Prediction and Outcome Study in PTSD and (Cluster C) Personality Disorders
Phase: NA
Conditions: Posttraumatic Stress Disorder (PTSD), Avoidant Personality Disorder, Dependent Personality Disorder, Obsessive Compulsive Personality Disorder
Sponsor: Arkin

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RESEARCH PROTOCOL  
  
PROSPER  
Prediction and Outcome Study  in 
PTSD and Personality disorders  
  
  
   
Version [8], 22 June 2020   
  
  
  
  
  
  
PROTOCOL TITLE:     

- PROSPER - Prediction and Outcome Study on PTSD and Personality disorders -  
  
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PROSPER  
Prediction and Outcome Study  in 
PTSD and Personality disorder  
Protocol ID  
ABR 61495 NL61495.029.17  
Short title  
PROSPER  
EudraCT number   
Not applicable  
Version  
8 
Date  
22 June 2020  
Administrative coordinator   
- J.M.G. Haanraadts, Raad van Bestuur  
Sinai Center, Laan van de Helende Meesters 2  
PO Box 2063, 1180 EB Amstelveen 
  T (020) 545 7275 / M (06) 3038 
9126  
h.haanraadts@sinaicentrum.nl  
Per 1-8-2017 Mw E. Vedel, Raad van Bestuur,   
Ellen.Vedel@sinaicentrum.nl  
Principal investigator  
  
- Dr. K. Thomaes, MD PhD  
Sinai Center, Laan van de Helende Meesters 2  
PO Box 2063, 1180 EB Amstelveen   
&  VU University Medical Center 
Department of Psychiatry  
PO Box 7057, 1007 MB Amsterdam  
Tel: 020-5457200/7224 (di-wo) / M    
Email: Kathleen.Thomaes@sinaicentrum.nl  
Authorized representative  
- Prof. Dr. J. Dekker  
Head of Research, Arkin - Research,   
Klaprozenweg 111, 1033 NN Amsterdam  
& Clinical Psychology, VU University,   
Van den Boechorstraat 1, 1081 BT Amsterdam  
Tel 020-5905000 Email: jack.dekker@arkin.nl  

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Project members  
  
- 
Prof dr. A.T.F. Beekman  
VU University Medical Center  
Department of Psychiatry  
PO Box 7057, 1007 MB Amsterdam  
Email: a.beekman@ggzingeest.nl  
- 
Prof. dr. O.A. van den Heuvel  
VUmc, Department of Psychiatry, Amsterdam  
Tel: 020-4440196; Email: 
oa.vandenheuvel@vumc.nl  
- 
Dhr. M. Blankers / Dhr. J. Peen, Arkin - 
Research,  
Amsterdam (datamanagement/clinical data)   
Email: mattijs.blankers@arkin.nl  
- 
Dhr. M. Eikelenboom, VUmc, Department of 
Psychiatry, Amsterdam (datamanagement/MRI 
and biological data)  
Email: m.eikelenboom@vumc.nl  
- 
Dr. C. Vriend, VUmc, Department of 
Psychiatry,  
Amsterdam. Email: c.vriend@vumc.nl  
Sponsor (in Dutch:  
verrichter/opdrachtgever)  
Mw. J.M.G. Haanraadts, bestuurder Sinai Center   
Laan van de Helende Meesters 2  
PO Box 2063, 1180 EB Amstelveen   
Tel: 020-5457200  
Per 1-8-2017 Mw E. Vedel, Raad van Bestuur,   
Ellen.Vedel@sinaicentrum.nl  
Subsidising party  
Stichting Steunfonds Joodse Geestelijke  
Gezondheidszorg (SSF JGG), Dhr. S. Glaser, 
voorzitter, Postbus 2063, 1180 EB Amstelveen, 020-
5457275.   
Independent expert  
Dhr H. Nusselder, psychiatrist, Arkin/Mentrum, 
Eerste  
Constantijn Huygensstraat 38, 1054 BR 
Amsterdam,  
Email: Hans.Nusselder@mentrum.nl; Tel: 06-
15055622  

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Laboratory sites   
MRI, laboratorium VUmc, via VUmc/Department of  
Psychiatry  
Pharmacy   
Not applicable  
 Coordinator study monitoring  
Not applicable    
PROTOCOL SIGNATURE SHEET  
  
Name  
Signature  
Date  
Sponsor or legal representative:  
Mw. J.M.G. Haanraadts  
Per 1-8-2017 Mw E. Vedel  
FOR SIGNATURES PLEASE SEE 
DOC:   
A1 ‘Aanbiedingsbrief PROSPER’  
  
Head of Departments:   
- Research Arkin / Clinical 
Psychology  
VU   
Prof. dr. J. Dekker  
- Psychiatry VUmc:   
Prof dr. A.T.F. Beekman  
  
  
Coordinating Investigator/Project 
leader/Principal Investigator:  
Dr. K. Thomaes, MD/PhD   
  
  
  
   
TABLE OF CONTENTS  
  
1. 
INTRODUCTION AND 
RATIONALE................................................................................................. 11  
2. 
OBJECTIVES 
................................................................................................................................... 17  
3. 
STUDY DESIGN 
............................................................................................................................... 18  
4. 
STUDY POPULATION 
..................................................................................................................... 22  
4.1 Population 
.............................................................................................................................. 22  

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4.2 Inclusion criteria 
.................................................................................................................... 22  
4.3 Exclusion criteria 
................................................................................................................... 22  
4.4 Sample size calculation 
......................................................................................................... 23  
5. 
METHODS 
..................................................................................................................................... 24  
5.1 Study parameters/endpoints 
............................................................................................... 24  
5.1.1 
Main and secondary study parameters/endpoints 
..................................................... 24  
5.1.2 
Secondary outcome parameters 
................................................................................. 24  
5.1.3 
Biological predictors 
...................................................................................................... 25  
5.1.4 
Psychological predictors 
............................................................................................... 25  
 
Table 1  
Overview of measurements: interviews and questionnaires 
..................................... 27  
 
Table 2  
Overview of add-on cognitive tasks and biological measurements 
.......................... 28  
 
Table 3  
Overview of duration of measurements (in minutes) 
................................................ 28  
5.2 Randomisation, blinding and treatment allocation 
................................................................. 28  
5.2.1 
Randomization 
..................................................................................................................... 28  
5.2.2 
Unblinding Procedure 
.......................................................................................................... 29  
5.3 Study procedures 
....................................................................................................................... 29  
5.4 Withdrawal of individual subjects 
.............................................................................................. 32  
5.5 Replacement of individual subjects after withdrawal 
............................................................... 32  
5.6 Follow-up of subjects withdrawn from treatment 
................................................................... 33  
5.7 Premature termination of the study 
......................................................................................... 33  
6. 
SAFETY REPORTING 
..................................................................................................................... 34  
6.1 Section 10 WMO event 
......................................................................................................... 34  

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6.2 AEs, SAEs and SUSARs 
......................................................................................................... 34  
6.2.1 
Adverse events (AEs) 
........................................................................................................... 34  
6.2.2 
Serious adverse events (SAEs) 
........................................................................................... 34  
6.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
.......................................... 35  
6.3 Annual safety report 
............................................................................................................ 35  
6.4 Follow-up of adverse events 
................................................................................................ 35  
6.5 Data Safety Monitoring Board 
............................................................................................. 36  
7. 
STATISTICAL ANALYSIS 
.................................................................................................................37  
7.1 Primary study 
parameters.....................................................................................................37  
7.2 Secondary study parameters 
............................................................................................... 39  
7.3 Other study parameters 
....................................................................................................... 39  
7.4 Interim analysis (if applicable) 
............................................................................................. 39  
8. 
ETHICAL CONSIDERATIONS 
....................................................................................................... 40  
8.1 Regulation statement ...................................................................................................... 
40  
8.2 Recruitment and consent ................................................................................................ 
40  
8.3 Benefits and risks assessment, group relatedness ......................................................... 
40  
8.4 Compensation for 
injury.................................................................................................... 41  
8.5 Incentives 
........................................................................................................................... 41  
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
........................................... 42  
9.1 Handling and storage of data and documents ............................................................... 
42  
9.2 Monitoring and Quality Assurance .................................................................................. 
42  
9.3 Amendments .................................................................................................................... 
42  

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9.4 Annual progress report .................................................................................................... 
43  
9.5 End of study report .......................................................................................................... 
43  
9.6 Public disclosure and publication policy ......................................................................... 
43  
10. 
STRUCTURED RISK ANALYSIS 
................................................................................................. 44  
10.1 Potential issues of concern .............................................................................................. 
44  
10.2 Synthesis ........................................................................................................................... 
44  
11. 
REFERENCES 
............................................................................................................................. 45  

