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To present the design, methods, and rationale of the Child/Adolescent Anxiety Multimodal Study (CAMS), a recently completed federally-funded, multi-site, randomized placebo-controlled trial that examined the relative efficacy of cognitive-behavior therapy (CBT), sertraline (SRT), and their combination (COMB) against pill placebo (PBO) for the treatment of separation anxiety disorder (SAD), generalized anxiety disorder (GAD) and social phobia (SoP) in children and adolescents. Following a brief review of the acute outcomes of the CAMS trial, as well as the psychosocial and pharmacologic treatment literature for pediatric anxiety disorders, the design and methods of the CAMS trial are described. CAMS was a six-year, six-site, randomized controlled trial. Four hundred eighty-eight (N = 488) children and adolescents (ages 7-17 years) with DSM-IV-TR diagnoses of SAD, GAD, or SoP were randomly assigned to one of four treatment conditions: CBT, SRT, COMB, or PBO. Assessments of anxiety symptoms, safety, and functional outcomes, as well as putative mediators and moderators of treatment response were completed in a multi-measure, multi-informant fashion. Manual-based therapies, trained clinicians and independent evaluators were used to ensure treatment and assessment fidelity. A multi-layered administrative structure with representation from all sites facilitated cross-site coordination of the entire trial, study protocols and quality assurance. CAMS offers a model for clinical trials methods applicable to psychosocial and psychopharmacological comparative treatment trials by using state-of-the-art methods and rigorous cross-site quality controls. CAMS also provided a large-scale examination of the relative and combined efficacy and safety of the best evidenced-based psychosocial (CBT) and pharmacologic (SSRI) treatments to date for the most commonly occurring pediatric anxiety disorders. Primary and secondary results of CAMS will hold important implications for informing practice-relevant decisions regarding the initial treatment of youth with anxiety disorders. NCT00052078.
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Child/Adolescent Anxiety Multimodal Study
(CAMS): rationale, design, and methods
Scott N Compton
, John T Walkup
, Anne Marie Albano
, John C Piacentini
, Boris Birmaher
, Joel T Sherrill
Golda S Ginsburg
, Moira A Rynn
, James T McCracken
, Bruce D Waslick
, Satish Iyengar
, Phillip C Kendall
John S March
Objective: To present the design, methods, and rationale of the Child/Adolescent Anxiety Multimodal Study
(CAMS), a recently completed federally-funded, multi-site, randomized placebo-controlled trial that examined the
relative efficacy of cognitive-behavior therapy (CBT), sertraline (SRT), and their combination (COMB) against pill
placebo (PBO) for the treatment of separation anxiety disorder (SAD), generalized anxiety disorder (GAD) and social
phobia (SoP) in children and adolescents.
Methods: Following a brief review of the acute outcomes of the CAMS trial, as well as the psychosocial and
pharmacologic treatment literature for pediatric anxiety disorders, the design and methods of the CAMS trial are
Results: CAMS was a six-year, six-site, randomized controlled trial. Four hundred eighty-eight (N = 488) children
and adolescents (ages 7-17 years) with DSM-IV-TR diagnoses of SAD, GAD, or SoP were randomly assigned to one
of four treatment conditions: CBT, SRT, COMB, or PBO. Assessments of anxiety symptoms, safety, and functional
outcomes, as well as putative mediators and moderators of treatment response were completed in a multi-
measure, multi-informant fashion. Manual-based therapies, trained clinicians and independent evaluators were used
to ensure treatment and assessment fidelity. A multi-layered administrative structure with representation from all
sites facilitated cross-site coordination of the entire trial, study protocols and quality assurance.
Conclusions: CAMS offers a model for clinical trials methods applicable to psychosocial and
psychopharmacological comparative treatment trials by using state-of-the-art methods and rigorous cross-site
quality controls. CAMS also provided a large-scale examination of the relative and combined efficacy and safety of
the best evidenced-based psychosocial (CBT) and pharmacologic (SSRI) treatments to date for the most commonly
occurring pediatric anxiety disorders. Primary and secondary results of CAMS will hold important implications for
informing practice-relevant decisions regarding the initial treatment of youth with anxiety disorders.
Trial registration: NCT00052078.
The purpose of this manuscript is to describe the
research design, rationale for the design choices, and
methods used to implement the Child/Adolescent Mul-
timodal Study (CAMS), a recently completed federally-
funded, multicenter, randomized compa rative treatment
trial that examined the short-term efficacy (12-weeks)
and long-term durability (36-weeks) of four treatments
for childhood and adolescent separation anxiety disorder
(SAD), generalized anxiety disorder (G AD), and social
phobia (SoP): cognitive-behavioral therapy (CBT), sertra-
line (SRT), their combination (COMB), and pill placebo
(PBO). The methodological challenges faced while devel-
oping and implementing the trial are also discussed.
Study Rationale
Anxiety disorders in ch ildren and adolescents are preva-
lent, [1] impairing, [2] and often precursors to
* Correspondence:
Contributed equally
Duke University Medical Center, Department of Psychiatry and Behavioral
Sciences, DUMC Box 3527, Durham, NC 27710, USA
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
© 2010 Compton et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use , distribution, and
reprodu ction in any medium, provided the original wor k is properly cited.
psychiatric disorders in later adolescence and adulthood
including additional subsequent anxiety disorders, major
depression, substance abuse, and suicide attempts [3,4].
With the exception of s peci fic phobias, SAD, GAD, and
SoP are the most common triad of anxiety diagnos es in
both community and clinical samples of children and
adolescents [5]. Pediatric anxiety disorders are highly
comorbid with one another as well as wi th other psy-
chiatric disorders such as attention-deficit/hyperactivity
disorder, major depression, and dysthymia [ 1,6]. Given
their high prevalence and psychiatric comor bidity, anxi-
ety disorders in children and adolescents often results in
impairment and distress that significantly interferes with
family, academic, and social functioning [1,2,7].
The past two decades witnessed critical scientific
advances in the treatment and understand ing of anxiety
disorders in yo uth that laid the groundwork f or the
launch of the CAM S trial. These advances included: ( 1)
a better understanding of the public health importance
of anxiety disorders in children and adolescents; [8,9]
(2) the development of valid and reliable anxiety specific
multi-informant and multi-method assessments (without
which research in pediatric anxiety would not be possi-
ble); (3) a growing empirical literature base supporting
the short-term efficacy and feasibility of both psychoso-
cial [10] and psychopharmacological[11] interventions
for the treatment of anxiety disorders in yo uth; (4)
room for improved outcomes in monotherapies[12] sug-
gesting that current treatments are prime candidates for
innovation;[13] (5) paucity of studies comparing the effi-
cacy of combination treatment (e.g., cognitive-behavioral
therapy plus medi cation) using a credible control condi-
tion in the same patient population; [13] and (6) general
agreement within the scientific community that the
results of a la rge co mparative treatment trial like CAMS
could meaningfully impact public policy [14].
With these factors in mind, the National Institutes of
Mental Health (NIMH) funded the CAMS trial to
further scientific knowledge on effective treatments for
pediatric anxiety disorders. CAMS was a 6-year, multi-
site (6 sites), randomized controlled trial (RCT). Four
hundred and eighty-eight children and adolescents
between the ages of 7-17 years with at least one DSM-
IV-TR diagnoses of SAD, GAD, or SoP were randomly
assigned to one of four treatment groups: CBT, SRT,
COMB or pill PBO. Results of the primar y outcomes
were recently published[ 15] and showed that at the end
of 12 weeks of acute treatment 80.7% (95% CI, 73.3 to
86.4%) of participants treated with COMB were rated as
treatment responders (defined as a Clinical Global
Impression-Improvement (CGI-I) score of 1 or 2) [16].
