Veränderungen Dynamischer Symptom-Netzwerke Unter Pharmakologischer, Psychotherapeutischer Und Kombinierter Behandlung Bei Depression (DYNDET)
Phase: PHASE4
Conditions: Depression - Major Depressive Disorder
Sponsor: Goethe University

 
Cover page for clinicaltrials.gov 
 
Document: 
Study Protocol 
 
Official study title: 
Mechanisms of change in pharmacological, psychological and combined 
treatment of depression: a study protocol 
 
NCT Number: 
NCT ID not yet assigned 
 
Document date: 
February 17th, 2026 
 
 
 
 
 
 
 
 
 

Mechanisms of change in pharmacological, psychological and combined 
treatment of depression: a study protocol 
 
 
Nenadić, I.1, Ebert, M.2, Nemani, A.2, Meller, T.1, Schmidt, L. 1, Noor, L. 1, Kreis, M.2, 
Strack, M. 1, Matsingos, A.1, Goretzko, D. 2, Hofmann, S.G.⁴, Kube, T.2, Grimm, O.3, 
& Stangier, U.2 
 
1 Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg, 
2 Department of Psychology, Goethe Universität Frankfurt 
3 Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe Universität 
Frankfurt 
⁴ Department of Psychology, Philipps-Universität Marburg 
 
 
Corresponding author:  
Igor Nenadić, Department of Psychiatry and Psychotherapy, Philipps-Universität 
Marburg, Rudolf-Bultmann-Str. 6, 35039 Marburg, Germany 
nenadic@staff.uni-marburg.de 
 
Paper to be submitted to: Trials 
 
 

Abstract 
Background: 
Although both antidepressant medications (AD) and cognitive-behavioral therapy 
(CBT) are established treatments for major depressive disorder, their mechanisms of 
change, and potential synergistic or inhibitory interactions in combination therapy, 
remain insufficiently understood. Traditional outcome measures focus on symptom 
severity, often overlooking intraindividual dynamics that may explain differential 
treatment effects. Recent advances in temporal network modelling offer a promising 
framework to capture these dynamics and assess how interventions reshape the structure 
and regulation of symptom networks. The Dynamic Networks in Depression Treatment 
(DYNDET) study aims to investigate how pharmacotherapy, psychotherapy, and their 
combination affect symptom connectivity and change processes over time. 
Methods: 
DYNDET is a randomized, controlled, open-label trial with three parallel treatment 
arms: (A) selective serotonin reuptake inhibitor (SSRI) pharmacotherapy, (B) cognitive-
behavioral group therapy for depression (CBGT-D), and (C) combined treatment. After 
individual screening by a study physician, a total of 90 participants will be randomized 
equally into the three groups. Following a 3-week ecological momentary assessment 
(EMA) baseline phase, participants receive an 8-week treatment. EMA data are 
collected seven times daily using a smartphone app (mpath) during the baseline phase. 
During treatment, participant data are collected once per day. The primary outcome of 
the DYNDET study is the change in the structure of symptom networks (the dynamic 
network from the baseline phase and the cross-sectional networks from the treatment 
phase), assessed via multilevel vector autoregressive (mlVAR) modelling across the 
EMA period and via network intervention analysis during the intervention period.  
Secondary outcomes include clinician-rated and self-report measures of depression 
severity, functioning, affect regulation, and cognition, as well as exploratory 
neuroimaging data in a subsample. The analytic strategy includes network intervention 
analysis, mixed-effects modeling, and moderation analyses based on baseline network 
features. 

Discussion: 
DYNDET is among the first clinical trials to explicitly examine how different treatment 
modalities modulate the dynamic structure of depressive symptom networks. By going 
beyond static symptom counts, this study will provide insights into differential and 
potentially complementary mechanisms of AD and CBT. Findings may inform more 
precise, individualized treatment planning and guide future research on network-based 
markers of therapeutic change. 
Trial registration:  
ClinicalTrials.gov: 2025-2718. Registered x 
Keywords 
Depression, Cognitive Behavioral Therapy, SSRIs, Network Analysis, Ecological 
Momentary Assessment 
Administrative information 
Title {1} 
Mechanisms of change in pharmacological, psychological and 
combined treatment of depression: a study protocol 
Trial 
registration 
{2a and 2b}. 
Clinicaltrials.gov, JWGUniversity, record 2025-2718, Registered x 
 
Protocol version {3} 
Research protocol, version 01, date 
Funding {4} 
This work is funded 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). 
Author details {5a} 
Igor Nenadić, Tina Meller, Lisa Schmidt, Madeleine Strack, 
Alexandros Matsingos, Laila Noor: all Department of Psychiatry 
and Psychotherapy, Philipps-Universität Marburg Rudolf-
Bultmann-Str. 8, 35033 Marburg, Germany  

Ulrich Stangier, Tobias Kube, Department of Psychology, Goethe 
Universität Frankfurt, Varrentrappstr. 40-42, 60486 Frankfurt am 
Main, Germany 
 
Arwin Nemani, Mareike Ebert, David Goretzko: all Department of 
Psychology, Goethe Universität Frankfurt, Theodor-W.-Adorno-
Platz 6, 60323 Frankfurt am Main, Germany 
 
Stefan G. Hofmann, Department of Psychology, Philipps-
Universität Marburg, Schulstr. 12, 35037 Marburg/Lahn, Germany 
Oliver Grimm, Department of Psychiatry, Psychosomatics and 
Psychotherapy, Goethe Universität Frankfurt, Heinrich-Hoffmann-
Str. 10, 60528 Frankfurt, Germany 
 
Name and contact 
information for the 
trial sponsor {5b} 
Igor Nenadić, Department of Psychiatry and Psychotherapy, 
Philipps-Universität Marburg, Rudolf-Bultmann-Str. 8, 35033 
Marburg, Germany  
Email: nenadic@staff.uni-marburg.de 
Role of sponsor {5c} 
Principal Investigator of the trial. 
Composition of the 
coordinating centre 
and trial steering 
committee {5d} 
  
Trial steering committee: Igor Nenadic, Oliver Grimm, Stefan G. 
Hofmann, Tobias Kube, Ulrich Stangier. 
 
