Does Maintenance CBT Contribute to Long-Term Treatment Response of
Panic Disorder With or Without Agoraphobia? A Randomized Controlled
Kamila S. White
University of Missouri, St. Louis
Laura A. Payne
University of California, Los Angeles
Jack M. Gorman
Franklin Behavioral Health Consultants, Bronx, New York
M. Katherine Shear
Scott W. Woods and John R. Saksa
Yale University School of Medicine
David H. Barlow
Objective: We examined the possibility that maintenance cognitive behavior therapy (M–CBT) may
improve the likelihood of sustained improvement and reduced relapse in a multi-site randomized
controlled clinical trial of patients who met criteria for panic disorder with or without agoraphobia.
Method: Participants were all patients (N ? 379) who first began an open trial of acute-phase CBT.
Patients completing and responding to acute-phase treatment were randomized to receive either 9
monthly sessions of M–CBT (n ? 79) or assessment only (n ? 78) and were then followed for an
additional 12 months without treatment. Results: M–CBT produced significantly lower relapse rates
(5.2%) and reduced work and social impairment compared to the assessment only condition (18.4%) at
a 21-month follow-up. Multivariate Cox proportional hazards models showed that residual symptoms of
agoraphobia at the end of acute-phase treatment were independently predictive of time to relapse during
21-month follow-up (hazards ratio ? 1.15, p ? .01). Conclusions: M–CBT aimed at reinforcing acute
treatment gains to prevent relapse and offset disorder recurrence may improve long-term outcome for
panic disorder with and without agoraphobia.
Keywords: maintenance treatment, treatment outcome, panic disorder, randomized controlled clinical
trial, cognitive behavior therapy
Panic disorder (PD) is associated with significant personal,
social, and economic costs. PD is prevalent (Kessler et al., 2005),
reduces quality of life (Mendlowicz & Stein, 2000), and ranks
among the most expensive psychiatric disorders (Batelaan et al.,
2007). The clinical course of PD has been characterized as chronic,
with high rates of relapse, particularly for women (Katschnig et al.,
1995; Keller et al., 1994; Yonkers, Bruce, Dyck, & Keller, 2003).
It is well-established that pharmacological treatments show higher
rates of PD recurrence following treatment discontinuation (25%–
85%; Mavissakalian & Perel, 1992; Otto, Pollack, & Sabatino,
1996; Rickels & Schweizer, 1998) compared to cognitive behavior
therapy (CBT; Haby, Donnelly, Corry, & Vos, 2006; Norton &
Price, 2007). Despite encouraging data supporting the relative
durability of CBT, many patients drop out, relapse, or fail to
achieve strong treatment response (Barlow, Gorman, Shear, &
Woods, 2000; Haby et al., 2006). For this reason, strategies to
maintain treatment gains and prevent recurrence over the longer
term are of clinical importance.
CBT is an effective treatment for panic disorder with and
without agoraphobia (PD/A; Craske & Barlow, 2008; McHugh,
Smits, & Otto, 2009). Results of randomized controlled trials
indicate that 50%–80% of patients with PD/A show a clinically
significant improvement in response to CBT (Aaronson et al.,
2008; Öst, Thulin, & Ramnerö, 2004; Schmidt et al., 2000), and
this improvement is relatively durable. For example, in a large
multi-site clinical trial (Barlow et al., 2000), the effects of CBT
This article was published Online First November 5, 2012.
Kamila S. White, Department of Psychology, University of Missouri, St.
Louis; Laura A. Payne, Department of Pediatrics, Pediatric Pain Program,
David Geffen School of Medicine, University of California, Los Angeles;
Jack M. Gorman, Franklin Behavioral Health Consultants, Bronx, New
York; M. Katherine Shear, Department of Psychiatry and School of Social
Work, Columbia University; Scott W. Woods and John R. Saksa, Depart-
ment of Psychiatry, Yale University School of Medicine; David H. Barlow,
Center for Anxiety and Related Disorders and Department of Psychology,
David H. Barlow receives grants, royalties, and honoraria pertaining to
some of the the psychological treatments described in the article. This
research was supported by National Institute of Mental Health Grants R01
MH45963, MH45964, MH45965, and MH45966.
Correspondence concerning this article should be addressed to Kamila S.
White, Department of Psychology, University of Missouri, St. Louis, MO
63121. E-mail: firstname.lastname@example.org
Journal of Consulting and Clinical Psychology
2013, Vol. 81, No. 1, 47–57
© 2012 American Psychological Association
alone were more enduring than medication treatments at 6-month
follow-up, a finding mirroring earlier analyses (Gould, Otto, &
Pollack, 1995). The available data show that 5%–30% of patients
who attain successful acute-phase remission status will relapse in
the 1–2 years following CBT discontinuation (Clark et al., 1994;
Heldt et al., 2011; van Apeldoorn et al., 2010). However, as
encouraging as those data are, single cross-sectional follow-up
assessments necessarily underestimate the presence of infrequent
panics and other fluctuating PD symptoms.
Data from longitudinal CBT follow-up studies support this
contention. For example, a follow-up study of patients with PD/A
treated with CBT found that most patients had a fluctuating post-
treatment course (Brown & Barlow, 1995). Although 75% of
patients were panic-free at 24-month follow-up, only 21% met
criteria for high end-state functioning at both 3 and 24 months
post-treatment and were panic-free for the year preceding the
24-month assessment. It is also noteworthy that this sample by
definition suffered from no more than mild agoraphobia at pre-
treatment. Similar results were reported by Burns, Thorpe, and
Cavallaro (1986) for agoraphobic patients treated with in vivo
exposure therapy. In that study, participants as a group evidenced
continued improvement at assessment points up to 8 years post-
treatment, but longitudinal evaluations showed that their clinical
courses were characterized by periods of setback. Thus, studies
that follow patients over the long-term to examine the durability of
treatment response and the timing of relapse are important.
