Process-based Therapy vs. Routine-CBT for Difficult-to-treat Anxiety Disorders and Depression
Phase: NA
Conditions: Depression, Anxiety Disorder
Sponsor: Goethe University

Title page 
Process-based Therapy vs. routine-CBT for difficult-to-treat mood and anxiety disorders: 
Study protocol for a randomized controlled trial 
 
 
Names protocol contributors 
Ulrich Stangier stangier@psych.uni-frankfurt.de, Viktoria Kohl v.kohl@psych.uni- 
frankfurt.de, Nora Görg goerg@psych.uni-frankfurt.de, Lucie Sendig sendig@psych.uni- 
frankfurt.de, Bettina Hufschmidt b.hufschmidt@psych.uni-frankfurt.de, Desiree Bonarius 
bonarius@psych.uni-frankfurt.de, Arwin Nemani nemani@psych.uni-frankfurt.de, Mareike 
Ebert ebert@psych.uni-frankfurt.de & Stefan G. Hofmann stefan.hofmann@uni-marburg.de 
All authors at: Institute for Psychology - Department of Clinical Psychology and 
Psychotherapy, Goethe University Frankfurt, Varrentrappstr. 40-42, 60486 Frankfurt am 
Main, Germany; except: Stefan G. Hofmann, Department of Clinical Psychology and 
Psychotherapy, Philipps University Marburg, 12, 35037 Marburg/Lahn, Germany 
 
 
Paper submitted to: Trials 

Abstract 
 
Background: 
 
Process-based Therapy (PBT) is a new framework to intervention planning, based on the use 
of ecological momentary assessment (EMA) data and dynamic and idiographic network 
analyses. Support for its applicability has been reported from a single-case studies. Here, we 
examine the feasibility and effectiveness in a larger clinical sample. We have translated a 
Training Manual of PBT and modified for delivery of CBT in Mental Health Service. The aim 
of this study is to test the relative efficacy of PBT compared to traditional CBT delivered in 
routine practice (r-CBT) for difficult-to-treat mood and anxiety disorders. 
Methods: 
 
The study is a randomized controlled trial (RCT) of PBT vs r-CBT for difficult-to-treat 
unipolar depression and anxiety disorders. In total, 80 patients are recruited at an outpatient 
clinic and included in two intervention arms. 
Primary outcome is emotional distress, secondary outcomes include psychological well-being 
and quality of life, adaptive behavior, psychological flexibility, and reflective functioning. 
Assessments of outcome variables are conducted before and after therapy and at 6 months 
follow-up. Weekly patient-rated outcomes are collected for every session to investigate 
process of change. Outcome assessors, blind to treatment allocation, will perform the 
observer-based symptom ratings, and adherence with manual will be monitored using self- 
report. 
Discussion: 
 
The current study will be the first RCT of PBT in a health care setting. The planned 
moderator and mediator analyses will clarify the mechanisms of change in psychotherapy and 

the association between personalized assessment based on dynamic network analysis and 
treatment effect. 
 
 
Trial registration: 
 
Clinicaltrials.gov JWGUniversity record III L5-519/05.000.002. Registered 27 June 2024 
 
Keywords 
Process-based Therapy, dynamic network analysis, difficult to treat depression, cognitive 
behavioral therapy, randomized controlled trial 
Administrative information 
 
Title {1} 
Process-based Therapy vs. routine-CBT for difficult-to-treat mood and 
anxiety disorders: Study protocol for a randomized controlled trial 
Trial registration {2a 
and 2b}. 
Clinicaltrials.gov JWGUniversity record III L5-519/05.000.002. 
Registered 27 June 2024 
Protocol version {3} 
Research protocol, version 02, 23. July 2024. 
Funding {4} 
This work is funded by the LOEWE Top Professorship for Stefan G. 
Hofmann of the Hessian Ministry of Science and Arts. 
Author details {5a} 
Ulrich Stangier, Viktoria Kohl, Nora Görg, Lucie Sendig, Bettina 
Hufschmidt, Desiree Bonarius, Arwin Nemani, Mareike Ebert: 
all Department of Clinical Psychology and Psychotherapy, Goethe 
University Frankfurt, Varrentrappstr. 40-42, 60486 Frankfurt am Main, 
Germany 

