Cognitive Behavioral Analysis System of Psychotherapy (CBASP) vs. Behavioral Activation (BA) in Persistently Depressed Treatment-resistant Inpatients: Efficacy, Moderators, and Mediators of Change
Phase: NA
Conditions: Persistent Depressive Disorder, Treatment-resistant Depression
Sponsor: University of Greifswald

 
                             
 
 
 
 
 
 
 
 
 
 
 
Cognitive Behavioral Analysis System of Psychotherapy (CBASP)  
vs. Behavioral Activation (BA)  
in persistently depressed treatment-resistant inpatients:  
Efficacy, moderators, and mediators of change 
Acronym: ChangePDD 
 
 
 
NCT Number: NCT04996433 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Date: 16.06.2021 
 
 

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University Greifswald 
Clinical Psychology and Psychotherapy 
Franz-Mehring Str. 47 
17487 Greifswald 
 
 
 
 
 
Study Protocol 
 
 
Cognitive Behavioral Analysis System of Psychotherapy (CBASP)  
vs. Behavioral Activation (BA)  
in persistently depressed treatment-resistant inpatients:  
Efficacy, moderators, and mediators of change 
Acronym: ChangePDD 
 
 
Cognitive Behavioral Analysis System of Psychotherapy (CBASP) vs. 
Behavioral Activation (BA) bei stationären Patienten mit persistierend 
depressiven und therapieresistenten Störungen:  
Wirksamkeit, Moderatoren und Mediatoren der Veränderung 
 
 
Version 3.0; 16.06.2021  
 
 
Coordinating Investigator 
 
Prof. Dr. Eva-Lotta Brakemeier 
University Greifswald 
Clinical Psychology and Psychotherapy 
Franz-Mehring-Str. 47 
17487 Greifswald 
Email: eva-lotta.brakemeier@uni-greifswald.de  
Phone.: +49 3834 420 3786 Fax: +49 3834 420 3736 
 
 
 

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Table of Contents 
 
 
1. Study Synopsis ........................................................................................................................ 7 
2. Responsibilities and Cooperation ............................................................................................ 9 
2.1. Responsibilities ................................................................................................................................ 9 
2.1.1. Investigator’s responsibilities ..................................................................................................... 9 
2.1.2. Further responsibilities ............................................................................................................. 10 
2.2. Coordinating and Participating Sites ............................................................................................. 10 
2.3. Financial support ........................................................................................................................... 12 
2.4. Signature and Consent statement................................................................................................. 12 
3. Scientific Background ............................................................................................................ 19 
4. Rationale and Hypothesis ..................................................................................................... 20 
4.1. Rationale ........................................................................................................................................ 20 
4.2. Hypothesis ..................................................................................................................................... 21 
5. Study Design......................................................................................................................... 21 
6. Outcome Measures............................................................................................................... 23 
6.1. Primary Endpoint ........................................................................................................................... 23 
6.2. Secondary Endpoints, Moderators and Mediators ....................................................................... 24 
6.3. Further Endpoints .......................................................................................................................... 25 
7. Methods of Data collection ................................................................................................... 26 
8. Study Population .................................................................................................................. 26 
8.1. Treatment groups .......................................................................................................................... 26 
8.2. Inclusion criteria ............................................................................................................................ 27 
8.3. Exclusion criteria ........................................................................................................................... 27 
8.4. Methods against bias .................................................................................................................... 27 
8.4.1. Randomization .......................................................................................................................... 27 
8.4.2. Blinding ...................................................................................................................................... 28 
8.4.3. Control of therapy allegiance .................................................................................................... 28 
8.4.4. Control of overlapping treatments ........................................................................................... 29 
8.4.5. Control of confounding factors ................................................................................................. 30 
8.4.6. Control of measurement bias ................................................................................................... 30 
9. Study Procedure ................................................................................................................... 30 
9.1. Study visit overview....................................................................................................................... 30 

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9.2. Visit 1 ............................................................................................................................................. 31 
9.3. Visit 2-5 .......................................................................................................................................... 32 
9.4. Visit 6-8 .......................................................................................................................................... 32 
9.5. Visit 9-11 ........................................................................................................................................ 32 
9.6. Visit 12-17 ...................................................................................................................................... 32 
9.7. Conduction of the Interventional Arm (CBASP) ............................................................................ 32 
9.8. Conduction of the Control Arm (BA) ............................................................................................. 33 
9.9. Concomitant Therapy .................................................................................................................... 34 
9.10. Study Sites ..................................................................................................................................... 36 
9.11. Treatment after end of study ........................................................................................................ 36 
9.12. Study Schedule .............................................................................................................................. 36 
10. Add-on Studies ..................................................................................................................... 37 
10.1 ChangePDD-EMA ............................................................................................................................ 37 
10.1.1 Theoretical motivation ................................................................................................................ 37 
10.1.12 ChangePDD-EMA study design ................................................................................................. 38 
10.1.2 ChangePDD-EMA data assessment and analysis ........................................................................ 39 
10.2 Effort Task ...................................................................................................................................... 40 
10.2.1 Theoretical motivation and hypotheses ..................................................................................... 41 
10.2.2 Task and computational model ................................................................................................... 41 
10.2.3 Study design ................................................................................................................................ 42 
10.3 Study design and instruments supplemented by add-on studies ................................................. 43 
11. Safety ................................................................................................................................... 44 
11.1. Adverse reactions .......................................................................................................................... 44 
11.2. Risk-benefit-assessment ................................................................................................................ 45 
11.2.1. Potential risks ............................................................................................................................ 45 
11.2.2. Potential benefit ....................................................................................................................... 46 
11.2.3. Conclusion ................................................................................................................................. 46 
11.3. Discontinuation criteria ................................................................................................................. 47 
11.3.1. Premature discontinuation of a patient ................................................................................... 47 
11.3.2. Premature discontinuation of the study ................................................................................... 47 
11.4. Data Monitoring Committee (DMC) .............................................................................................. 48 
12. Ethical and regulatory aspects ............................................................................................... 48 
12.1. Laws and regulations ..................................................................................................................... 48 
12.2. Independent ethics committee ..................................................................................................... 48 
12.3. Changes to the study protocol ...................................................................................................... 48 

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12.4. Informed consent and insurance .................................................................................................. 49 
12.5. Data safety ..................................................................................................................................... 49 
13. Statistics ............................................................................................................................... 49 
13.1. Sample size .................................................................................................................................... 49 
13.2. Statistical evaluation ..................................................................................................................... 50 
13.2.1. Primary endpoint ...................................................................................................................... 50 
13.2.2. Secondary endpoints................................................................................................................. 51 
13.2.3. Safety and tolerability endpoints .............................................................................................. 51 
13.2.4. Handling of dropouts ................................................................................................................ 51 
14. Data Management ................................................................................................................ 51 
14.1. Data collection ............................................................................................................................... 51 
14.2. Data processing ............................................................................................................................. 52 
13.2.1 EDC-System (eCRF) ...................................................................................................................... 52 
13.2.2 Data concealment for electronic transfer ................................................................................... 52 
13.2.3 Data discrepancies ...................................................................................................................... 52 
13.2.4 Registration ................................................................................................................................. 52 
13.2.5 Publication ................................................................................................................................... 53 
13.2.6 Open Data ................................................................................................................................... 53 
14.3. Quality assurance and quality control........................................................................................... 53 
14.3.1. Source data and subject files .................................................................................................... 53 
14.3.2. Monitoring ................................................................................................................................ 54 
15. Literature ............................................................................................................................. 54 
 
 
 

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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ATHF-SF 
Antidepressant Treatment History Form - Short Form 
ATR 
Adverse Treatment Reaction 
BA 
Behavioral Activation 
BADS 
Behavioral Activation Depression Scale 
BDI-II 
Beck’s Depression Inventory 
BDNF 
Brain-Derived Neurotrophic Factor 
BRS 
Brief Resilience Scale  
BSI 
Brief Symptom Inventory 
CBASP 
Cognitive Behavioral Analysis System of Psychotherapy 
CBASP-CAR /  
BA-CAR 
Observer based Competence and Adherence Rating of CBASP / BA 
CBT 
Cognitive Behavioral Therapy 
CRF 
Case Report Form 
CTQ 
Childhood Trauma Questionnaire 
DAS 
Dysfunctional Attitude Scale 
DIPS 
Diagnostic Interview for Mental Disorders 
DMC 
Data Monitoring Committee 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
EC 
Ethics Committee 
ECR-RD8 
Experience in Close Relationships – Revised 8-item version 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive Therapy  
EDC 
Electronic Data Capture 
ES 
Euthymia Scale 
FPFV 
First Patient First Visit  
GAF 
Global Assessment of Functioning 
GSE 
General Self-Efficacy Scale 
HDRS-24 
Hamilton Depression Rating Scale, 24-item version 

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Abbreviation 
Definition 
ICH-GCP 
International Conference on Harmonization - Good Clinical Practice 
IDS-SR 
Inventory of Depressive Symptoms, Self-Report 
IIP-32-R 
Inventory of Interpersonal Problems, 32-item version, revised 
IMI-R 
Impact Message Inventory – Revised 
ISF 
Investigator Site File 
ITT 
Intention to Treat 
KKS 
Coordinating Center for Clinical Trials 
LMM 
Linear Mixed-effects Models 
LQPT 
Lübecker Questionnaire of Preoperational Thinking  
LPLV 
Last Patient Last Visit 
MINI-ICF 
Measure of disorders of capacity as defined by the International 
Classification of Function 
MPQ 
Mental Pain Questionnaire 
PDD 
Persistent Depressive Disorder 
PI 
Principal Investigator (Coordinating Investigator) 
PID5BF + M 
Personality Inventory for DSM-5 Brief Form Plus Modified 
RCT 
Randomized Controlled Trial 
R-GPTS 
Revised-Green Paranoid Thoughts Scale 
RSQ 
Rejection Sensitivity Questionnaire 
SAB 
Scientific Advisory Board 
SAE 
Severe Adverse Event 
SATR 
Severe Adverse Treatment Reaction 
SCID-PD 
Structured Clinical Interview for DSM-5 – Personality Disorders 
SEPIPS 
Side Effects of Psychological Interventions Process Scale 
SNI 
Social Network Index 
TR 
Treatment-Resistance 
UCLA 
UCLA Loneliness Scale 
WAI 
Working Alliance Inventory 
WHO-5 
Well-Being Index 
WHOQoL 
World Health Organization Quality of Life 

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1. Study Synopsis 
Title of the Study 
Cognitive Behavioral Analysis System of Psychotherapy (CBASP) vs. 
Behavioral Activation (BA) in persistently depressed treatment-
resistant inpatients: Efficacy, moderators, and mediators of change 
Study Acronym 
ChangePDD 
Coordinating Investigator 
Prof. Dr. Eva-Lotta Brakemeier 
Indication 
Persistent depressive disorder (PDD) with treatment-resistance (TR) 
Objectives 
To compare CBASP conducted over 16 weeks (acute and continuation 
treatment) with BA (same dose and duration) in PDD inpatients with 
TR regarding efficacy, moderators and mediators of change 
Study Design 
Prospective, multicenter, evaluator-blinded, parallel-group, 
randomized controlled intervention trial with an active control 
condition 
Number of Patients 
To be assessed for eligibility: n = 1000 to be screened at sites 
To be allocated to study: n = 396 
To be analyzed: n = 396; Intention to Treat (ITT) Sample,  
14% expected dropout included 
Randomization 
Randomization with stratification for severity of depression and study 
site with an allocation ratio of 1:1 
Eligibility Criteria - Inclusion 
− 
Age 20-70 years  
− 
Primary DSM-5 diagnosis of PDD (300.4, 296.2x, 296.3x) 
− 
Total Hamilton Depression Rating Scale (HDRS-24) Score ≥ 20 
− 
Treatment-resistance (TR) (defined as a level of 3 or higher on 
the ATHF-SF or medication intolerance or one psychotherapy at 
least 25 sessions by a certified therapist in the current episode) 
− 
Sufficient knowledge of the German language 
− 
Written informed consent  
Eligibility Criteria - Exclusion 
− 
Bipolar I or II disorder  
− 
Active substance use disorders (abstinence shorter than 6 
months)  
− 
Schizophrenia spectrum and other psychotic disorders 
− 
Antisocial personality disorder 
− 
Acute suicidality  
− 
Previous CBASP or BA treatment within the last year 
− 
Inability to tolerate CBASP or BA (e.g., organic brain disorders, 
severe cognitive deficits) 
− 
Inability to participate in dayclinic or outpatient continuation 
treatment 
Test and Reference Treatment 
Experimental intervention: CBASP 
Control intervention: BA 
Time schedule 
− 
Study treatment per patient: 112 days (16 weeks) 
− 
Study duration per patient: 448 days (64 weeks, incl. follow-up) 
− 
First patient first visit (FPFV) to last patient last visit (LPLV):  
34 months (without follow-up), 46 months (incl. follow-up)  
− 
Duration of the entire study: 58 months 
− 
Recruitment period: 30 months 

