 7 )
x 0 .0 2 (0 .0 3 )
0 .3 2 (1 .3 7 )
x 0 .0 2 (0 .0 4 )
x 0 .1 4 (0 .1 6 )
x 0 .0 5 (0 .0 5 )
T im
e 2
– –
0 .0 0 4 **
(0 .0 0 2 )
0 .1 7 ** * (0 .0 3 )
0 .0 9 ** * (0 .0 2 )
– x 0 .0 3 ** * (0 .9 7 )
x 0 .0 6 (0 .0 5 )
0 .0 2 (0 .0 0 5 )
0 .0 0 3 (0 .0 0 2 )
D ru g r ti m e 2
– –
x 0 .0 0 2 (0 .0 0 2 )
x 0 .0 3 (0 .0 4 )
x 0 .0 0 1 (0 .0 2 )
– x 0 .0 1 (0 .9 9 )
– 0 .0 0 2 (0 .0 1 )
x 0 .0 0 1 (0 .0 0 3 )
S C B T r ti m e 2
– –
x 0 .0 0 1 (0 .0 0 2 )
x 0 .0 4 (0 .0 4 )
x 0 .0 3 (0 .0 2 )
– 0 .0 0 2 (1 .0 0 )
– x 0 .0 0 5 (0 .0 1 )
x 0 .0 0 4 (0 .0 0 3 )
D ru g r S C B T
r ti m e 2
– –
0 .0 0 4 (0 .0 0 3 )
0 .1 0 * (0 .0 5 )
0 .0 5 (0 .0 3 )
– x 0 .0 1 (0 .9 9 )
– 0 .0 1 (0 .0 1 )
0 .0 0 4 (0 .0 0 4 )
S C B T , S e lf -a d m in is te re d co g n it iv e b e h a v io r th e ra p y ; M I- A A L , M o b il it y In v e n to ry
fo r A g o ra p h o b ia
A lo n e ; B S Q , B o d y S e n sa ti o n s Q u e st io n n a ir e ; A C Q , A g o ra p h o b ic
C o g n it io n s Q u e st io n n a ir e ; C G I- S , C li n ic a l
G lo b a l Im
p re ss io n -S e v e ri ty
; C G I- I, C li n ic a l G lo b a l Im
p re ss io n -I m p ro v e m e n t ; S D S , S h e e h a n D is a b il it y S ca le .
* p < 0 .0 5 , **
p < 0 .0 1 , ** * p < 0 .0 0 1 .
6 D. Koszycki et al.
or SCBT by time effects for the BSQ; however, the p
values for the additive interaction effects of the two
treatments were 0.0078 and 0.0478 for the linear and
quadratic time effects respectively; thus, after adjust-
ment for multiplicity, there was a statistically signifi-
cant interaction effect of SERT and SCBT over time.
The predicted quadratic trends for the four groups are
displayed in Fig. 2d. The results show significant
quadratic rates of decline in all four groups; pairwise
comparisons of the quadratic trends among the four
groups using multiple degree of freedom contrasts in
the mixed-effects model revealed that the quadratic
trend in the SERT/SCBT group was significantly
different from the quadratic trends in the PBO
(p=0.0003), PBO/SCBT (p=0.0027) and SERT groups (p<0.0001), even after adjustment for multiplicity. Neither SERT nor PBO/SCBT was significantly dif-
ferent from PBO, and SERT was not significantly dif-
ferent from PBO/SCBT. The mean scores at week 12
were 26.6, 33.0, 30.1 and 34.7 in the SERT/SCBT, SERT,
PBO/SCBT and PBO groups respectively and Tukey–
Kramer-adjusted pairwise comparisons at week 12
revealed a significant difference between SERT/SCBT
and SERT (adj p=0.0180) and between SERT/SCBT and PBO (adj p=0.0014). Among patients advancing to extension treatment, the mean scores on the BSQ
(a) (b) 30 28 26 24 22 20 18 16 14 12 10
8 6
24
22
20
18
16
14
12
10
8
6
4
P re
d ic
te d
m ea
n (
% o
f th
e ti
m e)
P re
d ic
te d
f re
q u
ec n
y
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12 Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
Group PBO SCBT SERT/SCBTSERT
Group PBO PBO/SCBT SERT/SCBTSERT
Group PBO SCBT SERT/SCBTSERT
Group PBO PBO/SCBT SERT/SCBTSERT
Group PBO SCBT SERT/SCBTSERT
Group PBO SCBT SERT/SCBTSERT
(c) (d)
(e) (f )
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
P re
d ic
te d
m ea
n
P re
d ic
te d
m ea
n
P re
d ic
te d
m ea
n
P re
d ic
te d
m ea
n
35
30
25
20
15
55
50
45
40
35
30
25
20
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Fig. 2. Predicted mean scores from weeks 0 to 12 for core panic symptoms, dysfunctional cognitions and clinical global
impression: (a) frequency of anticipatory anxiety; (b) frequency of panic attacks; (c) Mobility Inventory for Agoraphobia
Alone (MI-ALL); (d) Body Sensations Questionnaire (BSQ); (e) Agoraphobic Cognitions Questionnaire (ACQ); (f) Clinical
Global Impression – Severity (CGI-S).