Stefan G. Hofmann, Department of Clinical Psychology and 
Translational Psychotherapy, Philipps University Marburg, Schulstr. 12, 
35037 Marburg/Lahn, Germany 
Name and contact 
information for the 
trial sponsor {5b} 
Prof. Dr. Ulrich Stangier, Varrentrappstr. 40/42, D-60486 Frankfurt; email: 
stangier@psych.uni-frankfurt.de 
Role of sponsor {5c} 
Ulrich Stangier: Principal Investigator of the trial. Stefan G. Hofmann: funder 
and Co-Principal Investigator. Study design, interpretation of data. Writing 
of the report. Decision to submit the report for publication. 
Viktoria Kohl, Nora Görg, Lucie Sendig, Bettina Hufschmidt, Desiree 
Bonarius: trial management and data collection., Writing of the report. 
Arwin Nemani, Mareike Ebert : analysis of data. Writing of the report. 

Introduction 
Background and rationale {6a} 
 
Unipolar depression and anxiety disorders represent the most common mental health 
problems encountered in mental health care [1]. These conditions frequently lead to 
prolonged suffering, psychosocial impairment, and substantial socio-economic burdens [2]. 
Thus, it is of major interest to optimize the efficacy of treatments in mental health services for 
these disorders. 
The results of recent meta-analyses show that CBT is effective for both depression C[3] and 
anxiety disorders [4]. However, it has become evident that remission rates following CBT for 
depression and anxiety disorders on average still remain slightly under 50% [5], and there has 
been a debate about the stagnating outcomes of CBT in depression [6] and anxiety disorders 
[7]. This highlights the importance of optimizing the efficacy of CBT. 
One promising way to improve outcome is to personalize treatment by matching the specific 
mechanisms underlying psychological treatment to the psychological processes contributing 
to the psychological dysregulation of the individual patient. The process-based approach [8] 
focuses on this principle by gathering individual data through ecological momentary 
assessments that are used to develop idiographic dynamic networks to identify the key 
process maintaining the maladaptive pattern [9], and by choosing interventions which target 
change processes matching to this key process [10]. In contrast to a latent disease model, 
which assigns symptoms to an underlying disease, a disorder is seen as an individual network 
of interacting processes that is maladaptive in specific contexts [11]. However, in an extended 
evolutionary meta-model, context-bound psychological processes, instead of symptoms, are 
captured in an ideographic network on different psychological dimensions [12] and change 
processes are conceptualized according to the basic evolutionary principles of variation, 
selection and retention [13]. Furthermore, in contrast to syndrome-based treatment packages, 

interventions are chosen according to the change processes which have been empirically 
supported in mediational analysis of RCTs [14]. 
Given the increased effort needed for the personalization, process-based therapy appears 
especially relevant for patients who do not respond to empirically supported treatments. In 
psychiatric care, treatment-resistance is defined as a non-response to an adequate treatment 
given a correct diagnosis [15]. However, there is a large variety of definitions about the 
number and type of unsuccessful treatment attempts required to meet the criteria for 
treatment-resistance, in particular for treatment of depression [16]. To avoid the theoretical 
difficulties of categorially excluding any response to a treatment, it has been recently 
suggested to prefer the more comprehensive term ‘difficult-to-treat’ depression [16,17]. In 
line with this recommendation, a Delphi method-based consensus on the definition of 
treatment-resistant anxiety disorders [18] proposed the term “difficult-to-treat” anxiety 
disorder due to its usefulness in the clinical context. 

Objectives {7} 
 
The main objective is to investigate the effects of PBT compared with r-CBT for outpatients 
with difficult-to-treat unipolar depression or anxiety disorders. Primary outcome is emotional 
distress, secondary outcomes include psychological well-being and quality of life. Apart from 
the primary and secondary outcomes, we aim to investigate whether PBT, as proposed 
theoretically, produces changes in psychological flexibility, variation, selection, and retention 
of adaptive behavior, reflective functioning and capacity for social and interpersonal pleasure. 
Furthermore, we will examine the possible mediating role of therapists’ adherence with the 
manual and patients’ changes in avoidance/ behavioral control and cognitive style on 
outcome. Lastly, we will investigate potential moderators of outcome, i.e. patient 
characteristics including treatment expectations and experiential vs. rational learning style, as 
well as therapeutic alliance, across and within treatment conditions. 
The primary outcome measure in this trial is the difference in symptoms of psychological 
distress between the two groups. We hypothesize that PBT leads to significantly greater 
reductions in symptoms of emotional distress, as compared to r-CBT after treatment and at 6 
month follow-up. Furthermore, we expect that the secondary outcome measures positive 
mental health and quality of life are significantly more improved following PBT than r-CBT. 
Based on the treatment targets in PBT, we also hypothesize that variation, selection, and 
retention of adaptive behavior, psychological flexibility, and reflective functioning will be 
improved to a significantly higher degree following PBT compared with r-CBT. In addition, 
we hypothesize that changes in avoidance/ behavioral control and cognitive style significantly 
mediate a positive outcome. Finally, we expect that a positive treatment expectations and an 
experiential learning style of the patients, as well as therapist’s adherence with the treatment 
manual, will significantly moderate treatment outcome. 
Trial design {8} 