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
  
ABR  
ABR form, General Assessment and Registration form, is the application 
form that is required for submission to the accredited Ethics Committee (In 
Dutch, ABR =  
Algemene Beoordeling en Registratie)  
AE  
Adverse Event  
AR  
Adverse Reaction  
CA  
Competent Authority  
CCMO  
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale  
Commissie Mensgebonden Onderzoek  
CV  
Curriculum Vitae  
DSMB  
Data Safety Monitoring Board  
EU  
European Union  
EudraCT  European drug regulatory affairs Clinical Trials   
GCP  
Good Clinical Practice  
IB  
Investigator’s Brochure  
IC  
Informed Consent  
IMP  
Investigational Medicinal Product   
IMPD  
Investigational Medicinal Product Dossier   
METC   
Medical research ethics committee (MREC); in Dutch: medisch ethische 
toetsingcommissie (METC)  
(S)AE  
(Serious) Adverse Event   
SPC  
Summary of Product Characteristics (in Dutch: officiële productinfomatie 
IB1-tekst)  
Sponsor  The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical company, academic hospital, 
scientific organisation or investigator. A party that provides funding for a 
study but does not commission it is not regarded as the sponsor, but 
referred to as a subsidising party.  
SUSAR  Suspected Unexpected Serious Adverse Reaction  
Wbp  
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)  

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WMO  
 
  
Medical Research Involving Human Subjects Act (in Dutch: Wet 
Medischwetenschappelijk Onderzoek met Mensen  
 
PM: See abbreviation of measures in section 5.1.1. and page 23   
 
  
SUMMARY  
Rationale: Evidence-based treatments for posttraumatic stress disorder (PTSD), such as 
Eye  
Movement Desensitization and Reprocessing (EMDR) and Imagination and Rescripting 
Therapy (ImRs), are highly effective treatments in the majority of the PTSD patients. 
PTSD is highly comorbid with personality disorders (PD), especially borderline personality 
disorder (BPD), and cluster C - avoidant, dependent, or obsessive-compulsive - 
personality disorders (CPD). It is not clear yet what treatment is most effective for those 
who suffer from both PTSD and PD. There is growing motivation in clinicians to offer 
PTSD treatments to PTSD with comorbid PD, because these treatments are highly 
effective, relatively short (weekly sessions, 3-6 months) and there is some evidence that 
with PTSD treatment, comorbid PD symptoms might resolve as well. PTSD treatments are 
less time-consuming than PD treatments and - at least in the short term - financially 
attractive. However, at least 30-44% PTSD patients do not sufficiently respond to these 
treatments. Moreover, a high number of PTSD patients are excluded from these 
therapies because of suicidality, self-destructive behaviour or other personality problems. 
Therefore, it might be more efficient to add a PD treatment at the same time. Evidence-
based treatments for personality disorders (PD), such as dialectical behaviour treatment 
(DBT) for BPD, and schemafocused treatment (SFT) for CPD are well established. These 
treatments are more intensive (twice a week for at least one year) than PTSD treatments. 
There is some evidence that integrated PTSDPD treatment is twice as effective on 
reducing PTSD symptoms than PD treatment alone, but integrated PTSD-PD treatment is 
not yet directly compared to PTSD treatment alone. This study will address this 
knowledge gap, including secondary outcome measures on functioning, quality of life 
and cost-effectiveness.  
The result of this study might be that one or the other treatment works better, depending 
on the personal profile of the patient. So far, some psychological factors have been found 

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to be associated with worse outcome of PTSD treatment. These are cognitive 
(educational level, working memory emotion regulation), affective (anger, sleep 
problems, dissociation), and relational factors (therapeutic alliance, attachment, social 
support). In addition, neurobiological factors are found to be associated with PTSD 
treatment outcome, such as increased activity connectivity of the limbic network and 
decreased activity and connectivity of the cognitive control networks, and disturbed 
hormonal levels and epigenetic factors (5-HTTLPR, BDNF, cortisol/FKBP5-methylation, 
oxytocin/OXTR). Because these candidate predictors are found on a group level (in non-
responders vs. responders), they cannot directly be used on an individual level. By using 
machine-learning techniques we might use these candidate predictors on an individual 
level to guide treatment choices and thereby personalise psychiatry.   
We hypothesize that in patients with PTSD with BPD, integrated DBT-EMDR treatment 
results in a higher effect size and higher response rate than EMDR-only (A1); in patients 
with PTSD and CPD, integrated SFT- ImRs treatment results in a higher effect size and 
higher response rate than ImRs only (A2). Furthermore, we hypothesize that non-
response to PTSD-treatment can be individually predicted by a machine-learning model 
with (B1) psychological factors (cognitive, affective, and relational) and (B2) 
neurobiological factors (neural factors, and hormonal/ epigenetic factors.  
  
Objective: In the current project, we will firstly study effectiveness of PTSD-treatment 
compared to integrated PTSD-PD-treatment in treatment-seeking, adult patients with 
comorbid PTSD and PD in a wide range of severity (minimally 4 criteria of a personality 
disorder). Secondly, we will investigate psychological (cognitive, affective, and relational) 
and neurobiological candidate predictors of treatment outcome, and use them in a 
machine-learning paradigm to come to a clinically useful and individual prediction 
instrument of treatment outcome.  
  
Study design: Two related randomized controlled trials (A1, A2) with prediction analyses 
(B1, B2).  
  
Study population: With the assumptions of a small effect size (< 0.5) of PTSD treatment in 
patients with comorbid PTSD and PD and a double effect size of integrated PTSD-PD-

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treatment (1.0), the number of persons needed to include is 50 persons per condition to 
reach for 80% power. Expecting a dropout rate of 25%, we will include 63 persons per arm, 
for 4 arms a total of 252 adult patients with PTSD and - at least 4 - PD symptoms. Of these 
patients, 80 next to 40 healthy matched controls will be asked for additional MRI 
research before and after treatment. In total, 292 persons will be included in this study.  
  
Intervention: In patients with PTSD and BPD: EMDR (3-6 months plus 6-9 months 
treatment pause) compared to integrated DBT-EMDR (12 months); in patients with PTSD 
and CPD:  ImRs (3-6 months plus 6-9 months treatment pause) compared to integrated 
ImRs-SFT (12 months).  
  
Main study parameters/endpoints: Primary outcome measure is PTSD symptom severity 
after 12 months. Secondary outcome measures are PD symptoms (SCID-5-PD), disability 
(WHODAS), quality of life (EQ-5D-5L) and health costs (Tic-P). At baseline (T0) and after 12 
months (T4) clinical interviews (CAPS-5, SCID-5-PD dimensional score) and self-rating 
scales (PCL-5) will be used. After 3 (T1), 6 (T2), 9 (T3), and 18 months (follow-up), 
questionnaires only will be used. At baseline, candidate predictors will be measured 
including above mentioned cognitive, affective, relational factors, and hormonal and 
epigenetic factors. In a subgroup, structural and functional MRI, with resting-state and an 
emotion processing (face recognition) will be performed.   
  
Nature and extent of the burden and risks associated with participation and benefits: 
The burden and risks associated with participation in this study is reasonable. All patients 
will receive psychotherapy, which is considered to be the most effective treatment for 
PTSD and PD. There is evidence that all four conditions are therapeutic in patients with 
PTSD and PD and no evidence yet what condition is more effective. Total time of the six 
measurements is approximately 5 hours per patient for interviews and 5 hours for 
questionnaires (see table 3), which are partly part of the routine outcome measurements 
(ROM). Questionnaires can be filled in at home. On the one hand, extensive clinical 
interviews and self-rating scales can be felt as disturbing because of fatigue, taken time 
and emotional burden. On the other hand, patients may feel well recognized by the time 
taken by specialized clinicians for them. Assessors will be well-trained and work in close 

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connection with the treatment teams. For predicting treatment response, biological and 
genetic measures are integrated in the study. These measurements include physical 
examination, blood samples and hair samples. The burden and risk associated with the 
baseline blood sample and hair sample is reasonable. For the subgroup of MRI research, 
participants will twice have a 60-minute MRI session during which they will perform 
affective-laden tasks during scanning. Functional MRI is a commonly used technique that 
is considered to be safe if you follow the safety instructions (e.g. no metal objects in the 
MRI room) and contraindications (e.g. no metal implants, not pregnant, no seriously 
claustrophobia). Lying in the scanner while performing affective-laden tasks in the 
scanner can occasionally give patients uncomfortable feelings of anxiety and distress by 
reliving of their traumatic experiences. During and after the scan procedure a debriefing 
will be held to cover this by the executor of the scan protocol. The principal investigators 
of this study have long experience with symptom provocation in the scanner (Thomaes: 
early traumatized PTSD patients with comorbid personality disorders: only 1 in 33 patients 
had a panic attack; OA van den Heuvel in patients with panic disorder, PTSD, OCD, 
Tourette, Parkinson, hypochondriasis: panic attacks were rare and not more frequently 
than healthy controls). In all, we consider the risk and burden associated with 
participation to be low.   
There are no benefits for individual patients participating in this study. Benefits for PTSD 
patients as a whole are that this study will provide important information about profiling 
patients guiding optimal treatment choices base on individual prediction models in 
patients with both PTSD and personality problems. It will help to know what works for 
whom and personalize mental health care as short as possible and at the main time most 
effective. It will help to understand why  
(working mechanisms) what treatment works best for whom.   
  
