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Th e u se r h as r e q ueste d e n han ce m en t o f t h e d ow nlo ad ed f il e . All i n -t e xt r e fe re n ce s un d erlin ed i n b lu e a re a d ded t o t h e o rig in al d ocu m en t an d a re l in ked t o p ub lic a tio n s o n R ese a rc h G ate , l e ttin g y o u a cce ss a n d r e a d t h em i m med ia te ly . A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder D. Koszycki 1,2*, M. Taljaard 3,4, Z. Segal 5and J. Bradwejn 2 1Faculty of Education, University of Ottawa, ON, Canada2Department of Psychiatry, University of Ottawa, ON, Canada3Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada4Department of Epidemiology and Community Medicine, University of Ottawa, ON, Canada5Departments 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 ; Bakkeret 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 thatcombined 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 (Markset 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 : [email protected]) Psychological Medicine, Page 1 of 11.fCambridge 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 (Gouldet al. 1993 ; Gould & Clum, 1995 ; Carlbringet al. 2003), with some studies reporting equivalence of self- to therapist-directed CBT (Lidrenet al. 1994 ; Parket al. 2001 ; Carlbringet al.

2005 ; Kiropouloset 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 ; Firstet 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 wasf17 (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 psychotropicswithin 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 (McAlisteret 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. 2D. 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 Fawcettet 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 assessfrequency of panic attacks and frequency of anticipat- ory anxiety, and the avoidance-alone subscale of the Mobility Inventory for Agoraphobia (MI-AAL ; Chamblesset 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 (Chamblesset al.

1984), and the Agoraphobic Cognitions Questionnaire (ACQ), which measures panic-related cognitions (Chamblesset 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 (Sheehanet 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 (t 2) to allow for possible quadratic trends over time ; Self-administered CBT and sertraline for panic disorder3 two-way interactions betweent 2and drug, andt 2and SCBT ; and three-way interactions between time, drug and SCBT, in addition tot 2, 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 thepvalue for any eﬀect in our regression models to bef0.05 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 theBonferroni-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.

4D. 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 invital 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, thepvalue 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) – Other a 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 asn( %) or mean¡standard deviation. aOther secondary diagnosis included hypochondriasis, learning disability, eating disorder and avoidant personality disorder. Self-administered CBT and sertraline for panic disorder5 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 (adjp=0.0331) and signiﬁcantly lower in SERT/ SCBT than in PBO/SCBT (adjp=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 time Table 2.Results of mixed model analyses Variable AnticipatoryPanic frequency MI-AAL BSQ ACQ CGI-S CGI-ISDS Work LifeSDS Social LifeSDS Family Life Intercept 22.0*** (2.81) 2.85*** (0.13) 2.31*** (0.12) 46.5*** (1.47) 31.2*** (1.06) 4.46*** (0.11)x3.81*** (0.02) 5.36*** (0.33) 5.49*** (0.32) 1.42*** (0.11) Drug 5.65 (3.97)x0.21 (0.17)x0.02 (0.17)x3.69 (2.07)x2.02 (1.50)x0.13 (0.15) 0.36 (1.43) 0.04 (0.47) 0.22 (0.46) 0.02 (0.16) SCBT 4.23 (3.93)x0.20 (0.17)x0.04 (0.17)x3.00 (2.05)x0.76 (1.49)x0.10 (0.15) 0.88 (2.42)x0.57 (0.47)x0.35 (0.45) 0.16 (0.16) DrugrSCBTx3.70 (5.63) 0.54** (0.26) 0.06 (0.25) 7.00** (2.94) 1.96 (2.13) 0.21 (0.21)x0.72 (0.48) 0.22 (0.67) 0.72 (0.65) 0.07 (0.23) Timex0.62*** (0.24)x0.03** (0.01)x0.07** (0.02)x3.04*** (0.36)x1.59*** (0.24)x0.13*** (0.02) 0.74*** (2.10)x0.10*** (0.03)x0.32 (0.08)x0.06* (0.03) Drugrtimex0.70* (0.33)x0.01 (0.02) 0.01 (0.03) 0.50 (0.51) 0.08 (0.33)x0.03 (0.02) 0.09 (1.10) –x0.10 (0.11) 0.006 (0.04) SCBTrtimex0.43 (0.33)x0.03 (0.02) 0.005 (0.03) 0.37 (0.50) 0.13 (0.33)x0.02 (0.02)x0.09 (0.92)x0.03 (0.04)x0.05 (0.11)x0.02 (0.04) DrugrSCBT rtime0.15 (0.47) 0.03 (0.04)x0.08 (0.05)x1.95** (0.73)x0.74 (0.47)x0.02 (0.03) 0.32 (1.37)x0.02 (0.04)x0.14 (0.16)x0.05 (0.05) Time 2 – – 0.004** (0.002) 0.17*** (0.03) 0.09*** (0.02) –x0.03*** (0.97)x0.06 (0.05) 0.02 (0.005) 0.003 (0.002) Drugrtime 2 ––x0.002 (0.002)x0.03 (0.04)x0.001 (0.02) –x0.01 (0.99) – 0.002 (0.01)x0.001 (0.003) SCBTrtime 2 ––x0.001 (0.002)x0.04 (0.04)x0.03 (0.02) – 0.002 (1.00) –x0.005 (0.01)x0.004 (0.003) DrugrSCBT rtime 2 – – 0.004 (0.003) 0.10* (0.05) 0.05 (0.03) –x0.01 (0.99) – 0.01 (0.01) 0.004 (0.004) SCBT, Self-administered cognitive behavior therapy ; MI-AAL, Mobility Inventory for Agoraphobia Alone ; BSQ, Body Sensations Questionnaire ; ACQ,Agoraphobic Cognitions Questionnaire ; CGI-S, Clinical Global Impression-Severity ; CGI-I, Clinical Global Impression-Improvement ; SDS, Sheehan Disability Scale.