The current trial is an investigator-initiated, pragmatic, parallel randomized clinical trial 
(RCT). Two equally sized intervention arms, PBT and r-CBT, are compared. In total, we 
include 80 patients recruited from a university outpatient clinic. A CONSORT diagram is 
provided in Fig. 1. 
 
 
Fig. 1 
 
Consort Flow diagram of the study design. 
EMA: Ecological Momentary Assessment 
PBT: Process-based Therapy 
r-CBT: Routine Cognitive-Behavioral Therapy 
 
Methods: Participants, interventions and outcomes 
Study setting {9} 
The study will be conducted within the outpatient clinic at the Department of Psychology, 
Goethe University Frankfurt. 
Therapists are psychologists in advanced training for CBT, who are randomized to either PBT 
or r-CBT. Therapists randomized to PBT receive 20 hrs. training focusing on personalization 
of treatment by 
1) deriving a hypothetical network model of the individual problem, 
 
2) guiding patients through the collection of EMA data, 
 
3) interpreting dynamic network models, 
 
4) drawing network-related treatment decisions, and 
 
5) applying interventions based on mechanisms related to the central knot of the network. 
 
Supervision of PBT treatments is offered by the first author. Therapists randomized to PBT 
receive a manual [19] containing essential procedures in network-based assessment and 
treatment. 

Therapists randomized to r-CBT do not receive additional training and are supervised as usual 
by supervisors licensed for CBT. 
Eligibility criteria {10} 
 
We aim to include 80 patients who meet the inclusion criteria: (1) a primary DSM-5 diagnosis 
of depressive or anxiety disorder, (2) at least two unsuccessful attempts of pharmacological or 
psychological treatment according to the German guidelines for the treatment of depression or 
anxiety disorders (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen 
Fachgesellschaften, AWMF), (3) age 18-65 years, (4) sufficient knowledge of the German 
language. Participating patients are not required to discontinue medication, but to keep 
medication constant over the treatment period. Patients will be excluded in case of (1) 
increased suicidality, (2) substance abuse or dependency, (3) diagnose of borderline 
Personality Disorder, (4) pervasive developmental disorder, psychotic disorder, eating 
disorder, bipolar disorder, or severe physical illness. Inclusion and exclusion criteria are 
assessed by intake clinicians using M.I.N.I. [20] adapted for DSM-5. Assessment of failure to 
respond to adequate treatment is based on an interview focusing on prior treatments and 
documents available from treating therapists or institutions. 
Who will take informed consent? {26a} 
 
Potential trial participants are initially informed about the purpose of the trial by therapists 
at intake interview after registration at the outpatient clinic of the Department of Psychology. 
Patients who are interested in a participation receive detailed information from trial 
management staff about potential benefits and risks; their right to refuse participation and to 
withdraw consent at any time; institutional affiliation of the trial at the university and 
sources of trial funding. Written consent is obtained according to the Declaration of Helsinki 
and as approved by the ethics committee of the Department of Psychology and Sports 
Sciences at Goethe University Frankfurt. 

Interventions 
 
Explanation for the choice of comparators {6b} 
 
Clinical guidelines of the Association of the Scientific Medical Societies in Germany 
(Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) 
recommend the application of evidence-based treatment manuals of CBT as standard therapy 
for patients with anxiety disorders [60] and depression [61]. For patients with treatment 
failure in the past, no specific recommendations are given, except the adaptation of treatment 
to possible reasons for nonresponse or, if accepted by the patient, general change in treatment 
modality (from psychotherapy to pharmacotherapy or reverse). Thus, based on the guidelines 
cited above, standard interventions for patients with treatment failures do not differ from 
routine care and usually comprise traditional cognitive and behavioral interventions, but not 
third wave therapies. 
 