 
1. INTRODUCTION AND RATIONALE  
  
Part A: Treatment outcome in PTSD with comorbid PD  
Posttraumatic stress disorder (PTSD) develops in about 9-18% of trauma-exposed persons 
and involves considerable impairments in functioning (Breslau et al., 1998). This syndrome 
consists of re-experiencing of traumatic details (e.g. flashbacks and nightmares), 
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and hyper-arousal, e.g. irritability, over-alertness symptoms (DSM-5). Evidence-based 
treatments for PTSD are trauma-focused cognitive behaviour therapy (TF-CBT) - including 
imaginary of prolonged exposure (IE/PE) and cognitive therapy (CT, i.e. without exposure 
element) - and eye movement desensitization and reprocessing (EMDR) (Balkom van et 
al., 2013, Bisson et al., 2013, Bisson et al., 2007). More recently, there is growing evidence 
of effectiveness of Imagination and Rescripting Therapy (ImRs) for PTSD, as a separate 
PTSD-treatment  (Raabe et al., 2015). Effect sizes of TF-CBT compared to waitlist/usual 
care are generally large (standardised mean difference, SMD -1.62; 95% CI -2.03 to -1.21; 28 
studies; n = 1256) (Bisson et al., 2013). Effect sizes of EMDR (SMD -1.17; 95% CI -2.04 to -
0.30; 6 studies; n = 183 respectively) are similarly large, and although EMDR is less well 
studied than TF-CBT (Bisson et al., 2013), it is practised increasingly.   
 PTSD treatments are highly effective treatments in the majority of PTSD. However, at 
least 3044% PTSD patients do not sufficiently respond to these treatments or drop out of 
treatment prematurely (Bradley et al., 2005, van Rooij et al., 2016). Even more PTSD 
patients are excluded from these therapies because of suicidality, self-destructive 
behaviour or other personality problems (Dorrepaal et al., 2014, Ehring et al., 2014). PTSD 
is highly comorbid with personality disorders (PD), around 60%, especially borderline 
personality disorder (BPD), and cluster C - avoidant, dependent and obsessive-compulsive 
- 
personality 
disorders 
(CPD) 
(Landelijke 
Stuurgroep 
Multidisciplinaire 
Richtlijnontwikkeling in de GGZ, 2008). This comorbidity is associated with more severe 
symptoms and worse functioning than PTSD or PD alone (Fría & Palma 2015). PDs are 
associated with significant personal and societal burden and tend to run a chronic course, 
at least in the first year (Gunderson et al., 2011, Bohus et al., 2013). Longer-term courses 
are more favourable: 88% of BPD patients achieved remission after 10 years, with the 
largest remission within 2 years (39.3%) and another part within 4 (22.3%) and 6 years 
(21.9%). Predictors of later remission were mainly childhood sexual abuse and a CPD 
(Zanarini et al., 2006).   
It is not clear yet what treatment is most effective for those who suffer from both PTSD 
and PD. There is growing motivation in clinicians to offer PTSD treatments to PTSD 
patients with comorbid PD, because these treatments are highly effective, relatively short 
(weekly sessions, 3-6 months), and there is some evidence that with PTSD treatment, 
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Clarke et al., 2008, Roberts et al., 2017, Kredlow et al., 2017). However, it may be more 
efficient to add a PD treatment at the same time. PTSD patients with (even mild) BPD 
symptoms were less likely to achieve good end-state functioning posttreatment (Feeny et 
al., 2002, Hembree et al., 2004) and dropped out twice as likely as PTSD patients without 
PD symptoms when receiving PTSD treatment alone (Zayfert et al., 2005). Worse end-
state functioning may lead to a higher relapse rate, which is over 20% in anxiety disorders 
(Penninx et al., 2011). This might be so because emotion dysregulation, interpersonal 
malfunctioning, attachment or other personality problems are not sufficiently dealt with 
in PTSD treatments.     
 Psychotherapy is the most effective treatment for all personality disorders (Leichsenring 
& Leibing, 2003). In BPD the strongest evidence exists for dialectical behaviour therapy 
(DBT) with moderate to large effect sizes for affective instability (SMD -1.07 [95% CI -1.61 - -
0.52]; n = 59) and anger (SMD -0.83 [95% CI -1.43 - -0.22]; n = 46, 2 RCTs), and moderate 
effect sizes in terms of impulsivity (SMD -0.61; 95% CI -1.14 to -0.09, n = 59), para-suicidality 
/ self-harm (SMD -0.54, 95% CI 0.92 to -0.16; n = 110, 3 RCTs) and general mental health 
(SMD 0.65 [95% CI 0.07 - 1.24]; n = 74, 2 RCTs) (Stoffers et al., 2012). For comparisons 
between different comprehensive psychotherapies in  
BPD, statistically significant superiority was demonstrated for DBT over client-centered 
therapy  
(Kliem et al., 2010), and schema-focused therapy (SFT) over transference-focused therapy 
(GiesenBloo et al., 2006). In CPD (avoidant, dependent, obsessive compulsive PD), no 
effect differences are found between different theoretical references, such as SFT and 
psychodynamic therapy (Svartberg et al., 2004). DBT and SFT both have their roots in 
cognitive behavioral therapy and working mechanisms are based on improving emotion 
regulation, consisting of strategies aimed at modulating and adjusting unpleasant 
emotional experiences (John & Gross, 2004; Pedersen et al., 2014). Although DBT and SFT 
are both improve emotion regulation skills, there are major differences in the explanatory 
models and techniques used in both methods (Fassbinder et al., 2016): DBT directly 
focuses on the acquisition of emotion regulation skills (mindfulness, distress tolerance, 
emotion regulation, interpersonal effectiveness) and patients are encouraged to train 
these skills on a regular basis; SFT focuses primarily on the avoidance of emotions and 
dysfunctional meta-cognitive schemas about the meaning of emotions by working with 
limited re-parenting, empathic confrontation and experiential techniques like chair 

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dialogs. As add-on to SFT, ImRs can be used specifically to focus on traumatic experiences 
(see above).  
 For PTSD with comorbid (B)PD an integrated DBT-PTSD-treatment is investigated in 3 
RCTs (Steil et al., 2011, Bohus et al., 2013, Harned et al., 2014). The first study showed 
moderate to large effect sizes of DBT-PTSD compared to waiting list, in terms of overall 
BPD severity (SMD -0.74 [95%CI -1.47 - -0.01]), depression (SMD -1.06 [95% CI -1.84 - -0.29]), 
and anxiety (SMD -0.96 [95% CI -1.72 - -0.20]) (Steil et al., 2011). The second study indicated 
that DBT-PTSD resulted in a greater mean change than waiting list on PTSD symptoms 
(CAPS 33.16 vs. 2.08), but not on BPD symptoms (Bohus et al., 2013). Integrated DBT-
PTSD-treatment was also compared to DBT-alone, and led to larger and more stable 
improvements in PTSD symptoms, doubled remission rate (80% vs. 40%), and decreased 
suicide rates (2.4 times less likely) and self-injury (1.5 times less likely), with moderate to 
large effect sizes for dissociation, trauma-related guilt cognitions, shame, anxiety, 
depression, and global functioning in completers (Harned et al., 2014). However, 
integrated PTSD-PD treatment is not yet directly compared to PTSD treatment alone.   
In summary, there is growing motivation in clinicians to offer PTSD treatments to PTSD 
with comorbid disorders, because these treatments are highly effective, relatively short, 
and there is some evidence that with PTSD treatment, comorbid PD symptoms might 
resolve as well. However, it may be more efficient to add a PD treatment at the same 
time. Evidence-based treatments for personality disorders (PD), such as dialectical 
behaviour treatment (DBT) for BPD, and schema-focused treatment (SFT) for CPD are well 
established. These treatments are more intensive (twice a week for at least one year) 
than PTSD treatments. There is some evidence that integrated PTSD-PD treatment works 
twice as good as PD treatment alone, but integrated PTSDPD treatment is not yet directly 
compared to PTSD treatment alone. This study will address this knowledge gap.  
  
Hypotheses A: We hypothesize that in PTSD with comorbid PD it is more effective to 
provide integrated PTSD-PD-treatment compared to PTSD treatment alone, primarily in 
terms of response rate in PTSD symptoms. Secondarily, we hypothesize that PD 
symptoms, disability and quality of life will improve and cost-effectiveness will be better 
with integrated treatment.   

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A1. In patients with PTSD with BPD, integrated DBT-EMDR treatment results in a 
higher response rate than EMDR-only;  
A2. In patients with PTSD and CPD, integrated SFT- ImRs treatment results in a higher  
response rate than ImRs -only.  
  