One of the most positive, although uncontrolled, studies of the
long-term effects of psychological treatment for PD was conducted
by Fava, Zielezny, Savron, and Grandi (1995) on 110 patients with
panic disorder with agoraphobia (PDA) who were treated with in
vivo exposure therapy emphasizing self-directed practice. In that
study, 81 participants achieved remission, defined as being panic
free for the past month and “much better” on a global measure of
improvement (Fava et al., 1995). Survival analysis estimated the
likelihood of staying in remission at 2, 5, and 7 years post-
treatment to be 96%, 77%, and 67%, respectively (projected re-
mission rates of 71%, 57%, and 49% for the intention-to-treat
sample). Although these numbers are good, several points bear
consideration. First, the sample was a consecutive series of pa-
tients meeting Diagnostic and Statistical Manual of Mental Dis-
orders (3rd ed., rev.; DSM–III–R; American Psychiatric Associa-
tion, 1987) criteria for PDA, including low as well as high levels
of agoraphobic avoidance. Many participants who were classified
as responders still had some residual agoraphobic avoidance.
Among those, two thirds relapsed within 5 years. The presence of
residual agoraphobia at the end of behavioral treatment is associ-
ated with relapse over time and this finding has been replicated in
other studies (Dow et al., 2007). This robust finding informed the
rationale for this study examining long-term strategies for PD/A.
In addition, in Fava et al.’s study, benzodiazepine use was permit-
ted, and a sizable proportion of patients (one fourth at the conclu-
sion of treatment) were taking benzodiazepines. Finally, the sur-
vival data are based on cross-sectional assessments that, as noted
earlier, substantially overestimate remission rates.
A major limitation of naturalistic studies is that they do not
involve prospectively planned maintenance treatment. Some do
report on intervening treatment, and most patients are found to
receive it. However, there is little information about the quantity or
quality of such treatment. For example, in Brown and Barlow’s
(1995) 2-year follow-up study of PD/A patients treated with CBT,
33% of the sample had sought additional treatment during the
follow-up interval, 23% specifically for panic attacks. Based on
their study with treatment completers, 27% sought additional treat-
ment due to a less-than-adequate response to initial treatment. All
of these findings indicate a need for clinical methods to sustain
acute treatment response and prevent relapse over time for patients
In this collaborative follow-up study, we developed a mainte-
nance CBT (M–CBT) and tested its efficacy as a long-term strat-
egy for the management of PD/A among responders to 3 months of
acute treatment. The two primary aims in this article are (1) to
examine whether 9 months of monthly M–CBT significantly im-
proved the likelihood of sustained improvement among patients
who responded to acute-phase CBT during those 9 months as well
as for the following 12 months (21 months total) compared to an
assessment only group over the same period, and (2) to examine
clinical predictors associated with loss-of-response (i.e., relapse)
compared to maintenance of response (i.e., survival) over a 21-
month follow-up among patients who responded to acute-phase
CBT. For patients who respond to acute-phase CBT, examining
whether M–CBT (i.e., strategies) sustains acute gains over time
may have useful clinical implications. In this study, the predictors
examined at the end of acute CBT on time to relapse during the
follow-up period included time, randomized group assignment,
age, sex, extent of clinical global improvement, panic disorder
severity, and agoraphobia severity. Demographic factors (i.e., age,
sex) were tested for any differential effects across condition, and
clinical predictors were examined for sustained improvement
across global (i.e., clinical global improvement) and specific mea-
sures (i.e., panic disorder severity). We also examined agoraphobia
symptoms based on evidence showing that residual agoraphobia is
linked with loss of response following acute CBT. We investigated
these aims in a multi-site randomized controlled clinical trial of
patients with PD/A. This study extends past research by examining
treatment-response in a detailed fashion over a relatively long
follow-up of 21-months in a study sufficiently powered to answer
questions about maintenance strategies and in the investigation of
the probability of remaining relapse-free across a number of clin-
ical predictors for PD/A.
A total of 379 patients were recruited in a multi-site clinical trial
examining long-term strategies for the treatment for PD/A at four
sites: Boston, New York, New Haven, and Pittsburgh. Patients
completed a baseline diagnostic interview and were enrolled in the
study at one of these four clinical sites. Inclusion criteria were (a)
a principal Diagnostic and Statistical Manual of Mental Disorders
(4th ed.; DSM–IV; American Psychiatric Association, 1994) diag-
nosis of PD/A; (b) age 18 years or older; (c) no substance abuse or
dependence within the last 6 months; (d) absence of active suicide
potential within the last 6 months; (e) absence of any history of
psychosis, bipolar I disorder, bipolar II disorder, or cyclothymia;
(f) no current application pending or existing for a medical dis-
ability claim; (g) no significant cognitive impairment; (h) free
from current uncontrolled general medical illness requiring inter-
WHITE ET AL.
vention; (i) absence of concurrent psychotherapeutic treatment
directed at anxiety or panic disorders; and (j) no concurrent psy-
chopharmacological treatment that may have anti-panic effects
(participants on anxiolytic medications were required to discon-
tinue medication/s by Session 9). A total of 256 patients completed
the acute phase of the study and post-treatment diagnostic inter-
view and assessment. For additional description and results from
the acute phase of the clinical trial, please see Aaronson et al.
(2008). In sum, the Acute CBT consisted of a modified version of
panic control treatment (Barlow & Craske, 2007; Craske & Bar-
low, 2007) delivered in 11 sessions and covered psychoeducation
on the nature of anxiety and panic, identification and correction of
maladaptive thoughts about anxiety and its consequences, and
interoceptive and situational exposure exercises. Some modifica-
tions included an earlier introduction of interoceptive exposure, the
elimination of breathing retraining except as an optional procedure
chosen by therapists for a small minority of patients to examine
hyperventilatory tendencies rather than as a strategy for reducing
anxiety, and an earlier introduction of paired interoceptive and
situation exposure practices.