 

Introduction 
Background and rationale {6a} 
A large number of randomized controlled trials have confirmed the efficacy of both 
antidepressant medications (AD) and psychological therapies, such as cognitive–
behavioral therapy) (CBT) in treating depression (Plessen et al., 2023; Cuijpers et al., 
2023), although depending on severity and types of treatment. In addition, a combination 
of psychotherapy and antidepressants generally has been shown to enhance therapeutic 
outcomes (Cuijpers et al., 2020), suggesting that they may work through complementary 
mechanisms. However, Whiston et al. (2019) found in their meta-analysis of trials 
focusing on CBT as psychological treatment that a combination with SSRIs was inferior 
to CBT alone, indicating an inhibitory effect of combining both treatments. With regard 
to differential effects of AD and CBT on specific indicators of response, results are often 
insignificant or inconsistent, as related to cognitive changes (Quilty et al., 2014; 
Courtney et al., 2022), affective changes (Boschloo et al., 2019) or neural response 
(Dunlop et al., 2017 ; 2023). 
Furthermore, there is a lack of knowledge about mechanisms of change in AD vs. CBT, 
as well as possible Complementary Mechanisms of change in the combination of both 
approaches. For instance, using network analyses of symptom change in depressed 
patients, Boschloo et al., (2022) found that the effects of SSRIs were primarily mediated 
by reduced depressed mood and anxiety, whereas changes in cognitions were found to 
be rather an indirect effect of the affective change. Lemmens et al. (2016) presented a 
scoping review of mediators of psychological treatments, which included, among others, 
cognitive change, activity level and rumination. However, in an RCT directly comparing 
the effects CBT and SSRIs with placebo (Fournier et al., 2013), a different pattern was 
observed, with medication leading to a greater reduction in cognitive symptoms and 
cognitive therapy to a greater reduction of atypical-vegetative symptoms than placebo.  
Neurobiological theories may provide a framework for understanding how these two 
treatments may differ in their effects on the brain. A commonly accepted model suggests 
that psychotherapy primarily engages "top-down" processes, affecting prefrontal 
cortical regions involved in cognitive control, emotion regulation, and awareness of 
emotional states (DeRubeis et al., 2008). In contrast, antidepressant medications are 

thought to work "bottom-up", acting directly on subcortical structures such as the 
amygdala or the limbic system, which are heavily involved in the generation and 
processing of affective states and visceral responses (Pizzagalli, 2011).  
In contrast to this hypothesis, a recent meta-analysis analyzing fMRI-studies with regard 
to neural effects of antidepressants found no convergence across foci of treatment-
associated alterations in functional imaging. As compared to untreated patients, patients 
treated with antidepressants showed changes in the left dorsolateral prefrontal cortex 
(Saberi et al., 2024). However, these changes are associated with working memory, 
attention and behavior, domains that are primarily supposed to be related to the effects 
of psychological treatments. Referring to the effects of psychological treatments, a 
former meta-analysis (Sankar et al., 2018) found that the activity of the left rostral 
anterior cingulate was increased in response to affective visual processing tasks, which 
was interpreted to reflect improvements in emotional responsivity following 
psychotherapy. Thus, it appears that both psychological and pharmacological treatments 
may act on prefrontal and limbic areas of the brain as well. 
Comparing the neural effects of psychological treatments and antidepressants, meta-
analyses also show inconsistent results. For instance, a former meta-analysis (Kalsi et 
al., 2017) indicated that psychological and pharmacological treatments lead to 
differential effects on the right paracingulate activity: whereas psychological treatments 
increase the activation of this area, pharmacological treatment might reduce this activity, 
supporting the hypothesis that psychological treatments may involve a top-down 
emotional regulation. However, this hypothesis was only partially supported by a recent 
meta-analysis (König et al., 2025) which found that CBT reduced limbic reactivity and 
altered activity in cingulate and prefrontal cortex, but the patterns of changes in various 
subregions of the cingulate cortex were inconsistent between studies, depending on task 
content, statistical evaluation, and interventions. 
A clearer understanding of differential treatment mechanisms can be achieved through 
a network perspective on psychopathology, which reconceptualises depression as a 
system of mutually reinforcing symptoms (Borsboom & Cramer, 2013). Rather than 
modelling depression as a latent construct, this framework maps the conditional 
dependencies among individual symptoms and quantifies their mutual influences 

(Borsboom, 2017). A growing body of evidence, as highlighted in the narrative review 
by Wichers et al. (2021) suggests that depression is best understood as dynamic system 
of mutually reinforcing affective, cognitive, behavioural states. At the symptom (macro) 
level, sadness, anhedonia, and fatigue often emerge as central “bridge” symptoms 
linking depression to comorbid conditions, underscoring their pivotal role across cross-
sectional studies. Intensive longitudinal momentary assessment (EMA) data further 
clarify dynamics at the micro-level: during psychotherapy, Snippe et al. (2024) found 
that emotional and cognitive improvements (e.g. reductions in worry and negative self-
thoughts, and changes in sad/happy mood) typically arise at the same time, whereas 
behavioural gains such as increased social interaction and activity tend to occur later, 
challenging classical models that posit behavioural activation precedes mood 
improvement. Randomized controlled trials of antidepressants and mindfulness-based 
cognitive therapy show symptomatic improvement occurs without consistent reductions 
in the dynamic connectivity among momentary affective states (Snippe et al., 2017), 
suggesting persistent underlying vulnerability despite symptom relief. Additionally, 
Helmich et al. (2023) empirically show that rising autocorrelation, a hallmark of “critical 
slowing down”, in momentary affect states frequently precedes transitions toward 
reduced depression during treatment, whereas variance-based early warning signals are 
less reliable, highlighting both the promise and current limitations of using such signals 
for personalized prediction. In pharmacological research, Bos et al. (2018) employed 
network analysis to assess SSRI treatment for major depression, finding not only an 
overall reduction in symptom severity but significantly increasing interconnectivity. 
This suggests that network models can reveal subtle but clinically meaningful 
reorganizations in symptom architecture that global scores would miss. Yet, most 
pharmacological and psychotherapeutic trials still rely on aggregate sum-scores, 
obscuring the micro-processes and change mechanisms through which treatments might 
exert their impact. 
Network Intervention Analysis (NIA) has begun to meet this need by embedding a 
treatment variable directly into the network and tracking which symptoms (“nodes”) 
show the earliest and strongest connections (“edges”) with the intervention node. Initial 
NIA work by Blanken et al. (2019) demonstrated that NIA can pinpoint not just which 