Part B: Predictors of PTSD treatment   
As yet, we cannot predict PTSD treatment outcome to individual patients. Certain 
candidate psychological predictors of treatment response are identified, at least on a 
group level. It was found that men with PTSD show worse treatment response than 
women (Tarrier et al., 2000, Karatzias et al., 2007). Younger age is associated with higher 
dropout (Rizvi et al., 2009). Type of trauma and severity of depressive symptoms were 
not found to be predictive of treatment response (Minnen van et al., 2002, Ehlers et al., 
2005, Ford & Kidd 1998, Rizvi et al., 2009, Forbes et al., 2002, Ronconi et al., 2015).  
  
Cognitive candidate predictors of PTSD treatment outcome are: educational level/ 
intelligence (Ehlers et al., 2005, Rizvi et al., 2009), working memory (Nijdam et al., 2015, 
Wild et al., 2008) and cognitive control of emotions, i.e. emotion regulation. Emotion 
regulation problems and an extern locus of control are associated with worse response to 
PTSD treatment (Cloitre et al., 2004, Arntz et al., 2007, Bardeen et al., 2013, Böttche 2016), 
including high suicide risk (Tarrier et al., 2000) and alcohol intake (Forbes et al., 2002). 
Borderline personality symptoms (affective instability and impulsivity) are related to 
worse end-state functioning (Feeny et al., 2002, Hembree et al., 2004, Barnicot et al., 2011) 
and higher drop-out from PTSD treatment (Zayfert et al., 2005, McDonagh et al., 2005), 
but not if symptoms are relatively mild (Clarke et al., 2008, Walter et al., 2012, Thornback 
et al., 2014).   
Affective factors found to be candidate predictors are related to hyper-arousal  
(anger/irritability, sleep problems/intrusions) or hypo-arousal (avoidance/numbing, 
dissociation), both key symptoms of PTSD. PTSD treatment is thought to be effective only 
when the patient’s affective state is within a window of tolerance: arousal enough to be 
able to work with the traumatic material but not too much overwhelmed by emotions 
(hyper-arousal) or disconnected from it (hypo-arousal). Severity of PTSD – if measured 
with a clinical interview – is associated with worse treatment response (Karatzias et al., 
2007, Taylor et al., 2003). Higher anger scores are related to worse response and higher 

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dropout (Forbes et al., 2003, Rizvi et al., 2009, Lloyd et al., 2014). Severity of dissociative 
symptoms is associated with worse response to PTSD-treatment  
(Ford & Kidd 1998, Lanius et al., 2010, Resick et al., 2012, Cloitre et al., 2010, 2012, Wolf et 
al., 2016,  
Bae et al., 2016), although this might not be true for mild dissociative symptoms 
(Hagenaars et al., 2010; Minnen van et al., 2016). Severe dissociation is however not 
predictive for worse treatment outcome in integrated PTSD-PD treatment (Zlotnick et al., 
1997, Chard et al., 2005, Dorrepaal et al., 2012, Cloitre et al., 2012, Kleindienst et al., 2016).   
 In addition, relational variables, such as quality of the therapeutic alliance (Cloitre et al., 
2004, Barnicot et al., 2011), credibility of the therapy (Taylor et al., 2003, Alfonsson et al., 
2016), attachment problems (Forbes et al., 2010), and especially a lack of social support 
are predictive of PTSD treatment response (Brewin et al., 2000; Yehuda et al., 2015).    
 Only few studies focused on neurobiological predictors of treatment response. It is 
assumed that PSTD treatments mainly rely on extinction and memory re-consolidation 
processes (Careaga et al., 2016). Extinction, in short, is the attenuation or disappearance 
of a previously learned response when that response is not reinforced. The amygdala and 
ventral anterior cingulate cortex (ACC) are associated with extinction processes and there 
is evidence that these neurobiological correlates normalize with treatment (Thomaes et 
al., 2014). Non-responders of TF-CBT showed greater amygdala and greater right ventral 
ACC activation in response to masked fearful faces before treatment compared to 
responders (Bryant et al., 2008a, Dickie et al., 2011, Schmidt et al., 2013, Rooij et al., 2016). 
A smaller ventral ACC volume and a smaller hippocampus volume were associated with 
poorer treatment response to TF-CBT (Bryant et al., 2008b, Rooij et al., 2015a). During 
viewing of negative picture before treatment, both decreased (Bryant et al., 2008a) as 
well as increased activity in the dorsal ACC – a region associated with emotion regulation - 
was found to be predictive of PTSD treatment response (Rooij et al., 2016), and this 
inconsistency of findings might point to heterogeneity in PTSD populations. In addition, 
non-responders showed an increased demand on the executive frontostriatal network 
during a response inhibition task (Falconer et al., 2013, Rooij et al., 2016) and increased left 
inferior parietal lobe activation, a region associated with attention processes (Rooij et al., 
2015b). In research into BPD response inhibition tasks are also used as a paradigm (see 
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Recently, research criteria and neurobiological models are set to prioritize factors 
to study and use them in a personalized precision psychiatry (RDoc-criteria of the National 
Institute of Mental Health, NIMH https://www.nimh.nih.gov/research-priorities/rdoc/; 
Heuvel et al., 2016, Williams 2016).  These models are close to the above-mentioned 
psychological candidate predictors of treatment outcome: 1) cognitive factors or 
‘cognitive’ brain networks, 2) affective factors related to the ‘limbic’ brain networks, and 
3) relational factors related to the ‘positive affect’ and social processing brain networks 
(see figure 1 below). Using these models will help to build a more dimensional instead of 
categorical psychiatric model that will be better applicable to treatment choice (Williams 
2016).   
Preliminary evidence exists on neurohormonal and associated (epi)genetic 
predictors of treatment outcome. A serotonin transporter gene promoter-region 
polymorphism (the LL 5HTTLPR genotype) was associated with greater responsiveness of 
PTSD to pharmacotherapy, while the S allele was associated with treatment non-response 
(Schmidt et al., 2013). Lower brain derived neurotrophic factor (BDNF) levels predicted a 
greater response to pharmacotherapy in PTSD (Schmidt et al., 2013). It is not clear yet if 
these factors might predict psychotherapy outcome as well. Cortisol levels and FKBP-5 
predicted PTSD susceptibility and might be useful as a treatment outcome marker too 
(Schmidt et al., 2013, Galatzer-Levy et al., 2017). The same holds for oxytocin and the 
oxytocin receptor (OXTR) gene (Bandelow et al., 2016; 2017)  
 Unfortunately, all those candidate predictors are found on a group comparison level only, 
and in few studies with small and heterogeneous groups of patients. Therefore, they are 
not yet applicable on an individual level for treatment choice. Single predictors have not 
shown a large explaining variance, in depressed or anxiety patients, while combining 
clinical with MRI data increased explained variance significantly (Serra-Blasco et al., 2016; 
Månsson et al., 2015; Ball et al., 2014; Doehrmann et al., 2013), using machine-learning 
models. Machine learning prediction models have also been made for pediatric obsessive-
compulsive disorder (Lenhard et al., 2017) and in depressed patients that received 
electroconvulsive therapy (Redlich and al., 2016). We will explore if candidate predictors 
of PTSD treatment outcome can be used in a machine-learning model to predict 
treatment outcome on an individual basis.  
  

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Hypotheses B: We hypothesize that non-response to PTSD-treatment and to integrated 
PTSD-PD treatment, can be individually predicted by a machine-learning model with:  
B1. Psychological factors:  Cognitive factors (educational level/IQ, working memory, 
emotion regulation), Affective factors (hyper-arousal: anger, sleep; hyper-arousal: 
dissociation), and Relational factors (therapeutic alliance, attachment, social 
support).  
B2. Neurobiological factors:  Neural factors (volumes ACC and hippocampus, activity 
and connectivity of salience and negative affect network and ventral and cognitive 
control network)), and Hormonal/ epigenetic factors (5-HTTLPR, BDNF, 
cortisol/FKBP5methylation, oxytocin/OXTR).  
  
2. OBJECTIVES  
  
The primary objectives of this study are:  
A. To investigate if in adult patients with PTSD and comorbid PD it is more effective to 
provide integrated PTSD-PD treatment compared to PTSD treatment alone in terms of 
response rate in PTSD symptoms:  
A1. In patients with PTSD with BPD, integrated DBT-EMDR treatment results in a higher 
effect size and higher response rate than EMDR-only.  

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A2. In patients with PTSD and CPD, integrated SFT- ImRs treatment results in a higher 
effect size and higher response rate than ImRs -only.  
B. To investigate individually prediction by a machine-learning model of PTSD treatment 
outcome in adult patients with comorbid PTSD and personality disorders (profiling), in 
order to improve treatment indication leading to more precise (personalized) and 
efficient treatments, with candidate predictors:  
B1. Psychological factors:  cognitive (educational level/IQ, working memory, emotion 
regulation), affective (hyper-arousal: anger, sleep; hyper-arousal: dissociation), and 
relational factors (therapeutic alliance, attachment, social support).  
B2. Neurobiological factors:  Neural factors (smaller ACC and hippocampus volume, 
increased right amygdala and ventral ACC activity and de/increased dorsal ACC 
activity), and Hormonal/ epigenetic factors (5-HTTLPR, BDNF, cortisol/FKBP5-
methylation, oxytocin/OXTR).  
  
