Providing Tools for Effective Care and Treatment of Anxiety Disorders (AD): Outcomes, Mediators and Moderators of Enhanced Extinction
Phase: NA
Conditions: Panic Disorder, Agoraphobia, Specific Phobias, Social Anxiety Disorder
Sponsor: Technische Universität Dresden

 
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Study Protocol (Version 3.1; 01.06.2014) 
 
 
 
Study Title: 
 
Optimizing Extinction Using Intensified Psychological Interventions 
(IPI) for Adult Anxiety Disorders (AD) 
 
- Study Protocol (Version 3.1) - 
 
Research Network on Mental Disorders (2014) 
 
granted by the German Federal Ministry of Education and Research 
 
 
 
Principal Investigator: 
 
Prof. Dr. phil. habil. Hans-Ulrich Wittchen 
 
Institut für Klinische Psychologie und Psychotherapie 
Technische Universität Dresden 
Chemnitzer Str. 46 
01187 Dresden 
Tel.: 
49 351 463 36985 
E-Mail: wittchen@psychologie.tu-dresden.de 
 
 
Study Centers:  
 
1. 
Wittchen, H.-U: Institut für Klinische Psychologie und Psychotherapie, Technische 
Universität Dresden 
2. 
Arolt, V.: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Westfälische Wilhelms 
Universität Münster  
3. 
Schneider, S.: Forschungs- und Behandlungszentrum für Psychische Gesundheit, Ruhr 
Universität Bochum  
4. 
Hamm, A.: Physiologische und Klinische Psychologie / Psychotherapie, Ernst-Moritz-
Arndt Universität Greifswald  
5. 
Kircher, T.: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Philipps-Universität 
Marburg 
6. 
Deckert, J.: Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie, 
Julius-Maximilians-Universität Würzburg 
7. 
Ströhle, A.: Klinik und Poliklinik für Psychiatrie und Psychotherapie, Charité-
Universitätsmedizin Berlin 
 

 
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Study Protocol (Version 3.1; 01.06.2014) 
0. 
Summary 
 
APPLICANT/ 
COORDINA-
TING INVES-
TIGATORS 
Professor Dr. Hans-Ulrich Wittchen & Prof. Dr. Volker Arolt (Co-PI) 
Institute of Clinical Psychology and Psychotherapy & CELOS 
Technische Universität Dresden 
Chemnitzer Strasse 46, 01187 Dresden 
Tel.: 0351-463-36985; Fax: 0351-463-36984 
wittchen@psychologie.tu-dresden.de 
TITLE  
Optimizing Extinction Using Intensified Psychological Interventions 
(IPI) for Adult Anxiety Disorders (AD)  
CONDITION 
DSM-5: Panic Dis. (PD), Generalized Anxiety Dis. (GAD), Agoraphobia (AG), 
Social Anxiety Disorder (SAD), Specific Phobias (SP), Separation Anxiety 
Dis.(SepAD), and associated comorbid conditions  
OBJECTIVE 
 
To examine the efficacy of intensified psychological interventions (IPI) aiming 
to augment extinction learning during exposure. In IPI we increase the 
number of exposure trials and decrease the spacing between sessions 
providing more “extinction trials” over a shorter duration. To stabilize 
treatment effects we provide spaced exposure training during follow-up 
(booster) in different contexts. We also based exposure on a positive 
prediction error model. We hypothesize that IPI results in stronger, faster and 
more pervasive effects in subjective, behavioural, physiological, neural and 
epigenetic indices at post and follow-up via optimizing extinction learning. To 
test the hypothesis, we propose a multicentre randomized clinical trial (RCT). 
Patients will be randomly allocated to either IPI or standard research 
exposure treatment as usual (TAU) as the control condition. Primary 
hypotheses: (1) IPI will be superior to TAU at post and follow-up on primary 
and secondary outcome measures and will recover faster. Secondary 
hypotheses are: (2) IPI is associated with enhanced positive prediction error 
to increase extinction learning during and after exposure and (3) will result in 
more pronounced changes in behavioural proxy measures (between session 
reduction of fear, anxiety, avoidance) of extinction learning. We also explore 
the effect of type of diagnosis and comorbidity as potential moderators of 
outcome and extinction. We further expect that IPI will be associated with 
lower direct and indirect health care costs.  
INTERVENTION 
 
Eligible patients are randomized to either IPI or TAU. Using a well established 
modular 12-sessions exposure-based treatment manual template 1,2, we 
compare two content-wise almost identical versions. However, IPI provides 
the manual`s behavioural exposure module (BE, sessions 6-10) in one week 
allowing for a higher number of exposure trials over a short time period, and 
provides “spaced trials” during the booster and follow-up period. In the control 
condition (TAU), the BE module will be provided over 4-5 weeks as is usual 
in research settings with one to two sessions/week and no spaced exposure 
trials during the follow-up phase.  
Follow-up period per patient: 6 month 
Duration of intervention per patient, excluding 6 months follow-up: 5-6 weeks 
(IPI), and 7-9 weeks (TAU)  
INCLUSION/ 
EXCLUSION 
CRITERIA 
Stratified sampling of patients in anxiety clinics. Key inclusion criteria: (1) 
Outpatients, (2) age: 15-70 years, (3) current primary DSM-5 anxiety 

 
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Study Protocol (Version 3.1; 01.06.2014) 
disorder, (4) severity at baseline (HAMA>18) and CGI>3, (5) written informed 
consent, (6) able to attend on his/her own or accompanied by significant 
other, (7) language competence. 
Key exclusion criteria: (1) any DSM-IV/5 psychotic, primary mood disorders 
(bipolar I, recurrent or chronic major depression), current substance use 
dependence, (2) concomitant psychological/psychiatric treatment, (4) acute 
suicidality, (5) general medical contraindications, (5) mono-symptomatic 
specific phobia.  
OUTCOME(S) 
Primary efficacy endpoint is the clinician-rated Hamilton anxiety score (SIGH-
A). Key secondary endpoint(s): CGI total score, patient rated generic (BSI) 
and diagnosis-specific symptom scores (i.e. FFS, PAS, MI), impairment/ 
disability days (CIDI Harvard Index, SDS), depression (dimensional: BDI, 
categorical: CIDI) quality of life (EQ-5D) and social functioning (SAS). As an 
objective and ecological valid measure for exposure trials we use a novel 
combined mobile mobility-EMS tool (see proposal ESPRIT). The range of 
measures is meant to demonstrate that IPI is associated with more pervasive 
changes in various domains. As proxy measure for extinction learning we 
use subjective measures of within-session and between-session exposure 
effects (anxiety ratings, expectancy ratings of central concerns). (Note: see 
further assessments in P3-P6.)  
Assessment of safety: suicidality assessment and adverse behavioural 
effects.  
STUDY TYPE 
Randomised controlled clinical trial with two active conditions associated with 
mediator and moderator analyses (see projects P3-6) 
STATISTICAL 
ANALYSES 
Efficacy: HAMA total score (standardized interview, SIGH-A)  
Description of primary efficacy: Superiority of IPI against TAU will be tested 
with t-tests for independent samples using an alpha level of 0.5. Intent-to-
treat (ITT), completer analyses will be conducted and mixed models 
(saturated for the joint effects of treatment group and time) fit to address 
dropout.  
Safety: N/A 
Secondary endpoints: ITT, completer analysis and mixed models as above 
but with two-sided tests in case of explorative analyses. Pearson correlations 
between dimensional comorbidity measures and outcomes will be 
calculated, Associations with categorical predictors will be analyzed with 
linear regressions.  
SAMPLE SIZE 
To be assessed for eligibility n=1.400 
To be allocated in a stratified way (by diagnosis) to trial (n = 720) 
To be analysed (n = 620) 
TRIAL 
DURATION 
First patient in: 6/1st year – last patient out (fup): 1/4th year 
Recruitment and enrolment: start: 6/1st year 
Duration of the entire trial: 36 months 
Recruitment period: 6/1st year – 5/3rd year 
CENTERS 
7: Greifswald, Berlin, Münster, Marburg, Dresden, Bochum, Würzburg 
 
 
 
 
 

 
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Study Protocol (Version 3.1; 01.06.2014) 
1. 
Evidence and study rationale 
 
1.1 
Extinction learning  
 
A widely accepted view on the nature of extinction holds that extinction is conveyed by 
forming a second, inhibitory CS-US association in addition to the formerly acquired excitatory 
CS-US association (fear memory). Fear memories are thus not erased, but can be retrieved 
under certain circumstances. This phenomenon, also known as return of fear, clinically 
presents as a reoccurrence of anxiety symptoms or relapse. A great body of preclinical 
evidence has investigated the conditions under which return of fear can be observed and 
emphasises the key role of context variables during fear extinction 1,2. Context information is 
critically linked to the extinction memory and acts as a gating mechanism as to whether the 
fear memory is inhibited or not. From a neurobiological viewpoint, context information during 
extinction is stored in the hippocampus and fear inhibition is signalled by concerted action of 
the ventromedial prefrontal cortex, the amygdala and the hippocampus. Potential context 
variables do not only encompass external or internal states, but also temporal characteristics 
of the treatment. One prominent example is the spontaneous recovery of fear where the time 
between treatment and relapse can be interpreted as a gradually changing context, making it 
difficult to recall the original inhibitory memory trace in this seemingly new context. In this 
view, the timing and spacing of exposure sessions (inter-trial intervals (ITI)) seems to be 
particular relevant and thus we focus this chapter on this topic.  
 
Extinction learning comprises several distinct phases: 1. The individual learns that a fear cue 
is no longer followed by the expected aversive consequences under the current circumstances 
or in the current context. 2. This learning experience is consolidated, and inhibitory 
associations are reinforced by repetitive exposure sessions 3. 3. In case of successful long-term 
extinction learning, extinction memory is recalled even if the previously feared cues occur in 
different contexts. Under critical circumstances recall of the extinction memory can be 
blocked and return of fear and even relapse can occur. Comparable learning and extinction 
processes are also important for contextual fear conditioning which occurs when aversive 
events appear unpredictable so that the context becomes the best, albeit imprecise, predictor 
of aversive events. Such contextual fear conditioning is an experimental model of sustained 
anxiety and explains avoidance and safety behavior at least in panic disorder patients 4.  
 