This study examines only 168 patients (65%) who were classi-
fied as Acute CBT responders. The 88 patients who did not meet
criteria for responder were assigned to the non-responder arm of
the long term strategies for treating PD/A trial (Payne et al., 2012).
The criteria for Acute CBT treatment response (see pp. 16–17 for
definition of treatment response) were purposely stringent to en-
sure that a sufficient number of individuals would be classified
into the second-stage study (i.e., acute CBT responders; acute CBT
non-responders). Nevertheless, the acute treatment response rate
was comparable to our previous multi-site clinical trial (Barlow et
al., 2000). Of the 168 patients who met criteria for responder, 11
were either not willing (e.g., moving) or did not qualify due to
study protocol violations (e.g., filing a claim for medical disability)
to be randomized resulting in a randomized sample of 157 re-
sponders. Patients were randomized to one of two groups: either
M–CBT (n ? 79) or Assessment Only condition (n ? 78). Of the
patients randomized to M–CBT, three randomized patients did not
enter treatment. We included data on all 157 randomized partici-
pants as the intent to treat sample. Study inclusion and exclusion
for the randomization study were, of course, identical to the
criteria for the acute phase of the study since those patients were
continued on to randomization. At randomization, all patients were
reminded of and agreed to adhere to initial study enrollment
criteria from the acute phase including the absence of concurrent
psychotherapeutic treatment directed at anxiety or panic disorders
and no concurrent psychopharmacological treatment that may have
anti-panic effects (e.g., selective serotonin reuptake inhibitors
[SSRIs], benzodiazepines). Responders were followed for a total
of 21 months following Acute CBT, and independent-evaluators
(IEs) who were blinded to patients’ progress in the study con-
ducted all assessments. IEs continued to assess for concurrent drug
or psychotherapeutic treatment throughout the study.
Therapists and Treatment
Therapists were experienced clinicians trained and supervised in
the M–CBT protocol by personnel at the Boston site. All therapists
were either doctoral-level clinicians (Ph.D. or graduate level
Sixteen therapists administered the M–CBT.
clinicians-in-training). Therapists were 22–52 years of age (M ?
37.8, SD ? 10) and reported 0.6–20 years of experience with CBT
(M ? 6.1, SD ? 5.1). They were 43% male, and most identified
themselves as cognitive-behavioral (85%) or psychodynamic
(10%) in orientation. In all but one case, the M–CBT therapist was
the same one who conducted the patient’s Acute CBT treatment.
Training included didactic instruction, hour-for-hour supervi-
sion of at least two training cases, and group supervision meetings
during which both specific application and general issues of the
treatment protocol were discussed. All M–CBT sessions were
audiotaped, and sessions were independently evaluated and rated
by trained and certified adherence raters for adherence and com-
pliance with the M–CBT treatment manual and other characteris-
tics of treatment delivery (e.g., therapist use of Socratic question-
ing, patient homework compliance, and rapport). Site coordinators
and therapists were provided with results of the Adherence and
Competence ratings in the cases in which therapists did not adhere
achieve high ratings (i.e., non-adherent session, low competence
rating). The therapist then underwent additional training and re-
ceived additional supervision before another case was assigned.
Maintenance CBT (M–CBT).
(1) encourage continued practice and application of the Acute CBT
treatment skills, and (2) teach relapse prevention strategies includ-
ing distinguishing normal symptom fluctuations from “lapses” and
“relapse,” anticipating and responding constructively to symptom
exacerbations, improving stress management skills, and examining
the costs of recovery.
All sessions were conducted according to an unpublished
M–CBT Therapist treatment protocol (Spiegel & Baker, 1999)
written and developed for this research study. Patient treatment
sessions were delivered according to the protocol and were tailored
to individual patient needs. As noted above, all patients in this
study met a high threshold for response criteria at the post-acute
assessment, although a few patients were still experiencing some
mild symptoms. One aim of M–CBT was to encourage continued
practice of acute CBT treatment skills. For example, for patients
with residual anxiety related to panic and somatic sensations,
continued work on cognitive restructuring skills and interoceptive
exposure was emphasized. For patients with residual or reemerg-
ing agoraphobic avoidance, continued situational exposure was
encouraged. Patients were urged to re-read portions of the acute
treatment client workbook, based on an earlier version of Barlow
and Craske (2007), during M–CBT as applicable. A second aim of
M–CBT was to teach relapse prevention strategies. For example,
patients were taught the distinctions between normal symptom
fluctuations and “lapses” and “relapse.” Identifying any unrealistic
or worrisome thoughts about the extent or durability of his/her
improvement in the months ahead, normalizing and challenging
patient’s thoughts as appropriate, decatastrophizing symptom in-
creases, and assisting the patient establish a plan to cope with
symptom increases were topics. The goal was to help patients act
as their own therapist when confronted with symptom increases or
a situation that may put them at increased risk for slips. A session
on costs of recovery encouraged patients to consider possible
disadvantages of improvement (e.g., increased social expectations,
more work responsibility, less time alone). Home practice was
assigned to accompany each monthly session.
Maintenance treatment consisted of nine monthly, 45–60-min
sessions delivered in individual therapy sessions. Sessions were
The aims of M–CBT were to
delivered with a minimum of 14 days between sessions to allow
patients’ time to complete assigned home practices, and sessions
were delivered within ?14 days from their nominal monthly dates.
Sessions were allowed to be skipped; however, patients who did
not complete at least six of nine sessions were removed from the
Independent-evaluator (IE) certification and measures.
Training and certification.
tensively trained bachelor-level staff, advanced psychology stu-
dents, a registered nurse (RN), and master’s-level and PhD-level
clinicians who underwent a rigorous training and certification
procedure under the direction of the Pittsburgh site to ensure
standardization of administration and diagnostic reliability. Many
evaluators who were previously trained on the Anxiety Disorders
Interview Schedule for DSM–IV: Lifetime Version (ADIS-IV-L;
Di Nardo, Brown, & Barlow, 1994) received additional training
under the direction of the Principal Investigator (PI) at the Pitts-
burgh site. All evaluators who were not already certified on the
ADIS-IV-L attended a 1-day didactic workshop with the PI in
which all measures and procedures used in the study were re-
viewed, including the Anxiety Disorders Interview Schedule–Lite
(ADIS-Lite), which is an adaptation of the ADIS-IV-L.