  
3. STUDY DESIGN  
  
The design of this study consists of two – connected - RCTs comparing PTSD-treatment to 
integrated PTSD-PD treatment in patients with PTSD and comorbid PD in a specialized 
treatment setting (figure 2):   
A1. EMDR versus integrated DBT-EMDR, and  
A2. ImRs versus integrated SFT- ImRs.   
Assessment points are: baseline (T0), after 3 months (T1), after trauma treatment has 
finished, around 6 months (T2), 3 months after T2 (T3), after 12 months (T4) and at 18 
months (follow-up, FU).  
 PTSD treatments specifically address the troubling memories of the traumatic event and 
the personal meaning of the event and consist of 12 to 18 sessions in maximum 6 months, 
and are:  
- EMDR (Eye Movement Desensitization and Reprocessing)   
EMDR was developed in 1987 by Shapiro (De Jongh & Ten Broeke, 1998). In EMDR the 
therapist induces a bilateral stimulation once the client has focused the attention on a 
disturbing image or memory related to the traumatic experience. The bilateral stimulation 
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the left to the right with the instruction for the client to follow this movement of the hand 
with the eyes. Attention is drawn to what traumatic memory and the dysfunctional 
thoughts about it are currently doing with the patient and not to what the patient was 
thinking during the traumatic experience.   
- ImRs (Imagination and Rescripting Therapy) (Arntz et al., 2007, Raabe et al., 2015).  
In ImRs, the patient imagines the (onset of a) traumatic experience and subsequently 
changes the original course of events by imagining different interventions and outcomes, 
thereby allowing for the change of original schematic representations and cognitions 
(Hackmann et al., 2011). ImRs implies changing the traumatic imagery in fantasy, to 
produce a more favourable outcome (without denying the trauma), imagining having 
control over the situation and being able to act according to one’s needs, to express one’s 
feelings and action tendencies. ImRs was hypothesized to alleviate PTSD symptoms as 
well as change trauma-related beliefs and schemas (e.g. powerlessness, victimization, and 
inherent badness). It is suggested that ImRs might be more effective in patients with 
emotions and cognitions like anger, irrational guilt, shame disgust and/or self-contempt 
(Arntz et al., 2007).  
 Integrated PTSD-PD treatment consist of a PTSD treatment interwoven in a PD treatment 
that takes at least twice sessions per week, for the duration of one year:   
- DBT (Dialectical Behavior Treatment), a manualized outpatient cognitive–behavioral 
treatment with two components: (a) weekly individual therapy and (b) weekly group 
skills training. Individual sessions focus on a hierarchy of target behaviors, which the 
patient tracks on a daily basis with diary cards. Behavioral analyses of the pattern and 
chain of thoughts, emotions, and events take place routinely to help the patient identify 
triggers and alternative strategies for coping. Change strategies such as problem solving 
and reinforcement techniques are used in combination with acceptance and validation 
of the patient’s experience. Group skills’ training is used to help patients develop less 
self-destructive and more adaptive means of coping with intolerable affects. These skills 
include awareness of emotions and reactions, interpersonal effectiveness, emotion 
regulation, and distress tolerance. Skills are then integrated into the individual treatment 
in problem situations, e.g. suicidal urges (Linehan, 1993).  
- SFT (schema focused treatment) is a form of psychotherapy integrating cognitive 
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systematic approach to treatment. The focus in SFT is on changing maladaptive schemes 
that patients develop early in life and thereby improve emotion regulation skills. Change 
is achieved through a range of behavioral, cognitive, and experiential techniques that 
focus on (1) the therapeutic relationship, (2) daily life outside therapy (also through 
homework assignments), and (3) past (traumatic) experiences (Young et al., 2003). 
Psychomotor therapy (PMT) is part of the SFT treatment protocol.  
 In the Sinai Centrum, 2 “Zorgpaden” will be implemented in Fall2017:   
“Zorgpad 1” with EMDR or ImRs (3-6 months) and Zorgpad 2” with EMDR-DBT or ImRs -
SFT (9-12 months). Therapists need to be “adherent-to-the model”, which will be 
ascertained by regular supervision with audiovisual recordings based on the different 
theoretical psychotherapeutic principles and therapies are delivered by protocol. At this 
moment, there is no clear scientific evidence and criteria are not explicitly defined for the 
one or the other treatment, except that patients with PTSD without comorbid PD have to 
be indicated for “Zorgpad” 1.   
Use of co-intervention: Patients may continue taking medication for PTSD throughout the 
study. Patients who started with new medication for PTSD within 1 month prior to the 
initial screening will be excluded from participation. No other psychological or new 
pharmacological therapy is allowed during treatment. Medication use is monitored during 
the study.  
Escape medication/treatment: Participants might start taking medication or another form 
of treatment/therapy in case of acute crisis during the study.  The use of these 
medications or crisis intervention during the study as co-intervention will not lead to 
exclusion from the study, but will be monitored, documented, and reported.  
Further treatment: After completion of the EMDR or ImRs a first follow-up assessment 
will be completed and the therapist will see the patient for an evaluation. If more 
treatment is acutely needed, a clinical evaluation is done and the indication staff will 
decide what treatment to offer to the patient. The kind, intensity and frequency of this 
further treatment will be monitored, documented and reported. All patients in Zorgpad 1 
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Months  
  
  
  
  
  
0  
  
  
  
  
  
3  
  
  
  
  
  
6  
  
  
  
  
  
9  
  
  
  
  
  
12  
  
  
  
  
  
 
 
 
B aseline assessment: Q & I ( PCL - 5 /CAPS - 5 + SCID - 5 - PD screener)  
T0: Further  assessments for included patients: Predictors + Biomarkers + MR I  
PTSD + BPD  
Condition 1:   
EMDR  
 
Condition 2:   
Integrated DBT  -  EMDR  
FU: PCL - 5  
PTSD + CPD  
Condition 1:   
ImRs  
 
Condition 2:   
Integrated SFT  -  ImRs  
T1: PCL - 5  
T2: PCL - 5 /CAPS - 5 + Biomarkers + MRI   
T3: PCL - 5  
T4: PCL - 5 /CAPS - 5 AND SCID - 5 - PD  

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18  
  

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Figure 2. Flow chart for two connected randomized controlled trials (RCTs) for patients with 
PTSD and borderline personality disorders  (BPD) resp. with PTSD and cluster C personality 
disorders (CPD)  
4. STUDY POPULATION  
  
 
4.1  Population  
The study population consists of all patients between 18-65 years old, referred to the SC 
with comorbid PTSD and PD, who are willing to participate in the study (informed 
consent); N = 252 patients (see 4.4), of which sub-group of 80 patients (N = 40 Condition 1 
+ 40 Condition 2) will participate in the MRI study (before and after treatment). For 
baseline MRI comparison, extra 40 healthy controls, matched on age, gender and 
educational level, will be recruited also for the MRI study via advertisements in local 
newspapers and through hersenonderzoek.nl. In total, 292 persons will be included in this 
study.   
A pilot episode will be introduced (September – December 2017) to test the feasibility of 
the study and inclusion rate. Feasibility is enhanced by the opportunity to build on the 
established expertise of the academic research group in Arkin – Research and VUmc in 
conducting effect studies, longitudinal and neurobiological studies.  
  