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Primary endpoint 
− 
Change in depression severity (HDRS-24 score) after 16 weeks 
Secondary and further 
endpoints 
Secondary endpoints:  
− 
Depressive and anxiety symptomatology (HDRS-24 and IDS-SR) 
assessed every second week during treatment and at week 64; 
IDS-SR also measured every second month during follow-up 
− 
Specific other important psychological variables (BSI, GAF, 
WHOQoL) assessed at week pre, 1, 5, 10, 16, and 64 
− 
Response, remission, dropout and relapse rates (according to 
HRSD-24 and hospitalization rates) assessed at week 5, 10, 16 
and 64 (relapse rate only at week 16 and 64) 
− 
costs and benefits (cost interview) assessed at week pre, 16, 64 
Further endpoints: 
− 
Other interesting psychological variables (BDI-II, BRS, DAS, ECR-
D(, ES, IMI-R, LQPT, Mini-ICF, MPQ, PID5BF+M, R-GPTS, RSQ, SES, 
SNI, UCLA, WBI, WHOQOL, WHO-5) assessed at week pre, 1, 5, 
10, 16, and 64 
Main moderators (assessed at baseline):  
− 
Childhood maltreatment (CTQ)  
− 
Epigenetic (BDNF methylation) 
Main mediators (assessed at baseline and week 1, 2, 4, 6, 8, 10, 12, 
14, 16, and 64):  
− 
Interpersonal problems (IIP-32-R)  
− 
Activities (BADS, actimeter-measured step-counts) 
Mediators only included in the two add-on studies: 
− 
Interpersonal Activation Diary (IAD; assessed daily at week 0, 1, 
2, 3, 4, 5, 6) 
− 
Social interaction and current mood (assessed daily at week 0, 6) 
− 
Effort Task (assessed at week 1, 5, 16) 
Safety:  
− 
(Severe) Adverse events, negative effects including side effects 
(SEPIPS) and medication will be monitored 
Statistical analysis 
Description of the primary efficacy analysis and population: 
(Generalized) Linear Mixed-effects Models (LMM) with random 
intercepts and slopes predicting outcomes from time, treatment 
group, and time x treatment group interaction based on the Intention 
to Treat (ITT) sample 
Secondary endpoints  
Sensitivity analyses:  
- 
LMMs with covariates  
- 
LMMs based on the completer sample  
- 
Pattern-mixture Models  
Moderator analyses:  
- 
LMMs with covariate x time x group interactions  
Mediator analyses:  
- 
Dynamic Panel Models 
Participating 
sites 
No. of sites to be involved: six 
1) Berlin, Charité, University Medicine Berlin 
2) Hannover, Hannover Medical School 
3) Lübeck, University Hospital of Lübeck  
4) Marburg, University Hospital of Marburg 
5) München, University Hospital of München 
6) Tübingen, University Hospital of Tübingen 

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2. Responsibilities and Cooperation 
2.1. Responsibilities 
 
The following Figure 1 gives an overview of all persons, committees, boards and sites involved 
in the study ChangePDD. 
 
 
Figure 1: Persons, committees, boards and sites involved in the study ChangePDD 
 
 
 
2.1.1. Investigator’s responsibilities 
The Principal Investigator (PI) / Coordinating Investigator (CI) Prof. Dr. Eva-Lotta Brakemeier 
is a highly experienced scientist and psychotherapist and has sufficient experience in 
conducting clinical studies. She is responsible for the project coordination and project 
management, especially for conducting the clinical study in accordance with this study 
protocol, the ethical principles that have their origin in the Declaration of Helsinki (current 
version) as well as with ICH Guideline for Good Clinical Practice (ICH-E6 (R2)) and the relevant 
national laws and applicable regulatory requirements.  
In particular, during the whole trial, she will keep the regular contact to all study parties for 
clinical and organizational questions including regular newsletters. For the initiation, she has 
to review and design the study protocol, study manuals, patient information, and informed 
consent form; in addition, she will revise the eCRF and coordinate the training of the 
participating sites and therapists as well as provide working instructions. During the 

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recruitment phase, she is responsible to revise the study documents, schedule the investigator 
meetings and presentations, participate in the meetings with project management at KKS, 
coordinate the training and supervision, communicate with and participate on meetings with 
DMC, progress reporting, generation and review of amendments, as well as supervise and 
evaluate SAE reports. During the follow up phase, she will coordinate the CBASP- and BA-CAR 
ratings as quality assurance and start preparation of the final reports. Concerning the analysis, 
she will prepare the final reports, presentations, and publications.  
She is supported in all these tasks by Maike Hollandt, the Clinical Project Management, and 
Dr. Tim Kaiser, an expert in psychotherapy research, located at the University of Greifswald.  
 
2.1.2. Further responsibilities 
To successfully manage the trial, the KKS Greifswald, the Trial Steering Committee and the six 
Participating Sites will cooperate intensively while being supported by the DMC and the SAB 
(see Fig. 1). 
The KKS Greifswald will support and mainly perform the study coordination. The KKS 
Greifswald is responsible for support concerning preparing and review of the clinical trial 
protocol and the informed consent form as well as the application to the ethics committees. 
Furthermore, the eCRF system will be managed by the KKS Greifswald. Monitoring will also be 
provided. 
The Statistician Prof. Dr. Johannes Zimmermann is responsible for biometrics. In the initiation 
phase, he draws up the statistical analysis plan as well as standards for the data management 
and conceptualizes the eCRF and specific data formats. In the recruitment and follow-up 
phase, he prepares safety analyses and reports these to the DMC. The main task is the blinded 
analysis of the data and the provision of the final statistical analysis. In all these tasks, he is 
supported by a coworker at pre- or post-doc level.  
The Leading Investigators of each site are responsible for recruiting and conducting study 
treatments while the Core Scientists support recruitment and conduction of study treatments 
as well as trainings and supervision.  
Further responsibilities will be specified in separate contracts between the participating 
parties. 
2.2. Coordinating and Participating Sites 
Table 1 lists all six participating sites including the respective leading investigators and core 
scientists (main contact persons) as well as the addresses.  
 
Table 1: Six participating clinical sites including the respective leading investigators and core 
scientists (main contact persons)  
 
Charité, Universitätsmedizin Berlin 
Klinik für Psychiatrie und Psychotherapie (CCM) 
Charité – Universitätsmedizin Berlin 
Charitéplatz 1 
10117 Berlin 
Prof. Dr. Philipp Sterzer (philipp.sterzer@charite.de) 
Tel.: +49-30-450-517215 / Fax: +49-30-450-517944 
Prof. Dr. Stephan Köhler (stephan.koehler@charite.de) 
Tel.: +49-30-450-617405 / Fax: +49-30-450-517903 

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Medizinische Hochschule Hannover 
Klinik für Psychiatrie, Sozialpsychiatrie und Psychotherapie 
Medizinische Hochschule Hannover 
Carl-Neuberg-Straße 1 
30625 Hannover 
Prof. Dr. Kai Kahl (kahl.kai@mh-hannover.de) 
Tel.: +49-511-532-2495 / Fax.: +49-511-532-2415 
Dr. Ivo Heitlandt (heitland.ivo-aleksander@mh-hannover.de) 
Tel.: +49-511-532-7367/ Fax.: +49-511-532-7375) 
Universität zu Lübeck 
Klinik für Psychiatrie und Psychotherapie 
Universität zu Lübeck 
Ratzeburger Allee 160 
23562 Lübeck 
PD Dr. Philipp Klein (philipp.klein@uksh.de) 
Tel.:  +49-451-500-98871 
Dr. med. Bartosz Zurowski (bartosz.zurowski@uksh.de) 
Tel: +49-451-500-98831 
Universitätsklinikum Marburg 
Klinik für Psychiatrie und Psychotherapie 
Rudolf-Bultmann-Straße 8 
35039 Marburg 
Prof. Dr. Tilo Kircher (tilo.kircher@staff.uni-marburg.de) 
Tel.: +49-6421-58-65200 / Fax: +49-6421-58-65197 
Dr. Ina Kluge (ina.kluge@staff.uni-marburg.de) 
Tel.: +49-6421-58-6219 
Klinikum der Universität München 
Klinik für Psychiatrie und Psychotherapie 
Nußbaumstr. 7 
80336 München 
Prof. Dr. Frank Padberg (frank.padberg@med.uni-muenchen.de) 
Tel.: +49-89 4400-53358 / Fax: +49 89 4400-53930 
Dr. Matthias Reinhard (matthias.reinhard@med.uni-muenchen.de) 
Tel.: +49-89 4400-55512 
Universitätsklinikum Tübingen 
Allgemeine Psychiatrie und Psychotherapie mit Poliklinik 
Calwerstraße 14 
72076 Tübingen 
Prof. Dr. Andreas J. Fallgatter (andreas.fallgatter@med.uni-tuebingen.de) 
Tel.:  +49-7071-29-84858 / Fax: +49-7071-29-5379 
Dr. Christian Frischholz (christian.frischholz@med.uni-tuebingen.de) 
Tel.:  +49-7071-29-86015  
 
 
 
 
 
 

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2.3. Financial support 
The study is supported by the German Research Foundation within the Program Clinical 
Trials. 
 
 
2.4. Signature and Consent statement 
 
I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization - Good Clinical Practice) and applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Principal Investigator (PI):  
 
Prof. Dr. Eva-Lotta Brakemeier 
 
 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization - Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Charité – Universitätsmedizin Berlin 
 
Prof. Dr. Philipp Sterzer 
22.3.2021 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Prof. Dr. Stephan Köhler 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization - Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Medizinische Hochschule Hannover 
 
Prof. Dr. Kai Kahl 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Dr. Ivo Heitlandt 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization - Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Universität zu Lübeck 
 
PD Dr. Philipp Klein 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Dr. Bartosz Zurowski 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization – Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Universitätsklinikum Marburg 
 
Prof. Dr. Tilo Kircher 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Dr. Ina Kluge 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization – Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Klinikum der Universität München 
 
Prof. Dr. Frank Padberg 
22.03.2021 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Dr. Matthias Reinhard 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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I have read this protocol and agree to conduct the study in accordance with the study protocol, 
the current version of the Declaration of Helsinki, ICH-GCP Guideline (International 
Conference on Harmonization – Good Clinical Practice) and, applicable national laws and 
regulatory requirements. I also agree to handle all information concerning this study 
confidentially. 
I will ensure that all personnel involved in the study under my direction will be informed about 
the contents of this study protocol and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
Universitätsklinikum Tübingen 
 
Prof. Dr. Andreas J. Fallgatter 
22.03.2021 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
Dr. Christian Frischholz 
 
 
 
Date  
 
Signature 
 
 
 
 
 
 
 
 
 
 

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3. Scientific Background 
Up to one third of depressed patients develop persistent depressive disorder (PDD) with an 
estimated lifetime prevalence between 3% and 6% (Angst et al., 2009; Murphy & Byrne, 2012). 
Given the high degree of suicidality, comorbidity, and non-response to outpatient treatments 
(Murphy & Byrne, 2012; Bschor et al., 2014; Murphy et al., 2017; Köhler et al., 2019), many 
PDD patients require hospitalization as guidelines recommend; accordingly, about half of all 
psychiatric inpatients with depression suffer from PDD (Härter et al., 2004; Hölzel et al., 2010; 
Bschor et al., 2014; DGPPN et al., 2015; Köhler et al., 2016). In Germany, about 70.000 PDD 
patients are currently treated as inpatients per year, causing an enormous economic burden 
of an estimated 1 billion € annually. Thus, they constitute one of the main cost drivers for 
depression care (Luppa et al., 2007). However, for these inpatients no evidence-based 
treatment exists (Köhler et al., 2016; Schefft et al., 2019). Despite an overall reduction in 
depression with long psychotherapeutic inpatient treatment (Keller et al., 2001), PDD 
inpatients reach lower response rates, report higher treatment dissatisfaction, and are more 
likely to relapse after discharge than acutely depressed inpatients (Härter et al., 2004; Keller 
et al., 2001). Since most inpatients are non-responders to standard treatments, new 
treatment-phase programs combining acute and continuation treatments are urgently 
needed to overcome treatment-resistance (TR) (Köhler et al., 2016; Schefft et al., 2019).  
CBASP is the only psychotherapy specifically tailored for PDD (McCullough et al., 2014) 
demonstrating efficacy as outpatient treatment through a growing number of RCTs (Keller et 
al., 2000; Schramm et al., 2011; Wiersma et al., 2014; Michalak et al., 2015; Schramm et al., 
2017; see Jobst et al., 2016 and Negt et al., 2016 for a review and meta-analysis). Thus, we 
modified CBASP as a manualized multimodal inpatient program for the severely ill PDD 
inpatients with TR (Brakemeier & Normann, 2012; Brakemeier, Guhn & Normann, in press). 
Our pilot studies indicate very good feasibility and promising outcome (Brakemeier et al., 
2011; Brakemeier et al., 2015; Sabaß et al., 2018; Guhn et al., 2019). Therefore, a randomized 
controlled trial is now mandatory for testing the superiority of the inpatient CBASP program 
vs. an evidence-based psychotherapy such as cognitive behavioral therapy (CBT), the ‘gold 
standard’ in depression treatment. We chose a specific version of CBT – behavioral activation 
(BA) (Kanter et al., 2009; Martell et al., 2015) – since BA is at least as effective as standard CBT 
in severely depressed patients (Cuijpers et al., 2007; Dimidjian et al., 2006; Spates et al., 2006; 
Shinohara et al., 2013; Richards et al., 2016) while being easier to train and to implement in 
inpatient settings (Snarski et al., 2011). In addition, we will address the important 
psychotherapy research question: what works for whom and why? (e.g., Norcross & 
Wampold, 2011).  
Moderator analyses will examine whether childhood maltreatment (Bernstein & Fink, 1998; 
Nemeroff et al., 2003; Brakemeier et al., 2018) and methylation of exon IV of the BDNF gene 
(Frieling & Tadić, 2013; Tadić et al., 2014) have an impact on the differential efficacy of the 
treatments. DNA methylation of the BDNF exon IV promoter region as an epigenetic 
mechanism will be assessed at baseline to address the dynamic changes of depressive 
symptoms and their treatment response. Epigenetic mechanisms are modulated by 
environmental stimuli and are adaptive to different disease stages (Menke und Binder, 2014). 
First evidence for epigenetic markers like BDNF as outcome predictor (in a pharmacotherapy 
depression trial) has been gathered (e.g., Frieling & Tadic, 2013; Lieb & Frieling, 2018). DNA 
methylation of one specific CpG located in the promoter region of BDNF exon IV has 
repeatedly been shown to accurately predict non-response to monoaminergic antidepressant 
drugs. As BDNF has been implicated in neurobiological processes fundamental to successful 
psychotherapy (ie. learning, memory, neural plasticity) it is reasonable to believe that 