For certification as an IE, trainees were required to conduct two
certification interviews and meet the following criteria: (1) match
with the trainer on the primary diagnosis; (2) agree within 1 point
on the ADIS-Lite Clinical Severity Rating (CSR); (3) agree within
5 points on the Hamilton Anxiety and Depression Scales (Hamil-
ton, 1959, 1960), with not more than 1-point difference on any one
scale item; (4) agree within 1 point on the Clinical Global Im-
provement Scale (CGI; Guy, 1976) rating; and (5) agree within 3
points on the Panic Disorder Severity Scale–Independent Evalua-
tor Version (PDSS-IE; Shear et al., 1997) total score; with not
more than 1 point difference on any one item. IEs were blind to
patients’ progress in the study.
Anxiety Disorders Interview Schedule–Lite (ADIS-Lite).
ADIS-Lite is an adaptation of the ADIS-IV-L, a semi-structured
clinical interview assessing anxiety, mood, substance use, and
somatoform disorders that has demonstrated excellent to accept-
able interrater reliability for the anxiety and mood disorders (Di
Nardo et al., 1994). The primary adaptation is the assessment of
symptoms within each diagnosis as present/absent rather than as a
dimensional rating (0–8) in the ADIS-IV-L.
Ten percent of all assessments were randomly selected for
diagnostic co-rating by assessment supervisors at the Pittsburgh
site. Intraclass correlation coefficients (ICCs) were calculated to
examine interrater reliability for the clinician-rated ADIS-Lite
diagnoses and CSRs (N ? 164) across the independently con-
ducted clinical interviews. Ratings from primary interviewers (IEs)
were compared with those of secondary raters. Interrater reliability
was mostly acceptable across the diagnoses (panic disorder, ICC ?
.89; agoraphobia, ICC ? .66; major depressive disorder, ICC ?
.99; generalized anxiety disorder, ICC ? .99; obsessive-
compulsive disorder, ICC ? .75; social phobia, ICC ? .91; spe-
cific phobia, ICC ? .80; dysthymia, ICC ? .50; and posttraumatic
stress disorder, ICC ? .49).
IEs at the four sites included ex-
ADIS–Agoraphobia Scale (Ag Scale).
phobic avoidance of 21 common situations (e.g., theaters, public
transportation). Scores for each item range from 0 (no avoidance)
to 4 (extreme avoidance). This measure has demonstrated unidi-
mensionality and good interrater reliability in past similar samples
(r ? .86; Brown, Di Nardo, Lehman, & Campbell, 2001). The Ag
Scale is an indicator of outcome in this study and demonstrated
good internal consistency (Cronbach’s ? ? .84). A subsample of
141 coded interviews were considered a match (75.9%; n ? 107)
across two independent raters and provide support for the interrater
reliability of the scale.
Panic Disorder Severity Scale–Independent Evaluator Version
The PDSS-IE (Shear et al., 1997) is a seven-item
measure for assessing the major features of PD/A that was dem-
onstrated to be the most sensitive measure of outcome for PD/A in
a previous clinical trial (Barlow et al., 2000). Each item is rated on
a 0 (none/mild) to 4 (extreme/severe) scale, and total scores range
from 0 to 14. The PDSS-IE score was one of the main outcomes
of the study. A random sample of 10% of the interviews was
selected for co-rating by an independent rater. Independent raters
listened to an audiotape of the interview and reliability between
raters was calculated using intraclass correlation coefficients. In-
terrater reliability (N ? 434; ICC ? .99) and internal consistency
(? ? .81) were both excellent in this study overall; interrater
reliability was not calculated for this maintenance study.
Clinical Global Improvement Scale (CGI).
1976) is a commonly used global rating instrument in clinical trials
consisting of 7-point scales for rating overall illness severity,
improvement, and treatment response. IEs used an anchored,
interviewer-rated global improvement ranging from 1 (very much
improved) to 7 (very much worse), and evaluators rated the patient
relative to their post-Acute CBT treatment status. The CGI has
good retest reliability among individuals with anxiety disorders
and good inter-rater reliability (Bandelow, Baldwin, Dolberg, An-
derson, & Stein, 2006; Zaider, Heimberg, Fresco, Schneier, &
Leibowitz, 2003). Results of a one-way random intraclass corre-
lation (Shrout & Fleiss, 1979) show a favorable degree of reliabil-
ity on the CGI from the end of Acute CBT to the end of Mainte-
nance CBT; the ICC was .78 with a 95% confidence interval from
0.58 to 0.79.
Structured Interview Guide for the Hamilton Anxiety Rating
Scale (SIGH-A) and Structured Interview Guide for the Hamil-
ton Depression Rating Scale (SIGH-D).
al., 2001) and the SIGH-D (Williams, 1988) are structured formats
for administering the Hamilton Rating Scales (Hamilton, 1959,
1960). Both measures have demonstrated good inter-rater and
test–retest reliability. In the current study recruitment sample, the
SIGH-D demonstrated excellent interrater reliability and internal
consistency (N ? 181; ICC ? .99; ? ? .84), as did the SIGH-A
(N ? 193; ICC ? .99; ? ? .86).
Concurrent treatment assessment.
lowed concurrent psychotherapeutic or drug treatment aimed at
anxiety or panic disorders. At the informed consent for random-
ization, all patients agreed to refrain from concurrent psychother-
apeutic treatment directed at anxiety or panic disorders including
any concurrent psychopharmacological treatment that may have
anti-panic effects (e.g., SSRIs, benzodiazepines). IEs assessed any
IEs rated panic-related
The CGI (Guy,
The SIGH-A (Shear et
The current study disal-
WHITE ET AL.
concurrent psychotherapy or drug therapy at the major assessments
and assessed for concurrent drug therapy at all study assessments.