symptoms of insomnia and depression improve during cognitive-behavioural therapy 
for insomnia (CBTI), but also the sequence in which these improvements emerge. 
Additionally, Jurado-González et al. (2024) applied NIA within a large randomized trial 
contrasting transdiagnostic group CBT plus usual care versus pharmacological 
treatment for emotional disorders. Their symptom-level network models revealed that 
psychological intervention had direct and lasting effects on core anxiety and depression 
symptoms (such as excessive worry, difficulty relaxing, and sad mood) that then have 
indirect benefits to associated symptoms across long-term follow-up. Furthermore, 
Fishbein et al. (2023) used NIA in a randomized controlled trial of Acceptance and 
Commitment Therapy (ACT) versus minimally enhanced usual care for anxious cancer 
survivors, examining both process and outcome variables. Contrary to traditional 
mediation expectations, they found that the ACT intervention produced direct 
improvements primarily in cancer-specific anxiety outcomes (fear of recurrence and 
cancer-related trauma symptoms) which then mediated indirect improvements in other 
psychological processes and outcomes. This network approach highlighted that certain 
outcomes, typically considered mere endpoints, functioned as active mechanisms 
transmitting treatment effects to other targets, thus capturing complex, multi-directional 
pathways of therapeutic change that cannot be seen with standard mediation models. 
The necessity and unique contribution of our study arises from several significant gaps 
in the current literature on depression treatment. Despite advances in applying network 
frameworks to both symptom-level and EMA data, most studies have focused on 
examining changes within a single treatment modality, predominantly psychotherapy or 
pharmacotherapy in isolation, rarely comparing these directly, or integrating 
combination treatments. Furthermore, prior research has often relied on cross-sectional 
or short time-frame longitudinal data, leaving unanswered questions about how 
symptom interactions shift through various treatment stages. Our project directly 
addresses these limitations by systematically comparing the change of symptom 
networks with network intervention analysis across three distinct treatment arms: 
monotherapy with CBT group therapy, monotherapy with pharmacotherapy, and 
combination treatment, in a real-world sample of outpatients with depression. This 
design provides the rare opportunity to identify not only which specific symptoms or 

processes respond most sensitively and rapidly within each treatment and how this might 
be connected to baseline EMA or fMRI data, but also whether, when, and how network 
structures reorganize differently depending on therapeutic modality or their 
combination.  
Building on this foundation, the study tests a set of core hypotheses in an exploratory 
framework reflecting the limited prior research systematically comparing these 
treatments (especially combined treatment) on a network level. We hypothesize that the 
three treatment conditions will differ significantly in their direct and indirect effects on 
change processes within depressive symptom networks. We further expect differences 
in the timing of treatment effects, with early improvement predicted by baseline network 
connectivity patterns unique to each modality. Distinct treatment arms may result in 
divergent post-treatment network connectivity and stability profiles, reflecting 
alternative mechanisms of symptom reorganization. Combination therapy will be 
explored for synergistic, additive, or inhibitory interactions affecting symptom network 
structure. Additionally, features derived from the baseline EMA network (e.g. symptom 
centrality, increased autocorrelation and variance) are hypothesized to moderate 
treatment response and help identify non-responders prior to therapy onset.  
Explanation for the choice of comparators {6b} 
Comparators of combined treatment are psychological and pharmacological treatment. 
Since proven effective treatment are applied, the comparison of combined treatment 
with active treatments appears to be adequate and a placebo arm is not considered to be 
necessary. However, a baseline phase will be implemented to assess also nonspecific 
(placebo) effects. 
Objectives {7}  
The primary objective of this study is to systematically compare and clarify the 
mechanisms of symptom change in depression across three treatment modalities (CBT 
group therapy, SSRI pharmacotherapy, and their combination) by leveraging a network 
approach to psychopathology. The research aims to: 
- Identify and contrast direct and indirect effects of each treatment on core 
depression symptoms, including affective, cognitive, and vegetative domains. 

- Examine the timing, trajectory, and stability of treatment effects across 
modalities, with a focus on how specific symptoms and symptom networks 
reorganize over the course of treatment. 
- Uncover potential synergistic, additive, or inhibitory interactions in combination 
therapy, clarifying whether combining treatments produces complementary or 
counteractive changes within symptom networks. 
- Evaluate baseline predictors of treatment response, such as EMA-based network 
centrality, to better understand which patients may benefit most from each 
intervention and to identify non-responders early.  
By integrating intensive longitudinal EMA data at baseline, pre- and post-treatment 
fMRI, and additional behavioural measures, the study seeks to advance a nuanced, 
multimodal understanding of how diverse interventions shift both symptomatic and 
neurobiological processes in depression. The project is intentionally exploratory, 
reflecting the current lack of direct comparative and mechanistic research focusing on 
change mechanisms across these treatment arms (especially regarding combination 
therapy for depression) on a network level. This project aims to gain improved insight 
into the nuanced, modality-specific pathways through which diverse depression 
treatments exert their effects, thereby advancing mechanistic understanding beyond 
conventional aggregate symptom measures. 
Trial design {8}  
This study will employ a parallel-group design with three arms: selective serotonin 
reuptake inhibitor (SSRI) pharmacotherapy, cognitive behavioral therapy (CBT) 
delivered in a group format, and a combination of both interventions. Before 
randomization, all participants will undergo a screening conducted by a study physician, 
which may take place via telephone, video call, or in-person. During this screening, 
current psychological symptoms and possible physical comorbidities will be assessed. 
Based on this information, the study physician will determine whether all three treatment 
conditions are equally suitable for the participant. If that is not the case, the individual 
will be unable to participate in the study and will instead receive an appointment at the 
psychiatric outpatient clinic to plan further treatment options. Only those for whom all 
conditions are appropriate will proceed to random allocation. Suitable participants will 

then be randomly assigned to one of the three treatment groups in a 1:1:1 ratio after 
completion of the baseline assessment, ensuring equal distribution across all arms. The 
total duration of the intervention will be eight weeks. Each treatment arm will include 
30 participants, resulting in a total sample size of 90. The study is primarily exploratory 
in nature, aiming to generate preliminary insights into the comparative effects of the 
interventions.  
 