COMB was superio r to both CBT alone (59.7%; 95% CI,
51.4 to 67.5%, p < 0.001) and SRT alone (54.9%; 95% CI,
46.4 to 63.1%, p < 0.001), as well as pill placebo (23.7%,
95% CI, 15.5 to 34.5%, p < 0.0001). CBT alone and SRT
alone were also superior t o pill placebo (p < 0.001, p <
0.001, respectively) but not statistically significantly dif-
ferent from one another (p = 0.41). A simi lar pattern of
response was found on the Pediatric Anxiety Rating
Scale ( PARS),[17] a clinician administered scalar assess-
ment scale. The overall findings from the acute phase of
the CAMS study suggest that there are t hree effective
treatments for youth suffering from one or more of t he
target anxiety disorders, with COMB bein g the most
Rationale for the CAMS Treatments
At the time CAMS was initiated, cognitive-behavior
therapy [18-20] and s elective serot onin reu ptake inhibi-
tors [21-24] had emerged as the most effective treat-
ments for pediatric anxiety disorders [25]. Despite
positive outcomes in previous RCTs,[12] response rates
were short of exemplary, with appro ximately 40-50% of
treated youth remaining symptomatic at the end of
acute treatment. Moreover, with the exception of one
small study[26] that compared CBT alone to medication
alone in youth with SoP, clinical trialists had not yet
compared the relative efficacy of psychosoci al and psy-
chopharmacological intervention s in t he same study
population. This had raised speculation that CBT trials
(often based in uni versity psychology clinics) and me di-
cation trials (often based in medical centers) were con-
ducted with different populations of anxious youth.
With respect to combination trials for childhood anxi-
ety disorders, only one study, conducted in a pediatric
obsessive-compulsive disorder (OCD) population,[27]
compared and demonstrated the superiority of combina-
tion treatment (CBT+SSRI) to CBT and SSRIs alone.
Therefore, CAMS provided an important and necessary
extension t o the em pirical literature by comparing CBT
alone, an SSRI alone, and their combination to pill pla-
cebo in the sa me clini cal populat ion recruit ed across
both medical center and psychology clinic sites.
Cognitive-Behavioral Therapy Studies
Cognitive behav ioral therapy for child and adolescent
anxiety disorders assumes that pathological anxiety is
the result of an interaction between somatic or physiolo-
gical ar ousal, cognitive dis tortions, and avoidance beha-
vior. Accordingly, CBT [28] addresses each domain
through: (1) corrective psychoeducation about anxiety
and feared situations; (2 ) developmentally appropriate
cognitive restructuring skills to address m aladaptive
thinking and to learn coping-focused thinking; (3)
somatic management techniques to target autonomic
arousal and related physiological reactivity; (4) gradu-
ated, systematic, and controlled exposure tasks to feared
situations/stimuli to eliminate avoidance behavior; and
(5) relapse prevention to consolidate and maintain treat-
ment gains.
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 2 of 15
To date, over 25 RCTs have evaluated CBT for the
treatment of anxiety disorders in youth [13]. The first
and most well-studied CBT program for childhood anxi-
ety disorders is Kendalls Coping Cat [18,19 ]. In two
initial trials, children treated with this protocol demon-
strated significant improvement on self- and parent-
reported measures of distress and coping, as well as
clinician ratings of child behavior and diagnostic status
when compared to waitlist c ontrols. Benefits have been
shown to maintain over long-term follow-up of 7.4
years [29]. Other controlled trials support the efficacy of
CBT in childhood anxiety for a wide range of ages (7-
17), conditions (OCD, SoP, SAD), and formats (group,
individual, and family) (see Silverman) [30].
Limitations of some studies in the CBT literature
include t he use of c ompleter rather than intent-to -treat
(ITT) samples, inclusion of participants with mild anxi-
ety or phobias, failure to track comorbid anxiety and
mood disorders, and relatively weak control conditions
including wait list and potentially active psychoe duca-
tion controls [25,31].
Pharmacotherapy Studies
Pharmacological treatment in children and adolescents
is supported by data suggesting the continuity of child-
hood anxiety disorders with adult anxiety and depressive
disorders [32-35] and efficacy of a range of antidepres-
sant medications in the treatment of adult anxiety disor-
ders, including SSRIs [36]. Prior to CAMS, controlled
trials of SSRIs i n childhood anxiety disorders support
the short-term efficacy and safety of these compounds
for the disorders targeted in CAMS, [21-24] as well as
for selective mutism[33] and OCD [35,37].
Setting the stage for the pharmacological protocol
used in CAMS was the Researc h Units in Pediatric Psy-
chopharmacology (RUPP) Anxiety Group [23]. These
investigators conducted a randomized, double-blind
comparison of fluvoxamine and pill placebo in children
and adolescents between the ages of 7 to 17 with SAD,
GAD, and SoP. Results showed fluvoxamine (a SSRI)
was significantly more effective than pill placebo in
reducing anxiety symptoms (ES = 1.1). Ho wever, limita-
tions of the RUPP study included use of clinician rather
than independent evaluator ratings of treatment
response and, similar to CBT trials, a substantial portion
of subjects remained symptomatic following treatment.
Despite these and other studies showing the anxiolytic
benefits of SSRIs, concerns with pharmacologic treat-
ments remain, including the lack of information about
the long-term safety and durability of medication treat-
ments for children with anxiety disorders. The black
box FDA warnings for the use of SSRI medications in
children and adolescents[38] coincided with the CAMS
trial and underscored the need for careful procedures to
study SSRI safety in children participating in CAMS.
Comparative Treatment Trials
CAMS is the fifth federally-funded, large, multicenter,
comparative treatment trial addressing prevalent and
disabling mental health conditions in children and ado-
lescents, and joins ranks with the other large compara-
tive treatment trials: Multimodal Treatment of Children
with ADHD Study (the MTA),[39] Treatment for Ado-
lescents with Depression Study (TADS),[40] Pediatric
OCD Treatment Study (POTS),[27] and Treatment of
Resistant Depression in Adolescents (TORDIA) [41].
Each of these large multisite comparative treatment
trials evaluat ed the most promising psychosocial and
pharmacological treatments for their time and targeted
psychiatric disorder. These landmark c linical trials have
had significant public health value by addressing com-
pelling practice-relevant questions (e.g., what treatment
should be provided first to a particular child?) and
demonstrated the added benefit of combination treat-
ments. Equally important, a nalyses of secondary out-
comes and moderator and mediators of treatment
response have, and will continue to, provided clinically-
relevant information for matching patient charac teristics
to treatment modality to better personalize care and
maximize patient outcomes.
Specific Aims and Design
The specific aims of CAMS were:
Aim 1. To compare the relative efficacy of each active
treatment (COMB, SRT, CBT) against PBO in reducing
anxiety symptoms and associated disability over 12
weeks of acute treatment.
Aim 2. To compare the relative efficacy of each mono-
therapy (SRT, CBT) against COMB in reducing anxiety
symptoms and associated disability over 12 weeks of
acute treatment.
Aim 3. To identify predictors, moderators, and poten-
tial mediators of acute response to treatment.
dropout, premature termination, safety and adverse
events, and consumer satisfaction.
CBT over a 6-month open follow-up period on func-
tioning, relapse and recurrence rates, and utilization of
other treatments.
Each of the above aims was addressed through a two-
phase clinical trial. Phase I involved a 12-week rando-
mized controlled trial comparing CBT, SRT, COMB,
against pill PBO. Phase II was a 6-month treatment
maintenance period, in which Phase I treatment respon-
ders were seen by their Phase I clinician(s) monthly.
Participants assigned to CBT received monthly booster
sessions, while those assigned to SRT rece ived monthly
medication monitoring visits. Phase I non- responders to
active treatments were referred to community providers.
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 3 of 15
However, Phase I PBO non-responders were provided
their choice of an active CAMS treatment at the end of
Phase I or at any time during Phase I if their symptoms
worsened. In as much as possible (e.g., with the excep-
tion of study dropouts), all subjects were evaluated at
schedul ed assessment points (Weeks 0, 4, 8, 12, 24, and
36) regardl ess of initial treatment response or participa-
tion in Phase II CAMS booster sessions or non-CAMS
treatments. In addition to parent, child, and clinician
questionnaires that evaluated changes across a wide
variety of domains, primary outcomes were assessed by
blind independent evaluators (IEs).
A schematic representation of the study is presented
in Figure 1. The six performance sites involved in the
trial were: New York State Psychiatric Institute; Duke
University Medical Center; Johns Hopkins Medical Insti-
tutions; Temple University; University of California at
Los Angeles; and Western P sychiatric Institute and
Clinic. A multi-layered administrative structure with
representation from all sites facilitated cross-site coordi-
nation and quality assuranc e. The CAMS Executive
Committee (EC) was comprised of a chair (Dr. John
Walkup), co-chair (Dr. Anne Marie Albano), executive
secretary (Dr. Scott Compton), lead study coordinator
(Dr. Courtney Keeton), and representation from NIMH
(Dr. Joel Sherrill). The EC met weekly via teleconference
calls and was responsible for overseeing the succe ssful
and consistent implementation of the study protocol
across all performance sites.