Patient self-report measures.
Demographic and medical history.
tional history, income, marital status, insurance, and employment
status were some of the demographic factors assessed using a
self-report questionnaire. A general medical and psychiatric his-
tory questionnaire assessed personal and family medical history
and current medication use. Some treatment history was confirmed
during the ADIS-Lite interview assessment (e.g., history of eval-
uation or treatment for emotional problems).
Anxiety Sensitivity Index (ASI).
1987) is a 16-item self-report scale that is used to assess anxiety
focused on panic-related bodily sensations. The scale demon-
strated excellent internal consistency (? ? .88) in our sample and
has been used extensively in research with patients with PD.
Work and Social Adjustment Scale (WSAS).
(Mundt, Marks, Shear, & Greist, 2002) is used to assess the degree
of interference caused by illness symptoms in five life domains
(work, leisure, social activities, home, and family) on a 0 (no
interference) to 8 (very severe interference) scale. Patients rate five
life domains to produce an overall impairment. The WSAS is a
modification of a scale introduced by (Hafner & Marks, 1976).
Total scores range from 0 to 40, and the scale has adequate
test–retest reliability (r ? .73; Mundt et al., 2002) and good
internal consistency (Cronbach’s ? ? .80) in our sample.
Adherence rater certification and measures.
Training and certification.
Adherence Raters were advanced
doctoral psychology students and Ph.D. level clinicians who re-
ceived extra training and certification under the direction of the
Project Director at the Boston site. Training included study of CBT
manuals and treatment of at least one case under supervision.
Certification involved rating two videotaped training cases that
were previously rated by the trainer. To be certified, candidates
were required to match with the trainer’s ratings on 70% of items
on one case and 80% of items on the other case. The Adherence
Raters assessed both therapist adherence and competence using a
single scale developed for this study. Adherence raters listened to
audiotaped M–CBT sessions and rated the Adherence and Com-
petence Scale. The Adherence raters also reported total session
duration and rated patient variables and other general therapist
variables. Two sessions from each case were rated by study Ad-
Adherence and Competence Scale.
petence Scale was developed for this study by the first author. The
scale is used to assess two primary therapist factors: protocol
adherence and competence in treatment delivery. The scale also
assesses other therapist factors (e.g., session management, encour-
agement of patient involvement in treatment use of Socratic ques-
tioning), patient factors (e.g., patient’s comprehension of the ma-
terial covered; patient participation in the therapy session;
completion of home practices, if assigned), and other general
therapist factors (e.g., session management, kept session/patient on
Each therapist was rated on whether they completed each of the
treatment session objectives: 0 ? No, 1 ? Yes, or N/A ? not
applicable, as appropriate. Each therapist was also rated on the
competence or quality of how they implemented each study aim on
a 5-point scale (0 ? did not do, 1 ? poorly, 4 ? excellently). Some
Sex, age, race, educa-
The ASI (Peterson & Reiss,
The Adherence and Com-
of the ratings were session specific (i.e., required elements of the
protocol), and some items were general or as needed elements
(e.g., address residual agoraphobic avoidance, if any remaining). A
total Adherence Score was calculated by taking the percentage of
total completed items within all session aims, as applicable (e.g.,
Adherence score ? 87% of all protocol aims were implemented).
A total Competence Score was calculated from the average quality
rating of all study objectives (e.g., Competence score ? 4.0
indicates that the treatment that was delivered was of “excellent”
The Institutional Review Boards at all four sites approved this
study and all patients signed a written informed consent form.
Following Acute CBT (described above), patients were classified
as either treatment responders or non-responders based on the
results of the post-treatment diagnostic assessment. As noted
above, responders and non-responders were randomized to sepa-
rate arms of the trial. Responders, the sample used in this study,
were randomized to receive either (a) Assessment only (no addi-
tional treatment) or (b) M–CBT (one session per month for 9
months). At randomization, all patients agreed to adhere to initial
study enrollment criteria including the absence of concurrent psy-
chotherapeutic treatment directed at anxiety or panic disorders and
no concurrent psychopharmacological treatment that may have
anti-panic effects (e.g., SSRIs, benzodiazepines). Responders were
followed for a total of 21 months following acute phase CBT, and
IEs who were blinded to patients’ randomization condition and
progress in the study conducted all assessments. The M–CBT
protocol and its content were available only to the M–CBT study
therapists, it was not in circulation, and it was not shared in any
way with IEs.
Response and relapse criteria.
response status at the end of the acute phase of the trial that
included a structured diagnostic interview and self-report battery.
Response status was defined as a 40% reduction of PDSS-IE score
relative to baseline (pretreatment) and a CGI score of “much” (2)
or “very much” (1) improved relative to baseline study entry.
During the maintenance phase, all patients were evaluated by IEs
in monthly telephone contacts in which they administered the
PDSS and CGI. The monthly IE assessments asked patients about
their symptoms during the past month. If a patient showed signs of
clinically significant deterioration (as indicated by ?40% increase
in PDSS-IE and a CGI of 6 or 7, compared to their post-acute
treatment symptom status) during one of the monthly assessments,
the patient would enter “setback,” which triggered a change to
weekly IE assessments. The study coordinator would contact the
patient to explain that the weekly assessments would begin to
monitor symptoms and to encourage the patient to practice the
exercises their therapist taught them. Weekly assessments were
conducted until the patient met relapse criteria and was referred for
treatment, or until the patient had two consecutive weeks in which
they no longer met setback criteria. Relapse status was defined as
2 consecutive weeks with both ?40% increase in PDSS score
relative to post-acute treatment score and a score of “much worse”
(6) or “very much worse” (7) on the CGI scale relative to post-
acute treatment status.