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epigenetic (dys-)regulation of the BDNF gene might also play a role in response to 
psychotherapy and might therefore be useful as a prognostic marker. Apart from the BDNF 
system, (dys-)regulation of several genes have been proposed to be involved in 
neurobiological pathways underlying psychotherapeutic processes (e.g. Vinkers et al., 2021). 
Epigenome wide association studies as well as candidate gene studies are possible to detect 
new genetic loci involved (Vinkers et al., 2021). Machine learning algorithms integrating 
epigenome wide methylation data have been shown to be potent predictive tools for e.g. age 
acceleration (“epigenetic clocks”) (e.g. Chaix et al., 2017)– in a similar way, it is likely that 
algorithms can be trained to learn based on the epigenome which therapy will suit best the 
individual patient’s needs. Thus, in our study, blood samples for epigenetic analyses will be 
drawn to assess potential biomarkers for CBASP/BA response. 
Regarding mediator analyses, we will investigate whether symptom improvements can be 
explained by an amelioration of interpersonal problems in CBASP (Horowitz et al., 2000; 
Jacobs & Scholl, 2005; Constantino et al., 2008; Klein et al., 2016) and an increase of activity 
levels in BA (Kanter et al., 2007; Rosenbaum et al., 2015; Forbes, 2020). A follow-up survey 48 
weeks after the end of interventions will provide valuable results regarding the long-term 
success of the treatments. 
Thus, the novel aspects of this trial are 1) comparing the multimodal CBASP inpatient program 
with a strong active comparator within treatment-resistant PDD patients by 2) applying a 
treatment-phase program while investigating 3) moderators and 4) mediators of change to 
guide personalized treatment and enable therapists to more specifically address 
psychotherapeutic needs of individual PDD patients in the future. Notably, 5) a cost-
effectiveness perspective further addresses health-economic issues and will enhance the 
relevance and potential benefit of CBASP (and BA) for public health (Drummond, 2007). 
Therefore, this trial will provide valuable information concerning allocation of resources 
(inpatient, dayclinic, and outpatient treatment) and may be of interest to decision makers in 
healthcare policy. Many hospitals in German-speaking (like Switzerland and Austria) and other 
countries (like USA, Denmark and Canada) already have implemented CBASP concepts. Due 
to the relatively short interventions, dose, and duration of the treatment-phase program, it is 
comparable to clinical practice, being at the same time affordable (for example by the German 
Health Care System). Notably, even in other countries the short inpatient intervention 
followed by dayclinic and outpatient treatment could be implemented. However, additional 
evidence needs to be provided before the CBASP inpatient program for treatment-resistant 
PDD is established on a broader scale influencing clinical practice. Thus, the results of this 
study have the potential to relieve the burden of this very serious and cost-intensive disease 
while improving human health. 
4. Rationale and Hypothesis 
4.1. Rationale 
About half of all psychiatric inpatients with depression suffer from persistent depressive 
disorder (PDD). Given their high degree of treatment-resistance, comorbidity, suicidality, and 
hospitalization rates, this patient group appears to be particularly difficult to treat and, from 
a health economic perspective, constitutes a major challenge. The Cognitive Behavioral 
Analysis System of Psychotherapy (CBASP) is the only psychotherapy specifically tailored for 
PDD. Originally developed as an outpatient treatment, we have modified CBASP for the 
severely ill PDD patients with TR as a multimodal inpatient concept. Our pilot studies indicate 

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very good feasibility and promising outcome. Therefore, a randomized controlled trial is now 
mandatory for testing the superiority of the inpatient CBASP program vs. the evidence-based 
Cognitive Behavioral Therapy (CBT), the ‘gold standard’ in depression treatment. Behavioral 
Activation (BA) was chosen as the control intervention because BA, as a specific variant of CBT, 
is at least as effective as standard CBT in severely depressed patients while being easier to 
train and implement in inpatient settings. Both therapies will be applied as a treatment-phase 
program (10-week inpatient/ dayclinic acute treatment followed by 6-week outpatient 
continuation group-treatment) in combination with standardized and guideline-based 
pharmacotherapy. The proposed prospective, multi-center, randomized study with 396 PDD 
patients with TR will therefore address the primary research question: Is the CBASP program 
more effective than the BA program in this patient group? Our hypothesis is that after 16 
weeks of treatment, CBASP will show a significant superiority over BA in reducing depressive 
symptoms. In addition, we will address the important psychotherapy research question: what 
works for whom and why? Moderator analyses will examine whether childhood maltreatment 
and methylation of exon IV of the BDNF gene have an impact on the differential efficacy of 
the treatments. Regarding mediator analyses, we will examine whether symptom 
improvements can be explained by an amelioration of interpersonal problems in CBASP and 
an increase of activity levels in BA. A follow-up survey 48 weeks after the end of the 
interventions will provide valuable results regarding the long-term outcome of the 
treatments. 
Finally, the health economic potential of the interventions will be investigated through cost-
benefit analyses in order to provide important information on the cost-effectiveness of 
implementation in routine care for health policy. Thus, the results of this study will have the 
potential to relieve the burden of this very serious and cost-intensive disorder while improving 
human health. In addition, moderator and mediator analyses may guide personalized 
treatment and enable therapists to more specifically address psychotherapeutic needs of 
individual PDD patients in the future. 
 
4.2. Hypothesis 
It is hypothesized that CBASP (being tailored for the burdened subgroup of TR PDD inpatients) 
is significantly more effective than BA (being tailored for depression in general) after 16 weeks 
of treatment-phase programs (overall 20 individual and 26 group therapy sessions). 
5. Study Design 
This prospective, multi-center, randomized study with 396 TR PDD patients will compare the 
two manual-based inpatient programs CBASP (Brakemeier & Normann, 2012; Brakemeier, 
Guhn & Normann, in press) (as experimental intervention) and BA (Martell et al., 2015) (as 
control intervention).  
To control group effects, we provide the treatment teams with precise study manuals for the 
CBASP- and BA-programs that describe all study treatments in detail. Since the risk of 
systematic errors is higher in inpatient psychotherapy studies than in outpatient studies due 
to more uncontrollable factors, we have done everything possible to minimize these 
uncontrollable factors, mainly by parallelization. Thus, the study manuals guarantee that both 
groups receive the same type, dose, and duration of study treatments, the same additional 
treatments, the same algorithm concerning medication, and the same dose of team training 
and supervision, etc. (see chapter 9). In addition, the study manuals clearly specify which 

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additional treatments are allowed for study patients. Furthermore, important conditions 
immanent in the inpatient setting also minimize confounding variables (such as same location 
and environment, same weather, same diet, same daily routine, same general hospital rules, 
same hospital climate, same chief physician, no or sparse interaction with family and friends, 
no work practice). In order to enable comparability of the participating sites and reduce a site 
effect, or a possible allegiance bias discriminating BA, the two interventions are carried out in 
each participating site on two separate specialized wards. 
The sufficient sample size (N=396) and the six recruitment sites in different regions of 
Germany will assure generalizability of results and representativeness of the sample. 
Furthermore, we kept exclusion criteria to a minimum (expecting a high rate of comorbidity) 
to even enhance generalizability of our findings. Inclusion/exclusion criteria are specified to 
yield a population of PDD patients with a high degree of TR (see 8.2 and 8.3).  
 
Power calculation for the proposed sample size of N=396 is based on a simulation study as 
recommended for linear-mixed effects models (Gelman & Hill, 2007). Please note that this 
estimate already takes into account that we expect about 14% missing data at the primary 
endpoint (i.e., after 16 weeks), because the simulation study already included assumptions 
about missing data.  Concerning expected dropout rates, based on the RCT trial by Schramm 
et al. (2017), where 3% of patients dropped out immediately after randomization, we expect 
that about 5% of patients to drop out of the study immediately after randomization (no 
treatment and follow-up), although all efforts will be made during the informed consent 
procedure to include only patients who are willing to accept both arms and to continue study 
visits until W64/T5 (even if they drop out of treatment). In addition, in our one-arm pilot study 
(Brakemeier et al., 2015), 92.9% of the patients (65 out of 70) were fully compliant with the 
CBASP inpatient regime. Since in BA the same dose and duration of psychotherapy is 
scheduled we expect about 90% compliance in the multicenter trial in both groups. Therefore, 
we expect 95% x 90% = 85.5% of randomized patients to have HDRS-24 non-missing in week 
16. Moreover, in our CBASP pilot study (Brakemeier et al., 2015), we observed only 12.9% 
losses to 6-months follow-up and 14.3% to 12 months follow-up. Therefore, we expect 15% 
of those who start treatment to have HDRS-24 missing in week 64, leaving 95% x 85% = 80.8% 
of those randomized with non-missing HDRS-24 in week 64.  
We anticipate that about 1.000 patients have to be screened in order to randomize 396 
patients (40% informed consent). In comparable studies slightly higher rates are found: in our 
own inpatient RCT study with depressed patients having received Electroconvulsive Therapy 
(ECT; Brakemeier et al., 2014) 61% informed consent and the RCT of Keller et al. (2000) 85% 
informed consent. The reason for why we are more conservative is that in the Brakemeier et 
al. (2014) trial the depressive patients while having been randomized had already successfully 
responded to inpatient treatment and were randomized to maintenance therapy. In the Keller 
et al. (2000) study all treatments were outpatient. PDD patients with TR who report for 
inpatient admission may be more difficult to motivate to participate in this inpatient RCT due 
to the severity and chronicity of the disease.  
Regarding internal validity, group effects, the comparability of the sites, a site effect, or a 
possible allegiance bias discriminating BA, we have taken many precautions, as described in 
the following. Randomization with stratification for severity of depression (HDRS-24; 
Hamilton, 1960) and study site will be performed with an allocation ratio of 1:1. Due to the 
nature of interventions, blinding of patients/therapists concerning the treatment program is 
impossible, but all assessments as well as data analysis will be blinded to treatment allocation. 
Notably, patients are blinded to the study hypothesis by the Informed Consent process, as 
patients are told in the patient information and educational discussions about the study that 

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they will in any case receive one of two different scientifically based psychotherapy programs, 
although it is unclear which of the two programs is more effective; one program focuses on 
coping with interpersonal problems, the other on building up activities that seem important 
for personal life (see Informed Consent Form). Similarly, the members of the treatment teams 
of each study ward are not informed about the study hypothesis; however, they are informed 
that it has not yet been scientifically clarified which therapy is more effective.  
Measures to ensure blinding will include locating the raters separately from the study wards, 
instructing patients not to mention information that could reveal their allocation, and 
providing back-up raters in case of unintentional unblinding. All blinded raters (student 
assistants at each participating site) will be trained in all instruments (HDRS-24, GAF, MINI-
ICF, IMI-R, cost interview). Concerning HDRS-24, raters will be certified by a central rating of 
three videotaped HDRS-24 interviews. Additionally, the adherence and competence of the 
psychotherapists with regard to the specific CBASP or BA techniques will be evaluated 
regularly (measured with the observer-rated video-based CAR instruments). Since the patients 
will evaluate their subjective acceptance, satisfaction with and effectiveness of received 
treatments and the atmosphere of the ward etc. with the standardized questionnaire RevieW 
every week of treatment, we will also consider these subjective evaluations in our analyses 
(see 6.2).  
 