Another essential governing committee, the CAMS
Steering Committee (SC), was comprised of principle
investigators, co-investigators, and study coordinators
from each site. The SC met weekly via teleconference
calls to review recruitment progres s at each site, discuss
and clarify questions sites might have regarding the
implementation of the protocol, address clinical con-
cerns with study participants, and report and discuss
adverse events and protocol deviations (if any). Subcom-
mittees for each treatment modality were also created.
The CBT and PT (pharmacotherapy) committees were
comprised of CAMS treatment clinicians, and met sepa-
rately via teleconference calls to provide cross-site
supervision and present and discuss clinical cases on a
rotating basis. The CBT committee h eld weekly confer-
ence calls, while the PT committee held bi-weekly con-
ference calls. The difference in the frequency of the calls
between the committees was due to differences in the
frequency of treatment visits. Participants assigned to
CBT met weekly with their therapist, while participants
assigned to PT met bi-weekly, with the exception of the
first four treatment visits, which were weekly. The IEs
also met bi-weekly via teleconference calls for cross-site
supervision. The goal of these meetings was to ensure
that the assess ments were administered similarly across
the 6 performance sites. Each performance site also had
cross-site responsibilities. Trial wide study coordination
was the responsibility of study staff at Johns Hopkins
Medical Institutions. CBT, PT, and IE quality assurance
was the responsibility of study staff at Temple Univer-
sity, University of Cali fornia at Los Angel es, and New
York State P sychiatric Institute, respectively. W estern
Psychiatric Institute and Clinic (first three years) and
Duke University Medical Center (last three years) served
as the data ce nters (Note: the data center was moved to
Duke University Medical Center because of unplanned
personnel changes at the original s ite). A schematic
representation of the organizational structure of CAMS
and list of performance sites is presented in Figure 2.
Randomization and Enrollment
To maintain reasonably go od balance among the four
treatme nt groups, partici pants were randomized using a
stratified block randomization procedure. Factors uti-
lized in this procedure were treatment site, age, and
Subjects were enrolled using a multiple g ating proce-
dure in which parents/guardians of prospective partici-
pants first completed an initial telephone screen (Gate
A). Following the phone screen, those families wh o met
basic eligibility criteria were then invited to the sites
clinic. At the clinic, informed consent and assent were
Figure 1 Child/Adolescent Anxiety Multimodal Study (CAMS)
Experimental Design.
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 4 of 15
obtained and then the IEs conducted a structured diag-
nostic interview (Gate B; note: the same IE conducted
all future assessments). If the child or adolescent met all
inclusion criteria, and no exclusion criteria, a baseline
assessment and randomization visit was scheduled a
week lat er (Gate C1 and C2). Immediately following the
baseline assessment (Gate C1), the family met with the
Principle Investigator (or his/her designate) to answer
any remaining questions the family might have about
the study. A secondary, yet important, purpose of this
meeting was to ma ke certain the family understood how
participation in a clinical trial differed from standard
clinical care (e.g., treatment followed a standardized
research protocol with appropriate clinical safeguards)
and to ensure the family was willing to accept randomi-
zation to a treatment condition (even if the family had a
preference for a particular treatment). Upon completion
of this informal re-consenting procedure, participants
randomization was revealed. The first treatment visit
typically followed immediately after Gate C2. The
expected average time from Gate A to Gate C2 (rando-
mization) was 2-3 weeks, with a range of 2 (minimum)
to 6 (maximum) weeks.
Participants completed their 12-wee k assessment (end
of acute treatment) by day 84 5 days). At the end of
Phase I, participants in the medication-only treatment
conditions (either SRT or PBO) were unblinded; how-
ever, the IE remained blinded to treatment status
throughout the entire trial. Based upon the IE evaluation
of clinical response a t the week 12 assessment, re spon-
ders (defined as CGI-I 2) entered Phase II. Non-
responders (CGI-I > 2) to any of the active treatments
were referred to the community for treatment or follow-
up care. PBO non-responders (CGI-I > 2) met with
Figure 2 Child/Adolescent Multimodal Study (CAMS) Organizational Structure and Performance Sites.
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 5 of 15
their clinician and were offered their choice of a CAMS
treatment (e.g., CBT, SRT, or COMB) for an additional
12 weeks. This treatme nt was provided during Phase II
by CAMS study clinicians. PBO responders entered
Phase II and con tinued to meet monthly with their clin-
ician. If at any time during Phase II, PBO responders
relapsed, they received the same option of their choice
of a CAMS treatment for an additional 12 weeks.
During Phase II, those participants receiving medica-
tion (e.g., participants in COMB or SRT) remained at
their Week 12 dose of mediation. Downward medication
adjustments were allow ed in response t o emergent side
effects. Participants who required a medication d ose
increase during Phase II were prematurely terminated
from the study and continued with the assigned assess-
ments. Participants categorized as CBT responders met
with their clinician for monthly 50-minute maintenance
CBT sessions. During these sessions no new material
was intr oduce d, b ut the CBT therapist was permitted to
revisit the stimulus hierarchy, and reinforce the neces-
sity of exposure activities to pr omote maintenance and
generalization. Responders in the COMB group received
both continued stable medication as well as monthly
CBT maintenance visits. At the end of Phase II all sub-
jects met with his/her clinician(s) and were given end-
of-treatment recommendations and, if necessary, refer-
rals for continued clinical care.
Design Rationale
As a group, the CAMS inv estigators had substantial
experience with multicenter comparative treatment trials
and carefully considered several different treatment
designs before deciding upon the final design for
CAMS. At the time CAMS was developed, there were
realistically three design choices that would allow for a
comparison of the two monotherapies and their combi-
SRT vs. SRT+CBT vs. PBO). This des ign had been used
successfully in several previously funded NIMH trials (e.
g., MTA,[39] TADS,[40] and POTS[27]) and had estab-
lished a precedent for large multicenter c omparative
treatment trials. Second, a 1 × 5 parallel groups design
(CBT vs. SRT vs. SRT+CBT vs. PBO+CBT vs. PBO)
that a dded a balanced pill PBO+CBT condition, for
which there was little precedent in the research litera-
ture. This design was carefully considered due to con-
cerns about the lack of a PBO+CBT control condition
in the first design option. And third, a fully 2 × 2 factor-
ial design (Factor One: CBT vs. Sham CBT; Factor Two:
Active Medication vs. Pill PBO) . After thorough consid-
eration of the scientific merits and feasibility of imple-
mentation of each of these designs, CAMS investigators
chose the unbalanced 1 × 4 parallel groups design with
pill PBO as the control condition as the best option.
The pill PBO condition was deemed necessary to
protect against a failed trial and to control for the effect
of positive engagement o n the part of clinicians a nd
treatment expectancies on the part of participants and
The 1 × 5 parallel groups design was a serious conten-
der but ulti mately rejected due to cost and the inherent
difficulty of creating a credible and inert sham psycho-
social treatment condition [31]. The addition of a PBO
+CBT treatment arm would have increased the total
cost of the trial by approxim ately 4 million US dollars.
For example, to be a ble to detect a between group dif-
ference of at least 10% between the active treatments
would require an increase in samplesizefromapproxi-
mately 140 to approximately 290 participan ts per acti ve
treatment group. Thus, the total sample size required to
complete the trial would have inc reased from 480 to
1015 participants, again cost prohibitive. A fully factorial
design, although scientifically attractive, was rejected as
it was deemed better suited for a true efficacy study
given that one of the treatment arms would have been
the pill PBO and shame psychosocial treatment. Ulti-
mately, despite its k nown limitations, [42] CAMS fol-
lowed in the footsteps of other large pediatric
compa rative treatment trials and chose an unbalanced 1
× 4 parallel groups design because it represented the
best compromise between ecological validity, feasibility
of implementation, scientific rigor, and cost.
Other alternative designs choices were also considered
for the follow-up maintenance period (Phase II) of the
CAMS trial, but ultimately rejected due to feasibility,
cost (e.g., re-randomizing Phase I non-responders to
new treatments), and ethical considerations (e.g., conti-
nuing PBO throughout phase II).