Methods: Participants, interventions and outcomes 
Study setting {9} 
The study will be conducted in Germany across two locations encompassing three study 
centres: the outpatient clinic of the Department of Psychiatry and Psychotherapy at 
UKGM Marburg; the outpatient cognitive behavioral therapy clinic at the Institute of 
Psychology, Goethe University (GU) Frankfurt; and the psychiatric outpatient clinic of 
the Department of Psychiatry, Psychosomatics and Psychotherapy at GU Frankfurt. All 
treatment will take place in an outpatient setting and be delivered on-site at the 
respective centres. In addition to the on-site treatment, participants will complete 
Ecological Momentary Assessment (EMA) and self-report questionnaires in their 
everyday environments using the smartphone-based application m-path. 
 
Eligibility criteria {10} 
Participants must be between 18 and 65 years of age and have sufficient proficiency in 
German to understand study procedures and provide informed consent. Eligible 
individuals must currently be experiencing a mild to moderate depressive episode. 
Individuals presenting with a severe depressive episode will be excluded from 
participation following the clinical assessment, as random allocation would not be 
appropriate in such cases, given the recommendation to offer combined 
psychopharmacological and psychotherapeutic treatment according to current 
guidelines. Furthermore, participants should not be undergoing psychotherapy or taking 
antidepressant medication at the time of enrolment. Additionally, they must own a 
smartphone and have regular access to the internet, as participation involves completing 

Ecological Momentary Assessment (EMA) and self-report questionnaires via the m-
path smartphone app. Written informed consent is required prior to participation. 
Individuals will be excluded if they have a diagnosis of bipolar disorder, exhibit acute 
suicidality, suffer from a substance use disorder, have a depression with psychotic 
symptoms, or have a severe medical or neurological illness. Participants with conditions 
that may interfere with fMRI and study procedures (e.g. metal implants, significantly 
impaired speech, or pregnancy) will also be excluded. 
Therapists involved in the study must be either licensed psychotherapists or advanced 
trainees and must be trained in the study’s group therapy manual. Physicians 
administering pharmacological treatment must be board-certified psychiatrists with 
experience in prescribing and monitoring SSRIs.  
 
Interventions 
Intervention description {11a} 
Intervention description {11a} 
All treatments comprise a 3-week baseline phase and an 8-week intervention phase. 
Baseline phase: Participants are instructed to judge the intensity of depressive symptoms 
among others 5x/day over 21 days. A mobile app (m-Path) will be used to prompt users 
to enter data at regular intervals. In addition, daily sleep assessments are conducted in 
the morning, and assessments of social events are conducted in the evening.  
Treatment phase: This phase comprises 8 weeks providing one of three treatments: 
A) 
Psychopharmacological treatment. 
B) 
Cognitive-behavioral group treatment (CBGT-D) 
C) 
Combination of psychopharmacological and cognitive-behavioral group 
treatment. 
 

Psychopharmacological treatment will be in accordance with the German guidelines for 
treatment of major depression (“Nationale Versorgungsleitlinie Unipolare Depression”, 
AWMF-register number nvl-005, version 3.2 of 2022; online: awmf.org). For this 
purpose, a selective serotonine reuptake inhibitor (SSRI), escitalopram, will be selected 
for out-patient treatment. Prior to drug treatment, subjects will be informed about the 
substance as part of a routine clinical management, according to the national guidelines. 
Laboratory tests and ECG will be performed (not part of study, but GCP). Patients will 
then be started on a dose of escitalopram 5mg daily for three days, which will be 
subsequently raised to the target dose of 10mg daily. Clinical re-evaluation during short 
clinical visits in out-patients after two and four weeks will include side effect 
management, if necessary. In case of insufficient clinical response (as per guideline 
criteria), clinicians will be able to raise the daily dose of citalopram to 15mg. 
 
CBGT-D includes the following components (Schaub et al., 2013):  
A) 
Psychoeducation: information about depression, cognitive-behavioral model. 
B) 
Behavioral Activation: enhancing engagement in pleasurable or meaningful 
activities. 
C) 
Cognitive Restructuring: identification and modification of negative thoughts 
and cognitive distortions. 
D) 
Social problem-solving. 
E) 
Homework Assignments. 
F) 
Relapse Prevention: Identification of early warning signs and coping strategies. 
Treatment is delivered using a manual which had been conceptualized for clinical 
routine care and evaluated in a randomized-controlled study (Schaub et al., 2018). 
 
Criteria for discontinuing or modifying allocated interventions {11b} 

Suicidal symptoms; severe side effects resistant to side-effect management; physical 
illness unrelated to study interventions (e.g. accidents, accidental brain trauma etc.). 
 
Strategies to improve adherence to interventions {11c} 
All psychotherapeutic sessions in our study are conducted by licensed psychotherapists 
or psychotherapists in advanced training who have received specific training in the 
standardized group therapy manual, while pharmacological interventions are overseen 
by board-certified psychiatrists experienced in SSRI prescription and monitoring. This 
high level of professional qualification and structured training ensures a consistent and 
trustworthy therapeutic environment, which increases participant confidence and fosters 
ongoing engagement with the assigned interventions, thereby supporting adherence. 
EMA during baseline and daily assessments during treatment will play a central role in 
our study. To enhance compliance and minimize missed assessments, participants will 
receive automated reminders via their mobile devices to complete EMA entries at the 
scheduled times. The study employs a contingency-based incentive scheme, in which 
the monetary reward is directly linked to the quantity and timeliness of completed EMA 
entries. This approach is designed to maximize participant engagement with the daily 
assessments, thereby improving data integrity and allowing immediate identification of 
adherence challenges. Monitoring of the EMA data throughout the study will allow for 
the prompt identification of deviations or non-adherence. Participants identified as non-
adherent will be contacted in a timely manner to address barriers and support re-
engagement with the study procedures. 
 