We acknowledge that there are various constructs and paradigms to assess extinction-related 
mechanisms of change (e.g. enhanced discrimination learning, enhanced safety learning, 
reduced vulnerability to reinstatement, or context renewal). However, we refrain from 
providing here a complete critical review of evidence. Instead we present a review of evidence 
and highlight the following critical state of the art reviews 1,2,5,6 (see also P3-P5).  
 
Preclinical evidence: Although being far from consistent, animal and human studies on the 
timing of extinction trials suggest that massed extinction can result in enhanced fear 
inhibition, albeit possibly more susceptible to return of fear in the long-term. Early animal 
research suggested that massed extinction resulted in more rapid extinction learning. 
However, some studies found no effects, opposite effects, or have found that massed 
extinction even results in greater return of fear 7. In mice, the most effective method of 
enhancing extinction is found with initial massed trials followed by subsequent spaced trials. 
In human subjects, evidence on the inter-trial interval in extinction is scant, and many of the 

 
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Study Protocol (Version 3.1; 01.06.2014) 
studies provide contradictory results. One study found that massed extinction trials result in 
higher conditioned responding compared to spaced extinction trials but have similar rates of 
spontaneous recovery, and another study found no difference in extinction based on ITI 
duration. Similar to the finding reported in mice above, there is some evidence that initial 
massed extinction trials followed by spaced trials may provide an advantage for humans at 
the end of extinction, but the benefits of this “expanding” practice might be washed out at 
renewal tests compared to subjects extinguished with constant ITI durations 8. There is further 
increasing evidence for a core role of “prediction error”, implying that focussing on violating 
patients central concerns about aversive outcomes is an important ingredient of successful 
extinction learning 2.  
 
Clinical evidence: Clinical application studies have attempted to discern the most effective 
length of time between exposure sessions and have varied in their results. Comparing 
different exposure schedules (massed one-session treatment, uniform time intervals, 
gradually expanding time intervals), massed treatments result in more return of fear than 
uniform or expanding schedules. Other studies find no differences in extinction levels for 
massed versus spaced exposure. Some researchers find a benefit of massed extinction for 
behavioral measures while others report a benefit of spaced trials, but none of these tested 
for long-term follow up. However, studies that include follow-up and generalization tests tend 
to find that while massed exposures result in immediate enhanced extinction learning, spaced 
exposures result in long term inoculation against return of fear on generalization tests. One 
possible explanation for a benefit of spaced exposures is that the spaced sessions allow for 
changes in context (e.g. the internal state of the participant, changes in the environment or 
time of day, etc.) that increase retrieval cues for the inhibitory memory and therefore make 
the extinction learning more robust and less context-dependent, which could produce 
enhanced long-term extinction learning 9. Also, the variability in the timing of exposure (e.g. 
condensed as well as spaced) may uncouple extinction memories from their temporal context 
2. 
 
To conclude, condensed exposure with short ITI results in faster extinction than spaced. This 
might however be at the expense of return of fear and clinically a higher chance of relapse. 
Therefore in the initial active treatment phase more trials with shorter ITI should be most 
promising for a rapid and more effective extinction learning. To stabilize this, subsequent 
spaced trials in different contexts is preferred.  
1.2 
Moderators for treatment outcome and extinction learning in AD 
 
Type of anxiety disorder: There are no systematic studies that directly compare outcomes and 
mediator processes across various forms of anxiety disorders 5. With the possible exception 
of Generalized Anxiety Disorder (GAD) where results seem to be characterized by slightly 
poorer outcomes than for Panic, Agoraphobia and Specific Phobia, we are also unaware of 
evidence and studies that have found substantial differences between AD when examining 
exposure-based treatments. Nevertheless the content of manuals and interventions tested 
are quite variable, making comparisons in terms of outcome problematic. Focussing on 
extinction learning as a common shared core mechanism of action for exposure therapy, we 
expect that our treatment manual will result in similar outcomes and patterns of mediations 
irrespective of diagnosis. We might speculate that GAD is less influenced by extinction based 
mechanisms, however evidence is lacking.  
 

 
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Study Protocol (Version 3.1; 01.06.2014) 
Comorbidity: Clinically, the failure to use exposure therapy for AD is justified with the 
assumption that these procedures do not work in comorbid diagnostic patterns 5. Specific 
research in this area is scarce 10, but there is no evidence from RCT on exposure-based 
treatments that depression and other comorbid constellations are associated with poorer 
outcomes. There seems to be also no evidence that depression moderates extinction-based 
mechanisms. Yet, it is fair to state that this hypothesis has so far only reviewed and examined 
for Panic Disorder and Agoraphobia 11 and that there is a strong need to specifically test this 
question in appropriate large scale studies across the full spectrum of AD 12.  
 
1.3 
Study rationale 
 
There is considerable evidence that exposure-based treatments for AD reveal higher effect-
sizes and greater persistence of improvement than cognitively focussed treatments without 
explicit exposure. However, relapse by return of fear is frequently observed, and the 
mechanisms of action underlying exposure remain debated and are yet to be studied in clinical 
samples. Novel preclinical research evidence suggests extinction learning as the core 
mechanism of action and provides according strategies to improve the effectiveness of 
treatment by optimized extinction. However, the preclinical evidence has not yet been 
systematically translated into clinical application and has never been rigorously tested. A 
translational research agenda is suggested to examine whether enhanced extinction learning 
components derived from preclinical research, applied within an “intensified” exposure-
based treatment, improves outcomes. In a multicentre randomised clinical trial linked to 
mechanistic subprojects, we test in n=720 patients with primary AD allowing for comorbidity 
whether intensified psychological interventions based on augmented extinction learning (IPI) 
result in faster, stronger and more persistent outcomes on subjective, clinical, behavioral, 
physiological and neural indices as compared to an, otherwise identical, standard research 
treatment without explicit enhanced extinction (TAU). We hypothesize that enhanced 
extinction elements (IPI) will result in (a) higher effect sizes, faster recovery, and (b) more 
pronounced changes in an array of systems, including elements of extinction learning and in 
objective behavioral measures assessed in intersession exposure trials. We also examine 
moderators of outcome (i.e. type of diagnosis, comorbidity) and explore whether IPI is 
associated with lower health care costs. 
As recently reviewed by us 5, clinical research and numerous meta-analyses of cognitive-
behavioral therapy (CBT) trials for the various forms of AD have shown - with little diagnostic 
variations - impressive effect sizes and persistence of improvement beyond the end of the 
therapy in 6 and 12 month follow-ups. Considerable agreement also exists that exposure-
based treatments typically reveal higher effect-sizes and greater persistence of improvement 
than cognitive treatments without explicit exposure. However, there are significant gaps on 
various levels: (1) Despite agreement that exposure, a procedure derived from extinction 
theory 6, is an essential core component, the debate related to the mechanism of action as 
well as the form, duration and density of effective exposure in treatment persists; clinical trial 
evidence systematically assessing these issues is lacking 1,5 with a few notable exceptions 13. 
(2) The considerable body of basic and preclinical advances regarding extinction learning 14,15 
has not yet been sufficiently translated into clinical interventions. It remains unclear to what 
degree supplemental elements of enhanced extinction learning also translate into improved 
outcomes in clinical anxiety, and a stepwise translational research agenda on fear extinction 
and extinction learning has been proposed 1. (3) Most clinical research in this field has been 
conducted either with a single measure of conditioned fear and at best in selected mono-

 
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Study Protocol (Version 3.1; 01.06.2014) 
symptomatic clinical cases. It remains unclear whether enhanced extinction is beneficial in all 
AD as well as comorbid patterns. (5) Patients with AD - at least in Germany - rarely receive 
appropriate anxiety treatment. In fact, studies have shown that exposure treatments are 
rarely applied at all, and if they are applied they seem to be provided without alignment with 
research standards or theory. This suggests indirectly that they might fail to stimulate 
appropriately presumed core mechanisms of action. Routine treatments in Germany are 
typically much longer (>50 weeks vs. RCT: 4-16), contain little to no exposure, are not 
manualized, and have considerably lower effect sizes 5. This might be at least partially due to 
the historically established practice, reinforced by insurance regulations favoring 
psychotherapy sessions of 50 min. once a week irrespective of method and diagnosis applied. 
This practice is unlikely to promote effectively essential mechanisms of fear inhibition. Clinical 
research has so far had little impact to change this situation.  
 
The proposed trial will address these critical issues by conducting a multicenter randomised 
clinical trial (RCT) in typical patients of anxiety clinics to test whether efficacy adjustments in 
exposure-based treatment packages, targeting elements of enhanced extinction learning, 
lead to superior results. At the same time the RCT will provide the data to address - within 
projects P3, P4 and P5 - the key question of extinction as a core mediating process as well as 
questions regarding moderators (i.e. diagnostic pattern, comorbidity). A resolution of these 
questions is expected to have significant effects on patients with AD and the way exposure-
based treatments are used in the psychotherapy sector.  
 
 
2. 
Multicenter randomised controlled clinical trial (P1) 
 
2.1 
Intervention scheme/trial flow  
Figure 1. Intervention scheme/trial flow 
 
2.1.1 Frequency and scope of study visits 
Baseline diagnostic (2-3h) assessment visits will be scheduled on two days. In both groups 14 
therapeutic sessions according to an established modular manual, of same length and content 
is provided. In IPI, however, the exposure module (sessions 6-10) is provided intensified over 

 
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Study Protocol (Version 3.1; 01.06.2014) 
a shorter duration of two weeks, ending 4 weeks earlier than TAU as the comparator. In TAU, 
the exposure module is provided as usual over a 6 weeks period. Post assessment will occur 
at approx. week 10 for both groups. The two booster sessions occur in the follow-up period. 
Patients are instructed to engage in spaced exposure trials across different contexts at post 
and during the two booster sessions. If eligible, additional visits are scheduled for the 
mechanistic projects (P3-5; see Figure 1 for details).  
 