Decision to Focus on Three Anxiety Disorders
The decision to ta rget children and adolescents with
DSM-IV-TR SAD, GAD, or SoP wa s made for both
pragmatic and theoretical reasons. From a pragmatic
perspective, there was a strong historical precedent to
[10,13,23,30]. SAD, GAD, and SoP share a similar
response to CBT and SSRI treatments, exhibit strong
associations with each other ( comorbidity), and as a
group, have historically been con sidered distinct from
other childhood-onset DSM-IV anxiety disorders (e.g.,
Primary Outcome Measures
CAMS had two primary outcome measures, one catego-
rical and one continuous: (1) responder status (i.e.,
res ponder or non-responder) based on the 7-point
Clinical Global Impression-Improvement Scale [16].
(CGI-I) score o f 1 ("very much i mproved) o r 2 ("much
improved); and (2) the total score o n the Pediatric
Anxiety Rating Scale (PARS) [17]. Scores on both out-
come measures were b ased on an interview with the
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 6 of 15
child and parent(s) by the IE. The child and parent(s)
were interviewed together as is standard pract ice for the
PARS (Note: whenever possible, ADIS assessments were
conducted separately). IEs were trained to handle ques-
tions of adolescent confidentiality and parent-child con-
flict that arose at times during joint interviewing.
The inability to fully mask the CBT and COMB condi-
tions in o ther pediat ric comp arative clinical trials has
been criticized because of the potential for differential
expectancy effects and di fferen ces in time and atte ntion
provided by clinicians [42]. From a pure efficacy perspec-
tive these criticisms are valid. However, in CAMS the
goal was ecologica l val idity with an emphasis on effec-
tiveness in as much was feasible. Moreover, masking of
the primary outcome variables was maintained by the use
of independent evaluators who were blind to treatment
status. Thus, the use of blind IEs removed rater expec-
tancy as a source of potential bias in outcomes.
Efforts to ensure that IEs maintained blindness were
multifaceted. First, on-site supervision for IEs was held
separate from any meetings with treatment clinicians.
For example, during each sites weekly research meeting,
IEs were excused from the meeting when the focus of
the meeting shifted to discussing clinical information
about study participants. Second, IE offices were
required to be in a location separ ate from the offices of
clinicians and other study staff (e.g., in a different area
or floor of the building). Third, all study staff were
trained to assist in maintaining the blind and partici-
pants were repeatedly reminded to refrain from discuss-
ing or mentioning their study treatment. Fourth, given
the significant experience CAMS investigators had with
prior clinical trials, rigor in maintaining the blind was as
good or better than previous multisite trials, although as
with any cli nical trial there was the occasional error. To
assess the impact that unblinding may have had on out-
comes, IEs were asked to complete a questionnaire fol-
lowing the week 12 assessment which asked them to
guess which treatment the participant received and indi-
cate their degree of confidence in this rating. Given the
rigorous efforts to maintain the blind, the f requency of
incidents that led to breaking the blind (e.g., seeing the
participant with a therapist) was minimal.
Participants were encouraged to complete all sched-
uled assessments and were compensated for time and
travel consistent with local IRB guidelines. Participants
who withdrew from treatment at any point during Phase
I o r Phase II were asked if they w ould be willing to
complete all future assessments, and if so, they were
classified as treatment drops. Participants whose clini-
cal picture worsened or developed a clinical crisis that
lead the site clinical team to recommend an out of pro -
tocol tre atment(s) were classified as prematurel y termi-
nated. Premat urely terminated participants continued
treat ment within their assigned treatment ar m (i n so far
as clinically possible), as well as all regularly scheduled
assessments. Participants who terminated prematurely
were distinguished from study drops who were partici-
pants who refused study treatment and assessments.
Stated diffe rently, study drops were defined as those
participants who withdrew consent for continued parti-
cipation in the study.
Sample Size and Power Estimates
The primary measure used for sample size estimation
was the IEs rating of Phase I treatment response. Using
chi-square, power estimates for detecting differences in
treatment response among the four treatment condi-
tions were computed using the following assumptions:
(1) H
= 0.60, P
= 0.60, P
= 0.80, and
= 0.30; (2) sample sizes of 136 for each active
treatment condition and 70 for the PBO condition; (3)
no adjustment for multiple comparisons; (4) power set
at 80%; and (5) alpha = 0.05, two-tailed test. Given these
assumptions, power analysis revealed that CAMS was
sufficiently powered to detect a 0.19 difference in Phase
I response rates between PBO and each active treatment
condition and a 0.17 difference in Phase I response rates
between COMB and each active monotherapy condition.
Sampling Frame and Participant Recruitment
CAMS re cruited a volunteer sample of children and
adolescents between the ages o f 7 and 17 years. Inc lu-
sion and exclusion criteria are presented in Tables 1
and 2. A complete description of the clinical characteris-
tics of the sample c an be found in Kendall and collea-
gues [43].
With the exceptions n oted below and in Table 2,
CAMS investigators sought to e nroll a sample of
anxious youth representative of the full range of ethnic/
minority backgrounds and as similar as possible to those
seen in general clinical/hospital practic e and community
clinical settings. Youth with a co-prim ary diagnos is
(defined as an ADIS CSR equal to that of at least one of
the t arget disorders) for which a different disorder-spe-
cific treatment was indicated were not include d (i.e.,
substance abuse disorder, eating disorder). However, to
enhance the generalizability of the results, youth with an
Axis I disorder(s) with an ADIS CSR less than that of
one of the target disorders, with the exception of those
disorders listed in Table 2, were included to ensure a
broadly representative sample of anxious youth. Given
that children with major depressive disorder (MDD)
respond to SSRIs and that standard CBT for anxiety dis-
orders does not specifically target symptoms of depres-
sion, participants who met DSM-IV criteria for MDD
(at any ADIS CSR level) we re excluded. This decision
was mad e to ensure a sample whose outcomes could be
most clearly interpreted as related to the anxiety disor-
ders of interest.
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 7 of 15
Using similar procedures, sites r ecruited p articipa nts
from mental health pediatric and primary care clinics,
community mental health centers, schools, churches,
community organizations, and paid and unpaid adver-
tisements in all forms of l ocal media. Special outreach
efforts dedicated to enhance minority enrollment were
made. These outreach efforts were planned and imple-
mented at each site in consultation with local academic
experts and minority community le aders, including edu-
cators and clergy. Specific outreach activities included
educational talks to schools, c hurches, and other com-
munity groups in minority neighborhoods, articles and
paid advertisements in minority-targeted press and
media, and direct mail.
English-fluency was a requirement for child enroll-
ment in CAMS, and parents were required to speak suf-
ficient English to provide informed consent for study
participation and completion of study treatment and
assessment requ irements. However, CAMS sites in areas
with high percentage of Spanish-speaking families
employed bilingual screeners and clinical staff in order
to increase the comfort level of bilingual parents and
enhance recruitment and retention of these families. In
addition, efforts were made at all sites to employ clinical
and research s taff representative of the ethnic/minority
makeup of the local population.