Relevant concomitant care permitted or prohibited during the trial {11d} 
During study participation, all concomitant pharmacological and psychotherapeutic 
treatments will be systematically documented. Concomitant somatic treatments required 
for general medical care (e.g., antihypertensive medication, antidiabetics, thyroid 
medication, analgesics) are permitted throughout the trial, provided that they are 
prescribed according to routine clinical practice and, where possible, kept stable. Such 
treatments, as well as any changes, will be recorded. In contrast, additional 

psychopharmacological treatments (e.g. initiation of further antidepressants, mood 
stabilizers, antipsychotics, or augmentation strategies outside the assigned study arm) 
and structured psychotherapeutic interventions (e.g. individual or group psychotherapy 
outside the assigned study arm) are not permitted during the randomized treatment 
phase, as they would confound the comparison of treatment conditions. If initiation of 
such treatment becomes clinically indispensable (e.g. due to symptom deterioration or 
emerging risk), this will be decided by the responsible clinician in accordance with good 
clinical practice. In these cases, participation in the allocated study intervention will be 
discontinued and the participant will be transitioned to routine care. Short-term 
symptomatic medications may be used as clinically indicated at the discretion of the 
treating physician and will likewise be documented. All concomitant medications and 
psychotherapeutic or counselling contacts will be monitored to evaluate their potential 
impact on study outcomes and to allow appropriate sensitivity analyses. 
 
Outcomes {12}  
The primary outcome of the DYNDET study is the change in the structure of symptom 
networks (the dynamic network from the baseline phase and the cross-sectional 
networks from the treatment phase), assessed via multilevel vector autoregressive 
(mlVAR) modeling across the EMA period and via network intervention analysis during 
the intervention period. Rather than focusing exclusively on symptom severity, the study 
emphasizes intraindividual network dynamics such as changes in node centrality, edge 
strength, and global connectivity measures. These include metrics such as outstrength 
and network temperature, which capture the stability and reactivity of the symptom 
system over time (Grimes et al., 2025). 
Secondary outcomes include observer-rated depression severity based on validated 
clinical interviews (HAM-D, MADRS, IDS-C), as well as patient-reported outcomes 
assessing functional impairment (SOFAS), affective and cognitive functioning (e.g., 
PANAS-SF, PTQ, AAQ-II, PDQ), and interpersonal factors (e.g., F-SozU, CSI-4). Data 
are collected using a combination of structured assessments and high-frequency 
ecological momentary assessment (EMA) to ensure both breadth and temporal 
precision.  

Functional MRI (pre- and post-treatment) data will be collected and may be used in 
exploratory analyses to investigate neural correlates of treatment-related change (Zhou 
et al., 2021; Boschloo et al., 2022). Integration of neuroimaging data into the main 
analytical framework is planned as a future extension, contingent on data quality and 
sample size. 
Ecological Momentary Assessment (EMA) via mpath 
In the baseline phase, participants will complete EMA via the mobile application mpath 
over a period of three weeks, with assessments administered five times per day, as well 
as each morning and evening. Items are rated on continuous visual analogue scales 
ranging from 0 to 100, capturing real-time variations in affect, cognition, motivation, 
physiology, social context, and daily functioning. Morning and evening surveys include 
items on sleep, expectations, emotional state, cognitive flexibility, social contact, and 
daily activities. High-frequency prompts assess momentary affect, energy levels, bodily 
complaints, repetitive negative thinking, and social needs. Additionally, participants 
provide a brief daily voice recording. During the subsequent 8-week treatment phase, 
participants complete a brief daily assessment focusing on key mechanisms of change 
and depression-related items. This reduced set of daily measures is specifically designed 
to monitor clinically relevant depressive symptoms throughout the course of treatment.  
 
Participant timeline {13}  
 
 
Inclusion 
Baseline 
Pre-
Treatment 
Treatment 
Mid-
Treatment 
Post-
Treatment 
 
Week 
Instrument 
0 
0-2 
2 
3-10 
(8 
weeks) 
7 
11 
Therapist 
fMRI 
X 
 
 
 
 
X 
EEG 
X 
 
 
 
 
 
AAT 
X 
 
 
 
 
 
Speech Task 
X 
 
 
 
 
 
Mini-Dips 
X 
 
 
 
 
 
TALD 
X 
 
 
 
 
 

HAM-D 
X 
 
 
 
 
X 
HAM-A  
X 
 
 
 
 
X 
SOFAS 
X 
 
 
 
 
 
D2  
X 
 
 
 
 
 
RWT  
X 
 
 
 
 
 
Pfadfindertest  
X 
 
 
 
 
 
ZST 
X 
 
 
 
 
 
Combination 
interview 
HAMD-D 
MADRS, IDS-C 
X 
 
 
 
 
X 
YMRS 
X 
 
 
 
 
X 
Patient 
EMA 
 
X 
Daily 
(5x/d) 
 
 
 
 
EMA DYNDET 
 
 
 
X 
Daily (1x/d) 
 
 
Speech Task 
 
X 
Daily 
 
 
 
 
FsozU  
X 
 
 
 
X 
 
CSI-4 
X 
 
 
 
X 
 
EE-Item 
X 
 
 
 
X 
 
ASQ 
X 
 
 
 
X 
 
PDQ 
X 
 
 
 
X 
 
PANAS-SF 
X 
 
 
 
X 
 
AAQ-2 (7 Items) 
X 
 
 
 
X 
 
BSI-18 
X 
 
 
 
X 
 
PTQ  
X 
 
 
 