Self-administered CBT and sertraline for panic disorder 7
were significantly lower in SERT/SCBT than in PBO at
weeks 16, 20 and 24 (adj p=0.0014, 0.0014, and 0.0063 respectively), and significantly lower in SERT/SCBT
than in SERT at weeks 16 and 20 (adj p=0.0104 and 0.0124 respectively).
There were no significant linear or quadratic drug
by time or SCBT by time effects for the ACQ, and the
tests for additive interaction of the two treatments
were also non-significant. The predicted quadratic
trends for the four groups are displayed in Fig. 2e.
There were significant quadratic rates of decline in the
mean ACQ scores in all four groups. At week 12, the
predicted mean scores on the ACQ were 20.1, 23.7,
21.4 and 25.1 in the SERT/SCBT, SERT, PBO/SCBT
and PBO groups respectively, with the difference
between SERT/SCBT and PBO statistically significant
(adj p=0.0058). Among patients advancing to exten- sion treatment, the mean scores on the ACQ remained
significantly lower in SERT/SCBT than PBO at
weeks 16, 20 and 24 (adj p=0.0049, 0.0038 and 0.0089 respectively).
CGI
The results of the mixed model analyses for the CGI-S
scale are summarized in Table 2. There were no sig-
nificant drugrtime or SCBTrtime effects, and the additive interaction effect for the two treatments was
also not significant. The predicted linear trends in
the four groups are displayed in Fig. 2f. There were
significant rates of decline in mean CGI-S scores in
all four groups, with estimated weekly rates of decline
of 0.19, 0.15, 0.14 and 0.12 in the SERT/SCBT, SERT,
PBO/SCBT and PBO groups respectively. The mean
CGI-S scores at week 12 were 2.0, 2.4, 2.6 and 2.9 in
the SERT/SCBT, SERT, PBO/SCBT and PBO groups
respectively, with a statistically significant difference
between SERT/SCBT and PBO (adj p=0.0048). Among patients advancing to extension treatment, the
mean scores on the GCI-S scale remained significantly
lower in SERT/SCBT than in PBO at weeks 20 and 24
(adj p=0.0465 and 0.0298 respectively). The results of the logistic regression analysis of
the CGI-I scale (categorized as ‘much improved’ or
‘very much improved’ versus other) are summarized
in Table 2. There were no significant linear or quad-
ratic drugrtime or SCBTrtime effects, and the tests for additive interaction were also non-significant.
There was a significant increase in the odds of im-
provement over time in all four groups. The predicted
probabilities of improvement at week 12 were 87.3%
for SERT/SCBT, 70.8% for SERT, 66.7% for PBO/
SCBT, and 64.1% for PBO; the difference between
SERT/SCBT and PBO was significant (p=0.0086). Among patients advancing to extension treatment, the
difference between SERT/SCBT and PBO remained
significant at weeks 20 (p=0.0019) and 24 (p<0.0001); additionally, the difference between SERT/SCBT and
PBO/SCBT was significant at weeks 20 (p=0.0015) and 24 (p=0.0003).
Patient-rated disability
The results of the mixed model analyses for the SDS
subscales are summarized in Table 2. The predicted
linear trends in the four groups are displayed in Fig. 3.