Although, the racial/ethnic diversity of the CAMS
sample (21%) is comparable with other published child
anxiety treatment studie s,[18,19,44] the recruitment of
ethnic minority populations into clinical trials remains
one of the most significant c hallenges common to all
studies. Establishing effective relationships with the lea-
dership o f minority organizations that serve ethnic min-
ority communities can facilitate minority recruitment
efforts [45]. Anecdotally, with respect to ethnic minori ty
recruitment efforts in CAMS, challenges faced by inves-
tigators were primarily logistical barriers. Most minority
participants, for example, had to trav el a great distance
to parti cipate in the trial. Study reimburs ement (pa ying)
for transportation did not seem to enhance e nrollment
and retention for these participants, suggesting that time
was the primary barrier. For future studies, one potential
Table 1 List of Inclusion Criteria
Inclusion Criteria Rationale
Ages 7 to 17 years inclusive Matches developmental sensitivity of treatments and study measures
DSM-IV diagnoses of SAD, SoP, or GAD Disorders of interest
ADIS CSR 4 for either SAD, SoP, or GAD Indicates symptom severity/impairment sufficient for DSM-IV diagnosis
IQ estimate > 80 Low IQ may limit the childs ability to profit from CBT
Free from anti-anxiety medications prior to baseline evaluations Potential confound with study treatments
Outpatient Inpatient populations are different from sample of interest
Table 2 List of Exclusion Criteria
Exclusion Criteria Rationale
The following Axis I disorders: These disorders require treatments not provided within the context of
the CAMS trial
Major Depressive Disorder
Bipolar Disorder
Psychotic Disorder
Pervasive Developmental Disorder
Uncontrolled ADHD (combined or primarily hyperactive type)
Eating Disorders
Substance Use Disorders
Any Axis I disorder (excluding those mentioned above), with an ADIS
CSR to the CSR of the disorders of interest (SAD, GAD, SoP)
Disorders of interest (SAD, SoP, GAD) must be the most severe and
disabling conditions affecting the child
School refusal behavior characterized by missing > 25% of school days
in most recent term
May require additional or different treatments
Suicidal or homicidal Unethical to randomize to PBO
Two previous failed trials of an SSRI or a failed trial of an adequate
course of CBT for the disorders of interest
Not likely to respond to study treatments; may require additional
Intolerance to sertraline Risk of side effects/adverse events
Confounding medical condition Potential medical risk or confounding issue
Pregnancy Potential risk of medication effects to fetus
Child or adolescent does not speak English Cannot complete study assessments and CBT
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 8 of 15
solution to minimize this problem would be to set-up
satellite tre atment and assessment cl inics wit hin local
minority communities. Although this solution would
likely lead to higher rates of minority participation, it
would likely be costly. Further attention to these and
other strategies that would enhance minority and ethnic
enrollment and engagement is warranted, not only to
ensure that re search samples are diverse and generaliz-
able, but also because these same barriers that impact
study participation likely impact the access and utiliza-
tion of clinical care in these communities.
Study Treatments
CAMS treatments reflected current state-of-the-art
interventions. Although study protocols established the
timing and c ontent of each intervention, treating clini-
cians were able to work collaborat ively with participants
and their families to maximize a dherence and benefit,
and minimize adverse events.
The CAMS medication management strategy was
designed to maximize treatment adherence and study
participation, enhance and maintain the doctor-patient
relationship, instill hope for improvement, and acquire
data necessary for medical decision-making without
implementing CBT. Medication visits lasted approxi-
mately 30 minutes (with the exception of the first which
laste d approximately 60 minutes) and were devoted to a
review of the participants symptomatology, overall func-
tioning, response to treatment, and presence of adverse
events, all in a context of supportive clinical care.
Pharmacotherapy (PT) visits were scheduled at weeks
1-4, 6, 8, 10 , 12 during Phase I. Interim phone visits
were scheduled at weeks 5, 7, 9, and 11. Monthly main-
ten ance v isits for tr eatment responders occurred during
the six-month follow-up period of Phase II. Consistent
with good medical practice, every effort was made to
use the mo st effective and tolerated dose of SRT. Medi-
cation was administered daily using a fixed-flexib le
dosing strategy that was linked to the PT therapist-
assigned, 7-point CGI-Severity score and the ascertain-
ment of clinically significant side effects. In general, par-
ticipants medication dose was adjusted upward in 50
mg/day increments if the clinician-rated anxiety se verity
on the CGI-S was 3 (mild) or greater. The dose was
held, or adjusted downward, if the participant had few
anxiety symptoms (CGI-S of 1 or 2) or if there were
impairing side effects.
Cognitive Behavioral Therapy
CAMS adapted the evide nce-based Coping Cat CBT
protocol [25,46]. Guidelines assisted the therapist in
adapting the manual flexibly and in a standardized man-
ner for a clients age and developmental level. The C.A.
T. Project,[47] a version of the Coping Cat modified for
use with adolescent participants, allowed therapists to
provide developmentall y appropriate CBT across the full
age range of the study. Across both child and adolescent
CBT protocols, the number of session was reduced from
16-20 60-minute treatment sessions (in the original pro-
tocols) to 14. Twelve of these sessions were individual
child/adolescent sessions and 2 were parent s essions,
which were scheduled immediately after the child ses-
sion at weeks 3 and 5. CBT responders received
monthly CBT maintenance sessions during the six-
month follow-up period of Phase II.
The first six CBT sessions taught new skills to the
child/adolescent (e.g., the FEAR plan), whereas the sec-
ond six ses sions provide opportunities to practice newly
learned skills (exposure tasks) within a nd outside of the
sessions. The overall goal of CBT was to teach youth to
recognize the signs of unwanted anxiety, let these signs
serve as cues for the use of more effect ive anx iet y man-
agement strategies, and face rather than avoid anxiety
provoking situations.
Combination Treatment
Participants in the combination treatment condition
(COMB) received all the components from the medica-
tion-only and CBT-only treatment conditions, with the
exception that the participant, parent(s), and c linician
were aware that the child/adolescent was receiving
active SRT and active CBT. Pharmacotherapy and CBT
visits typically took place on the same day, with the par-
ticipant seeing the PT therapist fir st. Clinicians wer e
encouraged to discuss the clinical status of each COMB
patient to allow for treatment integration. For example,
the PT t herapist could increase the dose of SRT (or
not), depending on whether the participant was making
sufficient progress in CBT. With the exception of one
site, COMB treatment visits were held at the same
Patient Safety and Adjunctive Services to Prevent Study
Participant safety was a foremost consideration, and
from a public health point of view, the ascertainment of
adverse events in each treatment condition was a critical
aspect of the trial. Primary concerns included possible
untoward reactions to study treatments and the risk that
the participant may not improve or may deteriorate dur-
ing treatment. CAMS p rotocols for monitoring safety
and providing additional treatment visits to manage
clinical crises and concerns that inevitably arise during
the course of a trial facilitated standardized, yet flexible,
clinically appropriate be st practice standards and max-
imized participant retention.
Side effe cts and adverse events were assessed immedi-
ately before each treat ment visit by th e study coordina-
tor by asking both the child and parent if they had
experienced or noticed any health or other problems
since the last treatment visit. Responses were recorded
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 9 of 15
and then provided to the treating clinician who reviewed
the list with the child and parent to determine its sever-
ity, association with study treatments, and actions to be
tak en by the study team. This 2-stage str ategy was used
to ensure standardized ascertainment of adverse events
across the four treatment conditions.
In response to FDA black box warning regarding the
risk for suicidality events associated with SSRIs,[38] and
in consultation with NIMH and the CAMS Data Safety
and Monitoring Board, a harm to self and others ques-
tionnaire was developed and implemented. The partici-
pants treating clinician administered this form at each
treatment session to document the onset or change in
harm-related ideation or behavior.
To ensure cross-site uniformity in the management of
clinically emergent situations, CAMS followed proce-
dures implemented in other pediatric comparative trials
[39,40]. Up to 2 additional treatment sessions ("ASAP
sessions) were permitted per participant in both Phase
I and II to manage any newly emergent clinical needs
and facilitate participant retention. Participants whose
clinical needs required more than two ASAP sessions
per study Phase were prematurely terminated by the
site team and referred for additional treatment outside
the study.
The CAMS assessment battery evaluated the impact of
treatment on the presence and degree of anxiety symp-
tomatology, associated comorbid symptoms, and psy-
chosocial functioning across multiple functional
domains. Additional assessments inclu ded a wide range
of demographic variables, comorbid symptomatology,
parental psychopatholog y, family functioning and envir-
onment, treatment adherence, cognitive self-ta lk, and
treatment-related expectancies and beliefs. Finally, mea-
sures were included for quality assurance purposes and
to assess the adequacy of the blind. A summary o f pri-
mary and secondary assessment measures, and the
domains measured, are provided in Table 3.
CAMS participants completed three full IE assess-
ment sessions: baseline, week 12, and week 36; and
three partial IE assessment sessions: weeks 4, 8, and
24. Participants were reimbursed for time and expense
involved in completing the a ssessments in accordance
with local IRB regulations.