Intervention description {11a} 
Both treatments comprise a 9-week baseline phase and a 20-week intervention phase. 
Baseline phase: In the PBT condition, a hypothetical network model of the problem is derived 
 
and EMA is conducted based on the key components of the model: situational context, 
cognition, emotion, body symptom, behavior, cognitive processing and motivational schema. 
Focusing on these dimensions, typical examples of maladaptive responses are determined, 
and subsequently adaptive counterparts representing the desired poles of the dimensions that 
should be targeted in the treatment are defined. Then, participants are instructed to apply the 
mobile app Status (Vacay ©) which prompts the judgement of the seven dimensions 
established in the hypothetical network model on a bipolar scale ranging from -100 
(maladaptive) to +100 (adaptive). Data are gathered in the situational context related to the 
problem. Therapists guide the adaptation of the items during the weekly sessions and help the 

patient to overcome difficulties in identifying situations and entering judgements of the 
components of the network model. EMA is completed when at least 100 measurements are 
taken. Then, a dynamic network analysis is computed for assessing autoregressive and cross- 
lagged effects of the variables [21]. These effects are estimated and visualized in a network 
representing variables as ‘nodes’, the effects between them as directed arrows (’edges’) and 
autoregressive effects as ‘self-loops’. 
In the baseline phase of r-CBT, qualitative self-observational data are collected, using 
unstructured handwritten diaries of situations related to the problem, including notes on 
behaviors, cognitions and emotions. Therapists assist patients in completing the diaries on a 
daily basis, support them to deepen the understanding of the problem and derive a behavioral 
analysis of the individual problem based on the SORKC model according to Kanfer and 
Saslow (1965; [22]), as required for the application of CBT in German routine mental health 
care. 
Treatment phase: This phase consists of 20 sessions for both treatment conditions. In PBT, 
treatment is initiated by a collaborative interpretation of the dynamic network model based on 
EMA collected during the baseline. Therapists are instructed to identify the central node, 
significant edges, self-loops and positive or negative feedback loops between the nodes [19]. 
Based on the outcome of the dynamic network model, interventions are selected on the basis 
of empirical evidence for mechanisms of change matching to the central node of the 
individual patient, besides feedback loops and self-loops, as the key process maintaining the 
maladaptive pattern [10]. Interventions are conceptualized in the evolutionary framework as 
variation, selection and retention of an adaptive mode of the central node related to the 
specific context of the problem [13]. The change of this variable is monitored using daily 
judgements on the basis of EMA. Further treatment planning focuses on additional targets to 
establish the adaptive modes of the dimensions as defined in the positive network model. 

In r-CBT, as opposed to PBT, a naturalistic setting is retained for treatment decisions. 
Treatment planning follows traditional theories about the effects of the interventions on 
factors maintaining the disorder, e.g. avoidance and exposure in anxiety disorder or reduced 
reinforcement of activities and behavioral activation in depression [23]. Interventions are 
selected on the basis of common treatment manuals related to diagnoses, e.g. CBT for 
depression. Individual data from the behavioral analysis are used to taylor the techniques to 
the problem behaviors or dysfunctional thoughts of patients. Treatment process focuses 
mainly on the implementation of the manualized interventions adapted to the individual 
patient as recommended in the National guidelines for treatment of depression and anxiety 
disorders. 
Criteria for discontinuing or modifying allocated interventions {11b} 
 
Adverse events will be monitored by the therapists, reviewed by the supervisors and reported 
to the PIs throughout the trial. 
Study treatment must be terminated for one of the following reasons: (a) Withdrawal of 
patient’s consent to study treatment or (b) Study treatment termination by the investigator. 
Study treatment of a patient will be terminated by the investigator for one of the following 
reasons: (a) severe serious complications which makes it necessary to stop the study treatment, 
including acute suicidailty or (b) 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 the primary reason for withdrawal will be recorded in the patient file. 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. Allocated 
interventions will be adapted on consultation of the supervisor, in case of worsening of the 
patient’s condition. 
Strategies to improve adherence to interventions {11c} 