IEs evaluated patients for
Data were analyzed using an intent-to-treat analysis based on
randomization assignment. We used Kaplan–Meier survival curves
and Cox proportional hazards regression models to examine the
relationship of time, randomization condition, and anxiety symp-
toms at the time of randomization to subsequent recurrence. Sur-
vival data were censored by dropout, and every effort was made to
contact patients to determine whether dropout was associated with
relapse. If dropout was unrelated to relapse, we made every effort
to continue data collection until study end or relapse. We assessed
for the interaction of these hypothesized predictors with treatment
condition, which if present would indicate treatment moderation.
We only tested for predictors (main effects and interactions) that
were justified empirically and theoretically as outlined a priori.
Data were analyzed using SPSS Statistics, Version 19.0.
The demographic and clinical characteristics for the study par-
ticipants at randomization study entry are reported in Table 1.
There were no demographic or clinical differences between pa-
tients randomized to M–CBT and those randomized to assessment
only follow-up at study randomization at p ? .05. These null
results help to validate the randomization schedule used in the trial.
Results are reported pooled and separately for visual inspection of
group means and standard deviations. Of the randomization sam-
ple (N ? 157), the majority were female (67%). Average age was
38 years (SD ? 12 years). The majority of the sample identified
themselves as Caucasian (84.7%). Marital status was married
(52.5%), never married (34%), and separated or divorced (13%).
Data on marital status were not available for a small percentage
(0.5%) of the study population. Only 6.4% of patients reported less
than 12 years of education. With regard to clinical characteristics,
43% of the sample had a secondary comorbid anxiety disorder, and
28% had a comorbid mood disorder either concurrently or a
history of significant comorbid mood disorder prior to study ran-
domization. Based on the ADIS-Lite interview, patients reported
an average duration of panic disorder of 440.4 weeks (SD ? 493.3;
Mdn ? 248.1), and approximately one half of patients (49%)
showed some residual symptoms of agoraphobia at study random-
ization based on the ADIS Ag Scale.
Group and Site Equivalence
Prior to examining multivariate analyses, analyses were con-
ducted to examine group and site equivalence. Analyses indicated
that time to relapse did not significantly differ across the four sites,
and the two randomization arms across the sites were not different
(i.e., with no differential odds of relapse) at p ? .05 during the
21-month follow-up. Post hoc analyses indicated that the patients
treated at the four treatment sites showed equivalent time to
relapse during the 21 months after acute treatment.
Classification of Treatment Completion Status
The M–CBT treatment protocol required that patients complete
a minimum of six of the nine sessions to be considered a treatment
completer. This minimum therapeutic dose was to ensure that
patients in the M–CBT condition received the critical elements of
Demographic and Clinical Characteristics at Randomization Study Entry Following Acute Treatment Response for PD (N ? 157)
Variable or characteristic
Overall (N ? 157) M–CBT (n ? 79) Assessment only (n ? 78)
Age at acute study entry (years)
Education (?12 years), %
Panic Disorder Severity Scale score
Clinical Global Improvement Scale score
Duration of current PD (weeks)
Current PD duration (weeks), Mdn
Lifetime comorbid anxiety disorder, %
Lifetime comorbid mood disorder, %
Residual symptoms of agoraphobia, %
Lifetime history of cardiac problems, %
History of psychiatric hospitalization, %
ADIS–Agoraphobia Severity score
Anxiety Sensitivity Index total score
Hamilton Anxiety Rating Scale score
Hamilton Depression Rating Scale score
Work and Social Adjustment Scale score
randomized to maintenance cognitive behavior therapy (M–CBT) and those randomized to assessment only follow-up at study randomization at p ? .05.
PD ? panic disorder; ADIS ? Anxiety Disorders Interview Schedule.
Values are means (and standard deviations) unless otherwise indicated. There were no demographic or clinical differences between patients
WHITE ET AL.
the treatment protocol within the study period. For the randomized
sample, the mean number of M–CBT sessions completed was 7.5
sessions (SD ? 0.3; Mode ? 9) among the 79 patients randomized
to the maintenance treatment.
Although attrition during the acute phase of the trial was slightly
higher than projected, this attrition was not systematic and did not
appear to threaten the validity of the current study (White et al.,
2010). In this maintenance study, attrition was small (see Figure
1), and analyses showed no differences in attrition between pa-
tients subsequently assigned to M–CBT or the assessment only
condition (all ?2s ? 1). The reasons some patients ended partici-
pation early was due to study protocol violations (e.g., use of a
prohibited medication, prohibited treatment; too many missed
M–CBT visits; n ? 8; 30%), they had other significant worsening
(n ? 6; 22%) or significant PD worsening (n ? 1; 3.7%), they
improved and did not want to continue (n ? 3; 11%), they were
discouraged and did not want to continue (n ? 1; 3.7%), or they
were lost-to-follow-up (n ? 8; 30%).
Treatment Adherence and Competence
Overall, the average independent ratings of therapist Adherence
were in the good-to-excellent range by the Adherence Raters
(? 80%), with the average Competence rating in the good-to-
excellent range (M ? 3.1, SD ? 0.6). Therapist–patient rapport
was rated high (M ? 3.2, SD ? 0.6) by Adherence Raters.
Co-rated tapes indicated excellent agreement among raters based
on a two-way random ICC (.94). Of the total number of M–CBT
sessions rated, 15% the individual CBT sessions were rated as
“inadequate” on the Adherence Score (i.e., yielding a non-adherent
IEs assessed patients’ non-study medication use at each time
point including use of benzodiazepines and antidepressants. Con-
sistent with the Acute CBT phase of the trial, data suggested good
adherence across the two groups, with few patients (n ? 5) failing
Eligible patients assigned to 11
sessions of Acute CBT (N = 379)
Patients who completed Acute CBT
(N = 256)
Refused (n = 19)
Dropout (n = 75)
Withdrawn (n = 29)
Responders to Acute CBT
3-MFU (N = 168)
Acute CBT (n = 88)1
9-Months of Maintenance
CBT (n = 79)
9-Months of Assessment
Only (n = 78)
(n = 68)
(n = 62)
Assessed for Eligibility (N = 434)
Ineligible (n = 55)
Arm and 9-MFU (n = 157)
long-term strategies for panic disorder with and without agoraphobia. CBT ? cognitive behavior therapy;
MFU ? month follow-up.1Patients referred to the Non-Responder Arm of the Long-Term Strategies for Panic
Disorder Trial (Payne et al., 2012).