For the subscale relating to work, the linear trend
model revealed no significant drugrtime or SCBTr time effects, and the test of additive interaction of drug
and SCBT over time was also not significant. The pre-
dicted means at week 12 were 1.8, 3.4, 2.8 and 4.0 in
the SERT/SCBT, SERT, PBO/SCBT and PBO groups
(a)
(b)
(c)
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
Group PBO PBO/SCBT SERT/SCBTSERT
Group PBO PBO/SCBT SERT/SCBTSERT
Group PBO PBO/SCBT SERT/SCBTSERT
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (weeks)
P re
d ic
te d
m ea
n
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
P re
d ic
te d
m ea
n P
re d
ic te
d m
ea n
2.0
1.5
1.0
0.5
0.0
Fig. 3. Predicted mean scores from weeks 0 to 12 for the
Sheehan Disability Scales (SDS) in the areas of (a) work,
(b) social life and (c) family life.
8 D. Koszycki et al.
respectively, with significant differences between
SERT/SCBT and PBO (adj p=0.0005) and between SERT/SCBT and SERT (adj p=0.0287). Among patients advancing to extension treatment, the mean
scores in the SERT/SCBT group remained signifi-
cantly lower than PBO at weeks 16, 20 and 24 (adj
p=0.0003, 0.0007, 0.0123 respectively). For the SDS subscale relating to social life, the
mixed model revealed no significant linear or quad-
ratic drugrtime, SCBTrtime, or drugrSCBTrtime effects. The predicted means at week 12 were 2.3, 3.4,
3.2 and 4.1 in the SERT/SCBT, SERT, PBO/SCBT and
PBO groups respectively; the difference between
SERT/SCBT and PBO was statistically significant (adj
p=0.0017). Among patients advancing to extension treatment, this difference remained significant at
weeks 16, 20 and 24 (adj p=0.0002, 0.0002 and 0.0039 respectively); moreover, scores were significantly
lower in SERT than in PBO at weeks 16 and 20 (adj
p=0.0295 and 0.0272 respectively). For the SDS subscale relating to family life, the
mixed model analyses revealed that there were no
significant drugrtime, SCBTrtime or drugrSCBTr time interactions. The predicted means at week 12
were 0.82, 1.03, 0.93 and 1.10 in the SERT/SCBT, SERT,
PBO/SCBT and PBO groups respectively, but these
were not significantly different. For patients entering
the continuation phase, the mean scores on the SDS
subscale relating to family life were significantly lower
in SERT/SCBT versus PBO at week 20 (adj p=0.0452) and in SERT/SCBT versus PBO/SCBT at week 24
(adj p=0.0375).
Discussion
This is the first multisite placebo-controlled trial of the
efficacy of a self-help intervention and pharmacother-
apy in patients with PD. Primary analyses of longi-
tudinal data revealed a significant difference in the
trend over time for the BSQ but not for any other
measure; specifically, sertraline plus SCBT produced
the greatest decline in fear of bodily sensations com-
pared to placebo and the active treatments. Secondary
analyses revealed that the combination of sertraline
and SCBT was the only active treatment that could be
differentiated from placebo at weeks 12 and 24. With
the exception of frequency of panic attacks and an-
ticipatory anxiety, combined treatment was superior
to placebo in reducing scores on the MI-AAL, BSQ,
ACQ, CGI-S, CGI-I and SDS subscales. One expla-
nation why combination treatment was not better than
placebo in reducing panic attacks and anticipatory
anxiety is that these core symptoms of PD can fluctu-
ate widely from week to week and their episodic
nature makes them subject to substantial variability
that can attenuate treatment differences (Pollack et al.
1998). The study also failed to demonstrate that co-
administration of sertraline and SCBT improved out-
come relative to the other active treatments. Although
sertraline/SCBT fared better than sertraline mono-
therapy in reducing week-12 scores on the BSQ and
SDS-work subscale, and better than placebo/SCBT
in reducing week-24 scores on the MI-AAL and
SDS-family subscale, no other differences emerged.
An unexpected finding in this study was that
sertraline alone did not fare better than placebo in
improving symptoms of PD. This contrasts with three
large randomized trials that demonstrated an advan-
tage of sertraline over placebo drug in the acute treat-
ment of PD (Londborg et al. 1998; Pohl et al. 1998;
Pollack et al. 1998). Because negative results are not
often reported by industry sponsors, we have no ac-
cess to unpublished data and cannot compare our
findings with other negative trials. Nevertheless, our
study closely resembles positive outcome trials in
terms of sample size, patient demographics and clini-
cal characteristics such as duration of PD and presence
of agoraphobia. Our study also resembles these trials
with respect to duration and dosage of sertraline
treatment and attrition rates. The only discernable
difference between this study and other trials is that
our study patients were more ill. They had more fre-
quent panic attacks at baseline and more co-morbid
Axis I disorders. Co-morbidity can make PD difficult
to treat and reduces the efficacy of selective serotonin
reuptake inhibitors (SSRIs) (Pollack et al. 2000). It is
therefore possible that the failure to detect a sertra-
line–placebo difference in the present study may be
attributed to the presence of a more severe disorder.