Quality Assurance
required certifications for the ethical conduct of
research and HIPAA training. Candidates wishing to be
study c linicians (i.e., CBT therapists, PT therapists) and
independent evaluators (i.e., IEs) underwent a rigorous
certification process which included: (1) a review of cre-
dentials (MA or PhD for CBT therapi sts; MD or NP for
PT therapists; and MA, RN, PhD, or MD for IEs) and
clinical experience treating a nxious youth; (2) reading
study related materials; (3) passing a test on the treat-
ment and study pro tocols (passing was defined as a
score of 80% or greater); (4) completing a training work-
shop; and (5) passing a videotape or audiotape review of
a training case(s) for evaluation of fidelity and compe-
tence by the QA reviewers (i.e., as noted earlier, Temple
University conducted QA for CBT sessions, UCLA for
PT sessions, and NYSPI for IE assessments). After certi-
fication, CBT, PT, and IE staff received onsite supervi-
sion by a study supervisor and ongoing cross-site
supervision during separate and independent one-hour
conference calls. CBT therapists had weekly onsite and
cross-site supervision, IEs had weekly onsite supervision
and every other week cross-site supervision, and PT
therapists had monthly onsite supervision and every
other week cross-site supervision. In addition to the
supervision provided onsite and cross-site via conference
call, there was an initial in person start-up training
in-person recalibration and training sessions for all
study staff throughout the 6-years of the trial. These
procedures allowed the investigative team to correct any
drift and address the management of clinical issues and
situations in a similar fashion tha t could potentially
impact the integrity of the trial while facilitating a colla-
borative study culture across sites.
Design Weaknesses and Challenges
The primary weakness of the CAMS design, and other
clinical trials similar to CAMS (e.g., MTA, TADS, and
POTS), is that the CBT and COMB participants were
not blinded. The only double-blinded treatment condi-
tions were SRT and PBO. CBT participants knew they
were receiving CBT and COMB participa nts knew they
were receiving both CBT and SRT. This leaves results
from the CAMS trial open to the criticism that partici-
pant and family expectancy effects may potentially bias
outcomes. However, as argued in other similar compara-
tive treatment trials,[48] the decision not to blind cer-
tain treatment conditions are design choices rather than
necessarily design flaws. In the case of CAMS, the
design chosen represented the best balance between
scientific rigor, potential for public health impact, ecolo-
gical validity, feasibility of implementation, and cost.
Moreover, CAMS investigators recognized this limita-
tion in the design chosen and took deliberate steps to
minimize threats to the internal validity of the trial by
using I Es who were blind to participants treatment
assignment to measure outcomes.
The CAMS study experienced challenges, as well as
successes, when it came to monitoring adverse events.
The CAMS Data Safety Monitoring Board (DSMB) initi-
ally approved an adverse event monitoring policy based
on procedures that were used in the TADS study [40].
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 10 of 15
Table 3 Primary and Main Secondary Assessment Measures
Measure Abbreviation Domain
Independent Evaluator
Anxiety Disorders Interview Schedule ADIS-RLV Diagnostic interview
Clinical Global Impression Scales CGI-S/I Severity and improvement
Family History Score Sheet FAMH1 Family history
Global Assessment Scale for Children CGAS Impairment and functioning
Guess Treatment GUESE IE blindness
Pediatric Anxiety Rating Scale PARS Anxiety severity
Supplemental Services Intake SSIN Extra-study interventions
Wechsler Intelligence Scale for Children - III WISC-III Intellectual functioning
Child and parent report: about child
Ambiguous Situations Questionnaire ASQ Threat bias
Child Anxiety Impact Scale CAIS Anxiety related interference
Coping Questionnaire CQ Perceived coping ability
Goal Attainment Scale GAS Anxiety symptom improvement
Mood and Feelings Questionnaire MFQ Depressive symptoms
Multidimensional Anxiety Scale for Children MASC Anxiety symptoms
Screen for Child Anxiety Related Emotional Disorders SCARED Anxiety symptoms
Child report only: about self
Negative Affectivity Self-Statement Questionnaire NASSQ Negative cognition (self-statements/self-talk)
Physical Symptoms Checklist PSC Physical symptoms
Parent report: parent about child
Child Behavior Checklist CBCL Behavioral problems/social and academic
Child and Adolescent Health Screening Report MEDHXC Medical history
Peterson Pubertal Developmental Scale PDS Pubertal status
Family Burden Assessment Scale BAS Burden on child on family
Parent report: parent about self
Brief Symptom Inventory BSI Parental psychopathology
State-Trait Anxiety Inventory - A Trait Scale STAI-T Parental anxiety
Brief Family Assessment Measure - III BFAM-III Family functioning
Child/Parent report: about treatment
Perception of Therapeutic Relationship PTR Therapeutic relationship
Satisfaction Questionnaire SQ Satisfaction with treatment
Clinician Measures
Adverse Events AEF Side effects
Harm to Self and Others HARM Suicidal ideation and risks
Session Summary Sheets SSS PT and CBT session summary
Concomitant Medication/Treatment Log CML/CTL Concomitant medication/treatment
Female Menstrual Cycle FMC Menstrual status/sexual activity
General Information Sheet GENINFO Demographic information
Pre-treatment Expectancy PTX Therapist/patient expectancies
Supplemental Services Follow-up SSFU Extra-study interventions
Treatment Assignment Reaction TAR Treatment expectancies
Vital Signs VITAL Vital signs
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 11 of 15
This policy consisted of only recording adverse events
that caused moderate to severe distress or resulted in
functional impairment. The implication of the policy
was that mild adverse events that did not result in func-
tional impairment were not recorded. However, several
months into the trial the DSMB reversed its decision
and mandated the collection and reporting of all adverse
events, including mild events. Further complicating
adverse event collection procedures, several years into
the study the DSMB required CAMS c linici ans to s ys-
tematically query and collect information about the pre-
sence of any harm related adverse events from all study
participants and parents at each study visit (i.e., non-sui-
cidal self-harm, suicidal ideation, homicidal ideation,
suicidal behavior, and homicidal behavior). Although
moderate and s evere adverse event data were systemati-
cally collected throughout the entire trial, the shifting
methods used to elicit and record adverse events com-
plicates the conclusions that can be made about the pre-
sence or absence of adverse events throughout the
entire trial for all subjects.
Despite this limitation, CAMS utilized an adverse
event procedure that was very effective. In response to
the finding in the T ADS study that CBT therapists did
not monitor adverse events as closely as did t he PT
therapists, a different procedure was implemented in
CAMS for eliciting adverse events than is typically used
in clinical trial s. In mo st clinical t rials, clinicians
(whether a psychologist or psychiatrist) asks the partici-
pant or parent(s) if they noticed any changes since their
last treatment visit. However, to avoid the problem
found in TADS, the elicitation of adverse events was
assessed immediately before each treatment visit by the
site project coordinator across all treatment conditions.
This ensured that the elicitation of adverse events did
not vary by treatment condition. This novel adverse
event monitoring procedure was effecti ve in standa rdiz-
ing the el icitation of adverse events across different
treatment c onditions and will allow for comparisons of
relative safety across the four treatment conditions.
Following the MTA, POTS, TADS and TORDIA
[27,39,40,49]all randomized controlled trials in which
most CAMS investigators participatedCAMS is now
the fifth large-scale multicenter comparative pediatric
treatment trial funded by the NIMH in the last decade.
CAMS benefitted from lessons learned in these earlier
studies and as a result used best available methods in
experimental design, trial exe cution and data analysis.
With respect to its public health goals, CAMS directly
addresses the lack of research examining the efficacy of
CBT alone and PT alone in the same population of
anxious children that were recruited, assessed, and
treated using similar methodologies. CAMS also
addressed the critical question of whether combining
treatments provides additional benefit. Result s of the
acute outcomes of the CAMS trial showed that all active
treatments were sup erior to pill PBO, that com bination
treatment was superior to the monotherapies, and that
the monotherapies were equivalent. These findings are
encouraging and sugges t that the re are three effective
interventions for the treatment of three o f the most
common anxiety disorders in child and adolescent
populations. The CAMS assessment protocol allowed
for the eva luation of changes in the symptom profile,
functional outcomes, and adverse events, as well as
putative mediators and m oderators of response, in an
explicit multi-measure, multi-informant fashion and will
provide a platform to address many public health ques-
tions. For example, results from the acute outcomes
reveals that that suicidal events are far less common in
anxious youth than in patients with depression,[50] with
no additional sertraline-associated suicidal events
reported [15]. Although the CAMS trial used e xperi-
enced and well-trained and closely monitored clinicians,
the CAMS manual-based protocols were designed to
directly translate into community practice making the
findings more relevant than they would have been had
less readily available treatments been used.