X 
 
NEO 
X 
 
 
 
X 
 
PATHEV 
X 
 
 
 
 
X 
CTQ 
 
 
X 
 
 
 
SISI 
 
 
X 
 
 
 
WHODAS 2.0 
 
 
X 
 
 
 

PSS 
 
 
X 
 
 
 
LEQ 
 
 
X 
 
 
 
AUDIT 
 
 
X 
 
 
 
BDI-II 
 
 
X 
 
 
X 
 
Abbreviations: 
fMRI, Functional Magnetic Resonance Imaging; 
EEG, Electroencephalography; 
AAT, Approach-Avoidance Task; 
Speech Task, Behavioral Speech Task; 
Mini-Dips, Mini-International Neuropsychiatric Interview; 
TALD, Thought and Language Disorder Scale; 
HAM-D, Hamilton Depression Rating Scale; 
HAM-A, Hamilton Anxiety Rating Scale; 
SOFAS, Social and Occupational Functioning Assessment Scale; 
D2, D2 Test of Attention; 
RWT, Regensburger Wortflüssigkeitstest; 
Pfadfindertest, Trail Making Test; 
ZST, Number-Symbol Test; 
Combination Interview (HAM-D/MADRS/IDS-C), Combination Interview encompassing the 
Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale and Inventory of 
Depressive Symptomatology Clinician-Rated; 
YMRS, Young Mania Rating Scale; 
EMA, Ecological Momentary Assessment; 
EMA DYNDET, Ecological Momentary Assessment (DYNDET study); 
Speech Task, Behavioral Speech Task as part of EMA; 
FsozU, Fragebogen zur Sozialen Unterstützung (22 Items); 
CSI-4, Couples Satisfaction Index (4-Item Version); 
EE-Item, Single-Item Expressed Emotion; 
ASQ, Affective Style Questionnaire; 
PDQ, Perceived Deficits Questionnaire ; 
PANAS-SF, Positive and Negative Affect Schedule – Short Form; 
AAQ-2 (7 Items), Acceptance and Action Questionnaire – version 2; 
BSI-18, Brief Symptom Inventory; 
PTQ, Perseverative Thinking Questionnaire; 
NEO, NEO Personality Inventory – Neuroticism Scale; 

PATHEV, Patient Questionnaire on Therapy Expectation and Evaluation; 
CTQ, Childhood Trauma Questionnaire; 
SISI, Single-item social identification measure; 
WHODAS 2.0, WHO Disability Assessment Schedule 2.0; 
PSS, Perceived Stress Scale; 
LEQ, Life Events Questionnaire (without free text); 
AUDIT, Alcohol Use Disorders Identification Test; 
BDI-II, Beck’s Depression Inventory II; 
 
Sample size {14} 
The target sample size for the DYNDET study is 90 participants, equally distributed 
across three treatment arms (SSRI, CBT group therapy, and combination therapy). This 
allocation reflects both methodological requirements and feasibility considerations 
rather than being based on formal power calculations. If the final sample is smaller than 
planned, the statistical scope will be adjusted accordingly, and network inference will 
be interpreted with appropriate caution. Exploratory analyses will still be reported 
transparently, even if not sufficiently powered for confirmatory inference.  
 
Recruitment {15} 
Participants will be recruited from three outpatient clinics in Germany: the Department 
of Psychiatry and Psychotherapy at the University Hospital Marburg and two associated 
units at Goethe University Frankfurt (Department of Clinical Psychology and 
Psychiatric Outpatient Unit). Recruitment strategies via clinician referrals, online 
platforms (e.g., university websites), printed flyers, and internal registries. After initial 
contact, interested individuals are screened via structured clinical interviews and 
standardized eligibility checklists. EMA feasibility and technological prerequisites (e.g., 
smartphone access, compliance capacity) are also evaluated prior to enrollment. 
 

Assignment of interventions: allocation  
Sequence generation {16a} 
Participants will be assigned to study arms using a computer-generated randomization 
sequence (in RStudio) to ensure allocation is unpredictable and free from systematic 
bias. The allocation sequence will be developed prior to participant enrollment and will 
use block randomization to maintain balanced group sizes across study arms. No 
stratification factors will be applied. 
Concealment mechanism {16b} 
To prevent prior knowledge of allocation and minimize selection bias, allocation 
concealment will be rigorously maintained. The sequence will be concealed from 
investigators enrolling and assessing participants by employing sequentially numbered, 
opaque, sealed envelopes. The envelopes will be prepared in advance, sealed, and 
numbered in strict order, and will only be opened after completion of the baseline 
assessment of the respective patient. 
Implementation {16c} 
An independent staff member, not involved in the assessment or enrollment of 
participants, will generate the allocation sequence. Enrollment and eligibility 
determination will be performed by trial investigators, while group assignment will 
occur via the concealed allocation mechanism described above. This separation of roles 
ensures that allocation is both secure and unbiased throughout the recruitment process. 
 
Blinding  
Due to the nature of the interventions, full blinding is not feasible. Participants are aware 
of their assigned treatment condition, as the interventions differ in format. Similarly, 
therapists and prescribing physicians are not blinded. However, clinical outcome 
assessments, specifically structured interviews such as the HAM-D, are conducted by 
trained raters who remain blinded to group allocation wherever possible. To reduce 
analytical bias, data analysis will be conducted on pseudonymized datasets, with group 
identifiers masked during preprocessing and statistical modeling stages (Schulz et al., 
2010). 

 
Who will be blinded {17a} 
The clinical outcome ratings post-treatment are conducted by trained raters who are not 
involved in treatment delivery and remain blinded to treatment allocation wherever 
feasible. 
 
Procedure for unblinding if needed {17b} 
If a blinded outcome rater inadvertently becomes aware of group allocation, this will be 
documented, and, where possible, subsequent ratings will be reassigned to a different 
rater who remains blinded. Any instances of loss of blinding and resulting deviations 
will be reported in the trial documentation and considered in sensitivity analyses. 
 