Study Flow Chart 
Figure 2: Study Flow Chart 
6. Outcome Measures 
6.1. Primary Endpoint 
The primary endpoint will be 

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− 
the change in HDRS-24 item score (Hamilton, 1960; Williams, 1988) from baseline to 16 weeks 
after randomization  
The HDRS is considered being the “gold standard” as the most frequently used and well-
validated clinician rated measure of depression severity (Carrozzino et al., 2020). As 
recommended by Carrozzino et al. (2020) we will use a semi-structured version of the 24 item 
version, including item definitions, anchor points and semi-structured interview questions. 
Each item is evaluated on a 3 to 5 level scale, for each of which a short description is given. 
The time frame of the asked symptomatology applies to the last week before the interview. 
On average, the processing time is 15 minutes. The range of the HDRS-24 is from 0 to 75. It is 
not recommended to make a diagnosis of depression based on cut-off value because the HDRS 
is primarily designed to be sensitive to changes and is therefore more suitable for measuring 
changes in the course. Most of the relevant trials we refer to use HDRS-24 change as primary 
outcome. The endpoint was set at week 16 after randomization, as CBASP is expected to show 
superiority over BA with a long duration and high dosage (see Cuijpers et al., 2010; Wiersma 
et al., 2014; Brakemeier et al., 2015; Schramm et al., 2017). HDRS-24 will be administered at 
screening (T0), week 1 (T1), 5 (T2), 10 (T3), 16 (T4), 64 (T5) by blinded observers being not 
otherwise involved.  
6.2. Secondary Endpoints, Moderators and Mediators 
Secondary endpoints will be the following questionnaires and interviews:  
− 
HDRS-24 (see above), assessed every second week and at week 64 
− 
IDS-SR (Rush et al., 2000), assessed every second week and every second month during follow-up 
− 
Brief Symptom Inventory (BSI; Derogatis & Spencer, 1993), assessed at week pre, 1, 5, 10, 16, and 
64 
− 
Global Assessment of Functioning (GAF; Hall, 1995), assessed at week pre, 1, 5, 10, 16, and 64 
− 
World Health Organization Quality of Life (WHOQoL; Angermeyer et al., 2000), assessed at week 
pre, 1, 5, 10, 16, and 64 
− 
Response (50% decrease on HDRS-24 score in comparison to baseline), remission (HDRS-24 of 10 
or less on the HDRS-24), relapse rates (defined as rehospitalization for symptomatic worsening 
and/or a combination of an increase in HAMD 24 from discharge of equal or greater than 10 points 
and a current HAMD 24 score of equal or greater than 18 points), and dropout, assessed at week 
5, 10, 16, and 64 (relapse-rate only at week 16 and 64) 
− 
Cost interview (Wagner et al., 2014) assessed at week pre, 16, and 64; through the cost interview, 
the direct medical costs (inpatient stays, doctor’s visits, emergency treatment, etc.), the direct 
non-medical costs (informal help, delinquent behavior, etc. and the indirect costs (days of 
incapacity to work, disability, unemployment) are recorded. In addition, a distinction is made as to 
whether the costs are due to mental disorders versus physical illnesses. 
In addition, the following other important psychological variables will be assessed as further 
endpoints at week pre, 1, 5, 10, 16, and 64: 
− 
Beck’s Depression Inventory (BDI-II; Hautzinger et al., 2006) 
− 
Brief Resilience Scale (BRS; Smith et al., 2008) 
− 
Dysfunctional Attitude Scale (DAS; Hautzinger et al., 2005) 

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− 
Euthymia Scale (ES; Carrozzino et al., 2019) 
− 
Experience in Close Relationships Scale – Revised 8-item version (ECR-RD8; Ehrenthal et al., 
submitted)  
− 
General Self-Efficacy Scale (GSE; Schwarzer & Jerusalem, 1995) 
− 
Impact Message Inventory revised (IMI-R; Casper et al., 2000) 
− 
Lübecker Questionnaire of Preoperational Thinking (LQPT; Kuehnen et al., 2011)  
− 
Measure of disorders of capacity as defined by the International Classification of Function (Mini-
ICF; Linden & Baron, 2005) 
− 
Mental Pain Questionnaire (MPQ; Fava et al., 2019) 
− 
Personality Inventory for DSM-5 Brief Form Plus - Modified (PID5BF+ M; Kerber et al., submitted; 
Bach et al., in press)  
− 
Rejection Sensitivity Questionnaire (RSQ;  Downey & Feldman, 1996; Staebler et al., 2011) 
− 
Revised-Green Paranoid Thoughts Scale (R-GPTS; Freeman et al., 2019) 
− 
Social Network Index (SNI; Cohen, 1997) 
− 
UCLA Loneliness Scale (UCLA; Döring et al., 1993; Russell, 1996) 
− 
Well-being Index (WHO-5; Krieger et al., 2014) 
The main moderators (measured at baseline) are:  
− 
Childhood maltreatment measured by Childhood Trauma Questionnaire (CTQ; Bernstein et al., 
2003; Wingenfeld et al., 2010)  
− 
Epigenetic (Brain-derived neurotrophic factor (BDNF) methylation) 
The main mediators (measured at baseline and week 1, 2, 4, 6, 8, 10, 12, 14, 16 and 64) are: 
− 
Interpersonal problems (Inventory of Interpersonal Problems-revised, IIP-32-R, 32-item version; 
Horowitz et al., 2000)  
− 
Activities (Behavioral Activation Depression Scale, BADS; actimeter-measured step-counts) 
Finally, the following instruments are also applied to measure other important constructs 
− 
Therapeutic relationship (Working Alliance Inventory, WAI; Wilmers et al., 2008) measured at 
week 1, 2, 4, 6, 8, 10, 12, 14, and 16) 
− 
Subjective evaluation of important specific and unspecific working mechanisms of treatment 
(Review of last Week, RevieW; Koy, 2019; measured every week during the 16 weeks of treatment) 
Nearly all measures have validated and are widely used, including the important CBASP or 
CBT/BA trials. 
 
6.3. Further Endpoints 
Safety will be assessed by monitoring adverse events, side effects and medication. (Severe) 
Adverse events (SAEs) and medication will be continuously monitored via a standardized 
questionnaire; negative effects including side effects of psychotherapy will be measured at 

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wk. 5, 10, 16, and 64 with the SEPIPS (Side Effects of Psychological Interventions Process Scale; 
Herzog et al., in prep.). 
7. Methods of Data collection 
The investigators are responsible for the performance of the trial in accordance with GCP guidelines 
and the study protocol as well as the correct data entry to the corresponding electronic case report 
form (eCRF). The self-reported questionnaires are completed by the patient herself/himself using 
tablets or computers electronically from the clinic and are thus directly integrated into the eCRFs. The 
study staff also enters the results of the clinical interviews directly into the eCRFs. The blood sample 
(approximately 10 ml) will be taken at the first study visit. Blood samples will be stored at the study 
centers and then transported twice a year to the central sample storage in the Hannover Unified 
Biobank (HUB). The blood will be evaluated in a study laboratory (Molecular Neuroscience laboratory 
at Hannover Medical School) regarding methylation of exon IV of the BDNF gene. The results are then 
entered into the eCRF by study staff. Blood respectively DNA samples will be stored for further 
exploratory genomic and epigenomic studies examining BDNF as a moderator for the response of 
depressed patients to methods of psychotherapy.  
All patients will receive an actimeter to measure the number of steps during the entire study.   
The data of the patients are documented with the EDC (Electronic Data Capture). The self-report 
questionnaires are entered directly by the patients. It should be noted that patients are invited to the 
clinic for all study visits so that they always use the certified equipment and study staff are always 
available to help with any questions. This will also contribute to a maximum good data quality. The 
data is entered directly into the eCRF via the web browser. As the system is a web application, a stable 
internet connection and an input device is required. Standardized input devices will be available to 
patients. Detailed instructions on how to use the EDC system are listed in the EDC manual, which is 
part of the ISF. 
Furthermore, all individual psychotherapeutic sessions will be videotaped (including sound) 
by standard video cameras for 1) supervision purposes, 2) conducting the CAR ratings 
(assessment of adherence and competence) and 3) research purposes in the field of 
psychotherapy process research. Standardized evaluation methods are used to assess which 
processes take place in the therapy sessions and how these processes are related to the 
therapy outcome. 
 
Selection of patients 
The investigators will keep a record of all study candidates who were considered for 
enrollment including screening failures that were never enrolled. A screening log form will be 
filed in the ISF. 
8. Study Population 
8.1. Treatment groups 
The study population consists of psychiatric inpatients with persistent depressive disorder 
who have been treatment-resistant. In total, the sufficiently large sample size (N=396) 
recruited at six participating sites in different regions of Germany (with a shared amount of 
patients) will assure generalizability and representativeness of results. Furthermore, we kept 
exclusion criteria to a minimum (expecting a high rate of comorbidity) to even enhance 

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generalizability of our findings. Inclusion/exclusion criteria are specified to yield a population 
of PDD patients with a high degree of TR. 
 
Patient recruitment 
The screening of the patients will be performed in the participating study sites. The 
recruitment of patients is supported by advertising measures, which will be produced 
between August and October 2020. For example, flyers will be sent and distributed to 
therapists in outpatient and inpatient practice and a website set up especially for the study 
will provide information about the study. Advertisements for the study will also be placed on 
other relevant websites (e.g. ‘Deutsche Depressionshilfe’, CBASP Network, etc.). It is expected 
that screening of 1.000 persons will result in 396 patients eligible for the study. The 
recruitment period will last for 30 months. 
 
8.2. Inclusion criteria 
− 
Age range: 20-70 years 
− 
Primary DSM-5 diagnosis of PDD (300.4, 296.2x, 296.3x) 
− 
Total HDRS score (24-item version) ≥ 20 at screening visit 
− 
TR: Treatment-resistance defined as a level of 3 or higher on the Antidepressant Treatment 
History Form – Short-Form (ATHF-SF; Sackeim et al., 2019) or medication intolerance or one 
psychotherapy (at least 25 sessions in the current episode conducted by a certified therapist) 
− 
Sufficient knowledge of the German language 
− 
Written informed consent  
8.3. Exclusion criteria 
− 
Bipolar I or II disorder, active substance use disorders (abstinence shorter than 6 months), 
schizophrenia spectrum and other psychotic disorders, or antisocial personality disorder (all 
according to DSM-5) 
− 
Acute suicidality 
− 
Previous CBASP or BA treatment within the last year 
− 
Inability to tolerate CBASP or BA (e.g., organic brain disorders, severe cognitive deficits) 
− 
Inability to participate in dayclinic or continuation treatment 
 
8.4. Methods against bias 
8.4.1. Randomization 
Randomization with stratification for severity of depression and participating site with an 
allocation ratio of 1:1 will be performed by a blinded statistician. To ensure allocation 
concealment, only the leading investigator at each site will see the result of the allocation. 
This procedure is intended to minimize the bias due to allocation concealment.The 

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randomization of an eligible patient can only take place if all inclusion criteria and none of the 
exclusion criteria are fulfilled.  
The group assignment is based on random permuted blocks with random block sizes and 
stratification for severity of depression (binary) and participating site. Regarding the severity 
of depression, an HRSD-24 score of at least 27 points was chosen as the binary cut-off 
criterion, since in the study by Schramm et al. (2017) the mean value of the HRSD-24 scale at 
the beginning of the study was also 27 points.  Stratified permuted blocks ensure balance 
between both treatment groups, the balance within each participating site, and balance of 
the major covariate (depression severity). The use of random block sizes ensures that the next 
randomization assignment cannot be guessed. 
 
8.4.2. Blinding 
Due to the nature of interventions, blinding of patients/therapists concerning the treatment 
is impossible. However, the patients/treatment team on the wards will be blinded regarding 
the primary study hypothesis (see 4.2) because the patients and the treatment teams will be 
told that it is not yet known which of the two psychotherapy programs is more effective in 
treating PDD patients with TR. In addition, the clinical raters (thus, all assessments) and the 
trial statistician (thus, the data analysis) will be blinded to treatment allocation during the 
analysis of the primary outcome. Ideally, the same clinical rater (student assistants at each 
participating site) will rate the patient at all measurement times. Procedures to ensure 
blinding will include locating the clinical raters separately from the study wards, instructing 
patients not to mention information that could reveal their allocation, and providing backup 
raters in case of unintentional unblinding. All blinded clinical raters will be trained in all 
instruments (HDRS-24, GAF, MINI-ICF, IMI-R, cost interview). Concerning HDRS-24, the raters 
are first trained through a three-hour (web-based) training session and then complete an 
evaluation of three standardized videotaped HDRS-24 interviews. Only if they have 
successfully completed these three ratings (which means that the difference is less than 3 
points for each rating), they will be admitted as study raters. Strict concealment of 
randomization will be guaranteed to exclude selection bias (see 8.4.1). Since randomization 
of therapists is impossible, demographic and professional characteristics of therapists will be 
assessed (instrument: THAT; Klug et al., 2002). 
 
8.4.3. Control of therapy allegiance 
Therapy allegiance, i.e. treatment preference of the investigators or therapists, has been 
discussed as an important influencing factor for results in psychotherapy research (Luborsky 
et al., 1999; Munder et al., 2013; Robinson, Berman & Neimeyer, 1990). Thus, several 
procedures have been implemented to minimize the allegiance effect:  
1. Several investigators have been involved in the design of this study who represent a “mix of 
therapy allegiances”.  
2. The two interventions are carried out in all sites with the same lengths and duration.  
3. The entire treatment team of each study ward will be trained and supervised either in BA or 
in CBASP by highly experienced CBASP/BA experts. Before study start, all 12 wards of the six 
participating sites will be trained (intensive training workshops, same amount for both arms) 
in one of the two concepts and fresh-up team trainings for both arms will be performed every 
six months. The same amount of training and supervision for each study ward will be offered 

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with the possibility that rather unexperienced BA wards receive more training/supervision 
inter alia by our BA experts. In addition, training on-site visits of the core team of less 
experienced sites on an experienced BA ward will be organized. 
 
8.4.4. Control of overlapping treatments  
The following measures will be taken to prevent confounding of treatment conditions through 
the overlap of treatment methods:  
− 
All study therapists are obligated to adhere to the therapeutic procedures and interventions 
described within the manuals. In addition, treatment fidelity, adherence and competence will be 
assessed: Trained study assistants will rate videotapes of 1 individual therapy session of each study 
patient on a random basis under supervision of the trial site psychologists. s. In addition, a separate 
team of the experts will randomly evaluate one videotaped individual session of each patient. 
Before treating study patients, the psychotherapists have to meet the criteria for mastery of CBASP 
or BA procedures as assessed by evaluation of their performance. The competence and adherence 
observer ratings for both individual and group sessions are oriented towards the already 
established assessment for cognitive therapy - the Cognitive Therapy Scale (CTS; Weck et al., 2010) 
- and are based on adherence scales for CBASP and BA that have already been used in other 
studies. We call our adapted instruments CBASP-CAR (Observer-based Competence and 
Adherence Rating of CBASP) and BA-CAR (Observer-based Competence and Adherence Rating of 
BA). The CAR evaluations refer to the therapeutic approach and the respective strategies of the 
two treatments (CBASP, BA). Hence, we will determine a minimum cut-off that reflects the 
demands on adherence of therapists. All values above the minimum cut-off will record therapist’s 
competence on the scale. In addition, after each session the therapist (both individual and group 
therapists) will fill out a check list regarding the employed interventions. The validity of the 
therapist statements will be checked through external assessment of the video recordings. In post-
hoc analysis it will be checked if the expected differences regarding intervention characteristics 
appear within the two therapies.  
− 
The two interventions are carried out on two separate specialized wards. Each study therapist will 
be involved in only one of the two psychotherapy programs and will accordingly only perform one 
of the two psychotherapies. 
− 
To evaluate therapist attitudes towards CBASP and BA, questionnaires will be applied at the 
therapy training, after the first study patient, and after study termination.  
− 
Possible influences through qualification differences of the therapists will be controlled as follows 
• 
All therapists have completed professional training or are in their at least second training 
year (out of three) for certification as licensed psychotherapist.  
• 
All therapists have completed a comprehensive training (at least 24 UE) within the 
respective treatment approach. All therapists will conduct two pilot cases with at least 8 
sessions supervised by at least 3 sessions. 
• 
Concerning their influence upon the efficacy of treatment, level of training and 
professional experience of the therapists will be collected and reviewed. 
 