4.2 Inclusion criteria  
In order to be eligible for study participation as a patient, he/she has to be at T0:  
- Diagnosed with PTSD (309.81) , and  
- Diagnosed with a personality disorder (301.81 borderline, 301.4 obsessive-compulsive, 
301.6 dependent, 301.82 avoidant), or at least the number of required symptoms 
minus 1 for at least one of those PDs (i.e. four symptoms for borderline, three 
symptoms for obsessive-compulsive, four symptoms for dependent, three symptoms 
for avoidant). 
To be eligible for the study, both patients and healthy controls have to:  
- Be aged between 18 and 65 years  
- Give written informed consent  
- Speak / understand Dutch sufficiently  
  

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4.3 Exclusion criteria  
A patient who meets any of following criteria will be excluded from participation in this 
study:  
- Current psychosis  
- Comorbidity interfering with treatment or randomisation (severe outward aggression, 
antisocial PD, treatment interfering addiction or eating disorders, somatic problems)  
- Primary diagnosis of paranoid, schizoid, schizotypal, narcissistic, histrionic or antisocial 
PD  
- Mental retardation  
For the healthy controls, current psychiatric diagnosis is an exclusion criterion.  
For the subgroup of patients and controls that also undergo MRI examination more 
exclusion criteria are: Pregnancy; Metal implants (such as pacemakers, etc.); Somatic 
disorders interfering with brain functioning; Claustrophobia; Other psychopharmaca 
than at-least-3months stabile dose SSRI or low-dose benzodiazepines  
  
4.4 Sample size calculation  
A power calculation was made based on Twisk (2007). We assume that PTSD treatment 
(EMDR or ImRs) have a small effect size (< 0.5) in the complex patient group with PTSD 
and comorbid  
CPD/BPD, while the integrated treatment will show double effect sizes (1.0) (Harned et 
al., 2014). With a minimal clinical relevant difference of a 0.5SD on the CAPS-5, and the 
assumptions of a SD of 20.0, an intra-person correlation coefficient of 0.7, 5 follow-up 
measurements, the needed number to include is 50 persons per condition to reach for 
80% power. Expecting a drop-out rate of 25%, we will include 63 persons per arm, or for 
4 arms in total 252 persons.   
In 2016, approximately 950 new patients were referred to the SC (Amstelveen). From 
these patients, ca. 450 had PTSD. From these PTSD patients, 168 had a comorbid PD 
and 188 more were not assessed for personality traits (“Uitgestelde diagnose”). We 
expect that introducing the assessment of axis II assessments with this study will result 
in an estimated 300 patients with PTSD and PD per year, and after 33% refusals or 
exclusions, in an estimated 2o0 patients possible to include per year.  To be sure to 
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Sinai Center, i.e. Amersfoort (400 patients, from which 216 PTSD patients, from which 
an estimated 100 PTSD + PD patients), and extend the inclusion period.    
From these 252 patients, 80 will be asked for additional MRI, next to 40 healthy 
controls (Total sample size = 292). An estimated 40 patients will be available for a 
second MRI after 6 months (total of 160 scan sessions).  
  
  
  
5. METHODS  
  
 
5.1  Study parameters/endpoints   
5.1.1 Primary outcome parameters  o Severity of 
PTSD (DSM-5) as measured with:   
•  CAPS-5 (Clinician Administered PTSD Scale, Weathers et al., 2014, 
Boeschoten et al., 2014). The first psychometric evaluation of the 
CAPS-5 showed good reliability, convergent and divergent validity 
(Weathers et al., 2017).  Severity of PTSD is measured on a 
continuous scale on the CAPS-5. All 20 symptoms of PTSD from the 
DSM-5 are assigned a severity score of 0-4. These 20 scores are then 
summed to calculate total PTSD symptom severity.  
5.1.2 Secondary outcome parameters o Presence of PTSD (DSM-5) as 
measured with: CAPS-5 (Clinician Administered PTSD Scale, Weathers et 
al., 2014, Boeschoten et al., 2014) o PCL-5 (PTSD Checklist for DSM-5; 
Weathers et al., 2013; Boeschoten et al., 2014; Bovin et al., 2016).  
o Presence and severity of personality disorders as measured with the 
SCID-5-PD (Structured Interview for DSM-5 Personality Disorders; First et 
al 2016) to assess presence and severity (dimensional score) of the DSM-
5 personality disorders  
o Demographic questionnaire  

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o Outcome Questionnaire -45 (OQ-45), with 25 items on psychiatric 
symptoms and 20 on interpersonal, occupational and social functioning 
(de Jong et al.,  
2008) o BDI (Beck Depression Inventory, 
Beck et al., 1988)  
o AUDIT (Alcohol Use Disorders Identification Test, Babor et al., 2001) to 
assess alcohol and drug abuse  
o SCID-5-S (American Psychiatric Association, 2017).  
o WHODAS 2.0 (World Health Organization Disability Assessment 
Schedule,  
Ustun et al 2010) o EQ-5D-5L (http://www.euroqol.org/eq-5d-
products/eq-5d-5l.html) to measure quality-adjusted life year (QALY)  
o Tic-P (Trimbos/iMTA questionnaire for costs associated with psychiatric 
illness) for health care consumption (Hakkaart-van Roijen et al., 2002)  
o NSSI screening; Screeningsvragenlijst opzettelijk zelfverwondend gedrag  
(Baetens & Claes, 2014) to assess selfinjury.  
o SMI-118 (Schema Mode Inventory 118 items, Young, Arntz, Atkinson, 
Lobbestael, Weishaar, Van Vreeswijk & Klokman, 2008).  
o YSQ-75 (Young Schema Questionnaire 75 items, Young & Brown, 1998). 
o The ITQ (International Trauma Questionnaire) assesses PTSD and 
complex PTSD (CPTSD) symptoms according to the diagnostic 
formulation published in the ICD-11 (Karatzias et al., 2016; Cloitre et al., 
2018). Since the CAPS-5 will be used to assess PTSD in the current study, 
patients will be asked to only complete the CPTSD items of the ITQ. The 
ITQ measures CPTSD through six five-point Likert scale (0-4) items 
related to three symptom clusters of difficulties in emotion-regulation 
(C1-2), negative self-concept (C3-4) and disturbed relationships (C5-6). 
Additionally, three five-point Likert scale items assess functionail 
impairment (social, occupational and other important areas of life) 
associated with CPTSD symptoms (C7-9). A diagnosis of CPTSD requires 
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score of ≥2 in each of the three CPTSD symptoms clusters, plus functional 
impairment associated with these symptoms. A patient can only receive 
a PTSD or a CPTSD diagnosis, not both. The ITQ has demonstrated 
adequate internal reliability and validity (Cloitre et al., 2018; Hyland et al., 
2017).  
  
5.1.3 Biological predictors (see table 2):  
o Biological parameters  
• 
Body measures: Weight, height, blood pressure  
• 
HPA axis (cortisol): Hair sample  
• 
Biomarkers: Fasting blood sample (BDNF, FKBP-5) & Full 
blood  
o MRI session in subsample (60 min)  
•  3 Tesla-MRI (GE, VUmc): functional MRI with a face 
recognition , Structural MRI, Resting state MRI, DTI. In 
between scans a visual analogue scale (VAS) will be applied 
to assess distress during the scan session.  
  
5.1.4 Psychological predictors o Trauma 
exposure as measured with:  
• CTQ (Child Trauma Questionnaire, Bernstein et al., 2003), 28-item 
questionnaire to check self-reported child trauma experiences, with 
5 subscales: physical, emotional and sexual abuse, physical and 
emotional neglect (5-point Likert scale), and 3-item scale to detect 
under-reporting    
• LEC-5 (Life Events Questionnaire, Weathers et al., 2013).  
o Cognitive factors  
• DERS (Difficulties in Emotion Regulation Scale; Gratz & Roemer, 2004; 
Lavender et al., 2015) a 36-item self-report measure that assesses 
state levels of emotion dysregulation across six domains: non-
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directed behaviors when distressed, difficulties controlling 
impulsive behaviors when distressed, limited access to effective 
emotion regulation strategies, lack of emotional awareness, lack of 
emotional clarity (5-point Likert scale).  
 
•     
• PAI-BOR (Personality Assessment Inventory- Borderline features 
scale, Distel, de Moor & Boomsma, 2009) to measure severity of 
borderline personality disorder symptoms. The PAI-BOR consists of 
24 items rated on a 4-points Likert scale. It measures four domains 
of BPS, affective instability, identity problems, negative relations 
and self harm.  
• Stop/signal task as a measure for interference/working memory.  
o Affective factors (Hyper-arousal: anger, sleep; hypo-arousal: dissociation)  
• STAS (State-Trait Anger Scale, Spielberger et al., 1994) on trait and 
state anger with 10 items per scale using a 4-points scale.   
• PSQI (Pittsburg Sleep Quality Index, Buysse et al., 1989) with 4 items 
on sleep time and 6 associated items (4-points scale).   
• DES-II (Dissociative Experiences Scale; Bernstein & Putnam 1986), 
28items to asses dissociative symptoms.   
o Relational factors (therapeutic alliance, attachment, social support) as 
measured with:  
• WAI (Working Alliance Inventory, Horvath & Greenberg, 1992; in 
Dutch: Werk Alliantie Vragenlijst, WAV, Vertommen & Vervaeke, 
1990), 12-items  
• RSQ (Relationship Scale Questionnaire, Griffin & Bartholomew, 1994) 
contains 30 statements on attachment rated on a 5-point scale   
• CPI (Close Person Inventory, Stansfeld & Marmot 1992) to assess 
social support.  
• Therapists will be asked to rate to which extent they believe in the 
effectiveness of the protocol, on a scale of 1 to 10.   
  
  

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Table 1: Overview of measurements: interviews and questionnaires  
MEASUREMENTS  
  
  
  
T0  
T1  T2  
T3  
T4  FU  
TIME POINTS (months)  
  
  
  
0  
3  
6&  
9  
12  
18  
SCREENING  
ROM Questionnaires  
Items  
  
  
  
  
  
  
  
Psychiatric symptoms  
OQ-45.2 (1996)  
45  
SR  
X*  
X  
X  
X  
X  
X  
PTSD symptoms  
PCL-5 1.1 (2014)  
22  
SR  
X*  
X  
X  
X  
X  
X  
PD symptoms  
SCID-5-PD screener  
119  
SR  
X  
  
  
  
  
  
Axis I disorders  
SCID-5-S screener  
??  
  