Adherence to interventions will be supported by the strategies included in the treatment 
manuals. In r-CBT, these strategies include exploration of possible reasons for non- 
compliance, psychoeducation about the treatment, and clarification of treatment goals. In 
PBT, exploration of motivational factors, validation of barriers and shared decision making in 
the selection of interventions will be applied. 
Relevant concomitant care permitted or prohibited during the trial {11d} 
 
Psychopharmacological treatment will be permitted if prescribed by a psychiatrist. Concurrent 
psychotherapy will be prohibited and leads to exclusion from the trial. 
Provisions for post-trial care {30} 
 
If continuation of treatment is considered as necessary by the patient and the therapist at post- 
treatment, patients will be offered psychotherapy in the outpatient clinic. 
Outcomes {12} 
Primary endpoints 
 
Emotional distress, as assessed by the total score of the DASS-21 [25], represents the primary 
outcome measure. 
Secondary outcomes 
 
Health-related quality of life will be assessed using the international standard Euroqol-5D 
(EQ-5D; [26]). Positive mental health including emotional, psychological and social aspects 
of well-being is assessed by the unidimensional Positive-Mental Health Scale (PMH, [27]) 
with 9 self-report items. The Anticipatory and Consummatory Interpersonal Pleasure Scale 
(ACIPS; [28]) is a 17-item self-report inventory and will be used to measure the pleasure 
patients experience in interpersonal situations. Psychological flexibility is measured by the 3- 
items self-report inventory Acceptance and Action Questionnaire Version 2 (AAQ-2; [29]). 
The Reflective Functioning Questionnaire (RFQ; [30]) is a 54-item self-report inventory 
assessing the respondent’s ability to understand the internal mental states of self and others. 

Mentalizing capacity is divided in two subscales, Certainty and Uncertainty about mental 
states. The Client Satisfaction Questionnaire (CSQ-8; [31]) is an 8-item self-report instrument 
constructed to measure satisfaction with health services, which will be used only at post- 
assessment. 
Weekly and daily patients’ self-ratings of treatment process 
 
The Processed Based Assessment Tool (PBAT; [32]) is a transtheoretical set of 18 self-report 
items, assessing variation, selection and retention of adaptive behavior. The Depression 
Anxiety Stress Scale-10 (DASS-10; [33]) is the short version of the DASS-21, a self-report 
inventory measuring stress, anxiety and depression in three subscales. The Cognitive- 
Behavioral-Therapy Skills Questionnaire (CBTSQ; [34]) is a 6-item self-report inventory 
measuring patients’ use of cognitive behavioral therapy interventions, with the dimensions 
behavioral activation and cognitive restructuring. 
The Status-PBT (Vacay ©, 2024) is a mobile application for EMA during baseline phase 
which uses personalized questions and captures six dimensions (thought, emotion, body 
sensation, behavior, cognitive processing, motivational schema) on bipolar continuous scales 
ranging from -100 to +100. Similarity of the context with typical problem situations as 
defined in the hypothetical network model is rated on a continuous scale ranging from 0 to 
+100. 
Therapists’ ratings 
 
The Mini International Neuropsychiatric Interview [20] will be applied in the Version 7.0 for 
DSM-5 and contains 18 modules for the major mental disorders. At the enrolment interview 
all modules be used to assess inclusion criteria and comorbidity, but the modules anorexia and 
bulimia nervosa, binge eating and prolonged grief are only carried out in full if there are 
indications in the interview. The presence of personality disorders is assessed according to the 
Structured Clinical Interview for DSM 5 for Personality Disorders (SCID-PD [35]). 

A check-list of interventions for therapists is used after each session to check adherence, 
based on literature reviews [36,37] and meta-analyses [38–40]. The Process-based Decision- 
making Questionnaire (PBDMQ) [24] contains 24 items and was developed to assess 
adherence with PBT. The “Clinical Global Impression Scale” (CGI; [41]) is 3-item observer- 
rated scale measuring the clinical impression of the severity of the mental disorder and is used 
to track changes in symptom severity. 
Moderators 
 
The Kolb Learning Style Inventory [KLSI; [42]) will be administered at pre-treatment to 
assess active experimentation vs. abstract conceptualization learning style. The 
Credibility/Expectancy Questionnaire (CEQ; [43]) comprises contains 6 items three items of 
the subscale credibility and another three items of the expectancy subscale. The Helping 
Alliance Questionnaire (HAQ-11; [44]) comprises 11 items and measures therapeutic 
alliance. The questionnaire will be completed by patients and therapists at pre- and post- 
treatment. 
Participant timeline {13} 
 
Patients are evaluated by clinicians to be eligible for participation in the study on the basis of 
inclusion and exclusion criteria described before. If patients are eligible for treatment, they 
will be provided with information about the project. Patients who consent to participate in the 
project will be included in the pretreatment assessment (see Table 1). Patients who cannot or 
will not participate in the study will be offered treatment as usual in the outpatient clinic. 
 