2.1.2 Treatment description 
Treatment is based on an established modular manual which has been initially developed 
primarily for Panic Disorder and Agoraphobia 16. The manual is highly structured with word-
by-word instructions for therapists and has been tested in multicenter RCTs. The compliance 
and treatment integrity has been investigated and is high 13. 
In order to extend the scope of the manual to all included anxiety disorders, a number of 
elements will be traced back to their generic form (e.g. the vicious circle of anxiety will not be 
explained solely for panic but for the somatic and cognitive features of the anxiety reaction as 
such). Other elements of the manual will be adapted to the respective diagnosis (e.g., 
exposure trials will be adapted to the specific feared stimuli of a given patient). All therapeutic 
elements will be taken from validated manuals on anxiety disorders and will be aligned to 
extinction as the suspected operating mechanism. 
Treatment will comprehend five phases: (1) In sessions 1-3, therapeutic report is established 
and patients will receive psychoeducation on normal and pathological anxiety. A diathesis 
stress model will be presented as a generic approach to anxiety disorders and models of the 
development of fear in a given situation will be discussed. Based on the patient’s “life line”, 
individual risk factors and antecedents of AD will be added to the diathesis stress model in 
order to develop a comprehensive conception of the development of AD in the patient. 
Patients are encouraged to monitor their fear reaction over the period of several days. 
Selected feared situations will be analysed via behavioral analysis, which leads to a discussion 
of the role of avoidance and safety behavior in the maintenance of AD.  
(2) In session 4, patients will be cognitively prepared for exposure. This phase includes 
confrontation with imagined feared situations (exposure in sensu) or with bodily sensations 
that resemble those of anxiety (symptom provocation). The rationale of extinction is explained 
in detail to foster learning during exposure. A thought experiment on extinction will be carried 
out which involves the recognition that fear cannot be a permanent state and may reduce 
anticipatory anxiety. Finally, a hierarchy of feared situations is to be established that can be 
used to derive exposure situations for the following phase. 
(3) In sessions 5-10, patients will undergo exposure in various feared situations with varying 
context conditions. During exposure trials, anxiety will be monitored continuously. Each 
exposure trial is introduced and summarized together with the therapist (e.g. to control the 
use of safety behaviours). The therapist is, however, not necessarily present during the whole 
exposure trial. If necessary, motivational strategies are applied prior to the trial.  
(4) The purpose of sessions 11-12 is to summarize learning experiences and to facilitate further 
generalization of the learned behavior. To that end, an individual training schedule is 
developed that encourages patients to continue with self-guided exposure (spaced in IPI). To 
prevent relapse, the phenomenon of return of fear is discussed. Patients are sensitized for 
situations in which return of fear is frequent and are instructed to create an emergency plan 
for such cases. 
(5) Two booster sessions (B1, B2) are planned in which the training schedule is controlled and 
a further “spaced exposure” training plan in various contexts is developed.  

 
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Study Protocol (Version 3.1; 01.06.2014) 
 
Therapy sessions are projected to last about 90 minutes, except for exposure sessions which 
may last longer. Between sessions, patients will receive homework that consists of preparing 
material for the following session and of self-guided exposure exercises. Treatment between 
IPI and TAU differs only in regard to the time schedule in sessions 5-12. 
  
2.1.2 Assessment battery 
The cross-diagnosis and diagnosis-specific process and outcome measures used in the study 
are summarized in Table 1.  
 
2.1.3 Strategies for data handling  
Data handling: The Coordination Center for Clinical Trials (KKS) Dresden will be responsible 
for the data management according to the Good Clinical Practice Guidelines. This includes the 
setup of a study database by means of study software REDCap 3.3. Data will be examined by 
programmed range checks, validity checks, and consistency checks. REDCap is a secure web 
application, including an audit trail, for managing online surveys and databases. The data 
management will be supported by Dr. Dipl.-Stat. Michael Höfler and CELOS staff and 
resources. The responsible data officers will be jointly coordinating centrally all aspects 
including data handling, management and analysis in Dresden. All participating centers are 
intimately knowledgeable about this set-up from previous studies and have an assigned data 
manager, who will manage and supervise the online transmission of data and site specific 
quality assurance procedures. Sampling and data collection will be continuously monitored 
for quality by CELOS staff and the KKS Dresden. Using the KKS data management system 
(REDCap) established for previous clinical trials in the BMBF Psychotherapy Funding initiative 
the existing comprehensive internet-based data entry platform that covers all stages and 
components from stratified sampling to analyses will be adapted. All procedural steps and 
assessments will be online with automatic recall and plausibility and quality assurance 
measures. The assessment packages for each visit include standardized computerised 
diagnostic data (DIA-X CIDI). Compliance with the trial specifications, treatment integrity and 
compliance, and the explicit manual specifications will be monitored by random video 
documentation. 
 
Table 1. Process and outcome measures  
construct 
Instrume
nt 
domain 
diagno
stics 
baseline 
intermedi
ate 
post 
follow-up 
Timeline 
 
 
week 1 
week 1 
week 8 
week 10 
week 34 
Duration1 
 
 
3 h 
2 h 
2h 
2h 
5h 
primary 
outcomes 
HAM-A / 
SIGH-A 
somatic and psychic 
anxiety symptoms 
X 
 
 
X 
X 
over-
arching 
symptom
-atology 
DIA-X 
categorical diagnosis 
X 
 
 
 
X 
CGI 
symptom severity 
X 
 
X 
X 
X 
BSI 
psychological 
symptoms 
 
X 
X 
X 
X 
BDI-II 
depressive symptoms 
 
X 
X 
X 
X 
ASI 
anxiety sensitivity 
 
X 
X 
X 
X 
diagnosis 
specific 
symptom
-atology 
DSM-5 
scales  
dimensional measures 
 
X 
X 
X 
X 
PAS 
panic and agoraphobia 
 
X 
 
X 
X 
ACQ 
agoraphobic 
cognitions 
 
X 
 
X 
X 
BSQ 
bodily symptoms 
 
X 
 
X 
X 

 
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Study Protocol (Version 3.1; 01.06.2014) 
MI 
avoidance behavior 
 
X 
 
X 
X 
PAS 
panic and agoraphobia 
 
X 
 
X 
X 
GAD-7 
worrying 
 
X 
 
X 
X 
LSAS 
social anxiety 
 
X 
 
X 
X 
impair-
ment & 
quality of 
life 
WHODA
S/CIDI 
quality of life 
 
X 
 
X 
X 
EQ5D 
 
 
X 
 
X 
X 
WHO-5 
 
 
X 
 
X 
X 
EMA 
behavior change  
 
X 
X 
X 
 
process 
variables 
Sess. 
protocol
s 
process exposure 
 
 
after each session 
 
CTS 
childhood traumata 
 
X 
 
 
 
 
C-Scale 
credibility of rationale 
 
 
 
X 
 
 
AAQ-II 
psychological flexibility 
 
X 
 
X 
X 
 
PFB-K 
partnership quality 
 
X 
 
 
X 
 
INEP 
therapeutic side 
effects 
 
 
 
X 
X 
 
STA-R 
therapeutic alliance 
 
 
X 
X 
 
HAM-A: Hamilton Anxiety Scale 17; SIGH-A: structured interview guide for HAM-A 18; CGI: Clinical Global Impression Scale 
19; DIA-X: Computerized Version of the Munich Composite International Diagnostic Interview (M-CIDI) 20; BSI: Brief 
Symptom Inventory 21; BDI-II: Beck Depression Inventory-II 22; ASI: Anxiety Sensitivity Inventory 23; DSM-5 Scales: 
Dimensional Anxiety Scales from the Diagnostic and Statistical Manual of Mental Disorders 24; PAS: Panic and Agoraphobia 
Scale 25; ACQ: Agoraphobic Cognitions Questionnaire 26; BSQ: Body Sensations Questionnaire 27; MI: Mobility Inventory 28; 
CTS: Childhood Trauma Screener 29; C-Skale: Credibility Scale 30; LSAS: Liebowitz Social Anxiety Scale 31; AAQ-II: Acceptance 
and Action Questionnaire 32; PFB-K: Partnerschaftsfragebogen Kurzform 33; EQ5D: EMA: Ecological Momentary 
Assessment; INEP: Inventar zur Erfassung Negativer Effekte von Psychotherapie 35; STA-R: Skala Therapeutische Allianz-
Revised 36; WHO-5: WHO Well-Being Index 44 
2.2 
Justification of design aspects 
 
2.2.1 Controls/comparator 
Given the existence of state-of-the-art exposure-based manuals with established efficacy 
there is no need to have an untreated control group. We thus test two variants of a highly 
standardized treatment manual. Both conditions are considered to be state of the art. 
Participants in both conditions, IPI and TAU, are expected to improve in the range of previous 
RCTs.  
Note: We use the acronym TAU (Treatment As Usual) for the control condition. This should not 
be misunderstood as meaning that TAU is the type of treatment typically applied in routine 
care by German providers. We refer, when using TAU to established manualized intervention 
programs for AD used in controlled clinical studies. Thus we provide a tough and rigorous test 
aiming to demonstrate that effects that are observed relate directly to modifications of 
extinction learning elements.  
 