The primary findings from the CAMS suggest b oth
CBT and SRT reduced the severity of anxious symptoms
in children and adolescents diagnosed with moderate to
severe SAD, GAD or SoP; however, the combination of
the two therapies showed the most benefit. Subsequent
papers reviewing secondary outcomes, the durability and
safety of each treatment and moderators and mediators
of study outcome will inform practice- relevant questions
regarding the treatment of youth with anxiety disorders.
List of Abbreviations
ADHD: Attention Deficit Hyperactivity Disorder; ADIS:
Anxiety Disorder Interview Schedule; CAMS: Child/
Adolescent Anxiety Multimodal Study; CBT: Cognitive
Behavioral Therapy; CGI-I: Clinical Global Impression-
Improvement; CGI-S: Cli nical Global Impres sion-Sever-
ity; COMB: Combination Therapy; DHHS: Department
of Health and Human Services; DSM-IV-TR: Diagnostic
and Statistical Manual of Mental Disorders-IV Edition-
Text Revised; DSMB: Data Safety Monitoring Board; EC:
Executive Committee; FDA: Food and Drug A dministra-
tion; GAD: Generalized Anxiety Disorder; IE: Indepen-
dent Evaluator; ITT: Intent-To-Treat; MDD: Major
Depressive Disorder; NIH: National I nstitute of Health;
NIMH: National Institutes of Mental Health; NYSPI:
New York State Psychiatric Institute; OCD: Obsessive-
Compulsive Disorder; PARS: Pediatric Anxiety Rating
Scale; PBO: Pill Placebo; PT: Pharmacotherapy; QA:
Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 12 of 15
Quality Assurance; RCT: Randomized Clinical Trial;
SAD: Separation Anxiety Disorder; SC: Steering Com-
mittee; SoP: Social Pho bia; SRT: Sertraline; SSRI: Selec-
tive Serotonin Reuptake Inhibitor; UCLA: University of
California at Los Angeles
Funding for this research project was supported by the following grants
from the National Institutes of Mental Health (NIMH): U01 MH64092 to Dr.
Albano; U01 MH64003 to Dr. Birmaher; U01 MH064003 to Dr. Compton; U01
MH63747 to Dr. Kendall; U01 MH64107 to Dr. March; U01 MH64088 to Dr.
Piacentini; and U01 MH064089 to Dr. Walkup. Sertraline and matching
placebo were supplied free of charge by Pfizer, Inc. Article processing
charges (APC) of this manuscript has been funded by the Deutsche
Forschungsgemeinschaft (DFG).
Author details
Duke University Medical Center, Department of Psychiatry and Behavioral
Sciences, DUMC Box 3527, Durham, NC 27710, USA.
The Johns Hopkins
Hospital, Division of Child and Adolescent Psychiatry, 600 North Wolfe Street,
Baltimore, MD 21287, USA.
New York State Psychiatric Institute-Columbia
University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA.
University of California at Los Angeles, Semel Institute for Neuroscience and
Human Behavior, 760 Westwood Plaza, 68-251B, Los Angeles, CA 90095, USA.
Western Psychiatric Institute and Clinic-University of Pittsburg h Medical
Center, 3811 OHara Street, Pittsburgh, PA 15213, USA.
Division of Services
and Intervention Research, National Institute of Mental Health, 6001
Executive Boulevard, MSC 9633, Bethesda, MD 20892, USA.
Baystate Medical
Center, 759 Chestnut Street, Springfield, MA 01199, USA.
Temple University,
Department of Psychology, Weiss Hall 1701 North 13th Street, Philadelphia,
PA 19122, USA.
Authors contributions
All listed authors made substantive intellectual contributions to the
conception, design, and implementation of the study. In addition, SNC was
principle investigator of the data center, secretary on the executive
committee, and drafted the manuscript. JTW was principle investigator of
the Johns Hopkins site, chair of the executive committee, and helped to
draft the manuscript. AMA was principle investigator of the New York State
Psychiatric Institute site, co-chair of the executive committee, chair of the
independent evaluator subcommittee, oversaw independent evaluator
quality assurance ratings, and helped to draft the manuscript. JCP was
principle investigator of the University of California at Los Angeles site, chair
of the assessment subcommittee, oversaw psychopharmacology quality
assurance ratings, and helped to draft the manuscript. BB was principle
investigator of the Western Psychiatric Institute and Clinic site and initially
set-up and oversaw the data center for several years. JTS was the National
Institutes of Mental Health representative on the trial, member of the
executive committee, and helped to draft the manuscript. GSG was co-
investigator of the Johns Hopkins site and site CBT supervisor. MAR was a
co-investigator of the New York State Psychiatric Institute site, chair of the
psychopharmacology subcommittee, and site psychopharmacology
supervisor. JTM was co-investigator of the University of California at Los
Angeles site and chair of the genetics subcommittee. BDW was a co-
investigator of the New York State Psychiatric Institute site. SI was chair of
the statistics subcommittee. PCK was principle investigator of the Temple
University site, chair of the CBT subcommittee, oversaw CBT quality
assurance ratings, and helped to draft the manuscript. JSM was principle
investigator of the Duke University Medical Center site. All authors read and
approved the final manuscript.
Competing interests
In the past two years, all other authors have received grant support from
the NIH/NIMH and all authors acknowledge that they received support from
Pfizer Inc in the form of free medication and matching placebo for this
study. SNC receives consulting fees and grant support from the Tourette
Syndrome Association. JTW has received consulting fees from Eli Lilly and
JAZZ Pharmaceuticals and lecture fees from CMP Media, Medical Education
Reviews, McMahon Group, DiMedix, and the Tourette Syndrome Association.
He has received free drug and matching placebo from Lilly, and free drug
from Abbott for NIMH-funded clinical trials. He has received fees for
consultation with defense counsel and submission of written reports in
litigation involving GlaxoSmithKline. AMA receives royalties from Oxford
University Press for the Anxiety Disorders Interview Schedule for DSM-IV,
Child and Parent Versions (though not for CAMS) and for manuals not used
in this study; and royalties from the Guildford Press. JCP has received grant
support from the Obsessive Compulsive Foundation, the Eisner Foundation,
grant and travel support from the Tourette Syndrome Association, royalti es
for treatment manuals on childhood obsessive compulsive disorder and tic
disorders (from Oxford University Press) and from other books on child
mental health (from Guilford Press and APA Books), and speaker honoraria
from Janssen-Cilag. BB has received grant support from the Fine Foundation
and has participated in forums sponsored by JAZZ Pharmaceuticals, Solvay
Pharmaceuticals Inc, and Abcomm Inc. He has given paid talks on the topic
of childhood bipolar disorder at a meeting sponsored by Solvay and
receives royalties for a book on children with bipolar disorder from Random
House, Inc. JTS is a full-time employee of the NIMH/NIH/DHHS. The views
expressed in this article are those of the authors and do not necessarily
represent the official views of the NIMH, the NIH, or the DHHS. GSG has
received additional grant support from the Obsessive Compulsive
Foundation. MAR has grant support from Neuropharm, Boehringer
Ingelheim Pharmaceuticals, and Wyeth Pharmaceuticals. She is a consultant
to Wyeth and receives royalties from APPI for a book chapter on pediatric
anxiety disorders. JTM is a paid consultant for Sanofi-Aventis and Wyeth, has
received lecture fees from Shire and UCB, and has additional grant support
from Aspect, Johnson & Johnson, Bristol-Myers Squibb, and Eli Lilly. BDW has
grant support from Baystate Health, Somerset Pharmaceuticals, and
GlaxoSmithKline. SI receives fees as a statistical consultant from Stanford
University and Westinghouse Corporation. PCK receives royalties from the
publication of the anxiety treatment materials (not from this study) and from
books on child mental health from Workbook Publishing. JSM is a
consultant or scientific advisor to Eli Lilly, Pfizer, Wyeth, Johnson and
Johnson, and GlaxoSmithKine. He is a stockholder in MedAvante, the author
of the Multidimensional Anxiety Scale for Children (MASC) for which he
receives royalties (though not for CAMS), has received study drug for TADS
from Eli Lilly, receives research funding from NARSAD and from Pfizer,
receives book royalties from Guilford Press and from Oxford University Press,
and was a member of a DSMB overseeing research conducted by Astra-
Zeneca or Johnson & Johnson.