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8.4.5. Control of confounding factors 
− 
The influence of the trial site upon efficacy of the respective treatment approaches will be 
investigated as a separate factor.  
− 
Patients will be asked not to engage in off-study psychosocial or psychiatric interventions during 
the 16 weeks of treatment period.  
 
8.4.6. Control of measurement bias 
− 
All clinical raters will have completed (web-based) training for rating HRSD. 
− 
Guidelines for all rating scales are available.  
− 
The interrater reliability will be determined on the basis of at least 3 recorded HRSD ratings.  
 
 
9. Study Procedure 
9.1. Study visit overview  
The following Table 2 summarizes the proposed frequency and scope of trial visits including 
all instruments and the duration of post-trial follow-up, as well as the six main measurement 
time points (T), and 17 trial visits (V).  
 
Table 2: Frequency and scope of trial visits 
 
  

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Note. Primary endpoint is marked red; * V1 is divided into V1a to V1d (see Figure 3); ** Randomization will be performed 
between T0/V1 and T1/V2; *** Blinded observer ratings; **** Two crosses per cell because the questionnaire RevieW is 
done weekly 
 
 
9.2. Visit 1 
Visit 1 (T0) is divided into Visit 1a – 1d and takes place during the screening phase. A detailed 
plan is shown in Figure 3.  
− 
Visit 1a can be carried out as a telephone or personal screening and lasts 20 – 30 minutes; the 
patient is informed about the study and the patient information is handed out or sent to 
her/him; inclusion and exclusion criteria are requested by a structured screening process  
− 
Visits 1b, 1c and 1d should follow each other as soon as possible (maximum interval of 1 week) 
− 
At the beginning of Visit 1b the patient should agree to participate in the study (informed 
consent). 
− 
In Visits 1b and 1c the corresponding interviews are conducted by the blinded rater (see Fig. 
3)  
− 
Between the Visits 1b and 1c, patients are asked to fill in the questionnaires at home on a 
tablet or computer; this work can also be interrupted and resumed later or on a following day; 
if the patients do not have a computer or tablet, they can complete the questionnaires after 
or before the study visits using standardized input devices provided by the study site.  
− 
If the patient has agreed to participate in the study (informed consent) in Visit 1b and has also 
been identified as suitable with regard to the inclusion and exclusion criteria, before visit 1d 
the randomization will be performed by a blinded statistician and this information is given to 
the patient at visit 1d; the date for admission on the ward will be fixed. 
 
Figure 3: Detailed Screening Flow 
 
 

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9.3. Visit 2-5 
− 
Visits 2-5 take place during the inpatient phase I 
• 
Visits 2 within the first two days after admission (week 1) 
• 
Visits 3 and 4 at the end of weeks 2 and of the inpatient treatment 
• 
Visit 5 at the last or penultimate day of the inpatient phase 
− 
Conduction of the corresponding instruments (see Table 2) 
− 
Visit 2 and 5 are main measuring points (T1 and T2) 
9.4. Visit 6-8 
− 
Visits 6-8 take place during the inpatient phase II / dayclinic phase 
• 
Visits 6-7 at the end of weeks 6 and 8 of the inpatient phase II / dayclinic phase 
• 
Visit 8 at the last or penultimate day of the inpatient phase II / dayclinic phase 
− 
Conduction of the corresponding instruments (see Table 2) 
− 
Visit 8 is a main measuring point (T3) 
9.5. Visit 9-11 
− 
Visits 9-11 take place during the continuation phase  
• 
Visits 9 and 10 at the end of weeks 12 and 14 of the continuation treatment  
• 
Visit 11 at the last or penultimate day of week 16 (last week of the continuation phase) 
− 
Conduction of the corresponding instruments (see Table 2) 
− 
Visit 16 is the main measuring point (T4, primary outcome) 
9.6. Visit 12-17 
− 
Visits 12-17 take place during the naturalistic follow-up.  
• 
Visits 12-16 at the end of weeks 24, 32, 40, 48, and 56 of the naturalistic follow-up  
• 
Visit 17 at the last or penultimate day of week 64 (last week of the naturalistic follow-up) 
− 
Conduction of the corresponding instruments (see Table 2) 
− 
Visit 17 is a main and the last measuring point (T5) 
 
9.7. Conduction of the Interventional Arm (CBASP) 
The CBASP program will follow a strict standardized treatment manual being based on 
(Brakemeier & Normann, 2012; Brakemeier, Guhn & Normann, in press).  
During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment 
the patient will receive the following CBASP treatments per week: 
− 
2 individual therapy sessions (duration: 50 min per session) 
− 
2 group therapy sessions (duration: 100 min per session) 

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− 
1 nurse contact (therapeutic exchange with a nurse) (duration: 25 min per contact) 
− 
1 exercise therapy (duration: 75 min per therapy) 
During the 6-week outpatient treatment the patient will receive the following CBASP 
treatment per week: 
− 
1 group therapy session (duration: 100 min per session) 
All individual sessions will be videotaped (including sound) for supervision purposes, for 
conducting the CAR ratings (assessment of adherence and competence) and for research 
purposes in the field of psychotherapy process research. Standardized evaluation methods 
are used to assess which processes take place in the therapy sessions and how these 
processes are related to the therapy outcome. 
 
 
In addition, the following workshops and supervisions are conducted for the CBASP treatment 
team:  
− 
one start-up site workshop before study start conducted for the entire treatment team by one of 
the following CBASP experts: Prof. Dr. E.L. Brakemeier, Dr. A. Guhn; PD Dr. J.P. Klein, Prof. Dr. S. 
Köhler; duration 9 hours (12 UEs) 
− 
one start-up expert workshop before study start (after the start-up site training workshop) 
conducted for 4 participants per site (overall 24) by John Swan and Marianne Liebing-Wilson; 
duration 9 hours (12 UEs) 
− 
fresh up training every six months conducted by one of the following CBASP experts: Prof. Dr. E.L. 
Brakemeier, Dr. A. Guhn; PD Dr. J.P. Klein, Prof. Dr. S. Köhler; duration 9 hours (12 UEs) 
− 
weekly CBASP supervisions by a site supervisor for all individual therapists; duration 60 minutes  
− 
every second month CBASP team supervisions by external experts (one of the following persons: 
Prof. Dr. E.L. Brakemeier, Dr. A. Guhn; PD Dr. J.P. Klein, Prof. Dr. S. Köhler); duration 120 minutes 
9.8. Conduction of the Control Arm (BA) 
The BA program will follow a strict standardized treatment manual being based on (Martell 
et al., 2015).  
During the 5-week inpatient phase I and the 5-week inpatient phase II / dayclinic treatment 
the patient will receive the following BA treatments per week: 
− 
2 individual therapy sessions (duration: 50 min per session) 
− 
2 group therapy sessions (duration: 100 min per session) 
− 
1 nurse contact (therapeutic exchange with a nurse) (duration: 30 min per contact) 
− 
1 exercise therapy (duration: 75 min per therapy) 
During the 6-week outpatient treatment the patient will receive the following BA treatment 
per week: 
− 
1 group therapy session (duration: 100 min per session) 
All individual sessions will be videotaped for supervision purposes, for conducting the CAR 
ratings (assessment of adherence and competence) and for research purposes. 
 

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In addition, the following workshops and supervisions are conducted for the BA treatment 
team:  
− 
one start-up site workshop before study start conducted for the entire treatment team by one of 
the following BA experts: Dr. E. Fassbinder, Prof. Dr. K. Kahl, Prof. Dr. U. Schweiger; duration 9 
hours (12 UEs) 
− 
one start-up expert workshop before study start (after the start-up site training workshop) 
conducted for 4 participants per site (overall 24) by Prof. Dr. J. Kanter, duration 9 hours (12 UEs) 
− 
fresh up training every six months conducted by one of the follwing BA experts: Dr. E. Fassbinder, 
Prof. Dr. K. Kahl, Prof. Dr. U. Schweiger; duration 9 hours (12 UEs) 
− 
weekly BA supervisions by a site supervisor for all individual therapists; duration 60 minutes  
− 
every second month BA team supervisions by external experts (one of the following persons: Dr. 
E. Fassbinder, Prof. Dr. K. Kahl, Prof. Dr. U. Schweiger); duration 120 minutes 
 
9.9. Concomitant Therapy  
To control group effects, it is clearly defined which additional treatments/services are 
permitted and which are prohibited for study patients (see Table 3). To control group effects, 
it is clearly defined which additional treatments/services are permitted and which are 
prohibited for study patients. With the permitted treatments/services, strict attention must 
be paid to ensuring that study patients in both treatment groups participate equally 
(parallelization).   
 
Table 3: Permitted and prohibited treatments/services 
 
 
Permitted  
(if performed in parallel for both study groups) 
Prohibited 
Inpatient 
treatment  
phase I 
(5 weeks) 
standardized physiotherapy group  
(up to 3/week) 
Mindfulness-based groups offered by 
therapists 
standardized occupational therapy group  
(up to 3/week) 
All further psychotherapeutic or non-
psychotherapeutic group offers or individual 
sessions  
algorithm-based study medication* 
Crisis talk 
Only if absolutely necessary for daily 
structure and performed in parallel for both 
study groups 
relaxation-group  
mindfulness-based offered by nurses 
patient café 
excursion 
morning exercise 

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patient group 
 
Permitted  
(if performed in parallel for both study groups) 
Prohibited 
Inpatient 
treatment 
phase II or 
dayclinic 
treatment 
(5 weeks) 
standardized physiotherapy group  
(up to 3/week) 
Mindfulness-based group offered by 
therapists 
standardized occupational therapy group  
(up to 3/week) 
All further psychotherapeutic or non-
psychotherapeutic group offers or individual 
sessions 
algorithm-based study medication* 
Only if absolutely necessary for daily 
structure and performed in parallel for both 
study groups 
relaxation- or mindfulness-based group 
offered by nurses 
patient café 
excursion 
morning exercise 
patient group 
 
Permitted 
Prohibited 
Outpatient 
treatment 
6 weeks 
algorithm-based study medication* 
All further treatments by the clinic/ward 
If possible in these 6 weeks, outpatient 
psychotherapy should pause 
 
 
 
 
 
*Medication add-on treatment 
Most patients will be on medication at study entry due to the severity of illness. All patients 
will receive an optimized, algorithm-based antidepressant medication following the current 
S3-Guidelines on Unipolar Depression (DGPPN et al., 2015; Middleton et al., 2005). In case of 
nonresponse:  
− 1st line dose escalation (if appropriate) 
− 2nd line lithium augmentation 
− 3rd line augmentation with 2nd generation antipsychotics or evidence-based 
combinations of antidepressants 
− 4th line change of antidepressant. 
Only the following psychopharmacological rescue medication may be prescribed during the 
course of the study: 
− Zopiclone (on demand up to 7.5 mg/day orally) or Quetiapine (on demand up to a dose 
of 50 mg/day orally) for sleep disturbances.  

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− Promethazine (on demand up to 75 mg/day orally) or Quetiapine (on demand up to 50 
mg/day orally) for agitation. 
 
After discharge from inpatient setting or dayclinic, all patients will continue on their last 
medication, which may be further optimized according to the S3-Guideline (DGPPN et al., 
2015) if needed during continuation treatment. Medication is documented in the eCRFs and 
will be treated as covariates in the final efficacy analysis. 
 
9.10. Study Sites  
The participating sites that were selected by the Coordinating Investigator have adequate staff 
and experience in treating overall 400 patients and in conducting clinical studies with the same 
or similar indications. The participating sites include experienced psychotherapists and 
physicians and supportive staff with adequate time, the targeted patient population and 
technical expertise to complete the protocol. 
 
9.11. Treatment after end of study   
After the end of the study treatment (i.e. after 16 weeks) a naturalistic follow-up takes place 
for 48 further weeks (12 months). During this time, due to the naturalistic character patients 
may receive any therapy, but CBASP patients should not receive BA therapy and BA patients 
should not receive CBASP therapy. After the end of the study (i.e. after the follow-up), patients 
can receive the other treatment if they are interested and indicated, whereby study staff will 
help to arrange appropriate CBASP or BA treatment places (inpatient or outpatient).  
 
9.12. Study Schedule   
Schedule 
• 
Recruitment period (months): 30 
• 
Study treatment per patient (days): 112 (16 weeks)  
• 
Study duration per patient (days): 448 (64 weeks, incl. follow-up) 
• 
First patient in to last patient out (months): 34 (without follow-up), 46 (incl. follow-up)  
• 
Duration of the entire study (months): 58 
End of the study is defined as “Last Patient Out” and database closure. 
 
In the Figure 4 the preparation, pre-trial visits to and initiation of sites, recruitment, follow-
up, data cleaning/analysis, and amount of funding required at each milestone is summarized.  
 