IPI and TAU. Using an existing, well studied and frequently used manual template 16 modified 
for the purpose of this RCT, the manual has 12 therapy sessions (plus baseline, post, booster 
and FU) with identical therapeutic modules (i.e. rapport/diagnostic assessment, 
psychoeducation, cognitive- and behavioral exposure interventions), adapted to the type of 
AD and the purpose of the study. The experimental condition IPI differs only with regard to 
the temporal structure (higher number of trials in a shorter duration) in the behavioral 
exposure module in sessions 5-10, provided in only two weeks and (b) instructed spaced 
exposure trials during sessions 11-12. These modifications are associated with respective 
manualised instructions and assessment tools (see 3.3.5). In the control intervention (TAU) 

 
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this BE module will be provided over 6 weeks and no instructed spaced trails in different 
contexts are provided. One essential content modification in both conditions is to evoke a 
positive prediction error. Patients are asked for the aversive consequences that they expect 
to be associated with the respective standard exposure trial and about the probabilities that 
these consequences might occur prior, during and after exposure trials. The contingency 
expectancies are discussed with the patient including probability ratings for aversive 
consequences in subsequent exposure trials, in order to facilitate learning that the 
consequences did not occur at the rate expected or were not as aversive as expected. We 
provide this component in both groups, because we assume that the positive prediction error 
will specifically enhance extinction learning only in IPI.  
 
2.2.2 Dose, mode and scheme of intervention 
Session 1-5 of the interventions in both groups will be identical in IPI and TAU (e.g. building 
up therapeutic rapport, psychoeducation, monitoring, identifying antecedents, techniques to 
reduce anticipatory anxiety). However, the temporal structure of sessions 5-10 and 11-12 are 
different, while all other sessions are identical. In the follow-up phase booster sessions 
participants are instructed for spaced inter-trial exposure in different contexts. Due to the 
study-specific requirements of documentation, assessments and quality assurance (video, 
patient compliance ratings etc.) each session lasts about 90 min.  
 
2.2.3 Additional treatments 
Patients concomitantly treated by other psychotherapists or psychiatrists for any mental 
health reason are excluded. We enrol patients that prior to inclusion were on medication, but 
wish to stop for whatever reason after tapering out for at least 8 weeks, monitored by urine 
tests. In case of acute suicidality during treatment, patients will be seen by the site 
psychiatrists and eventually withdrawn from the trial. 
 
2.2.4 Inclusion/exclusion criteria and recruitment strategy.  
To increase relevance for routine care, we intentionally keep exclusion criteria minimal. Key 
inclusion criteria: (1) outpatients, (2) age: 15-70 years, (3) current primary DSM-5 anxiety 
disorder, (4) severity at baseline (HAM-A>18) and CGI>3, (5) written informed consent, (6) 
able to attend on his/her own or accompanied by significant other, (7) language competence. 
Key exclusion criteria: (1) any DSM-IV/5 psychotic, primary mood disorders (Bipolar I, 
recurrent or chronic Major Depression), current Substance Dependence, (2) concomitant 
psychological/psychiatric 
treatment, 
(4) 
acute 
suicidality, 
(5) 
general 
medical 
contraindications, (5) mono-symptomatic Specific Phobia as the primary diagnosis. 
 
2.2.5 Outcome measures  
• Consistent with all clinical trials and guidelines 36 the primary efficacy endpoint is the 
clinician-rated Hamilton Anxiety Rating Scale (interview version, SIGH-A). Although the 
HAM-A lacks sensitivity for reflecting changes induced by psychological treatment, we are 
unaware of any established alternative that would work for all AD. We currently also explore 
the ADIS global measure of clinical severity (0-8) as an option; given this dilemma, we opted 
for a broader range of “secondary” outcome measures (see below).  
• Other core generic outcome measures are (ordered by relevance); the Clinical Global 
Impression Scale (CGI), patient rated psychological (BSI) and depressive symptoms (BDI-II), 
anxiety sensitivity (ASI), and impairment/disability days (CIDI Harvard Index; WHODAS 2.0), 
The choice of these generic measures is meant to maximize comparability with other studies. 

 
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They serve as core measures to determine clinical treatment efficacy and differences 
between conditions in the first place. They also will be used to determine speed of recovery, 
being administered every 2nd session. To test diagnosis-specific effects we use as secondary 
endpoint(s) the DSM-5 dimensional anxiety-scales (DSM-5) and established diagnosis 
specific measures (i.e. PAS, ACQ, BSQ, MI, GAD-7, LSAS). 
• A more reliable, objective and ecological valid evaluation of behavioral effects in everyday 
life is used to assess quantity, frequency and appropriateness of prescribed and natural 
exposure trials within sessions and between sessions. We use an innovative e-health tool 
that simultaneously records geographic position, mobility (actography), together with 
event-related momentary assessments of mood and anxiety ratings (ecological momentary 
assessment; EMA). Patients will be supplied with smartphones for objective assessments in 
real life situations.  
• Subjective assessments, directly linked to experiences during standardized exposure 
protocol sessions, allow for (i) the quantification of subjective levels of anxiety and 
expectations about central concerns and (ii) the derivation of proxy measures of within- and 
between-session extinction, including emotional learning as well as changes in contingency 
expectations. Beyond the coupled experimental paradigms (P3, P4) we relate clinical 
outcome data to extinction learning as the central mechanism of change. For each patient 
an extinction curve on multiple response output measures (i.e. cognitive, autonomic) will 
provide information about consolidation of extinction memory, reactivation and 
reinstatement of fear memory as well as recall of extinction memory for each patient. These 
explorative proxy measures will be related to diagnostic groups and treatment outcome 
variables.  
• To examine the impact of the intervention on the patient life and functioning we measure 
the generic quality of life as well as all direct and indirect health care costs (CIDI health 
economic module). 
• In addition the CIDI, standard sets of predictors (personality, biographical and family genetic 
factors; baseline CAPI M-DIAX CIDI interview) are covered.  
 
2.2.6 Determination of primary and secondary measures 
As endpoints we use the standard total scores, derived from the respective scales (i.e. HAM-
A). We explore the additional use of composite scores.  
 
2.2.7 Methods against bias 
• Randomisation: Participants are allocated randomly to the two study conditions. No 
restrictions of feasibility apply; there is no reason to take any prognostic factor into account, 
because sites use a stratified recruitment scheme. 
• Multicenter trial: 7 centers will equally contribute patients, all of which have similar patient 
populations. Centers are also all involved in behavior therapy curricula from which therapists 
are sampled. Thus, significant side effects are unlikely and if they occur they will be 
controlled for.  
• Blinding of condition is not feasible in psychotherapy studies.  
• Assessments: Center staff will be trained (2-days course) in the assessment procedures that 
are standardized, computerized and accompanied by SOPs. Initial screening is based on the 
M-CIDI screener, prior to the more detailed baseline psychopathological and psychological 
assessment with the computerized clinical diagnostic interview (M-CIDI-CL) supplemented 
by the assessment of various constructs (personality, anxiety sensitivity, behavioral 
inhibition, family genetic module) with the embedded outcome measures. The 

 
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computerization allows for immediate access to standardized data files across sites, reduces 
data cleaning efforts and enhances objectivity and quality. 
• Therapy and manual: All details including the standardized exposure sessions in-vivo are 
specified in the treatment manual. The manual is modular, highly structured by session with 
verbatim instructions (see 16), has been tested in RCTs primarily for comorbid Panic Disorder 
and phobic patients and is widely used. The compliance and treatment integrity has been 
investigated and is high 13.  
• Therapists and adherence: Manual compliance is monitored, repeated violations lead to the 
exclusion of the therapist. Each center designates a minimum of 4 and up to 8 licensed 
therapists with at least 1 year experience. There will be a total of four 2-day training 
seminars, before and during the study, conducted by the central study center in Dresden 
and including a video adherence procedure protocol. Based on continuous adherence 
ratings, therapists will be licensed, non-compliant therapists will be excluded. During the 
trial all sessions are taped; a random 5% is checked by monitoring. 
• Monitoring: All sites will receive regular (4) visits by study monitors to check randomly 
protocol adherence. Both assessment and therapy sessions will be monitored. Project 
violations will be documented, and lead to exclusion of patients, therapists or the center.  
 
2.2.8 Proposed sample size and power calculations 
Focusing on the HAM-A total score as the core primary outcome measure for determining the 
sample size, we expect - building on the meta-analytic results and pilot tests - that patients in 
IPI group will reduce the HAM-A-score (end of treatment) by 12 points. In the TAU group we 
expect a reduction by 10 points. Using a power of 80%, a test significance level of alpha= 5%, 
a standard deviation of 10 points and a one-sided t-test to detect differences between the IPI 
and TAU group, a total of 310 patients are needed per group. Based on previous such trials 13 
drop-out rates during treatment including follow-up of 10%-15% are expected. Total n to be 
enrolled is 720 and to be analyzed 620. 
 
2.2.9 Compliance/Rate of loss to follow-up 
The rate of non-compliance and other drop-out has been determined based on a similar study 
that was just completed 13. The loss of 15% to follow-up is lower than in previous studies, 
presumably due to the treatment density.  
 
2.2.10 Feasibility of recruitment  
Each center has to screen approx. 200 patients to enroll an equal number of approx. 110 
patients over two years, to reach the goal of approx. 90 patients with post and follow-up for 
analysis (= 620 patients total). All centers have provided firm evidence to reach these targets, 
confirmed by the fact that such target numbers were actually exceeded in previous trials.  
 
2.2.11 Stopping results 
Treatment will be discontinued on request of the patient (e.g. not willing to conduct the trials, 
not able to attend sessions) or in case the therapist after consulting with the supervisor comes 
to the decision that treatment is associated with substantial risks for the patient (i.e. need for 
drug treatment, suicidality). These cases will be counted as drop out. Based on the results of 
prior such studies as well as prior research we do not see any reason for findings that make 
failure criteria for the trial likely. Participating centers will be closed in case of repeated failure 
of recruitment or continued violation of the SOP and protocol. In this case we have two backup 
centers (Tübingen and Chemnitz) to replace them.  