*p<0.05, **p<0.01, ***p<0.001. 6D. Koszycki et al. or SCBT by time eﬀects for the BSQ ; however, thep 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 signiﬁcantlydiﬀerent 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 (adjp=0.0180) and between SERT/SCBT and PBO (adjp=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 8 624 22 20 18 16 14 12 10 8 6 4 Predicted mean (% of the time) Predicted frequecny 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) GroupPBO SCBT SERT/SCBT SERT GroupPBO PBO/SCBT SERT/SCBT SERT GroupPBO SCBT SERT/SCBT SERTGroupPBO PBO/SCBT SERT/SCBT SERT GroupPBO SCBT SERT/SCBT SERT GroupPBO SCBT SERT/SCBT SERT (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 Predicted mean Predicted mean Predicted mean Predicted mean 35 30 25 20 1555 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 disorder7 were signiﬁcantly lower in SERT/SCBT than in PBO at weeks 16, 20 and 24 (adjp=0.0014, 0.0014, and 0.0063 respectively), and signiﬁcantly lower in SERT/SCBT than in SERT at weeks 16 and 20 (adjp=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 (adjp=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 (adjp=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 (adjp=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 (adjp=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 ’versusother) 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, thediﬀerence 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 1.0Group PBO PBO/SCBT SERT/SCBT SERT Group PBO PBO/SCBT SERT/SCBT SERT GroupPBO PBO/SCBT SERT/SCBT SERT 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) 0123456789101112 Time (weeks) Predicted mean 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 Predicted mean Predicted mean 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. 8D. Koszycki et al. respectively, with signiﬁcant diﬀerences between SERT/SCBT and PBO (adjp=0.0005) and between SERT/SCBT and SERT (adjp=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 (adjp=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/SCBTversusPBO at week 20 (adjp=0.0452) and in SERT/SCBTversusPBO/SCBT at week 24 (adjp=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 variabilitythat can attenuate treatment diﬀerences (Pollacket 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 (Londborget al. 1998 ; Pohlet al. 1998 ; Pollacket 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) (Pollacket 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 (Gouldet al. 1993 ; Lidrenet al. 1994 ; Febrarroet al. 1999 ; Carlbringet al. 2001 ; Febbraro, 2005). However, not all studies have found that self- directed CBT is eﬀective (Holdenet 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 disorder9 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 (Furukawaet 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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