 
Table 1 Overview of measurements 

 
Inclusion 
Baseline 
(Sess. 1-9) 
Pre- 
Treatment 
Treatment 
(Sess. 10-30) 
Post- 
Treatment Follow Up 
Week 
Instrument 
0 
1-9 
10 
11-31 
32 
57 
Ther 
apist 
M.I.N.I/ 
SCID-PD 
X 
CGI 
X 
X 
X 
X 
HAQ-11 
X 
week 7 
X 
X 
FAMOS 
X 
Intervention 
Checklist 
X 
week 9 
X 
weekly 
PBDMQ 
X 
Every 4 
weeks 
X 
Every 4 
weeks 
Patie 
nt 
DASS-21 
X 
X 
X 
X 
EQ-5D 
X 
X 
X 
X 
PMH 
X 
X 
X 
X 
ACIPS 
X 
X 
X 
X 
AAQ-II 
X 
X 
X 
X 
RFQ 
X 
X 
X 
X 
PBAT 
X 
X 
X 
weekly 
X 
X 
DASS-10 
X 
weekly 
CBTSQ 
X 
X 
X 
weekly 
X 
X 
EMA/diary 
X 
daily week 
5-9 
X 
EMA: daily 
(central node) 
X 
EMA: daily 
week 32-33 
HAQ-11 
X 
week 7 
X 
X 
KLSI 
X 
CEQ 
X 
CSQ 
X 
 
 
Abbreviations: 
 
M.I.N.I., Mini-International Neuropsychiatric Interview; 
 
SCID-PD, Structured Clinical Interview for DSM 5 – Personality Disorders; 
CGI, Clinical Global Impression Scale 
HAQ-11, Helping Alliance Questionnaire; 

FAMOS, Fragebogen zur Analyse Motivationaler Schemata, Kurzversion (Brief Assessment 
of Motivational schemata); 
DASS-21, Depression Anxiety Stress Scale 10 Items; 
EQ-5D, EuroQol 5 Dimensions; 
PMH, Positive Mental Health Scale; 
 
ACIPS, Anticipatory and Consummatory Interpersonal Pleasure Scale; 
AAQ, Acceptance and Action Questionnaire 
KLSI-12, Kolb Learning Style Inventory; 
CEQ, Credibility Expectancy Questionnaire; 
RFQ: Reflective Functioning Questionnaire; 
CSQ-8, Client Satisfaction Questionnaire 
PBAT, Process-Based Assessment Tool; 
DASS-10, Depression Anxiety Stress Scale 10 Items; 
CBTSQ, Cognitive Behavioral Therapy Skills Questionnaire 
PBDMQ, Process-based Decision-making Questionnaire 
EMA: Ecological Momentary Assessment. 
Sample size {14} 
 
Sample size estimation is based on the expected outcome in DASS-21, with treatment 
condition as between-subjects factor and a within-subjects repeated measurement factor (pre, 
post, follow-up). Since no previous trial has examined the effects of PBT, the expected effect 
size is set to a moderate effect of f= .25. Using an alpha level (α) of = .05 and a power of = 
0.8 with correlation among repeated measures estimated at r= 0.4, 78 patients are needed (39 
in each arm) to detect significant differences. To compensate for non-starters, a total sample 
of 80 patients will be randomized. 
Recruitment {15} 

The outpatient clinic of the Department of Psychology has previously been engaged in several 
clinical trials. The number of attending patients is about 1000 patients per year. Thus, 
adequate participant enrolment can be expected to reach target sample size. 
Assignment of interventions: allocation {16} 
 