Figure 4: Diagram reflecting the preparation, pre-trial visits to and initiation of sites, 
recruitment, follow-up, data cleaning/analysis, and amount of funding required at each 
milestone 

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10. Add-on Studies 
In the following, two add-on studies are described, which are used to investigate further 
mediators and mechanisms of change of the two treatment programs. After consenting to the 
main ChangePDD study, the patients are informed about these two add-on studies and can 
then decide whether they want to participate in one or both of the additional studies. 
Participation in these add-on studies is therefore not obligatory for the study patients but 
optional. Thus, the two studies are described separately in this chapter 10. In order to get an 
overview of the design and the instruments when patients participate in both add-on studies 
in addition to ChangePDD, we have adapted Table 2 and Figure 3 accordingly (see 10.3). 
 
10.1. ChangePDD-EMA 
In this add-on study, in addition to the questionnaire-based measurement of symptoms 
described above (see chapter 6), data on affect, interpersonal behavior, social context, and 
loneliness are collected using an EMA (Ecological Momentary Assessment) approach. 
Responsible for this add-on study are Prof. Dr. Stephan Köhler, Dr. Anne Guhn, Prof. Dr. 
Johannes Zimmermann, Dr. Tim Kaiser, Prof. Dr. Philipp Sterzer and Prof. Dr. Eva-Lotta 
Brakemeier. As already mentioned, participation in this supplementary study is optional and 
does not influence inclusion in the main ChangePDD study. The add-ons to the regular study 
design and data analysis are described below. 
 
10.1.1 Theoretical motivation  
 
Compared to healthy controls and patients with episodic depression, PDD patients report 
more hostile-submissive interpersonal styles (Bird et al., 2018). However, there has been less 
research on the “in-the moment assessment” of social experiences in patients in PDD with 
regard to dynamic interplay of affect, interpersonal behavior and social context. Ecological 
Momentary Assessment (EMA) provides an ecologically valid tool to monitor daily experiences 
and its influence on social interaction. Recent research indicates a close relationship between 

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negative affective experiences during social interactions and the perceived effectiveness and 
enjoyment of those experiences at the end of the day (Geyer et al., 2018). In addition, a recent 
non-controlled CBASP study reports less loneliness after 10 weeks of inpatient CBASP 
(Reinhard et al., accepted). To what extent this is specific to CBASP or will also be a 
concomitant effect in BA warrants investigation. 
The ChangePDD trial is particularly suitable to target the assessment of social interactions and 
behavioral activation in PDD patients as well as treatment change through therapeutic 
strategies that target both social interactions (CBASP) and mobility (BA). By the use of a 
smartphone application, participants are asked daily short questions about their current 
mood, interpersonal strength, behavioral activation/avoidance, social stress, and feelings of 
loneliness. This will be done over the course of the ChangePDD trial starting one week before 
admission to the ward and ending one week after the end of the outpatient treatment (see 
figure 5).  
 
 
10.1.12 ChangePDD-EMA study design 
 
In addition to data collection of the main mediators described above (see 6.2: IIP-32-R, BADS 
and actimeter-measured step count) collected during the treatment phase within ChangePDD 
(see Table 2), this add-on study will collect EMA data during three phases: 1) 1 week pre-
treatment, 2) 16 weeks of ChangePDD treatment, 3) one week post-treatment (total 18 weeks 
of EMA data collection). During the pre- and post-treatment weeks, 5 assessments per day are 
conducted and during the main study phase only one assessment per day is conducted (see 
Figure 5).   
 
Figure 5: Study Design ChangePDD-EMA 
 
 
 
Patients will be informed about this add-on study ChangePDD-EMA during study visit 1c, 
where they will sign the informed consent.  
 
The assessment will be conducted via the app “Ethica”. The app “Ethica” is DSGVO-compliant. 
The encryption matches a standard in the industry according to the producers. There will be 
a strict anonymization of the data with a clear division between personal data (meta data; 
accessible only by personnel for technical purposes) and study data (anonymous; accessible 
only by scientists). Participants are able to withdraw their consent at any point, resulting in 
the elimination of their data. At no point in time will assessed data be passed on to third 
parties. The servers on which the data is stored are located in Canada. A detailed description 
of 
the 
data 
protection 
concept 
can 
be 
found 
on 
the 
provider’s 
website: 

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https://ethicadata.com/legal#privacy-policy. Several scientific EMA-studies have been 
conducted via this program worldwide and in Europe. 
Furthermore, the app “Ethica” is compatible with Android and Apple and will be installed on 
the patients smartphone after their informed consent. After completing the study it will be 
deleted. 
 
10.1.2 ChangePDD-EMA data assessment and analysis 
The Interpersonal-Activation-Diary (IAD) was developed following Zimmermann et al. (2019) 
for this add-on study and consists of 23 items (see Table 4). These domains, which include 
interpersonal strength, behavioural activation/avoidance, social stress, and loneliness are 
hypothesized to be mechanisms of change especially of CBASP (interpersonal strength, social 
stress, loneliness) and of BA (behavioural activation/avoidance).  
 
  
During the pre- and post-treatment weeks there will be 5 times daily request for data entry 
between 10 a.m. and 8 p.m. 
• First to fourth survey 
a) 1 item on mood: How are you currently feeling? Response format: visual analogue 
scale with the poles very bad - very good) 
b) 1 item on social context: Where are you right now? Response options: I am alone, I am 
with a family member, my partner, my colleagues, a friend or acquaintance) 
• The last (5th) survey (8 p.m.): IAD + (+ = plus three items).  
 
During the ChangePDD treatment phase the assessment will be once a day in the evening (e.g. 
8 p.m.) containing the IAD.  
 
Table 4 Item overview of the Interpersonal-Activation- Diary (IAD)  
 
No. Construct 
Item* 
 
 
Interpersonal Strength 
1 
„Connect“ 
I liked being with other people. 
2 
“Engage” 
I was more outgoing, in order to get in touch with others. 
3 
“Lead” 
I was able to ask other people for what I wanted. 
4 
“Direct” 
I could fend for myself. 
5 
“Balance” 
I was able to say “no” to others. 
6 
“Restrain” 
I was able to listen and think before acting in relationships. 
7 
“Cooperate” I was cooperative. 
8 
“Consider” 
I felt enriched when I was able to help others. 
 
Activation-Avoidance 
1 
Activation 1 
I was an active person and achieved the goals I set for myself. 

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2 
Activation 2 
I made good decisions regarding which activities I partake in and which 
situations I seek out. 
3 
Activation 3 
I did many and different activities. 
4 
Activation 4 
I am content with the kind and number of activities I did. 
5 
Activation 5 
I did things I enjoy. 
6 
Avoidance 1 
I was mainly focused on avoiding uncomfortable things or fleeing from them. 
7 
Avoidance 2 
There were things to do, which I did not complete. 
8 
Avoidance 3 
I spent a lot of my time thinking about my problems again and again. 
 
Social Stress 
1 
Social Stress  I was ignored, dismissed or rejected by others. 
2 
Social Stress  I was let down by a person close to me. 
3 
Social Stress 
I was accused, criticized or talked down by someone. 
4 
Social Stress  I was used or betrayed by someone. 
 
Loneliness 
1 
Loneliness 
I was alone or had little social contacts. 
2 
Loneliness 
I felt lonely today. 
3 
Loneliness 
I felt excluded today. 
*Note: eight items each on interpersonal strength and behavioral activation and avoidance four items 
on social stress (modified according to Zimmermann et al., 2019) with the addition of another item on 
loneliness from the Personality Dynamics Diary (PDD; Zimmermann et al., 2019) as well as two items 
on loneliness from the Psychological Item Pool for Corona Outbreak (PIPCO; Buecker et al., 2020). 
 
 
Data Analysis 
All data assessed in the context of the ChangePDD-EMA Add-on study will be analyzed using 
Dynamic Structural Equation Models (Asparouhov et al., 2018).  
 
 
 
10.2. Effort Task 
In addition to the goals of the ChangePDD study, in this add-on study moderators and 
mediators of change of BA are examined. These mediators and moderators will be assessed 
by means of combining a behavioral effort task with computational modelling, allowing us to 
estimate mechanisms underlying depressive symptoms and processes assumed to lead to 
change due to BA. The task and design could also allow us to identify predictors of response 
to BA on an individual patient level. Dr. Isabel Berwian, Prof. Henrik Walter, Prof. Quentin 
Huys and Prof. Eva-Lotta Brakemeier are responsible for this add-on study. As already 
mentioned, participation in this supplementary study is optional and does not influence 
inclusion in the main ChangePDD study.  
 

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10.2.1 Theoretical motivation and hypotheses 
Patients with depression show reduced engagement in rewarding activities (APA, 2013). The 
decision to engage in rewarding activities (e.g. going out, meeting friends) compared to 
“depressive” behaviors (staying in bed) can be viewed as a trade-off between the anticipated 
reward and the anticipated effort for each behaviour (Berwian et al., 2020). The reduction in 
rewarding activities seen in depression might hence result from decreased anticipated reward 
or from increased anticipated effort. Behavioral Activation (BA), a widely disseminated first-
line therapy for depression (Lewinsohn, 1974; Nagy et al., 2020) contains component 
interventions that aim to directly address these aspects: planning, scheduling and monitoring 
of rewarding activities. The aim of planning is to ensure activities are realistic and achievable, 
thereby reducing the probability that effort will be spent without achieving a goal. The aim of 
scheduling rewarding activities is to ensure rewards are experienced. Finally, monitoring one’s 
responses and feelings after rewarding activities helps to compare it to earlier expectation of 
effort and reward. The underlying assumption is that the experience of successful planning 
and rewarding activities re-establish reward and effort expectations.  
These 
theoretical 
assumptions 
lead 
to 
the 
following 
two 
core 
hypotheses: 
1) Experience of reward or effort moderates and predicts response to BA.  
2) Anticipation of effort or reward is a mediator of this response.  
As a secondary hypothesis, we suggest:  
1) The above effects are stronger in patients receiving BA compared to patients receiving 
CBASP.  
10.2.2 Task and computational model 
We propose to employ an online physical effort for reward task to mimic decisions and 
behavior of effort and reward.  
Task: The task is illustrated in Figure 5. Participants perform the task online at home on their 
computer, or they can also perform it in the lab on a computer. On each trial, patients need 
to decide between investing little effort (few button presses) for a small reward or more effort 
(more button presses) for a larger reward. Patients need to indicate their decision with the 
first button press within 4 sec and afterwards have 40 sec to execute their effortful behavior 
allowing to measure effort experience. On a subset of trials, participants are asked to rate 
their momentary happiness which we use as a proxy to assess reward experience. The task 
duration is around 25min. The task is written in javascript and can hence be run in any modern 
web browser. The data is saved on a GDPR-compliant cloud server within the EU (Google 
Firebase). Data will be pseudonymized throughout.  
Analysis: To disentangle and quantify anticipation and experience separately for effort and 
reward we employ a generative computational model that captures the entire decision- 
making process. The model computes the values of a high effort/reward and a low 
effort/reward option including parameters relating to the effort and reward sensitivity 
implemented as a trade-off between necessary effort and the resulting reward (anticipation), 
the vigour used to execute the effortful behavior and the reaction to the reward (experience). 
The computed values are fed into a softmax function to determine the probability of making 

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a high effort/reward choice (Niv et al., 2007; Huys et al. 2013; Hauser et al., 2017; Berwian et 
al., 2020).  
In our previous work (Berwian et al., 2020), we could show with the application of a 
computational model to the data collected by means of an earlier version of the task, that 
remitted, previously depressed, patients invested less effort for reward due to increased 
effort anticipation and that longer decision times prior to discontinuation (captured by larger 
boundaries in a drift-diffusion model) predicted later relapse better than chance in a 
validation sample. Hence, the task is established, could be used to disentangle effort 
anticipation and experience in a patient sample and provided robust effects. Based on our 
experience, we optimized the task as described above and established its validity by means of 
pilot data from healthy controls.  
Analyses will be pre-registered. Moderation and mediation will be analyzed with linear mixed 
models with covariates x time x group interactions and mediation with dynamic panel models 
as outlined in the study protocol. Prediction will be examined using logistic regression in 
combination with an elastic net. The data will be split in advance into a training and validation 
sample.  
Figure 5: Physical effort for reward task 
 
10.2.3 Study design 
The study design of the ChangePDD study is already established and depicted in Table 2. The 
additional task will be conducted at T1, T2, and T4 (V2, V5, and V11; see Table 2add-on). Data 
collected at T1 allows us to test hypothesis 1, while data collected at T2 and T4 allows us to 
assess hypothesis 2. 
In addition, we will collect data with the task in matched healthy controls at T1 and T4. The 
healthy controls will be recruited in the context of the MAPPDD study. In the MaPPDD study, 

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144 healthy controls will be recruited using the infrastructure and funding already provided 
by the main study ChangePDD. Healthy controls will be recruited at the same six recruiting 
sites as the patients in ChangePDD. Each site will recruit 24 healthy controls, respectively. 
Screening will be performed to ensure that healthy controls are matched with patients 
regarding age and gender so that the healthy controls do not differ significantly from the PDD 
patients in the group comparison. 
10.3. Study design and instruments supplemented by add-on studies 
In order to get an overview of the design and the instruments when patients participate in 
both add-on studies in addition to ChangePDD, we have adapted Table 2 and Figure 3 
accordingly. 
 