Data collection 
Plans for assessment and collection of outcomes {18a}: An overview over 
assessments and collection of outcome during baseline, treatment and post-treatment 
period is given in Table 1. 
 
Plans to promote participant retention and complete follow-up {18b}: Participant 
retention during baseline, treatment and post-treatment 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} 
All data will be managed in accordance with the EU General Data Protection Regulation 
(GDPR) and institutional data protection protocols. Self-report and interview data will 
be pseudonymized at the point of entry. EMA data are collected via a secure mobile 
application (m-path) and transmitted using encrypted channels. Study data will be stored 
on secure servers with access restricted to authorized personnel. Data integrity is ensured 
through automated quality checks, regular manual audits, and double entry for critical 
clinical variables. After the study concludes, data may be shared in anonymized form 

for secondary analysis, contingent on ethical approval and data use agreements. Long-
term archiving (minimum 10 years) is guaranteed in line with university policy and good 
scientific practice. 
 
Statistical methods 
Statistical methods for primary and secondary outcomes {20a}:  
Analyses will be conducted in accordance with current standards in network 
psychometrics and time-series modeling. To examine the effects of treatment allocation 
on symptom dynamics (Research Question 1), we will use network intervention analysis 
(Fishbein et al., 2023), a method capable of capturing both direct and indirect effects of 
experimental conditions on network structure. Group comparisons of network 
connectivity and structure (Research Questions 2 and 4) will be conducted using 
network comparison tests and global strength metrics (van Borkulo et al., 2015; Blanken 
et al., 2019). Differences in early versus delayed treatment response will be assessed 
using logistic regression (Zhou et al., 2021). To address Research Questions 5 and 6, 
mixed-effects models and moderated logistic regressions will be used to evaluate 
whether baseline temporal characteristics, such as outstrength and symptom variance, 
moderate treatment response (Grimes et al., 2025). These models will include time-by-
group interactions and random effects to account for within-subject dependency. 
The analytic strategy may vary depending on the operationalization of change processes 
(e.g., as nodes or edges). Planned analyses will be implemented in R using appropriate 
packages for temporal and multilevel network modeling (e.g., mlVAR, qgraph, mgm).  
 
Methods for additional analyses {20b}:  
Additional exploratory analyses may incorporate fMRI data, particularly to investigate 
associations between changes in psychological networks and neural circuits. However, 
these neuroimaging analyses are considered supplementary and not part of the primary 
inferential framework. 
 
Methods in analysis to handle protocol non-adherence and any statistical methods 
to handle missing data {20c}:  

Per-protocol analysis will include all participants attending at least 80% of 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. 
 
Composition of the data monitoring committee, its role and reporting structure 
{21a}. The risk profile of this study is classified as minimal, as the interventions do not 
pose a significant threat to the physical or psychological well-being of the participants. 
Consequently, a dedicated, independent Data and Safety Monitoring Board (DSMB) is 
not required. General data quality and participant safety will be continuously monitored 
and reviewed within the framework of the LOEWE Dynamic Centre and its integrated 
Data Hub, ensuring high standards of oversight and scientific integrity 
 
Interim analyses {21b}: N/A (An interim analysis is not planned). 
  
Adverse event reporting and harms {22} 
All interventions in this study, including pharmacological treatment with SSRIs and 
CBT group therapy, are recognized and established therapies delivered in accordance 
with current clinical guidelines. Nevertheless, monitoring for adverse events remains a 
core part of the study's safety procedures. Adverse events will be systematically 
documented throughout the trial, regardless of their suspected relationship to the 
intervention. Reports of symptoms, side effects, or other medical occurrences will be 
collected via participant self-report. Each reported adverse event will be evaluated by 
qualified study personnel for its severity and potential relationship to the intervention in 
line with standard clinical practice. Any serious adverse events, including those 
requiring hospitalization or resulting in significant health changes, will be promptly 
reported, as required by applicable regulations. These safety protocols are designed to 
align with established good clinical practice, ensuring the well-being of participants 
even though the treatments themselves are not experimental or investigational. Regular 
review of adverse events will be conducted to identify any emerging safety concerns, 
and appropriate measures will be taken as needed. At the conclusion of the trial, an 
aggregated summary of all reported (serious) adverse events will be provided, 
maintaining full transparency. 

 
Frequency and plans for auditing trial conduct {23} 
The conduct of the study will not be audited by an independent committee.  
 
Research ethics approval {24} 
Applied for (Ethikkommission des Fachbereiches Medizin, Philipps-Universität) 
Marburg / Ethics committee, Marburg University Medical School, Marburg, Germany) 
 
Plans for communicating important protocol amendments to relevant parties {25} 
Changes to the study protocol will be communicated to the ethics committee and the 
trial registry. 
Who will take informed consent? {26a} 
Written informed consent is obtained from all participants prior to any study-related 
procedures. During the consent process, individuals are informed about the aims, 
structure, duration, and potential burdens of participation, including frequent EMA 
prompts and optional neuroimaging assessments. Participants are also informed of their 
right to withdraw from the study at any time without providing a reason and without 
penalty. Consent materials are formulated in accessible language, and study staff ensure 
comprehension through verbal explanation and clarification. All consent procedures 
follow institutional guidelines and the ethical standards outlined in the Declaration of 
Helsinki. 
Additional Consent Provisions for Collection and Use of Participant Data and 
Biological Specimens in Ancillary Studies {26b} 
At present, no ancillary studies involving additional collection or use of participant data 
or biological specimens are planned within this trial. Should any ancillary studies be 
considered in the future, additional informed consent will be obtained from participants, 
detailing the purpose, procedures, and data use specific to such studies, in accordance 
with applicable ethical and 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.  
Provisions for post-trial care {30} 
All interventions provided in this trial, including group cognitive behavioral therapy and 
pharmacological treatment with SSRIs, are established treatments delivered according 
to recognized clinical guidelines. After study completion, participants will continue to 
receive standard care from their usual healthcare providers, and clear guidance will be 
given, where appropriate, to support the ongoing management of their mental health. 
Should any medical or psychological support be required as a consequence of trial 
participation, referral to appropriate care services will be arranged. In line with ethical 
and regulatory requirements, any harm clearly related to study procedures will be 
documented and managed in accordance with institutional policies; participants will be 
informed about the available support should the need arise. No further care or additional 
post-trial interventions beyond standard clinical care are planned for this study in 
accordance with current guidelines and the nature of the interventions used. 
 