If eligibility for the study is confirmed, and informed consent to randomization is given, 
patient will be randomized. To allocate study participants to treatment conditions, a 
randomization list is created by the data management staff using the statistical software R. 
The group allocations is printed out individually and placed in sealed envelopes. For each 
newly included participant, a member of the trial management staff draws an envelope and 
reads off the group allocation. The same procedure is used to randomize therapists to the 
treatment conditions. 
Blinding {17} 
 
No blinding of participants, care providers, outcome assessors or data analysts after 
randomization is planned. 
Data collection {18} 
 
Plans for assessment and collection of outcomes {18a}: An overview over assessments and 
collection of outcome during baseline, treatment and follow-up period is given in Table 1 and 
the instruments are described in section {12}. 
Plans to promote participant retention and complete follow-up {18b}: Participant 
retention during baseline, treatment and follow-ups will be supported by the staff of the trial 
management. Participants who discontinue or deviate from intervention protocols will be 
requested to complete questionnaires at the measurement points according to the schedule 
presented in Table 1. 
Data management {19} 

The trial will use electronic data collection and documentation, which is hosted by the 
company Vacay©. Entry of questionnaires will be performed by the participants. Coding, 
security and storage of data will be ensured by the staff of the trial management. Access to the 
data is only allowed for persons who are documented as trial personnel and have received a 
training. The given data will be checked electronically for its plausibility and consistency in a 
multistage procedure. Detected inconsistencies and missing or implausible data will be 
clarified with queries (electronically or paper-based) and necessary changes will be carried 
out. At the end of trial, the database will be closed after data cleaning process. The 
pseudonymized patient data recorded are stored by Vacay in accordance with legal 
requirements. 
Confidentiality {27}: Personal information about potential and enrolled participants will be 
pseudonymized and collected, shared, and maintained in accordance with the European data 
protection regulation. 
Additional consent provisions for collection and use of participant data and biological 
specimens {33}: N/A (no biological specimens are collected as part of this trial). 
 
 
Statistical methods {20a} 
 
Statistical methods for primary and secondary outcomes {20a}: 
 
The primary outcome measure is the change in emotional distress from pre treatment to post 
treatment, using the DASS-21 as primary outcome measure. Intention-to-treat analyses will 
be employed in this trial. For the statistical analysis of the primary outcome we will use a 
repeated measures ANOVA with treatment condition as the between-subjects factor and time 
(pre-treatment and post-treatment) as the within-subjects factor.. We will use a repeated 
measures MANOVA including a time treatment interaction to assess the effects of secondary 

outcomes, which are assumed to be moderately inter-correlated, followed by univariate 
repeated measures analyses. 
For statistical analysis, the computer program SPSS ® (Statistical Package for Social 
Sciences, version 28) will be used. 
Interim analyses {21b}: N/A (An interim analysis is not planned). 
 
 
Methods for additional analyses{20b}: To examine potential mediator and moderators of 
treatment effects, Structural Equation Modeling (SEM) and Cross-Lagged Panel Modeling 
(CLPM) will be employed using the R Package “lavaan” [45]. 
Dynamic network analysis of EMA data at baseline and at post-treatment will be computed 
using the R package "graphicalVAR", with penalization paramaters optimizing network 
structure [21, 46, 47] and detrending using the “forecast” R package [48]. Interpretation will 
focus on outstrength centrality to asses variable importance [49]. 
Methods in analysis to handle protocol non-adherence and any statistical methods to 
handle missing data {20c}: 
Per-protocol analysis will include all participantes attending at least 12 treatment sessions. 
For intend-to-treat analysis, missing data will be replaced, multiple imputation by chained 
equations will be used, employing the “mice” R Package [50]. 
Plans to give access to the full protocol, participant level-data and statistical code {31c} 
Individual participant data are intended to be shared after deidentification on a third-party 
website. 
 
Trial governance {5d} 
 
The first author, U.S. is the principal investigator (PI) and initiated the project together with 
the senior author, S.G.H.. The study does not have a data monitoring committee. 