Table 2add-on: Frequency and scope of trial visits of ChangePDD and the two add-on studies 
 
 
 
 Note. Primary endpoint is marked red; * V1 is divided into V1a to V1d (see Figure 3); ** Randomization will be performed 
between T0/V1 and T1/V2; *** Blinded observer ratings; ****In week pre and week 6, the IAD + (+ 2 items) will be used; 
***** Two crosses per cell because the questionnaire RevieW is done weekly 
 
 
 
 
 
 
 
 

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Figure 3add-on: Detailed Screening Flow supplemented by the two add-on studies 
 
 
11. Safety 
11.1. Adverse reactions 
Adverse Event (AE) is defined as any disadvantageous incident that occurs a person receiving 
either psychotherapeutic intervention, regardless of possible associations with the treatment 
received.  
The following AES are defined for the study ChangePDD: 
− 
Exacerbation of symptoms, e.g., generalization of symptoms 
− 
Appearance of new symptoms 
− 
Appearance of passive suicidal thoughts 
− 
Appearance of active suicidal plans or intentions 
− 
Occurrence of problems in the patient-therapist relation 
− 
Further disadvantageous incidents as assessed by the therapist 
Adverse Treatment Reaction (ATR) is defined as any AE due to a received treatment. The 
decision on the causality of AEs is made by the therapists and is supervised and controlled by 
the PI and Co-PIs and the DMC.  
 
Serious Adverse Events (SAE) and Serious Adverse Treatment Reactions (SATR) are defined 
as an AE or ATR resulting in:  
− 
Death 
− 
Life-threatening event, e.g. suicidal attempt 
− 
An incident requiring hospitalization 

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− 
An incident leading to significant or permanent disability or invalidity.  
(S)AEs and (S)ATRs are documented after each study treatment session (see 9.7 and 9.8) using 
an Adverse Event eCRF. In the eCRF, the corresponding therapist is asked to describe any 
adverse event, its duration (start/end date), intensity (mild, moderate, severe), assessment of 
causality (treatment related, probably related, unlikely related, not related, not assessable), 
the actions taken and the outcome of the action taken. In addition, the corresponding 
therapist is asked to assess whether the documented AEs and ATRs are judged serious (SAE, 
SATR).  
In case of changing the individual therapists, the reasons for this change are documented in a 
separate form.  
Adverse Event documentation is monitored during the study as part of the regulatory 
Monitoring conducted by the KKS Greifswald.  
SAEs and SATRs must be reported electronically (via fax or e-mail) to the PI and the KKS 
Greifswald immediately within 24 hrs using a Serious Adverse Event report form that provides 
further details on the incident.  
Patients who withdraw from study interventions due to one or more of the above mentioned 
reasons will be followed up in accordance with good clinical practice until a solution is found 
or the event is no longer considered clinically significant. 
 
11.2. Risk-benefit-assessment 
11.2.1. Potential risks 
As all patients are treatment-resistant and there is no placebo group, ethical concerns seem 
limited. Study participants will be treated with methods for which efficacy has been 
demonstrated in prior studies in severely depressed patients. The in/exclusion criteria were 
chosen to minimize the risks to patients.  
However, in any psychotherapeutic treatment, there can be a temporary burden of actively 
dealing with topics discussed in the therapy sessions and possibly avoided so far. Under 
certain circumstances this can lead to the occurrence or increase of suicidal tendencies 
(suicidal thoughts or plans). Patients are regularly questioned on the subject of suicidal 
thoughts; in addition, they are asked to contact the study staff or appropriate emergency 
services at any time if they have suicidal thoughts.  
Completing the questionnaires and conducting the interviews throughout the study 
(especially at the beginning) can also be potentially stressful for patients. 
Patients are asked to immediately report any deterioration in their health status to the study 
staff, regardless of whether it is related to the scientific study. During the inpatient stay, 
patients can visit therapists from their treatment team at any time and during the dayclinic 
phase they can contact study staff (contact details are provided on the study information 
sheet). If stress becomes too great, patients can stop filling out questionnaires, conducting 
interviews or even participating in the entire study at any time without experiencing any 
disadvantages. If the study is discontinued, the patients will continue to be treated in the clinic 
as a 'non-study patient' according to the indication.  
During the clinical trial, patients are also given a one-time blood sample (approx. 10 ml). The 
taking of a blood sample is usually associated with a very low risk. There may be slight pain at 
the puncture site or bruising, which may be visible for a few days. In extremely rare cases, a 
blood clot may form (thrombosis), a localised inflammation or infection may occur at the 
puncture site, or permanent damage to blood vessels or nerves may occur. 

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The DMC will monitor safety issues every 6 to 12 months. The informed consent process will 
be carefully conducted.  
 
11.2.2. Potential benefit 
In this study, two psychotherapy programs (CBASP and BA) are examined with regard to their 
effectiveness in treating PDD with TR. It is known that both therapies have a positive influence 
on PDD. Whether one of the two therapies is better than the other in this indication is to be 
found out with this study. By participating, the study patients generally make a valuable 
scientific and health policy contribution to improving inpatient psychotherapy concepts in the 
short and long term. 
The following concrete advantages and opportunities may also result from participation in the 
study for study-patients:  
− 
Shortening of the waiting time until admission to the clinic 
− 
Valuable and comprehensive diagnostics of the individual problems during the entire treatment 
− 
An intensive psychotherapeutic inpatient and dayclinic depression treatment  
− 
Participation in an outpatient group therapy after discharge to maintain the success and to prevent 
relapse  
− 
Being part of a larger scientific study with close supervision by trained staff who are always 
available to patients  
The overall results of this scientific study should contribute to finding an effective treatment 
for the group of PDD patients with treatment-resistance and increase the allocation of the 
patient to the individually more suitable therapy approach.  
With regard to the health policy perspective, the following potential benefits should be 
pointed out: Considering the seriousness of the disease with its high risks for suicidality, low 
response to standard treatments as well as the enormous economic burden of an estimated 
1 billion € annually in Germany, new evidence-based treatment programs are urgently needed 
to overcome TR and severely improve the current treatment of patients with PDD. The results 
provided by this study then have the potential to enable the establishment of the inpatient 
CBASP program in Germany (as well as other countries) and thereby vastly improving the 
current treatment of this serious disease. 
 
11.2.3. Conclusion 
In view of the limited ethical concerns and potential risks mentioned and the continuous 
monitoring of safety issues, the overall potential risks in conducting the study appear to be 
low. Therefore, the described benefits of conducting the study, which have the potential to 
provide the results needed to significantly improve the current treatment of severe PDD with 
treatment-resistance, will outweigh the costs and potential risks.  
 

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11.3. Discontinuation criteria 
11.3.1. Premature discontinuation of a patient 
In accordance with the Declaration of Helsinki, the patient’s participation in the study is 
voluntary and each patient may withdraw from the study at any time without giving reasons 
for this decision. The decision to withdraw from the study treatment must be without any 
prejudice for the patient. 
Study treatment of a patient may be terminated by the investigator for one or more of the 
following reasons: 
− 
Active suicidality 
− 
Physical health of the patient is a risk due to clinical judgement 
− 
Occurrence of an AE/SAE (Averse Event/Serious Adverse Event) with therapeutic implications 
− 
A newly emerging exclusion criterion 
− 
Withdrawn of the informed consent 
− 
Non-compliance with the study protocol 
If the investigator terminates the treatment of the patient prematurely, he has to inform the 
patient about his decision and has to record the primary reason for withdrawal in the patient 
file and to document the end of treatment in the eCRF. If the patient caused the premature 
withdrawal the data collected before termination may be used if the patient agrees and an 
informed consent for follow up is signed by the patient. 
 
11.3.2. Premature discontinuation of the study 
Single site 
If a Leading Investigator has ethical concerns because of the performance at one of the sites, 
the Coordinating Investigator (PI) and the Co-PIs must be informed immediately.  
The Coordinating Investigator together with the KKS Greifswald are authorized to discontinue 
this study at any time in any single site. Possible reasons for termination of the site could be 
but are not limited to: 
− 
Unsatisfactory enrollment with respect to quantity or quality 
− 
Inaccurate or incomplete data collection 
− 
Unexpected accumulation of safety issues 
− 
Major failure to adhere to the study protocol 
Study as a whole 
The Coordinating Investigator together with the KKS Greifswald have the right to terminate 
this clinical study as a whole at any time. Possible reasons for termination of the study could 
be but are not limited to: 
− 
Unexpected accumulation of safety issues 
− 
Change of risk-benefit considerations 

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A premature discontinuation of a single site or of the study as a whole must be documented 
adequately with reasons being stated and information must be conveyed according to 
national requirements (e.g. Ethics Committee). 
 
11.4. Data Monitoring Committee (DMC) 
A Data Monitoring Commitee (DMC) has been established for this study consisting of one 
psychologist (Prof. Dr. Matthias Berking), one psychiatrist (Prof. Dr. Stefan Röpke), and one 
biostatistician (Prof. Dr. Michael Eid) – all highly experienced researchers in the field of clinical 
trials. The function of the DMC is to monitor the course and progress of the study against the 
predefined milestones and – if necessary – to give recommendations to the study 
administration for discontinuation, modification, or continuation of the study. The underlying 
principles for the DMC are ethical and safety aspects for the patients. It is the task of the DMC 
to examine whether the conducting of the study is still ethically justifiable, whether security 
of the patients is ensured, and whether the process of the study is acceptable. For this, the 
DMC is informed about the adherence to the protocol, patient recruitment, and the observed 
adverse events. The DMC will meet three times: 1) 6 months after "first patient in", 2) 18 
months after "first patient in" and 3) 30 months after "first patient in", which should 
correspond to "last patient in" according to the study plan.   
The outcome of the meetings is communicated to the Trial Steering Committee and the 
Leading Investigators of each site  so that any administrative action required can be 
implemented. 
In addition, Prof. Dr. Pim Cuijpers, Prof. Dr. Giovanni Fava, and Prof. Dr. Martin Hautzinger 
constitute the international Scientific Advisory Board (SAB). Due to their excellent expertise in 
conducting and analyzing clinical trials, they have been invited for providing independent 
advice and consulting regarding scientific, ethical, and data security issues, the dissemination 
process and external developments that are relevant to the progress and impact of the 
project. 
12. Ethical and regulatory aspects 
12.1. Laws and regulations 
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of 
human patients. The study will be conducted in compliance with the guidelines of GCP and 
the 
applicable 
national 
laws 
and 
regulations 
(Berufsordnung 
der 
Ärzte 
und 
Psychotherapeuten) to assure that the rights, safety, and well-being of the participating 
patients are protected consistent with the ethical principles that have their origin in the 
Declaration of Helsinki. 
12.2. Independent ethics committee 
The study will only be started after consultation with the responsible ethics committee and 
only if there are no ethical concerns. The principal investigator (Prof. Dr. Brakemeier) is 
responsible for submitting the application to the Ethics Committee. 
12.3. Changes to the study protocol 
After the commencement of the clinical study, the Coordinating Investigator may amend the 

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protocol. If those amendments are substantial and are likely to have an impact on the safety 
of the study patients or to change the interpretation of the scientific documents in support of 
the conduct of the study, or if they are otherwise significant, the Coordinating Investigator 
shall notify the involved ethics committees. 
If the opinion of the Ethics Committee is favourable the Coordinating Investigator shall 
proceed to conduct the clinical study following the amended protocol. 
Amendments will be signed by all signatories of the protocol. All investigators will 
acknowledge the receipt and confirm by their signature on the amendment that they will 
adhere to the amendment. A copy of the signature page will be filed in the Investigator Study 
the original will be filed in the Trial Master File. 
12.4. Informed consent and insurance 
A patient can only be included to the study if he/she has given his/her consent. A 
physician/therapist has to inform the patient verbally and in written form about the nature, 
meaning and scope of the study in an appropriate and understandable manner. The patient 
must have had sufficient time to make the decision. At the same time, with the consent, 
he/she must have declared that he/she agreed to the data being recorded as part of the study. 
The patient is informed that he/she can withdraw his/her consent at any time and without 
giving reasons without incurring disadvantages. If new information emerges during the course 
of the study that could influence the patient's willingness to participate, the Informed Consent 
Form will be changed accordingly. The patient is informed of the changes by a 
physician/therapist. Subsequently (assuming sufficient time to consider), the consent of the 
investigating physician/therapist and the patient must be signed again. An original of the 
patient's written information and consent is given to the patient. A second original is kept safe 
at the study site in the Investigator Site File (ISF).  
During the study, no additional invasive or stressful examinations are carried out. The course 
of the study corresponds to the clinical routine. There are no study-related risks for the 
patient. Accordingly, it is not planned to take out subject insurance. An accident insurance is 
taken out for all patients for their dayclinic visits and the subsequent follow-up visits. 
12.5. Data safety 
The provisions of the data protection laws (EU-DSGVO) are observed. It is ensured that all 
examination data are pseudonymized adequately in accordance with the data protection 
regulations before scientific exploitation. An assignment of the personal data to the study data 
is only possible by the locally responsible study physician/therapist. 
The study management (Prof. Dr. Eva-Lotta Brakemeier) receives the pseudonymized study 
data only for the purpose of scientifically evaluating the observational study. Exceptions to 
this are the video-based data of psychotherapies, which are used as described for supervision 
purposes, the CAR Ratings and research (concerning psychotherapy and depression research). 
13. Statistics 
13.1. Sample size 
Analysis populations 
The Intent-to-treat (ITT) population will be defined as all patients randomized, regardless of 
whether they actually received treatment.  