 
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2.3 
Statistical analyses 
 
Statistics for the core primary outcome measure (HAM-A): In order to demonstrate that the 
IPI and TAU treatments differ, we use a one-tailed t-test with the following hypotheses:  
H0: 
µHAMADiff-IPI = µHAMADiff-TAU; HA: µHAMADiff-IPI > µHAMADiff-TAU . 
Here µHAMADiff-IPI  and µHAMADiff-TAU are in each case the differences between the HAM-A baseline 
and the HAM-A value after the end of therapy in the treatment groups IPI and TAU. 
 
Trial data will be analyzed both on an intent-to-treat (ITT) and per-protocol basis. To test 
whether groups have different outcomes for the major end points at (i) post and (ii) follow-
up t-tests for independent samples will be used one-sided with an alpha level of 0.5. This will 
be also done for secondary and explorative analyses (in that case with two-sided tests). To 
quantify effect sizes for differences between groups at post-treatment and at follow up 
Cohen´s d (with the pooled standard deviation at baseline in the denominator) will be used. 
To assess temporal changes in symptoms we will compare scores at initial assessment with 
those at t1 through t5. Individual outcome as a function of pretreatment characteristics will 
be modeled with multiple linear regression and associated analyses of variance.  
Data will be analyzed with STATA and, if necessary, statistical weights will be used to adjust 
for different sampling probabilities in different study centers. LOCF-analyses (intent-to-treat) 
will be carried out as well as completer analyses and mixed models (saturated for the 
combined effects of time and group on outcome) to assess whether dropout changes the 
conclusions. Moderator analyses (predictors of treatment effects within IPI and TAU patients) 
will address type, respectively group of disorders as well comorbidity using dimensional and 
categorical measures. Pearson correlations between such comorbidity measures and 
outcome will be calculated. Associations with categorical predictors will be analyzed with 
linear regressions using dummy variables and quantified with mean differences in treatment 
outcome (and their 95% confidence intervals). 
 
2.4 
Ethical considerations 
 
The study will be conducted in full accordance with the Declaration of Helsinki, the German 
data protection act, and the GCP-Guideline and is sensitive to ethical considerations 5. The 
study protocol, amendments to the protocol (if applicable), therapy contents, patient 
recruitment procedures, information and informed consent form will be presented to the TUD 
ethics committee for approval. Subsequently, the study protocol will be approved by the 
respective site’s ethics committees.  
 
2.5 
Quality assurance and safety 
 
2.5.1 Quality assurance and monitoring 
All participating centers are highly experienced with multicenter quality assurance and 
management procedures specified in SOPs and used in this RCT. All staff will be trained by 
CELOS and KKS Dresden and will go through three 2 days training sessions for (i) assessment, 
(ii) the treatment manual and (iii) general procedures of data entry, quality assurance and data 
management using web-based system MACRO. Subsequently there will be a 2 week site 
implementation phase, in which the coordinating center staff will visit and monitor the site 
personnel (month 4). Prior to the start there will be a third 2-days training to assess reliability 

 
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Study Protocol (Version 3.1; 01.06.2014) 
for assessment instruments and final adjustment in procedures (linkages to associated 
projects). All sites are requested to monitor all assessment and treatment sessions by tapes. 
Tapes will be randomly (5%) checked by the coordinating center to detect protocol violations 
as soon as possible. 1-day booster training sessions for assessment and the manual will be 
conducted every 3 months. 
 
2.5.2 Safety 
To ensure safety and minimize risk only licensed psychotherapists will conduct the treatments 
and interviews. All serious adverse events will be immediately reported to the principal 
investigator who will discuss with its members consequences for the trial. This procedure is 
analogous to that of pharmacological trials according to GCP. 
 
3. 
Add-on project Psychophysiology (P3): Behavioral and psychophysiological markers 
of extinction learning and outcome 
 
3.1 
Background and aims 
 
The most effective treatment of anxiety disorders share exposure techniques as a core 
ingredient. Exposure treatment needs to be tailored in a way to promote extinction learning 
and prevent return of fear. The current research proposal aims to investigate the process of 
extinction learning across a large group of anxiety disorder (AD) patients prior to and after 
exposure therapy. We want to assess extinction learning at all levels of the emotional network, 
including verbal report (US-expectancy ratings), physiological arousal (sympathetic nervous 
system activity), and amygdala dependent modulation of defensive reflexes (fear potentiated 
startle). We expect that extinction learning is impaired in AD patients and will improve after 
exposure therapy. We hypothesize that extinction learning will improve to a greater degree 
after IPI than TAU. We expect that the response output measures are related to neural 
network activation (see P4). We expect extinction learning parameters being related to 
moderators of clinical outcome. 
Furthermore, clinical anxiety is characterized by an incapacity (or reduced ability) to recognize 
both danger and safety signals and consequently to overestimate danger 37. The impaired 
recognition of danger signals prompts a continuous search for safety and a sustained feeling 
of apprehension. This symptomatology is well modelled by paradigms like contextual fear 
conditioning. In a context-conditioning paradigm the subjects cannot predict the aversive 
event (US) and consequently show a sustained fear response. Sustained fear is a long-lasting 
state of apprehension induced by the inability to identify the source of threat 38-39. As this 
technology is available at 4 sites (Dresden, Würzburg, Bochum, Marburg), we will here add a 
virtual reality (VR) paradigm to the assessments within P3 as an elegant and innovative tool 
to realize contextual fear conditioning in an ecological fashion in humans in analogy to animal 
models. By means of a VR context conditioning paradigm we are able to investigate the 
mechanisms underlying the acquisition and extinction of such sustained fear. Notably, we 
assess extinction learning on the cognitive (ratings), behavioral (startle responses and 
avoidance/approach) and physiological (skin conductance) level of responses. We expect 
extinction learning deficits in anxiety patients which will be improved after treatment.  
Project P3 is essential for the identification of extinction learning being a mediator for 
outcome. Beyond it provides a range of experimental data regarding the mechanism of 
sustained fear and extinction in its role in AD. By applying two experimental paradigms 
covering sustained fear (VR) and extinction to all patients giving informed consent, 

 
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Study Protocol (Version 3.1; 01.06.2014) 
moderators of clinical outcome (e.g., type of AD, comorbidity, severity etc.) can be related to 
the mediating process. Moreover, by investigating the neural networks (P4) and (epi)genetic 
modulation (P5) of extinction learning we might provide evidence for central mediator and 
moderator mechanisms. 
 
3.2 
In- and exclusion criteria, recruitment strategy 
 
Patients. Eligible patients from the RCT (P1) will be included in P3. Due to the startle procedure 
patients with severe hearing problems will be excluded from P3.  
Controls. In conjunction with P4 we will recruit control subjects from the general population 
in the local area of the respective trial site. Controls will be matched for gender, age (+/- 5 
years), education, handedness, and smoking. Inclusion criteria: 1) aged 15-70 years, 2) 
informed consent. Exclusion criteria: any lifetime psychiatric disorder according to DSM-5 
criteria (excluding nicotine dependence); severe hearing problems; general medical 
contraindications (e.g. neurological or cardiovascular diseases). 
 
Due to the shared experimental paradigms, patients and controls will participate in two 
experiments (the VR experiment and a fear conditioning procedure) in the 
psychophysiological lab on day 1, while extinction learning and reinstatement will be tested 
in the fMRI scanner on day 2. Those patients not eligible for fMRI will complete the extinction 
paradigm in the psychophysiological lab on day 2 (see Figure 2 for details). 
 
RCT: 700 patients 
 
P3: 430 patients, 150 controls 
 
 
Day 1: psychophysiology 
(duration: 1 h) 
 
 
430 patients 
 
 
150 controls 
 
 
 
 
Day 2: fMRI 
(duration: 2h) 
 
Day 2: psychophysiology/VR 
(duration: 2h) 
300 patients 
 
130 patients 
100 controls 
 
50 controls 
 
 
 
Figure 2. Patient flow for experimental add-on study 
 
3.3 
Experimental procedure 
 
Extinction learning comprises different phases. First, the individual learns that a feared cue (or 
context) is no longer associated with the expected aversive outcome. With repeated 
extinction trials, extinction memory is consolidated and can be recalled even under stressful 
circumstances or in different contexts. Here we want to investigate fear conditioning and 
extinction learning in the laboratory. It is aimed to relate these multiple psychophysiological 
measures of extinction learning to neural network activation during extinction examined in 
P4, and its (epi)genetic modulation (see P5). We will use a delayed extinction paradigm, 
meaning that during day one subjects will learn that one cue (CS+ neutral face 1) is associated 

 
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Study Protocol (Version 3.1; 01.06.2014) 
with the aversive US (pulsed tactile electrostimulation on the forearm; 500ms in individually 
adjusted intensity reflecting “uncomfortable, but not painful” experiences) while the other 
cue (CS- neutral face 2) is never paired with the US. To ensure successful learning by all 
subjects (extinction learning can only be investigated in a meaningful way when the fear 
responses are reliably acquired) we will explicitly instruct all subjects that one of the two 
stimuli is followed by the US. To ensure successful conditioning subjective and physiological 
responses during acquisition were compared to responses during a short pre-conditioning 
phase (presenting CS+ and CS- alone for three times each) conducted immediately prior to 
conditioning. Duration of the task on day 1 is about 10 minutes (total duration of the 
assessment including electrode preparation, adjustment of electrostimulation, and 
expectancy ratings: 1h). 
Extinction starts at day 2 with a reactivation of the fear memory (the CS+ followed by the US 
once). Then CS+ and CS- will be presented 20 times each without any US. Directly after 
extinction learning, fear will be reinstated by presenting the US alone (3X). Recall of extinction 
memory will then be tested by 10-CS-trial each. In order to maximize synergies between P3 
and P4 and to minimize the load for included patients, the second part of the delayed 
extinction paradigm will be conducted within the MRI scanner as part of project in eligible 
subjects (Table 2). 
The VR context conditioning paradigm (delivered only at day 1) consists of six phases 
(exploration, two conditioning phases, a behavioral test, and two extinction phases) separated 
by verbal assessments. During the exploration phase, subjects explore each virtual office for 
2 min by means of a joystick. During the two conditioning phases, subjects hear the desperate 
female scream (US) in one room (CTX+), but never in the other room (CTX-). Importantly, the 
US is presented unpredictably during the visit of the CTX+. A trial starts in a corridor (the inter-
trial interval, ITI) and then subjects are passively guided into one virtual office. Each context 
(CTX+ and CTX-) is entered three times during the conditioning and extinction phases. For the 
behavioral test, participants are in the middle of the corridor and have to actively enter one 
virtual office. Subjects can make the choice by using a joystick. The extinction phases are 
similar the conditioning phases, except that no US is delivered. Startle-eliciting stimuli are 
delivered in each room as well as in the corridor. Duration of the task is approx. 1 h. 
 