X*  
  
  
  
  
  
INTERVIEWS                DAY 1  Semi-structured interviews  
Duration  
Type    
  
  
  
  
  
PTSD  
CAPS-5 1.2 (2015)  
45 min  
INT  
X  
  
X  
  
X  
  
Axis I-disorders  
SCID-5-S  
45 min  
INT  
X*#  
  
  
  
X  
  
Personality disorders  
SCID-5-PD  
120 min  
INT  
X#  
  
  
  
X  
  
  
    
 
 
 
 
 
  
  
QUESTIONAIRES         DAY1  
Additional questionnaires   
Items  
  
  
  
  
  
  
  
Demographics  
Demographic questionnaire  
PROSPER (2017)  
30  
INT  
X*  
  
  
  
  
  
Life events  
LEC-5 1.1 (2014)  
17  
SR  
X*  
  
  
  
  
  
Child trauma  
CTQ (NESDA 2004)  
25  
SR  
X  
  
  
  
  
  
Emotion regulation  
DERS NL (2004)  
36  
SR  
X  
  
X  
  
X  
  
Complex PTSD 
 ITQ (2018) 
 9 
 SR  
 X 
  
X 
  
 X 
  
Anger  
STAS NL (ZAV 1982)  
10  
SR  
X  
  
X  
  
X  
  
Sleep  
PSQI NL (1989)  
10  
SR  
X  
  
X  
  
X  
  
Dissociation  
DES-II (1986)  
28  
SR  
X  
  
X  
  
X  
  
Depression severity  
BDI-II (2002)   
21  
SR  
X  
  
X  
  
X  
  
Alcohol / drugs  
AUDIT (MATE-nl 2.1 2010)  
10  
SR  
X  
  
X  
  
X  
  
Self harm behaviour  
NSSI screening (NL versie  
2014)  
7  
SR  
X  
X  
X  
X  
X  
X  
Borderline personality 
symptoms  
PAI-BOR (2009)  
24  
SR  
X  
  
X  
  
  
X  
  
    
 
 
 
 
 

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DAY2  Additional Questionnaires   
  
 
 
 
 
 
Therapeutic alliance  
WAV (1990)  
12  
SR  
  
X  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
  
Attachment  
RSQ (1994)  
30  
SR  
X  
  
X  
  
X  
  
Social support  
CPI (NESDA 2004)  
4  
SR  
X  
  
X  
  
X  
  
General functioning  
WHODAS 2.0 (2014)  
12  
SR  
X  
  
X  
  
X  
X  
Quality of live  
EQ-5D-5L 2 (2010)  
9  
SR  
X  
  
X  
  
X  
X  
Health care consumption  
Tic-P (2012)  
32  
SR  
X  
  
X  
  
X  
X  
  
    
 
 
 
 
 
AUDIT = Alcohol Use Disorders Identification Test; BDI = Beck Depression Inventory;; CPI = Close Person Inventory; CTQ = Child Trauma  
Questionnaire; DES-II = Dissociative Experiences Scale; INT = interview; LEC-5 = Life Events Checklist; SCID-5-S; OQ-45 = Outcome  
Questionnaire 45; PCL-5 = PTSD Checklist for DSM-5; PSQI = Pittsburg Sleep Quality Index; ROM = Routine Outcome Measurement;  
RSQ = Relationship Scale Questionnaire; DERS = Difficulties in Emotion Regulation Scale; ITQ = International Trauma Questionnaire; SR = 
self-report questionnaire; SCID-5-PD = Structured Clinical Interview for DSM-5 Personality disorders; STAS = State Trait Anger Scale; Tic-
P = Trimbos/iMTA questionnaire for costs associated with psychiatric illness; WAI = Working Alliance Inventory, WHODAS = World 
Health Organization Disability Assessment Schedule 2.0.; NSSI = Non Suicidal Self-Injury screener; PAI-BOR: Personality Assessment 
Inventory- Borderline features scale.  
* Healthy controls will only fill out these questionnaires and interviews  
& Timing of the T2 measurement will be directly after trauma treatment, around 6 months  
# The SCID-5-P at T0 is part of the regular intake procedure at the Sinai Centre   
Table 2: Overview of add-on cognitive task, biological measurements, including MRI  
MEASUREMENTS  
  
DURATION  
T0  
T1  
T2  
T3  
T4  
FU  
in months  
  
  
0  
3  
6&  
9*  
12  
18  
COGNITIVE TASKS AT DAY 2  
10 min  
  
  
  
  
  
  
Working memory  
N-back  
10  
X*  
  
  
  
  
  
Interference  
Stop/Signal task  
15  
X*  
  
  
  
  
  
PHYSICAL EXAMINATION AT DAY 2  
30 min  
  
  
  
  
  
  
Body measures  
Weight, height  
10  
X  
  
  
  
  
  
Blood pressure  
Systolic and diastolic  
5  
X  
  
  
  
  
  
HPA axis (Hair)  
Hair sample (cortisol)  
5  
X  
  
X  
  
  
  
Biomarkers  
Fasting blood sample 
(5HTTLPR, BDNF, FKBP5, 
oxytocin/OXTR)   & Full blood  
10  
X  
  
X  
  
  
  
MRI SESSION IN SUBSAMPLE WITHIN 2 WEEKS  
60 min  
  
  
  
  
  
  

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Functional MRI   
Face recognition task  
15  
X  
  
X  
  
  
  
  
  
  
  
  
  
  
  
  
Structural MRI  
  
7  
X  
  
X  
  
  
  
Resting state MRI  
  
10  
X  
  
X  
  
  
  
DTI  
  
10  
X  
  
X  
  
  
  
DTI = Diffusion Tensor Imaging, MRI = Magnetic Resonance Imaging.   
& Timing of the T2 measurement will be directly after trauma treatment, around 6 months  
* Timing of the T3 measurement will be 3 months after T2, around 9 months  
  
Table 3: Overview of duration of measurements (in minutes)  
  
T0  
T1  
T2  
T3  
T4  
Follow-up  
Interviews  
45  
-  
45  
-  
195  
-  
Questionnaires  
91 
15  
88 
15  
88 
27  
n-back  
10  
-  
-  
-  
-  
-  
TOTAL  
141 (ca. 2.5 hrs)  
15  
128 (ca. 2 hrs)  
  
15  
278  (ca. 4,5 hrs)  
27  
Blood/hair  
30  
-  
30  
-  
-  
-  
MRI  
90  
-  
90  
-  
-  
-  
TOTAL for subgroup 
with MRI/blood/hair  
261 (ca. 4 hrs)  
15  
218 (ca. 3,5 hrs)  
15  
278  (ca. 4,5 hrs)  
  
27  
  
5.2 Randomisation, blinding and treatment allocation  
  
5.2.1 Randomization  
An independent central research assistant will randomize participants to 
condition after checking all in- and exclusion criteria. Randomization will be based 
on block randomization (n=4 per block) per site, to guarantee a balance between 
conditions per site and over time.  For both RCTs there will be a separate 
randomization procedure depending on comorbid PD diagnosis:  
A1. If PTSD + BPD: EMDR vs. integrated DBT-
EMDR A2. If PTSD + CPD: ImRs vs. integrated SFT- 
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5.2.2 Unblinding Procedure  
Blinding of participants and therapists to condition is not possible as it will be clear to 
both therapists and patients which treatment is given.  
  
5.3 Study procedures  
  
The study will lead to separate although integrated research projects for 3 PhDs.   
  
A1: Is EMDR treatment more effective compared to integrated DBT-EMDR in patients 
with PTSD with comorbid BPD?  
1. Systematic review and meta-analysis: do personality or dissociative symptoms 
predict effectiveness of PTSD treatment?  
2. Do patients in the present study show higher response rate and effect sizes in 
integrated DBT-EMDR-treatment compared to EMDR-treatment alone after 12 
months?  
3. Is DBT-EMDR-treatment more effective as compared to EMDR-treatment alone in 
terms of PD symptoms, general psychiatric symptoms, disability, quality of life and 
health costs?  
4. Do psychological (cognitive, affective, relational) factors predict (integrated DBT-) 
EMDRtreatment outcome?  
  
A2: Is ImRs more effective compared to integrated SFT- ImRs in patients with PTSD 
with comorbid CPD?  
1. Systematic review and meta-analysis: do personality or dissociative symptoms 
predict effectiveness of PTSD treatment?   
2. Do patients in the present study show higher response rate and effect sizes in 
integrated SFT- ImRs -treatment compared to ImRs -treatment alone after 6-12-18 
months?   
3. Is SFT- ImRs -treatment more effective as compared to ImRs -treatment alone in 
terms of PD symptoms, general psychiatric symptoms, disability, quality of life and 
health costs?   