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The Per Protocol (PP) population will be a subgroup of the ITT population that includes all 
patients who have been included in the trial, have no major protocol violation and who have 
participated in at least 16 individual sessions and 16 group therapies. 
Safety population 
The safety population will be defined as all patients randomized who received at least one 
session of CBASP or BA. 
Sample size 
Power calculation was based on a simulation study as recommended for linear-mixed effects 
models (Gelman & Hill, 2007). We intended the sample size to be large enough so that the 
power to detect a difference in the changes between treatments (CBASP vs. BA) of at least 3 
HDRS points after 16 weeks is roughly 90% (assuming alpha = .05). This target effect size is in 
line with the NICE guidelines (Middleton et al., 2005), stating that a difference between groups 
of at least three points on the HDRS (and only two points for depression with TR) is clinically 
relevant. This also corresponds to Schramm et al. (2017) reporting a significant difference 
between CBASP and nonspecific psychotherapy of 2.5 on the HDRS after 20 weeks of 
outpatient-treatment (d = 0.31). Notably, this criterion is also supported by our CBASP meta-
analysis that showed a significant combined overall effect size of small to moderate magnitude 
of CBASP versus other treatments or treatment as usual (TAU) (g = 0.34–0.44) (Negt et al., 
2016). For the simulation study, Schramm et al. (2017) has been followed, in defining time as 
log transformed weeks after treatment onset and set the target treatment x time interaction 
effect to γ = 1.06 (=3/log(16+1)). The remaining parameter values (e.g., random variances and 
covariance) were selected according to the results of Schramm et al. (2017), who shared their 
original HDRS data with us. Given these parameter values, the expected standard deviation of 
HRDS scores after 16 weeks is SD = 8.85, and thus the target effect of three HRDS points 
corresponds to a standardized effect of d = 0.34. Moreover, it is assumed that each person is 
assessed four times across the 16 weeks interval. A 14% dropout at primary endpoint is 
expected (assuming a linear increase of missing data across time). Given these parameters, 
the simulation (performed with the statistical platform R using 2000 resamples) suggests that 
a total sample size of N = 396 yields a power of 90% to detect the target interaction effect. 
Note that this estimate already takes into account that we expect about 14% missing data at 
the primary endpoint (i.e., after 16 weeks). Simulations including effects of covariates (e.g., 
recruitment sites) result in virtually identical estimates. 
 
13.2. Statistical evaluation 
13.2.1. Primary endpoint 
Differences in HDRS-24 change between experimental (CBASP) and control (BA) group will be 
analyzed using a linear mixed-effects model (LMM). In particular, the HDRS-24 scores across 
the 16 weeks will be predicted from log transformed time (i.e., weeks after treatment onset), 
treatment group, and their interaction. To account for unexplained individual differences in 
baseline status and rate of change, (correlated) random coefficients for the intercept and 
slope will be included. A p value <0.05 is considered to be significant. To consider the influence 
of strata (depression severity and participating site) and possible confounders (e.g., age, 
gender), the effect of respective baseline values will be explored (including interaction effects 
with time and treatment group). The primary analysis will be conducted in the intention-to 
treat (ITT) population using maximum likelihood estimation (ML) taking into account all 
available data points. ML yields accurate parameter estimates if values are missing at random 

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(MAR; i.e., values are missing at random conditional on other information in the model). 
Sensitivity analyses (including pattern mixture models; Hedeker & Gibbons, 1997) will be 
conducted to test whether the assumption that values are MAR is tenable. In case that 
missingness depends on other observed variables not included in the statistical model, a 
multilevel multiple imputation approach will be used (Enders et al., 2016). In case of 
nonnormally distributed residuals or heteroscedasticity, robust standard errors or, if 
appropriate, robust LMM will be used (Koller, 2016). Additionally, a per protocol analysis will 
be conducted to compare the results with the ITT population. Other details of the statistical 
analysis will be fixed in the Statistical Analysis Plan, to be prepared before start of the study 
(first patient in). All statistical analysis will be done with the software R (current version: 3.6.3) 
and Mplus (current version: 8.4). 
13.2.2. Secondary endpoints 
Secondary endpoints will also be analyzed with (generalized) LMM. Moderator variables will 
be evaluated within these models by including interaction effects of moderator baseline 
values with time and treatment group. Mediator variables will be evaluated using dynamic 
panel models (Falkenström et al., 2017).  
13.2.3. Safety and tolerability endpoints 
Safety analyses will be performed for all patients having started one of the treatments. 
Patients will be analyzed according to treatment received. Rates of adverse events and SAEs 
will be calculated with corresponding two-sided 95% confidence intervals. 
13.2.4. Handling of dropouts 
It is expected that 5% of the patients will drop out of the study directly after the 
randomization, and further 10% will drop out during treatment. Therefore, we expect 95% x 
90% = 85.5% of randomized patients to have HDRS-24 non-missing in week 16. All available 
data points will be used to estimate model parameters using maximum likelihood estimation. 
Thus, we will include earlier data points from patients who drop out of the study as long as 
they do not withdraw consent. Moreover, all efforts will be made during the informed consent 
procedure to include only patients who are willing to accept both arms and to continue study 
visits until W64/T5 irrespectively of compliance.  
The dropout patients receive the standard treatment of the corresponding ward, so that 
clinically there are no disadvantages for the patients due to a dropout. 
14. Data Management 
14.1. Data collection 
All data on patients collected in eCRFs and CRFs during the course of the study will be 
documented pseudonymously, i.e. the patient will be identified only by the pseudonymized 
identification number. Investigator must ensure that the patient’s encryption is maintained. 
The patient identification list should be kept in strict confidence at the study site in the ISF. 
The investigator at each study site is responsible for keeping the identification list and 
informed consent forms locked up. 
Most of the information required by the protocol and collected during the trial is entered 
directly into the eCRF electronically by patients or by the investigators or a designated 
representative. Some information required under the protocol that cannot be entered directly 

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into the eCRF electronically is entered into the CRF by the investigators or a designated 
representative.  
The investigator will maintain a list of individuals authorized to enter or correct data (study 
delegation log).  
14.2. Data processing 
14.2.1 EDC-System (eCRF)  
The data of the patients are documented within the EDC (Electronic Data Capture) system 
eHealth-Platform. Data will be entered by study personnel as well as directly by patients. The 
data of the actimeter are read from the clock during the bi-weekly study visit and entered into 
the eCRF by the study personnel (rater). Data are entered directly via web browser to the 
eCRF. Detailed instructions for using the EDC system are specified in the EDC Manual, which 
is part of the ISF. 
In order to use the EDC system all staff who are entering and monitoring data are provided 
with training materials and required documentation by the KKS Greifswald. All data which are 
collected during the trial have to be documented in the eCRF by authorized persons according 
to the Delegation log. Specific user roles within the system enforce accordance with the 
Delegation Log. 
The EDC system has an implemented audit trail. This assures that any documentation and/or 
changes to database items are traceable anytime. Changes or corrections are permitted to 
authorized persons who have access to the system with user specific access rights. This access 
is documented in the audit trail. Users with monitoring function are not able to enter or 
change patient’s data. They have the possibility to view the data write protected (review 
function) and they can create SDV marks in case of queries. Discrepancies which appear at 
data management are forwarded to the monitors or to the site directly. 
 
14.2.2 Data concealment for electronic transfer 
The eHealth-Platform uses personalized certificate to ensure authorized access. Stored data 
are further secured with regular backups. At the end of study, the database will be closed after 
data cleaning process. 
 
14.2.3 Data discrepancies 
In a multistage procedure, the obtained data will be checked electronically for their plausibility 
and consistency. Detected inconsistencies and missing or implausible data will be clarified 
with queries and necessary changes will be carried out.  
 
14.2.4 Registration 
Before recruitment and data collection starts, the trial will be registered at Clinical trials 
(http://clinicaltrials.gov) and DRKS (www.germanctr.de). Prof. Dr. Eva-Lotta Brakemeier is 
responsible for the first registration and following updates. 
 

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14.2.5 Publication 
The study results are presented at scientific symposia and published in international journals 
according to the criteria of the CONSORT declaration, regardless of the result. At least within 
one year after completion of the study, the main manuscript will be completed for publication. 
Any formal presentation or publication of data collected as a direct or indirect result of this 
study will be considered by the investigators as a joint publication. It therefore requires the 
agreement of the Coordinating Investigator and the Co-Principal Investigators. The authorship 
will be determined by mutual agreement. 
The results of this study may be presented at scientific symposia or published in a scientific 
journal only after review and written approval by the Coordinating Investigator and the Co-
Principal Investigators. The Investigators of the participating centers agree not to make 
presentations based on data collected individually or from a subset of centers prior to the 
publication of the first main publication, unless otherwise agreed by all other investigators, 
the Coordinating Investigator, and the Co-Principal Investigators.  
The Coordinating Investigator, the Co-Principle Investigators and all Leading Investigators will 
receive copies of all communications, presentations or publications within a reasonable time 
in advance (at least 10 working days for an abstract or oral presentation material and 35 
working days for a manuscript). These guidelines are provided to check the communications 
for accuracy, to ensure that confidential information is not inadvertently disclosed, to allow 
for appropriate input or additional information that may not have been available to the 
Investigator, and to allow for co-authorship.    
 
14.2.6 Open Data 
In accordance with the Open Science specifications of the German Psychological Association 
(DGPs), anonymized data is made available to the public via the Open Data portal of the Open 
Science Foundation (ww.osf.io). The data will be stored when data collection is completed, 
but not before 01.01.2028. This step allows third parties to reproduce the analyses reported 
in scientific publications and to perform ad hoc analyses. The data is permanently stored on 
servers located in Germany. As soon as they are uploaded and published, these anonymized 
data cannot be deleted and are therefore also excluded from the deletion of the data in case 
of revocation of the study participation. 
 
14.3. Quality assurance and quality control 
14.3.1. Source data and subject files 
The investigator has to keep a written or electronic subject/patient file for every subject 
participating in the clinical study. In this file, the available demographic and medical 
information of a subject has to be documented, in particular the following: name, date of 
birth, sex, height, weight, subject history, concomitant diseases and concomitant drug 
(including changes during the study), statement of entry into the study, study identification, 
subject number, the date and process of informed consent, all study visit dates, predefined 
performed examinations and clinical findings, observed (S)AEs (if applicable), and reason for 
withdrawal from the study if applicable. lt must be possible to identify each subject by using 
this patient file. 

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Additionally, any other documents with source data, especially original printouts of data that 
were generated by technical equipment have to be filed. All these documents have to bear at 
least subject identification and the printing date printed by the recording device to indicate to 
which subject and to which study procedure the document belongs. The medical evaluation 
of such records should be documented as necessary and signed/dated by the investigator. 
 
For the current study, documents considered to be source data include (but are not limited 
to): 
• 
Patient’s record (patient’s clinic and/or office chart, hospital chart). 
• 
Patient Informed Consent Form 
• 
Laboratory results 
• 
Pharmacy records 
• 
Treatment notes 
• 
Scores 
• 
Any other records maintained to conduct and evaluate the clinical study 
 
14.3.2. Monitoring  
During the course of the study each participating site will be visited for monitoring before, 
during and after the study. During each of these visits, source data verification will be 
performed based on the monitoring plan, generated by the KKS Greifswald. The monitoring of 
the study takes place by the trained staff of the KKS Greifswald. Content, amount and details 
of the monitoring visits are described in the monitoring plan. Additionally, on-site and remote-
monitoring visits are defined. 
In general, any discrepancies in the data collection should be discussed and clarified with the 
study team during the monitoring visit and corrections/additions should be done according to 
GCP requirements.  
All Monitoring visits are documented according to KKS-specific SOPs. 
15. Literature 
Angermeyer, M. C., Kilian, R., & Matschinger, H. (2000). WHOQOL-100 und WHOQOL-BREF. 
Handbuch für die deutschprachige Version der WHO Instrumente zur Erfassung von 
Lebensqualität. Hogrefe. 
Angst, J., Gamma, A., Rössler, W., Ajdacic, V., & Klein, D. N. (2009). Long-term depression 
versus episodic major depression: Results from the prospective Zurich study of a 
community sample. Journal of Affective Disorders, 115(1–2), 112–121. 
https://doi.org/10.1016/j.jad.2008.09.023 
Asparouhov, T., Hamaker, E. L., & Muthén, B. (2018). Dynamic Structural Equation Models. 
Structural Equation Modeling: A Multidisciplinary Journal, 25(3), 359–388. 
https://doi.org/10.1080/10705511.2017.1406803 
Association, A. P. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). (American 
Psychiatric Pub, 2013). 
Bach, B., Kerber, A., Aluja, A., Bastiaens, T., Keeley, J. W., Claes, L., Fossati, A., Gutierrez, F., 
Oliveira, S. E. S., Pires, R., Riegel, K. D., Rolland, J.-P., Roskam, I., Sellbom, M., Somma, A., 
Spanemberg, L., Strus, W., Thimm, J. C., Wright, A. G. C., & Zimmermann, J. (in press). 
International assessment of DSM-5 and ICD-11 personality disorder traits: Toward a 
common nosology in DSM-5.1. Psychopathology. https://doi.org/10.1159/000507589  

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Bajbouj, M., Aust, S., Spies, J., Herrera-Melendez, A.-L., Mayer, S. V., Peters, M., Plewnia, C., 
Fallgatter, A. J., Frase, L., Normann, C., Behler, N., Wulf, L., Brakemeier, E.-L., & Padberg, 
F. (2018). PsychotherapyPlus: Augmentation of cognitive behavioral therapy (CBT) with 
prefrontal transcranial direct current stimulation (tDCS) in major depressive disorder—
study design and methodology of a multicenter double-blind randomized placebo-
controlled trial. European Archives of Psychiatry and Clinical Neuroscience, 268(8), 797–
808. https://doi.org/10.1007/s00406-017-0859-x 
Beesdo-Baum, K., Zaudig, M., Wittchen, H.-U., (2019). Strukturiertes Klinisches Interview für 
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