Table 2. Description of the delayed fear extinction and the VR context conditioning 
paradigms (shared paradigm P3 & P4) 
 
Day 1 (lab only) 
Day 2 (fMRI; if not eligible: lab only) 
 
Instructed fear 
conditioning 
Fear extinction 
learning 
Reinstatement test 
VR paradigm: 
 
 
 
Conditioning phase: 
 
 
 
Frequency CTX+ 
12 
 
 
Frequency CTX- 
12 
 
 
Frequency US 
12 
 
 
Extinction phase: 
 
 
 
Frequency CTX+ 
20 
 
 
Frequency CTX- 
20 
 
 
Conditioning 
& 
extinction paradigm: 
 
 
 
Frequency CS+ 
13 
20 
10 

 
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Study Protocol (Version 3.1; 01.06.2014) 
Frequency CS- 
13 
20 
10 
Frequency US 
6 
1 
3 (CS/US) 
Dependent 
variables: 
 
 
 
FPS recording 
X 
- (lab: X) 
- (lab: X) 
SC recording 
X 
X 
X 
HR recording 
X 
- (lab: X) 
- (lab: X) 
Expectancy ratings  
X 
X 
X 
Questionnaire on VR 
experiences 
X 
 
 
FPS: fear potentiated startle; SC: skin conductance; HR: heart rate; Expectancy ratings: expectancy of US 
occurrence (0-100%): X: assessment; -: no assessment (technical restrictions in the MRI environment) 
  
3.4 
Assessment tools 
 
Fear conditioning and extinction paradigm. After attaching the sensors for physiological data 
collection (EMG, EDA, ECG) subjects are told that two pictures were presented repeatedly. 
Subjects are informed that no electric stimulation will be conducted during the first phase 
(pre-conditioning). After this phase the experimenter attaches the electrode for electric 
stimulation to the participants left forearm. The intensity of the electric stimulation is 
individually adjusted within five warned presentations to a level that is experienced as 
“uncomfortable, but not painful”. Then, subjects were informed that during the second phase 
(conditioning) one of the two shown pictures (CS+, known allocation) is be followed by an 
electric stimulation during most presentations (electric stimulation during 6 of ten trials). 
During extinction and reinstatement at day 2 subjects are told that electric stimulation might 
be possible again. However, electric stimulation only occurs during the fear memory 
reactivation (one electric stimulation during initial CS+ presentation prior to extinction) and 
prior the reinstatement test (three electric stimulation alone during inter-trial-interval).  
Two pictures depicting male faces with neutral expressions serve as CS+ and CS-, respectively. 
Picture duration is about 6 sec. Electric stimulation (500 msec pulsed stimulations) starts 5500 
msec after picture onset, if conducted.  
Recordings of electromyographic (EMG) activity over the left orbicularis oculi muscle serve as 
to measure the eyeblink component of the startle response. A digitized 50-msec burst of white 
noise (105 dBA, rise/fall time <1 msec) is amplified by a recording mixer and is presented 
binaurally through headphones to serve as startle-eliciting stimulus. During the majority of 
trials CS presentations are followed by an acoustic startle probe either 4.5 or 5.0 s after picture 
onset (pre-conditioning: 2 of 3; conditioning: 8 of 10; extinction: 16 of 20; reinstatement: 8 of 
10). Moreover, startle probes are also presented during the ITI that varied between 6 and 10 
sec (pre-conditioning: N=3; conditioning: N=8; extinction: N=16; reinstatement: N=8). 
Additionally, skin conductance (recorded from the hypothenar eminence of the palmar 
surface of the subject’s non-dominant hand) and the ECG (Einthoven-II-lead) are measured 
continuously. After each phase (pre-conditioning, conditioning, reactivation, first half of 
extinction, second half of extinction and reinstatement) subjects are rating shock 
expectancies, intensities of distress/unpleasantness and arousal during both pictures, and 
unpleasantness of perceived shocks.  
VR paradigm. The VR environment is created with the Source Engine from the Valve 
Corporation (Bellevue, USA), which is also used for the game Half-Life 2. The VR environments 
consists of two offices separated by a corridor. All spaces have a gray floor. The offices have 

 
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Study Protocol (Version 3.1; 01.06.2014) 
the same square footage, but differ in the arrangement of the furniture. The corridor is empty 
and presents the doors to the offices. The VR environment is presented using Oculus Rift 
Development Kit 2 (960 x 1080 pixel resolution; Oculus VR, Inc., Menlo Park, California). The 
simulation is controlled by the software CyberSession (VTplus GmbH, Würzburg). In case 
subjects experience motion sickness within VR, recording will be interrupted and the 
experimenter will offer a glass of water to the subject. The experimenter will require the 
subject to remain in the laboratory under supervision until the motion sickness dissolves. In 
the VR study, the sensors for the physiological recording (EMG, EDA; ECG) are first attached 
and then the participants are positioned into the VR by wearing the Oculus glasses (Oculus 
Rift Development Kit 2, Inc., Menlo Park, California). Subjects are informed that no scream or 
startle-eliciting stimulus is delivered during the exploration and that they can actively explore 
the virtual rooms. Afterwards, subjects are informed that during the conditioning phases the 
scream can be presented and, if they follow carefully the experiment, they can notice the 
relationship among the stimuli. No further information are delivered before the test phases.  
The recording of the EMG and the electrodermal activities are the same as described above. 
Seven startle-eliciting probes are presented before the conditioning every 7-15 s. During each 
phase, 18 startle probes are presented (CTX+ = 6, CTX- = 6, ITI = 6). Startle probes are separated 
by at least 10 s, and 7 s after room entry as well as before room exit no startle probe is 
delivered.  
 
 
3.5 
Statistical analyses 
 
To test the effects of conditioning, extinction and reinstatement on startle blink magnitudes, 
skin conductance response, heart rate response, and expectancy ratings analyses of variance 
with repeated measurements are conducted with within-subjects factors of Phase (pre-
conditioning vs. conditioning vs. extinction vs. reinstatement) and Cue (CS+ vs. CS-). To test 
the effect of interindividual differences between patients (e.g. primary diagnosis, severity, 
comorbidity, chronicity, depression) on test performance (e.g. intensity and speed of 
conditioning, extinction, and reinstatement) mixed models of variance or correlation analyses 
are conducted. 
The statistical analysis for the contextual fear is similar to the above mentioned analyses. 
Namely, five separated analyses of variance with repeated measurements are calculated for 
each dependent variable (startle blink magnitude, skin conductance, hear rate response, 
anxiety and expectancy ratings). In parallel, the within-subjects factor phase (Conditioning 1, 
Conditioning 2, Extinction 1, Extinction 2) and context (CTX+, CTX-, ITI) are considered. In the 
same manner, the clinical diagnoses or interindividual differences are considered.  
 
 
4.  
Add-on project Neuroimaging (P4): Neural response and fear circuitry related to 
extinction learning and outcome 
 
4.1 
Background and aims 
 
Eligible RCT patients with AD from all seven P1 centers will undergo fear extinction in the MRI 
scanner before and after exposure-based therapy using functional Magnetic Resonance 
Imaging (fMRI). Using a shared paradigm with P3 we will examine the neuronal correlates of 
fear extinction and reinstatement. In addition, a paradigm on emotion processing; structural 

 
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Study Protocol (Version 3.1; 01.06.2014) 
scans and a resting state examination will be conducted. Brain regions of interest will be 
amygdala, (para-) hippocampal and anterior cingulate cortex. We hypothesize that (1) im-
paired extinction learning and exaggerated emotion processing in AD as compared to healthy 
controls relies on sustained amygdala and reduced anterior cingulate cortex activation, while 
enhanced reinstatement is related to (para-) hippocampal function; (2) augmented extinction 
learning in IPI is associated with stronger reduction in amygdala activation and enhanced ACC 
activation as compared to TAU, providing indirect evidence for neural mediating processes. 
All eligible RCT 1 (P1) patients treated either with IPI or TAU (expected n = 300) and 100 
healthy controls will be investigated before and after treatment. Maximizing synergies 
between P3 and P4, we will use an identical fear conditioning and extinction task. While 
subjects will undergo fear conditioning in P3 on day 1, extinction and a reinstatement test will 
be assessed in a 3T MRI scanner on day 2 (including autonomic markers of conditioning and 
expectancy ratings; see Table 2), thus allowing for consolidation of fear memories. Amygdala 
reactivity will be tested by an emotional face-matching paradigm. T1w anatomical scans will 
be assessed for normalization and explorative morphometric analysis. Resting state activation 
will be assessed as a measure of non-task related functional connectivity. Established MRI 
quality procedures from the “Panic-Net” (phantoms, reliability testing) will be applied. 
Project P4 is conducted in all seven centers within a strictly enforced multicenter protocol. P4 
is the essential cornerstone of the consortium program, because it aims at providing evidence 
for extinction learning being indeed a core mediating process which is reflected in pervasive 
changes in the neural fear circuitry. Using the RCT patients (P1), and being nested with the 
experimental behavioral and psychophysiological paradigms used in P3, we are to our 
knowledge the largest such fMRI study. This also allows exploring the potential moderating 
role of type of AD, comorbidity and prior psychopharmacology for extinction learning. P4 will 
be able to relate fMRI to psychophysiology assessed using the same methodology as in P3. P4 
will be closely linked to P5 and P6 to study the impact of epigenetic variation and 
pharmacological treatment. Joint analysis of our data about in vivo brain processes (P4) 
together with psychophysiological data (P3), (epi)genetic data (P5), and clinical data (P1) joins 
neurobiology and observable behavior. 
 