Flowchart of patients eligible, enrolled, randomized, and treated in the controlled clinical trial for
to persistently adhere to the prohibited medication schedule for the
Maintenance Treatment and Its Impact on Outcome at
We used product-limit survival analyses to examine the effect of
randomization (i.e., M–CBT or assessment only follow-up) on
time to relapse. At 21-month follow-up, the estimated proportion
surviving in the maintenance group was 94.8% ? 3%, but in the
assessment only group, the estimated proportion surviving was
81.6% ? 5%. Analyses indicated that after attrition, patients
randomized to the M–CBT (n ? 72) had a longer time to relapse
after acute-phase treatment response compared to patients random-
ized to the assessment only follow-up condition (n ? 62), gener-
alized Wilcoxon rank ?2(1) ? 5.09, p ? .05. Figure 2 depicts the
probability of remaining relapse-free from PD/A (i.e., maintaining
treatment response) from acute study entry. Inspection of the
survival curves indicated that among the patients receiving
M–CBT, the greatest risks for relapse occurred between 28 and 31
weeks (i.e., the approximate end of M–CBT) and at 60 weeks. For
patients in the assessment only condition, the risk for relapse was
comparatively even across Phase 2 of the study; however, the
single greatest risk for relapse occurred between 30 and 40 weeks.
Put another way, overall rates of relapse were significantly lower
for M–CBT (5.2%) compared to the assessment only condition
Multivariate Cox proportional hazards models were fitted to the
data on the total sample. Models examined the impact of hypoth-
esized predictors at randomization (i.e., the end of Acute CBT) on
time to relapse during the follow-up period, including age, sex,
pre-randomization panic disorder severity (PDSS-IE score), ago-
raphobia severity (Ag Scale score), clinical global improvement
(CGI score), as well as randomization group assignment. In the
prediction of relapse-free survival, age, sex, PDSS-IE score, and
CGI score at the end of acute CBT were not independently pre-
dictive of the odds of relapse at p ? .05. However, ADIS Ag Score
at randomization was independently predictive of time to relapse
during follow-up (hazards ratio ? 1.15, p ? .01), with higher
agoraphobia scores (indicating more residual avoidance at the end
of acute CBT treatment, albeit in the context of meeting responder
criteria) having a shorter time to relapse compared to those with
lower agoraphobia scores. In other words, there was a 15% in-
crease in the rate of relapse occurring for every unit of increase in
agoraphobia score in the model.
The two-way interaction for Age ? Pre-Randomization
PDSS-IE was significant at p ? .01, indicating that increased age
had a significant association among patients with higher panic
acute-phase treatment responders who were randomized to receive either maintenance cognitive behavior
therapy (94.8%; n ? 72) or assessment only follow-up (81.6%; n ? 62) during Phase 2 of the clinical trial:
generalized Wilcoxon rank ?2(1) ? 5.09, p ? .05. Due to variability in duration of study components (i.e.,
treatment implementation and assessment completion), Phase 2 of the study began at approximately Week 20,
and follow-up extended over approximately 90 weeks following randomization.
Plot of probability of remaining relapse-free from panic disorder with and without agoraphobia in
WHITE ET AL.
disorder severity on time to relapse; younger age did not confer
similar relations with PDSS-IE scores and time to relapse. All
other hypothesized two-way and three-way interactions were en-
tered on subsequent blocks and were non-significant at p ? .05. In
all survival analyses, standard errors were small suggesting no
problems with multicollinearity, and plots indicated that the pro-
portional hazard assumption was satisfied.
At the symptom level, a set of linear regression analyses re-
vealed that the combined sample showed reductions in PDSS
scores over time. Bivariate linear regression analyses revealed that
panic disorder symptoms at the end of acute CBT was a significant
predictor of both 9-month outcome (? ? .41, p ? .01) and
21-month outcome (? ? .45, p ? .01), accounting for 16.8% and
20% of the variance in long-term outcome, accordingly. By con-
vention (Cohen, 1988), both analyses showed linear findings with
medium effect sizes. Mahalanobis distance tests were examined
for residuals, but no outliers were identified or excluded.
We also conducted a descriptive analysis of setbacks and relapses
during the randomization study by group. In the assessment only arm
of the study, a total of 26 patients entered the “setback” mode. Of
these, 14 recovered and continued study participation, and 12 partic-
ipants were removed from the study because they met criteria for
relapse. There were a total of 15 participants who relapsed during the
study, including the 12 participants who had entered setback mode,
one participant who was determined to have an earlier relapse than
initially calculated (so did not previously enter setback mode), and
two participants who were determined to have relapsed without com-
plete data. In the M–CBT group, 11 participants entered “setback”
mode at some point during the study. Of these, five participants
recovered and continued participation, and five individuals were re-
moved from the study because they met criteria for relapse. The final
participant of these 11 was removed from the study due to a signifi-
cant worsening of non-panic disorder symptoms. The M–CBT arm
resulted in six relapses—five of whom had already entered “setback”
mode, and one individual who was classified as relapsed at the final
Work and social functioning at follow-up.
analyses to examine changes in work and social impairment be-
tween the two groups from randomization to the long-term follow-
up. First, the pooled mean for the total sample on the WSAS at
21-month follow-up was low (Mp? 2.59, SDp? 4.46, Mode ? 0),
which indicated that this sample of acute treatment responders was
experiencing mild levels of interference at the long-term follow-
up. Second, results of a one-way analysis of covariance
(ANCOVA) indicated that treatment group assignment was signif-
icantly related to changes in WSAS scores at follow-up, after
covarying for WSAS scores at randomization, F(1, 118) ? 3.80,
p ? .04, f2? .05. Planned contrasts revealed that there was
significantly greater change on the WSAS total score (i.e., indi-
cating less work and social interference) at follow-up in the
M–CBT group compared to the assessment only condition,
t(118) ? 1.95, p ? .04, ?p
with changes over time at p ? .05.