Received: 6 August 2009
Accepted: 5 January 2010 Published: 5 January 2010
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Cite this article as: Compton et al.: Child/Adolescent Anxiety Multimodal
Study (CAMS): rationale, design, and methods. Child and Adolescent
Psychiatry and Mental Health 2010 4:1.
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Compton et al. Child and Adolescent Psychiatry and Mental Health 2010, 4:1
Page 15 of 15
... Figure 1 depicts a concrete example of an adaptive intervention for young children who are initially diagnosed with pediatric anxiety disorder. In this example of adaptive intervention, first, clinicians offer the medication sertraline [4] for initial 12 weeks. If the child does not show an adequate response to it at the end of week 12, the clinician offers to augment the treatment with a combination of the medication sertraline and cognitive behavioral therapy [5] for additional 12 weeks. ...
... Each subject is randomly assigned to one of the initial treatment options and the assigned treatment is conducted for the first 12 weeks. At the end of week 12, each subject's response to the treatment is assessed based on Clinical Global Impression-Improvement Scale [4] and categorized as a responder or as a nonresponder. Based on this, those who do not respond to the initial treatment are again randomly assigned to one of two secondary treatment options: One is a switch strategy whereby the child is switched to the stage 1 treatment option they were not offered at first. ...
... In a SMART such as the one shown in Figure 2, research outcomes may be collected at the end of week 24 or throughout, from baseline to week 24. Research outcomes may be continuous, e.g., Pediatric Anxiety Rating Scale [4] or discrete, e.g., Clinical Global Impression-Improvement Scale [4]. Note that the measure of response versus non-response at week 12 is not necessarily a research outcome. ...
Full-text available
... Exploratory analyses examined associations between FPS threat learning indices and treatment response in a subsample of pediatric patients who completed the task prior to receiving treatment. Patients received up to 12 weekly sessions of standard exposure-based CBT (Compton et al., 2010;Walkup et al., 2008). Treatment response was assessed using the Pediatric Anxiety Rating Scale (PARS) at pretreatment, mid-treatment, and post-treatment (Research Units on Pediatric Psychopharmacology Anxiety Study Group, 2002) administered by treating therapists (n = 46, 34.59 % of patients; 28 female participants, M age = 12.98 years). ...
Background Major theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes. Methods Youths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8–50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial interval as baseline to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients. Results Patients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome. Conclusion ITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.
... These results suggest that SCAARED is a suitable tool for screening for anxiety disorders in the adult population. SCAARED is sensitive to response to treatment (Compton, Peris, et al. 2014;Compton, Walkup, et al., 2014) and biological changes in the brain (Perlman et al., 2014). In future studies, SCAARED could be useful for screening for anxiety disorders in psychiatric settings and primary care and psychiatric clinics, and In future studies, SCAARED could be useful for screening for anxiety disorders in psychiatric settings and primary care and psychiatric clinics. ...
Full-text available
Background: The aim of this study was to investigate the psychometric properties of the Persian version of the Screen for adult anxiety related disorders (SCAARED) in Tehran. Method: The present study was a descriptive-survey method and a cross-sectional method. The present research population consists of patients referring to hospitals and psychiatric clinics in Tehran, as well as male and female students in Tehran. The sample of the present study included 300 participants (150 patients with a diagnosis of anxiety disorders and 150 non-clinical samples), who were selected by random sampling method. Inclusion criteria included age 18 to 50, minimum diploma, lack of mental retardation, and lack of acute physical illnesses such as cancer or severe pain. The participants, after completing the demographic questionnaire and conducting a Structured Clinical Interview for DSM-5 Disorders-Clinical Version (SCID-5-CV), completed the SCAARED and the Personal Wellbeing Index-Adults (PWI-A). Finally, face and content validity and construct validity, test-retest reliability, Cronbach's alpha, and factor analysis were used. Results: The results of the present study confirmed the face validity and content of the present scale. A review of Cronbach's standardized alpha showed that SCAARED has a reliability of 0.966, and therefore, the Persian version of these questionnaires is a reliable tool. Also, the results showed a correlation between the two implementations of the questionnaire; in addition to the strong correlation at the level (p < .01) between the factors of the questionnaire and the factors with the total score, there was a strong correlation between the first and second implementation in four factors and the overall score. Therefore, it can be concluded that the SCAARED has good test-retest reliability. Also, there is a positive correlation between the factors and the overall score of the SCAARED with anxiety disorders based on Structured Clinical Interview for DSM-5 Disorders (p < .01), which indicates the favorable convergent validity of the SCAARED questionnaire. There is a negative correlation between the factors and the overall score of the SCAARED with the PWI-A at the level (p < .01), which indicates the favorable divergent validity of the SCAARED, and the results of exploratory factor analysis of the questionnaire were confirmed. Conclusion: The Persian version of the SCAARED is a tool with appropriate validity and reliability.
... Leyfer et al. 2019) but excluded if the strategy was introduced during other, non-exposure components of treatment (e.g. Compton et al. 2010). (ii) Reported an association between features of exposure practice (i.e. ...
Cognitive Behavioural Therapy (CBT) is the first line treatment for anxiety disorders in youth however many adolescents do not benefit. Behavioural exposure is believed to be the critical ingredient of CBT and research with adults has shown that labelling affect, but not positive coping statements, enhances exposure outcomes. However, many CBT protocols for young people involve using positive coping statements alongside exposure. We compared the effects of exposure with positive coping statements, affect labelling, and neutral statements on fear responses in adolescents (age 13–14 years) with public speaking anxiety as they delivered a series of speeches in front of a pre-recorded classroom audience. Self-rated anxiety, heart rate, and observer ratings of expressed anxiety were assessed pre-test, immediate post-test and at 1-week follow-up. Neither affect labelling nor positive coping statements enhanced exposure on any measure from pre-test to 1-week follow-up. While there was an initial advantage of exposure with positive coping statements for post-speech self-reported anxiety, this effect was not maintained, and there was a significant increase in anxiety from immediate post-test to 1-week follow-up in this condition, compared to the other conditions. The short-term benefits from generating positive coping statements may explain why this is often employed in the treatment of anxiety problems in young people, but also indicate that it may not confer any advantage in the longer term. These intriguing findings highlight the urgent need for further attention to improve understanding of how to optimise exposure in young people and maximise treatment outcomes.
... The study was conducted at a single, outpatient site and recruited adolescents (age 12-17 years, inclusive) with generalized, separation, and/or social anxiety disorder (pediatric anxiety triad) [51]. Exclusion criteria included patients with >1 prior SSRI trials of adequate dose and duration; a clinically significant, prolonged QTc; co-occurring DSM-5 mood, eating, bipolar, or psychotic disorder; intellectual disability; history of alcohol or substance use disorder within six months of screening (nicotine use is permitted); female patients of childbearing potential who were sexually active and not practicing a reliable method of contraception; patients who were pregnant, breast feeding, or lactating; or patients who were unable to attend the study visits. ...
Full-text available
Current pharmacologic treatments for pediatric anxiety disorders (e.g., selective serotonin reuptake inhibitors (SSRIs)) frequently use “one size fits all” dosing strategies based on average responses in clinical trials. However, for some SSRIs, including escitalopram, variation in CYP2C19 activity produces substantial variation in medication exposure (i.e., blood medication concentrations). This raises an important question: would refining current SSRI dosing strategies based on CYP2C19 phenotypes increase response and reduce side effect burden? To answer this question, we designed a randomized, double-blind trial of adolescents 12–17 years of age with generalized, separation, and/or social anxiety disorders (N = 132). Patients are randomized (1:1) to standard escitalopram dosing or dosing based on validated CYP2C19 phenotypes for escitalopram metabolism. Using this approach, we will determine whether pharmacogenetically-guided treatment—compared to standard dosing—produces faster and greater reduction in anxiety symptoms (i.e., response) and improves tolerability (e.g., decreased risk of treatment-related activation and weight gain). Secondarily, we will examine pharmacodynamic variants associated with treatment outcomes, thus enhancing clinicians’ ability to predict response and tolerability. Ultimately, developing a strategy to optimize dosing for individual patients could accelerate response while decreasing side effects—an immediate benefit to patients and their families. Identifier: NCT04623099.