4.2 
In- and exclusion criteria, recruitment strategy 
 
Patients. Eligible patients from the RCT (P1) who have undergone P3 will be included in P4. 
Based on previous experience we estimate that approximately 40% (n = 300) patients from P1 
will be included for P4. Additional MRI-related exclusion criteria apply: (1) ferromagnetic 
objects in the body that cannot be removed, (2) tattoos or permanent makeup in the face and 
neck area, (3) pregnancy, (4) self-report of lifetime history of neurological disorders, (5) 
general medical conditions that preclude from MRI assessment.  
Controls. In conjunction with P4 we will recruit control subjects (n = 100) from the general 
population in the local area of the respective trial site. Controls will be matched for gender, 
age (+/- 5 years), education, handedness, and smoking. Inclusion criteria: 1) aged 15-70 years, 
2) informed consent. Exclusion criteria: any lifetime psychiatric disorder according to DSM-5 
criteria (excluding nicotine dependence). Additional MRI-related exclusion criteria: (1) 
ferromagnetic objects in the body that cannot be removed, (2) tattoos or permanent makeup 
in the face and neck area, (3) pregnancy, (4) self-report of lifetime history of neurological 
disorders, (5) general medical conditions that preclude from MRI assessment.  
 
4.3 
Experimental paradigms and (f)MRI assessments 

 
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Extinction learning. In conjunction with P3 we will conduct the second part delayed extinction 
learning paradigm on day 2 in the MRI scanner, while subjects underwent the fear acquisition 
phase on day 1 in P3 only (see 3.2, 3.3 and Table 3 for details; task duration: 20min). Skin 
conductance as an autonomic marker of extinction learning will be assessed during scanning. 
Emotional reactivity task. In order to assess neural reactivity in emotion processing areas (e.g. 
amygdala) we will conduct an emotional face matching task (“Hariri-Task) 40. Subjects are 
presented three faces with two of them showing the same emotional expression. Subjects are 
instructed to match the two identical facial expressions. Control comparisons include the 
matching of identical geometrical forms (task duration: 6min). 
Resting state activity. In order to identify task-unrelated neural networks associated with 
anxiety disorders 41 we will conduct a resting state assessment (duration: 10min). 
Structural scan. For the analysis of morphometric differences, as well as for normalization and 
segmentation procedures (related to the fMRI task data) a high-resolution T1w MPRAGE 
sequence will be conducted (duration: 8min). 
 
4.4 
Assessment tools 
 
Table 3. Assessment tools in P4. 
Domain 
Test 
Duration (min) 
Neuropsychological screening 
 
 
- 
Handedness 
EHI 
2 
- 
Working memory 
Digit span 
5 
- 
Executive functions 
Trail-Making-Test 
5 
Questionnaires 
 
 
- 
MRI anxiety 
Questionnaire on MRI 
experience42  
5 
- 
Contingency assessment 
Interview 
5 
EHI: Edinburg Handedness Inventory 43 
 
Total duration (f)MRI assessments: approx. 60min 
Total duration P4 (including neuropsychological screening (Table 3), preparation, electrode 
attachments etc.): approx. 2h 
 
4.5 
(f)MRI data acquisition and analysis pathway 
 
Imaging experiments will be performed in 3-Tesla scanners at all sites. Each session will consist 
of a standard anatomical protocol, i.e. a sagittally acquired Magnetization Prepared Rapid 
Gradient Echo Imaging (MPRAGE) sequence and a series of whole-brain echo-planar imaging 
(EPI) scans acquired to measure blood oxygen-level dependent (BOLD) functional activity. 
Measures of quality control in this multicenter study have been previously established and 
will be applied (including reliability and phantom assessments at each site). Structural and 
functional image processing will be conducted with SPM8 (Welcome Trust Centre for 
Neuroimaging, UCL, London, UK). Functional images will be realigned and unwarped to correct 
for movement artefacts. Structural images are coregistered to the functional scans and all 
volumes are normalized to the MNI (Montreal Neurological Institute, Quebec, Canada) 
reference brain. Functional images are subsampled and smoothed with a Gaussian kernel 
(iterative smoothing will be applied for multicenter data). Individual images will be carefully 

 
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Study Protocol (Version 3.1; 01.06.2014) 
checked for excessive movement artefacts. First-level statistical analysis will be carried out for 
all subjects applying the general linear model (GLM). The expected blood oxygen level-
dependent (BOLD) signal change will be modelled by a canonical hemodynamic response 
function for the regressors of interest; the six movement parameters of the rigid body 
transformation applied to the realignment procedure will be further introduced as covariates 
into the model. On the second level, random effects group analyses will be performed by 
entering contrast images into flexible factorial analyses as implemented in SPM8, in which 
subjects are treated as random variables. Significance thresholds will be established using 
cluster threshold approaches (Monte Carlo simulation). In addition to an exploratory whole 
brain analysis, an a priori region of interest analysis will be conducted on target regions of the 
fear network. Estimated beta values will be used for correlational analyses with performance 
measures and clinical symptoms. 
 
5. 
Add-on project (epi)genetics (P5): (Epi)genetic effects related to extinction learning 
and outcome 
 
5.1 
Background and aims 
 
Anxiety disorders and components of fear conditioning in particular are genetically 
determined. Several risk genes of anxiety and particularly extinction have been identified, with 
some of them also driving response to cognitive-behavioral therapy. First pilot studies imply 
epigenetic mechanisms such as DNA methylation in the pathogenesis of anxiety.  
Here, for the first time the role of DNA methylation in the pathogenesis, as predictors of 
therapy response and as potential correlates of extinction elements in psychological 
interventions of anxiety disorders will be investigated accompanying the RCT (P1). The 
identification of (epi)genetic markers - intertwined with psychophysiological and neural 
network markers (P3/4) - in the etiology, course and comorbidity of anxiety disorders may aid 
in developing resilience-increasing preventive measures in high-risk groups. Additionally, the 
definition of epigenetic signatures as a core mechanism of action of fear extinction in 
exposure-based interventions and thereby an objective biomarker of treatment outcome is 
hoped to contribute to the development of a more targeted, personalized treatment of 
anxiety disorders based on epigenetic information. 
 
5.2 
In- and exclusion criteria, recruitment strategy 
 
Patients. Eligible patients from the RCT (P1) will be included in P5. Additional genetic-related 
inclusion criteria: (1) Caucasian background. Additional (epi)genetic-related exclusion criteria: 
(1) impaired blood coagulation, (2) lifetime diagnosis of severe somatic disorder (such as 
cancer), (3) illegal drug use (including cannabis), (4) excessive alcohol and nicotine use 
(exceeding 14 glasses of beer/week or 20 cigarettes/day). The following characteristics do not 
constitute exclusion criteria, but will be documented: (1) body mass index, (2) smoking status, 
(3) hormonal contraception, (4) current somatic medication. 
Controls. Not applicable. 
 
5.3 
Procedure and assessments 
 
As displayed in Figure 1, blood samples will be collected at three time-points: after study 
inclusion (baseline), at post-assessment (after session 12) and after 6-month follow-up. Blood 

 
23 
Study Protocol (Version 3.1; 01.06.2014) 
samples include 10ml EDTA blood for each assessment and will be carried out by trained 
medical personnel supervised by a physician. Blood samples will be stored at the individual 
centres at -20°C and sent to the Laboratory of Functional Genomics at the Department of 
Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, on dry ice once 
a month, where DNA will be extracted and stored at -80°C. 
Samples will be analyzed for DNA variation/methylation patterns of candidate genes of 
anxiety and/or modulators of emotional-associative learning (e.g., COMT, MAO-A, 5-HTT, 
BDNF, CNR1, NPSR1).  In case new candidate genes will be discovered, these will additionally 
be included in the analysis. Furthermore, a genome-wide DNA analysis and a genome-wide 
DNA methylation analysis will be conducted. It has to be mentioned that genome-wide DNA 
analyses (“fingerprint”) have certain implications regarding data protection, i.e. there is a 
principle risk of re-identification. We will address this issue explicitly in the consenting 
procedure. In contrast, genome-wide DNA methylation analyses do not allow for re-
identifiaction since these signatures are temporally variable due to constant environmental 
influences on methylation patterns.  
 
5.4 
Statistical analyses 
 
(Epi)genetic information from candidate genes / methylome-wide data will be tested in 
relation to clinical, psychophysiological and neural data using t-tests, (M)ANOVA for repeated 
testing (including pre-post effects) or regression analyses. Correction for multiple comparisons 
will be applied, resulting in a corrected statistical threshold of p < 0.05. 
 