2? .03. The covariate was not associated
Our findings demonstrate that M–CBT, compared to an assess-
ment only control condition, sustains acute treatment gains, pre-
vents relapse, and reduces work and social impairment among
patients who responded to an initial course of CBT for PD/A over
a 21-month follow-up. These results are noteworthy because,
although the effects of CBT are thought to be lasting, few data
from controlled studies provide support for the long-term efficacy
of acute CBT, particularly data collected longitudinally (monthly)
over time, in this case 21 consecutive months. These findings have
implications for the long-term management of PD/A.
The M–CBT in this study was a manualized protocol aimed at
reinforcing acute CBT skills and preventing PD/A recurrence, and
further research is needed to dismantle the protocol components as
well as examine the contribution of non-specific factors to the
maintenance treatment effect. The decision to include an assess-
ment only (i.e., untreated) condition as the main comparison group
was necessary to assess how many patients maintained a sustained
acute treatment response without any post-acute intervention. This
approach is the most usual strategy employed by clinicians for
patients who respond very well to treatment, since there is the
assumption by many therapists that patients who respond this well
have really learned something new, have mastered CBT skills, and
require no further treatment (an assumption shared by many of our
therapists prior to the study). Indeed, most patients in assessment
only did retain their responder status. However, a significant
minority (18%) relapsed, and this was markedly reduced by
monthly maintenance CBT. Nevertheless, this maintenance trial
did show that few patients reported seeking non-study therapies. In
addition, a longer follow-up will be important to examine the
longitudinal durability of M–CBT for PD/A. Our results require
replication and extension over follow-up intervals that span several
years, because it is possible that remission and relapse may not
become problematic until later. As noted, Fava et al. (1995), using
situational exposure based treatment for agoraphobia, found a
linear decrease in likelihood of staying in remission (i.e., 96% at 2
years, 77% at 5 years, and 67% at 5 years).
This trial employed rigorous assessment methods but was not
without some limits. First, the reliability estimates for some of our
clinical interview factors (e.g., PTSD, dysthymia, agoraphobia)
were low. All patients in this study were required to have panic
attacks at recruitment, and therefore the base rate for some of these
disorders may be lower than expected. Fortunately, this study did
not solely depend upon either of these factors, and patients were
required to meet diagnostic criteria for PD and agoraphobia as
assessed using the ADIS Ag Score, a highly reliable measure.
Also, it is theoretically possible for a patient to have 2 consecutive
weeks in between the monthly assessments during long-term
follow-up where s/he would have met criteria for relapse if as-
sessed, but was able to recover prior to the next monthly assess-
ment. In this study, efforts to mitigate this possibility included
encouraging patients to contact the study coordinator if symptoms
increased, and the study coordinator could initiate IE assessments.
Until longer-term follow-up data are available, results of this
multisite randomized controlled clinical trial suggest that the best
treatment approach to the long-term care of patients with PD/A
includes acute CBT followed by a limited number of monthly
maintenance treatment. Our results show that with monthly main-
tenance therapy, patients show reduced chance of relapse and
improved work and social functioning. Moreover, it is likely that
monthly maintenance therapy would be cost-effective in light of
the burden of disability and substantial societal cost associated
with PD (Batelaan et al., 2007), while recognizing that identifying
more precisely who is at relatively greater risk for relapse, and
targeting those individuals with maintenance therapy would ulti-
mately be the most cost effective strategy. Our findings reveal
functional but moderate group differences, and it is possible that
even more cost-effective maintenance CBT approaches and mo-
dalities (i.e., self-directed, online, smart phone applications) will
be tested in future work. In this study, the most robust predictor
was the presence of relatively greater residual symptoms of ago-
raphobia immediately following treatment, albeit in a perhaps
select group of individuals who had responded very well to ther-
apy. It may be conceivable to develop specific identifiers or
algorithms to determine who is most likely to benefit from main-
It is unclear if maintenance therapy must last for 9 months, even
at the somewhat infrequent interval of once a month sessions.
Possibly less frequent or even fewer sessions would be equally
beneficial but, in the absence of parametric studies, we are unable
to make any recommendations along this line. We purposely
included more substantial maintenance sessions than might other-
wise be given to provide a robust test of their benefit. Neverthe-
less, the likely public health benefits across large numbers of
patients are evident. It is possible that more naturalistic data
collection on differing dosages of relapse prevention strategies
could be collected across multiple anxiety disorder clinics in the
course of their usual and customary clinical care, and that this
should shed some light on the question of dosages. For now, a
reasonable clinical strategy would indicate continuing mainte-
nance treatment until agoraphobia as well as panic disorder symp-
toms are no more than minimal in a given patient.
Finally, the observation of relapse, occurring in a somewhat
linear fashion over time in the assessment only group, albeit at
relatively low levels underscores a need to discover more precisely
the basic mechanisms of action in these treatments in order to
make therapies more efficient and effective. Findings from basic
cognitive and neuroscience suggest that effective treatments for
anxiety disorders have as one crucial component the creation of
new memories overriding old fear-based associations (Bouton,
2002; Bouton, Mineka, & Barlow, 2001; Bouton & Woods, 2008).
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2010). Other findings from laboratory research point to basic
windows of opportunities lasting several hours after prompting of
fear and anxiety in which new memories can be formed and
consolidated that would more effectively override fear- and
anxiety-based responding (Monfils, Cowansage, Klann, & Le-
Doux, 2009). Further improvement in these treatments may also
mitigate any erosion of therapeutic gains that does occur. Findings
along these lines would move us toward the desired goal of more
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Received September 30, 2011
Revision received August 21, 2012
Accepted August 27, 2012 ?