Dissemination plans {31a} 
Study results will be disseminated through peer-reviewed publications, with at least one 
main manuscript reporting the primary analyses of symptom network change over time. 
Further publications will address secondary and exploratory outcomes, including 
potential neurobiological correlates of symptom dynamics. Findings will also be 
presented at national and international scientific conferences in the fields of clinical 
psychology, psychiatry, and network science. In line with open science practices, key 
study materials (e.g., analysis scripts, preregistration protocols) will be made available 
via platforms such as the Open Science Framework (OSF). Anonymized datasets may 
be shared upon reasonable request and subject to ethical approval. Participants will 
receive a lay summary of results following study completion, made available in 
accessible language and format. 
 

Authorship eligibility guidelines and any intended use of professional writers {31b} 
Authorship for all study publications will be determined in accordance with 
internationally recognized standards. Individuals who have made substantial 
contributions to the conception, design, conduct, analysis, or interpretation of the study, 
as well as drafting or critically revising manuscripts, will qualify for authorship. All 
authors will be required to approve the final version of any manuscript prior to 
submission for publication. Contributions that do not meet full authorship criteria will 
be acknowledged appropriately. No professional writers will be employed in the 
preparation of study manuscripts; all publications will be authored by members of the 
research team and collaborators involved in the study. 
 
Plans to give access to the full protocol, participant level-data and statistical code 
{31c} 
Access to the full, final study protocol, anonymized participant-level data, and the 
statistical analysis code will be made available to qualified researchers upon reasonable 
request. Data sharing will comply with all relevant legal and ethical regulations. 
Requests can be submitted to the principal investigators, who will review and facilitate 
access in accordance with institutional policies. 
Plans for collection, laboratory evaluation and storage of biological specimens for 
genetic or molecular analysis in this trial/future use {33} 
Not applicable. 
 
Discussion 
This paper outlines the study protocol for a randomized controlled trial (RCT) 
examining mechanisms of change in group cognitive behavioral therapy (CBT), 
antidepressant medication, and a combination of both treatments in patients with 
depression. Ecological momentary assessment (EMA) will be employed to monitor 
symptom fluctuations during a baseline phase. Changes in network structure during the 
treatment phase will then be compared from baseline to post-treatment. Additionally, 
brain imaging data will be collected at both baseline and post-treatment to investigate 

the relationship between network perturbations and alterations in brain activation 
patterns. 
 
Limitations 
Several limitations of the study should be acknowledged: 
 
(a) Lack of a placebo or waitlist control condition. 
Although there are valid arguments against including a non-active control condition in 
clinical trials, its absence may affect the internal validity of the study. Any observed 
differences in change processes across treatment conditions cannot be clearly attributed 
to the interventions themselves, as they may reflect the passage of time or other non-
specific study effects. However, the inclusion of a baseline phase without active 
treatment may help control for these factors. 
 
(b) Treatment preference and compliance. 
Because randomization occurs after the baseline assessment, participants are blinded to 
treatment allocation when completing baseline measures. Nevertheless, individual 
treatment preferences may influence willingness to proceed with the assigned condition, 
potentially leading to a higher number of non-starters and threatening internal validity. 
 
(c) Influence of depression severity and pretreatment course. 
Severity of depression and pretreatment course (i.e., chronic, recurrent, or first episode) 
are known to moderate treatment effects and may significantly impact change processes 
(Van Borkulo et al., 2015; Kelley et al., 2023). Due to the limited sample size, we are 
unable to control for both factors simultaneously. We have therefore opted to stratify 
participants by severity and conduct post hoc analyses on the impact of pretreatment 
course. However, any imbalance between conditions with regard to pretreatment course 
may still compromise internal validity. 
 
(d) Challenges in long-term follow-up. 
Given the high relapse rate associated with depression, long-term follow-up is necessary 
to evaluate the sustainability of change processes and the prevention of relapse or 

recurrence. Although we intend to assess long-term outcomes, we anticipate a high 
attrition rate, which may limit the validity of the longitudinal findings. 
 
Strengths 
A major strength of this study is its inclusion of three active treatment conditions, 
allowing for direct comparisons of change processes in monotherapies and combined 
treatment. This design enables the identification of both synergistic and potentially 
antagonistic interactions between group CBT and pharmacological treatment. 
To our knowledge, this is the first study to examine differences in network changes 
using a design that compares combined psychological and pharmacological 
interventions with the respective monotherapies. As treatment personalization becomes 
increasingly important for enhancing therapeutic outcomes, identifying mechanisms of 
change represents a significant advancement. With this study, we aim to contribute to 
the development of more precise and individualized treatment allocation strategies for 
patients with depression. 
 
 
Trial status 
 
Research protocol, version x.  
 
Declarations 
Acknowledgements 
This work is funded by the LOEWE DYNAMIC center of the Hessian Ministry of 
Science and Arts (Grant Number: LOEWE1/16/519/03/09.001(0009)/98). 
 
Authors' contributions 
IN, ME, TM and US conceived the trial and drafted the study protocol. ME and AN 
developed the EMA assessment and dynamic network analyses. LS, OG, SGH and TK 
contributed to the trial design and protocol development and obtained ethical approval.  

All authors conduct recruitment and data collection. IN, ME and US drafted the article 
and all authors read, edited, and approved the final manuscript. 
 
Funding 
This work is funded 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). 
 
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. 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. 
 
Ethics approval and consent to participate 
The protocol has been approved by the Ethics Committee at the Department of 
Psychology (Registration number: 2025-2718). Protocol amendments will be 
communicated at https://clinicaltrials.gov and detailed in publications.  
 
Consent for publication 
Not applicable. 
 
Competing interests 
All authors declare that they have no conflicts of interest. 
 
 

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