6. 
Trial time flow and milestones 
 
 
Figure 3. Project schedule and associated milestones 

 
24 
Study Protocol (Version 3.1; 01.06.2014) 
7. 
References 
 
1. 
Vervliet, B., Craske, M. G. & Hermans, D. (2013). Fear extinction and relapse: State of 
the art. Journal of Experimental Psychopathology, 3, 322-245. 
2. 
Craske ,M., Liao, B., Brown, L. & Vervliet, B. (2012). Role of inhibition in exposure 
therapy. Journal of Experimental Psychopathology, 3, 322-245. 
3. 
Bouton, M. E. (2002). Context, ambiguity, and unlearning: Sources of relapse after 
behavioral extinction. Biological Psychiatry, 52, 976-986. 
4. 
Davis, M., Walker, D. L., Miles, L. & Grillon, C. (2010). Phasic vs sustained fear in rats and 
humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacoly, 35, 
105-135. 
5. 
Neudeck, P. & Wittchen, H.-U. (2012). Exposure therapy. Rethinking the model – refining 
the method (Eds.). New York: Springer. 
6. 
Boschen, M. J., Neumann, D. L. & Waters, A. M. (2009) Relapse of successfully treated 
anxiety and fear: Theoretical issues and recommendations for clinical practice. 
Australian & New Zeeland Journal of Psychiatry, 43, 89-100.  
7. 
Moody, E. W., Sunsay, C. & Bouton, M. E. (2006). Priming and trial spacing in extinction: 
Effects on extinction performance, spontaneous recovery, and reinstatement in 
appetitive conditioning. Quarterly Journal of Experimental Psychology, 59, 809-829. 
8. 
Orinstein, A. J., Urcelay, G. P. & Miller, R. R. (2010). Expanding the intertrial interval 
during extinction: Response cessation and recovery. Behavior Therapy, 41, 14-29. 
9. 
Rowe, M. K. & Craske, M. G. (1998). Effects of an expanding-spaced vs massed exposure 
schedule on fear reduction and return of fear. Behavior Research and Therapy, 36, 701-
717. 
10. 
Craske, M. G., Waters, A. M., Nazarian, M., Mineka, S., Zinbarg, R. E., Griffith, J. et al. 
(2009). Does neuroticism in adolescents moderate contextual and explicit threat cue 
modulation of the startle reflex? Biological Psychiatry, 65, 220-226. 
11. 
Emmrich, A., Beesdo-Baum, K., Gloster, A. T., Knappe, S., Hofler, M., Arolt, V., Deckert, 
J. et al. (2012). Depression does not affect the treatment outcome of CBT for panic and 
agoraphobia: Results from a multicenter randomized trial. Psychotherapy and 
Psychosomatics, 81, 161-172. 
12. 
Craske, M. G., Rauch, S. L., Ursano, R., Prenoveau, J., Pine, D. S. & Zinbarg, R. E. (2009). 
What is an anxiety disorder? Depression and Anxiety, 26, 1066-1085. 
13. 
Gloster, A. T., Wittchen, H.- U., Einsle, F., Lang, T., Helbig-Lang, S., Fydrich, T. et al. (2011). 
Psychological treatment for panic disorder with agoraphobia: A randomized controlled 
trial to examine the role of therapist-guided exposure in situ in CBT. Journal of 
Consulting and Clinical Psychology, 79, 406-420.  
14. 
Bouton, M. E., Westbrook, R. F., Corcoran, K. A. & Maren, S. (2006). Contextual and 
temporal modulation of extinction: Behavioral and biological mechanisms. Biological 
Psychiatry, 60, 352-360. 
15. 
Milad, M. R. & Quirk, G. J. (2012). Fear extinction as a model for translational 
neuroscience: Ten years of progress. Annual Review of Psychology, 63, 129-151. 
16. 
Lang, T., Helbig-Lang, S., Westphal, D., Gloster, A. T. & Wittchen, H.-U. (2011). 
Expositionsbasierte Therapie der Panikstörung mit Agoraphobie. Göttingen: Hogrefe. 
17. 
Hamilton, M. (1959). The assessment of anxiety states by rating. British Journal of 
Medical Psychology, 32(1), 50-55. 

 
25 
Study Protocol (Version 3.1; 01.06.2014) 
18. 
Shear, M. K., van der Bilt, J., Rucci, P., Endicott, J., Lydiard, B., Otto, M. W. et al. (2001). 
Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating 
Scale (SIGH‐A). Depression and Anxiety, 13(4), 166-178. 
19. 
Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology. U.S. Department 
of Health, Education, and Welfare. Washington: DC. 
20. 
Wittchen, H.-U. & Pfister, H. (Eds.) (1997). DIA-X-Interviews: Manual für Screening-
Verfahren und Interview; Interviewheft Längsschnittuntersuchung (DIA-X-Lifetime);  
Ergänzungsheft (DIA-X-Lifetime); Interviewheft Querschnittuntersuchung (DIA-X-
Monate); Ergänzungsheft (DIA-X-Monate); PC-Programm zur Durchführung des  
Interviews (Längs- und Querschnittuntersuchung); Auswertungsprogramm. Swets    and 
Zeitlinger, Frankfurt. 
21. 
Derogatis, L. R., & Spencer, P. M. (1993). Brief Symptom Inventory: BSI. Upper Saddle 
River, NJ: Pearson. 
22. 
Beck, A. T., Steer, R. A., & Brown, G. K. (1996). Manual for Beck Depression lnventory-II. 
San Antonio, TX: Psychological Corporation. 
23. 
Reiss, S., Peterson, R. A., Gursky, D. M. & McNally, R. J. (1986). Anxiety sensitivity, anxiety 
frequency, and the prediction of fearfulness. Behavior Research and Therapy, 2, 1–8. 
24. 
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association. 
25. 
Bandelow, B. (1999). Panic and Agoraphobia Scale (PAS). Hogrefe & Huber Publishers. 
26. 
Chambless, D. L., Caputo, G. C., Bright, P., & Gallagher, R. (1984). Assessment of fear of 
fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions 
questionnaire. Journal of Consulting and Clinical Psychology, 52(6), 1090. 
27. 
Chambless, D. L., Caputo, G. C., Bright, P., & Gallagher, R. (1984). Assessment of fear of 
fear in agoraphobics: the body sensations questionnaire and the agoraphobic cognitions 
questionnaire. Journal of Consulting and Clinical Psychology, 52(6), 1090. 
28. 
Chambless, D. L., Caputo, G. C., Jasin, S. E., Gracely. E. J., & Williams, C. (1985). The 
mobility inventory for agoraphobia. Behavior Research and Therapy, 23, 305-310. 
29. 
Grabe, H. J., Schulz, A., Schmidt, C. O., Appel, K., Driessen, M., Wingenfeld, K., Barnow, 
S., Spitzer, C., John, U., Berger, K., Wersching, H., & Freyberger, H. J. (2012). Ein 
Screeninginstrument für Missbrauch und Vernachlässigung in der Kindheit: der 
Childhood Trauma Screener (CTS). Psychiatrische Praxis, 39, 109-115. 
30. 
Borkovec, T. D., & Nau, S. D. (1972). Credibility of analogue therapy rationales. Journal 
of Behavior Therapy and Experimental Psychiatry, 3(4), 257-260. 
31. 
Liebowitz, M. R. (1987). Social phobia. Modern Problems in Pharmacopsychiatry, 22, 14-
173. 
32. 
Bond, F. W., Hayes, S. C., Baer, R. A., Carpenter, K. M., Guenole, N., Orcutt, H. K., Waltz, 
T., & Zettle, R. D. (2011). Preliminary psychometric properties of the Acceptance and 
Action Questionnaire–II: A revised measure of psychological inflexibility and experiential 
avoidance. Behavior Therapy, 42(4), 676-688. 
33. 
Kliem, S., Job, A. K., Kröger, C., Bodenmann, G., Stöbel-Richter, Y., Hahlweg, K., & Brähler, 
E. (2012). Entwicklung und Normierung einer Kurzform des Partnerschaftsfragebogens 
(PFB-K) an einer repräsentativen deutschen Stichprobe. Zeitschrift für Klinische 
Psychologie und Psychotherapie, 41(2), 81-89.  
34. 
Rabin, R. & de Charro, F. (2001). EQ5D: A measure of health status from the EuroQol 
Group. Annals of Medicine, 33, 337-343. 

 
26 
Study Protocol (Version 3.1; 01.06.2014) 
35. 
Ladwig, I., Rief, W. & Nestoriuc, Y. (in press). Hat Psychotherapie auch Nebenwirkungen? 
– Entwicklung des Inventars zur Erfassung Negativer Effekte von Psychotherapie (INEP). 
Verhaltenstherapie. 
36. 
Brockmann, J., Kirsch, H., Hatcher, R., Andreas, S., Benz, S. & Sammet, I. (2011). 
Dimensionen der therapeutischen Beziehung aus Patienten-Perspektive - Entwicklung  
der “Skala Therapeutische Allianz-Revised STA-R“. Psychotherapie, Psychosomatik, 
Medizinische Psychologie, 61, 208-215. 
37. 
Baldwin, D. S., Rafiq, R. & Talat, B. (2013). Overcoming barriers in the pharmacological 
treatment of anxiety disorders. Neuropsychiatry, 3, 33-44. 
38. 
Lohr, J.M., Olatunji, B.O. & Sawchuck, C.N. (2007). A functional analysis of danger and 
safety signals in anxiety disorders. Clinical Psychology Reviews, 27, 114-126. 
39. 
Davis, M., Walker, D.L., Miles, L. & Grillon, C. (2010). Phasic vs. sustained fear in rats and humans: 
Role if the extended amygdala in fear vs. anxiety. Neuropsychopharmacology, 35, 105-135. 
40. 
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D. et al. (2002). 
Serotonin transporter genetic variation and the response of the human amygdala. 
Science, 297, 400-403. 
41. 
Sylvester, C. M., Corbetta, M., Raichle, M. E., Rodebaugh, T. L., Schlaggar, B. L., Sheline, 
Y. I. et al. (2012). Functional network dysfunction in anxiety and anxiety disorders. 
Trends in Neurosciences, 35, 527-535. 
42. 
Lueken, U., Muehlhan, M., Wittchen, H.-U., Kellermann, T., Reinhardt, I., Konrad, C. et 
al. (2011). (Don't) panic in the scanner! How panic patients with agoraphobia experience 
a functional magnetic resonance imaging session. European Neuropsychopharmacoly, 
21, 516-525. 
43. 
Oldfield, R. C. (1971). The assessment and analysis of handedness: the Edinburgh 
inventory. Neuropsychologia, 9, 97-113. 
44. 
World Health Organization: Regional Office for Europe (1998). Well-Being measures in 
primary health care: The DepCare Project. Consensus meeting, Stockholm.