In contrast to the favorable outcome with the com-
bined treatment of sertraline and SCBT, placebo plus
SCBT showed no advantage over placebo alone.
Several studies have reported that self-directed CBT
with varying degrees of therapist contact is more ef-
fective than a control condition in alleviating core
symptoms of PD (Gould et al. 1993; Lidren et al. 1994;
Febrarro et al. 1999; Carlbring et al. 2001; Febbraro,
2005). However, not all studies have found that self-
directed CBT is effective (Holden et al. 1983; Hecker
et al. 1996). A limitation across positive outcome trials
is that a high proportion of patients were on stable
doses of anti-panic medication. As a result, we cannot
rule out the possibility that the addition of a self-help
intervention augmented response to pharmacother-
apy. The generalizability of these self-help studies is
also limited by the fact that the sample sizes were
small and most participants were mildly ill. Our
study, based on a larger number of patients, suggests
that SCBT without any therapist assistance may not be
an effective intervention for patients with moderate to
Self-administered CBT and sertraline for panic disorder 9
severe PD, who may require therapist-directed CBT or
adjunctive pharmacotherapy. One important caveat of
this study is that we did not include an SCBT alone
treatment cell. SCBT plus placebo drug is not equiv-
alent to SCBT alone and patients may have different
expectations about being treated with or without
medication, which could affect outcome. Studies in-
volving therapist-delivered CBT have reported that
placebo drug enhances the effects of CBT during acute
treatment (Furukawa et al. 2007). Thus, it is possible
that SCBT alone would have fared worse than it did in
the present trial. Although we realize that the addition
of an SCBT only group would have been preferable, it
was beyond the limited resources of this study.
To summarize, this multicenter trial suggests that
sertraline combined with SCBT may be an effective
treatment for PD. The current data could not confirm
the efficacy of sertraline monotherapy or self-directed
CBT without concomitant medication or therapist as-
sistance in the treatment of PD. Future studies of self-
help interventions should be carried out in primary
care settings where the majority of PD patients initially
present.
Study registration
This study was approved by Health Canada and car-
ried out entirely in Canada. The study was completed
prior to the requirement for registration with Clin-
icalTrials.gov or any other registry.
Acknowledgments
This work was supported by the Canadian Institutes
of Health Research (POP-15247) and Pfizer Canada.
We thank Dr V. Hadrava of Pfizer Canada for his
generous support during the study. Data management
was provided by Dr N. B. Segal of SciMed, Consulting,
Scarborough, Ontario. The participating sites were:
Clarke Institute of Psychiatry, University of Toronto,
Toronto (Dr J. Bradwejn); Royal Ottawa Hospital,
University of Ottawa, Ottawa (Dr D. Bakish); Centre
Universitaire de Sante de Sherbrooke (CUSE), Uni-
versity of Sherbrooke, Sherbrooke (Dr J.-P.
Boulanger); PsycHealth Centre, Winnipeg (Dr M.
Enns); Victoria Hospital, London (Dr R. Kraus); Hotel-
Dieu de Levis, Levis (Dr C. Lajeunesse); Kelowna
General Hospital, Kelowna (Dr P. Latimer); University
of Western Ontario Hospital Campus, London (Dr E.
McCrank); Centre Hospitalier Pierre Janet, Hull (Dr R.
Payeur); Centre Hospitalier Universitaire de Laval,
Universite de Laval, Quebec (Dr J. Plamondon);
Western Canada Behavior Center, Calgary (Dr R.
Reesal); Vancouver Hospital, Vancouver (Dr O.
Robinow); University of Alberta Hospital, Edmonton
(Dr P. Silverstone); and Chedoke McMaster Hospitals,
Hamilton (Dr M. Van Ameringen).
Declaration of Interest
Dr J. Bradwejn acted during and subsequent to the
completion of this study as a Principal Investigator for
clinical trials sponsored by Wyeth, Novartis, Johnson
and Johnson, and SmithKline Beecham. He also acted
as a consultant for Servier and as a speaker for
SmithKline Beecham and Servier.
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