Discussion 
 
The current study will be the first RCT investigating the evaluation of PBT in a mental health 
care setting. Since EMA is an important component of PBT that may contribute significantly 
to its effectiveness through reactivity to self-observation [51], we intend to disentangle the 
effects of intense self-monitoring before treatment from the effects of personalized 
interventions based on idiographic dynamic network analyses within treatment. 
Analogue studies with students have shown that the collection of EMA data using the Status- 
PBT generate meaningful idiographic dynamic networks, depending on the quality of data 
collection [52–54]. There is a potential risk that the patients in PBT may not be able to 
recognize relevant dimensions of their problems in the initial sessions during baseline phase. 
Although therapists in the present trial are encouraged to adapt the definition of variables for 
EMA thoroughly within the initial sessions and guide the use of EMA, patients may not use 
the app after situations referring to the context of the problem and fail to cover relevant 
processes occurring in daily life. On the other hand, the capacity to perceive mental states 
may be increased through EMA [55]. Therefore, besides collecting qualitative data about the 
personal relevance of the results of dynamic network analyses presented to the patients, we 
also assess changes in mentalization as a possible effect of intense self-monitoring during the 
baseline. 

The second important component of PBT is the personalization of treatment based on a) 
information about the individual network of the problem, and b) matching interventions based 
on their effective components to the central node of the network [10]. This approach is 
opposed to r-CBT in the control condition, which uses treatment protocols based on 
diagnoses, consisting of fixed sets of treatment modules. Thus, PBT may improve the 
effectiveness of treatment by using empirical idiographic information of temporal and causal 
relationships between possible maintaining factors [14]. However, it should be noted that data 
used in PBT to determine if an intervention should be allocated are still based on nomothetic 
(i.e., group-based) research data based on diagnostic categories (e.g. for depression: [39]). 
Further steps of the development of idionomic approaches to treatment decisions may include 
continuous dynamic network analyses of individual EMA data over the whole treatment, thus 
monitoring changes in the network and adapting interventions to them on different stages in 
the treatment [56]. A promising perspective may also be the application of control theory 
methods in the context of psychological dynamic networks [57-59], as they could provide a 
means to account for predicted intervention effects on an idiographic network, however, the 
application of such methods application in treatment studies requires further development. 
Despite these limitations, our study may provide a first proof of concept for the application of 
the process-based approach in a sample of patients with difficult-to-treat depressive and 
anxiety disorders. Using a randomized design and a manual for network-based assessment 
and algorithms for personalized treatment decisions, the current study will add to the 
preliminary results of single case studies [58], providing information on the efficacy of PBT 
as compared to r-CBT. The moderation and mediation analyses provide insight into the 
mechanisms of change and the relationship between treatment effects and patient 
characteristics. Future research may focus on the enhancement of PBT by developing 
personalized algorithms for treatment decisions on the basis of control theory, with special 
attention to patients who might not benefit from routine CBT in mental health care. 

Trial status 
Research protocol, version 02, July 8th 2024. Training of therapists and outcome assessors is 
ongoing. Recruitment begins April 2024 and will be completed on 30th September 2025. 
Declarations 
 
Ethics approval and consent to participate 
 
The protocol has been approved by the Ethics Committee at the Department of Psychology 
(Registration number: 2023-48). Protocol amendments will be communicated at 
https://clinicaltrials.gov and detailed in publications. 
Consent for publication 
 
Not applicable. 
 
Availability of data and material 
 
The study protocol is made publicly available through this publication. The main results are 
intended to be published in a high-impact peer reviewed journal within 6 months after the trial 
end date (approximately 2026/27). Individual participant data will be available for 
investigators whose proposed use of the data has been approved by an independent review 
committee identified for this purpose. Data will be available beginning 6 months and ending 
36 months following article publication. 
Competing interests 
 
All authors declare that they have no conflicts of interest. 
 
Funding 
 
This work is funded by the LOEWE Top Professorship for Stefan G. Hofmann, and supported 
by the DYNAMIC center, which is funded by the LOEWE program of the Hessian Ministry 
of Science and Arts (Grant Number: LOEWE1/16/519/03/09.001(0009)/98). 

Authors' contributions 
 
US and SH conceived the trial, drafted the study protocol and treatment manual, trained 
therapists and diagnosticians, and supervised implementation and coordination of the study. 
VK and NG contributed to the trial design and protocol development and obtained ethical 
approval. ME and AN developed the EMA assessment and dynamic network analyses. 
LS, BH and DB conduct recruitment and data collection. US drafted the article and all authors 
read, edited, and approved the final manuscript. 
Acknowledgements 
 
We would like to thank Steve Hayes, University of Nevada, for supporting our trial and 
developing the treatment manual. 
 
 
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