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4. Do psychological (cognitive, affective, relational) factors predict (integrated SFT-) 
ImRs treatment outcome?  
  
B: Predictors of PTSD-treatment   
1. Literature review: what is known on working mechanisms of PTSD treatment and 
do neurobiological findings predict PTSD treatment outcome?  
2. Are PTSD treatments in this PTSD + PD population mainly working on increasing 
extinction of fear responses? Is this associated with decreasing salience, negative 
affect and cognitive control network activity and connectivity?  
3. Do biomarkers (ACC volume, amygdala and ventral ACC and dorsal ACC activity, 
and/or hormonal/epigenetic factors (5-HTTLPR, BDNF, cortisol/FKBP5-methylation, 
oxytocin/OXTR) individually predict treatment outcome of PTSD treatment?  
  
Timing of assessments  
  
  
Baseline (T0) visit  
All patients coming to the Sinai Center are asked to fill in the ROM questionnaires 
before the intake as part of standard care (OQ-45, LEC-5/PCL-5, SCID-5-PD screener, see 
Table 1). As part of the standard intake procedure at the Sinai Centre, patients who 
score positively on the SCID-5PD screener will be interviewed with the M.I.N.I.-plus and 
the SCID-5-PD. Patients with potential eligibility based on the in- and exclusion criteria 
described earlier receive the study information folder from the psychologist who 
performed the intake with them . If a patient is interested and gives their consent, the 
intaker informs the researchers to contact the patient. One of the researchers will 
explain the study to the possible participant and provide the information folders. After 
a consideration period of at least one week, they will be asked whether they want to 
take part in the research.   
At T0/Day 1, the study- intaker will explain the study information once more. If informed 
consent is obtained, in- and exclusion criteria will again be checked to assess the 
patient’s potential eligibility for participation (Dutch language, , LEC-5/PCL-5, SCID-5-PD 
screener ) and if the patient is included, the CAPS-5 will be performed.   

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After the interview, the patients receive an online code to fill in additional 
questionnaires online at the center or at home, if the patient has access to the internet 
(see Table 1). Total duration of the measurements of To/Day 1 will be ca. two hours (see 
Table 3).  
At T0/Day 2, patients are invited for the physical examination (weight and height to 
calculate Body Mass Index (BMI), blood pressure, hair sample by a research assistant 
and fasting blood sample as well as questions on cigarette smoking, alcohol and coffee 
consumption, medication and drug use) and they will be asked to perform a working 
memory task (N-back-task) outside the scanner and to fill in the last set of 
questionnaires (see Table 1) either at the Sinai Center or online at home. Total duration 
of the measurements of To/Day 2 will be ca. 40 minutes (see Table 3).  
Blood samples will be collected in 3 x 6ml tubes and the frozen samples will be stored 
at -80°C for intended future assaying of inflammatory markers (see Coelho et al., 2014), 
neuropeptides (such as oxytocin, 5HT), and epigenetics (such as FKBP5-methylation, 
OXTR- & 5HTTLPRgenes). The tubes will be stored without personal data linked to it, 
and they will only be marked with a subject number as described in section 9.1. below. 
Cortisol level (HPA-indicator) will be assessed in hair. This sample can be collected non-
invasively by cutting a 1-cm distal to the scalp (1 month’s exposure) sample of hair 
(Russell et al., 2012). All samples will be stored for 15 years (according to Archiefwet 
1995).   
  
  
In a subgroup: MRI session  
Exclusion criteria for MRI research will be checked (metal implants, pregnancy, somatic 
disorders interfering with brain functioning, other  (psycho-)pharmaca than at-least-3-
months stabile dose SSRI or low-dose benzodiazepines, claustrophobia). A separate 
visit for MR scanning will be planned within 2 weeks of T0, before the start of 
treatment, without causing a delay in treatment start. MRI sessions take at maximum 
60 minutes (30-min functional MRI with a face recognition, and a suppression vs. 
reappraisal task, 5-min structural MRI, 8-min resting state MRI; and 8-min DTI) plus 30 
min preparation. Next to patients, 40 healthy control persons, matched for age, 
gender, and education, will be asked to participate in one MRI session (no repeat MRI). 
These healthy control persons will be recruited via advertisements in local papers.  

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T1 , T3 and FU  
Patients do not have to come to the study center for T1, T3 and FU and can fill in the 
questionnaires via a login code at home if they have access to the internet (see Table 
1.). Child trauma and life events questionnaires are only done at baseline (CTQ, LEC-5). 
Total duration of these measurements (T1, T3 and FU)  will be between 15 and 30 
minutes (see Table 3).  
  
T2 visit   
From all participants whose blood and hair was collected at baseline,  blood and hair 
will be collected at T2 as well (duration 30 minutes). All participants who participated in 
the fMRI study at baseline will have their second MRI at T2. (duration 90 minutes). At 
T2, the CAPS-5 will also be conducted and participants will fill out the same 
questionnaires as at T0, except for the CTQ and LEC-5. Total duration of these 
measurements of  will be ca. 2 hours (see Table 3).  
  
Extra contact moment  
For participants in the trauma-treatment only group, there will be an extra moment of 
contact 3 months after T3, with a short reminder about the following measurements 
and attention for the wellbeing of the client.  
  
T4 visit  
This is the same as T0, except for the informed consent procedure and except for the 
N-back task and physical examination and trauma questionnaires that will be done at 
T0 only (CTQ, LEC-5). Total duration of these measurements  will be 4,5 hours (see 
Table 3).  
  
Treatment visits  
These will be scheduled as usual. For durations of specific treatments see 3.  
  

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5.4 Withdrawal of individual subjects  
Subjects can leave the study at any time for any reason if they wish to do so, without 
any consequences. The principal investigators can decide to withdraw a subject from 
the study for urgent medical reasons.   
  
Reasons to terminate a patient’s participation include:  
- The patient withdraws her/his consent  
- The nature of the patient’s treatment is changed to coercive treatment (based on 
judicial ruling)  
- The investigator considers a patient’s continued participation in the study to be 
unjustifiable on medical or psychiatric grounds (i.e., because of side effects or unusual 
risks of the treatments).   
If an individual patient is discontinued due to one of the above-mentioned reasons, this 
patient will be treated as usual in normal daily practice. The treating physician remains 
the primary caregiver during the study and will be contacted at the baseline visit and 
updated throughout the study. The treating physician will contact the study team in 
cases of important changes and will be responsible to apply for legal custody if 
appropriate.  
All patients leaving the study early, regardless of the reason, will be requested to return 
to the site for an “early termination” visit to finalize participation. If the patient is not 
willing to complete all measures, priority will be given to the PCL-5 and OQ-45.  
There are no consequences if a patient also refuses this.  
  
5.5 Replacement of individual subjects after 
withdrawal Not applicable.  
  
5.6 Follow-up of subjects withdrawn from treatment  
Patients who drop-out out of (part of) the treatment remain in the study and will still 
be asked to complete the follow-up measures. Priority will be given to the online 
assessment with the  
PCL-5 and OQ-45.   
  

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5.7 Premature termination of the study  
There are no criteria, other than mentioned under section 6, for a premature 
termination of the study.  
  
6. SAFETY REPORTING  
  
 
6.1  Section 10 WMO event  
  
This study will be performed according to the Declaration of Helsinki (64th WMA 
general assembly; October 2013) and the International Conference on Harmonisation – 
Good Clinical Practice (ICH-GCP). The definitions of adverse events and serious adverse 
events described in these guidelines will be used for the present study.   
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the 
subjects and the reviewing accredited Ethical Review Board (ERB) if anything occurs, 
on the basis of which it appears that the disadvantages of participation may be 
significantly greater than was foreseen in the research proposal. The study will be 
suspended pending further review by the accredited ERB, except insofar as suspension 
would jeopardise the subjects’ health. The investigator will take care that all subjects 
are kept informed.   
Subjects are entitled to get information and to ask questions, before, during and after 
being part of the research to th researchers. Apart from the provided information, 
there is an independent expert involved. He can provide information for patients, but is 
not involved in this study himself. In this study the independent expert is a psychiatrist 
working in one of the companies within Arkin, named Mentrum. He is not involved in 
the Sinai Center.   
  
6.2 AEs, SAEs and SUSARs  
6.2.1 Adverse events (AEs)  
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the study. All adverse 
events reported by the subject or observed by the investigator or his staff will be 
recorded.  

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6.2.2. Serious adverse events (SAEs)  
We do not expect any serious adverse event (i.e. any untoward medical 
occurrence or effect that results in death; is life threatening (at the time of the 
event); requires hospitalisation or prolongation of existing hospitalisation; results 
in persistent or significant disability or incapacity; is a congenital anomaly or birth 
defect; any other important medical event that may not result in death, be life 
threatening, or require hospitalization, may be considered a serious adverse 
experience when, based upon appropriate medical judgement, the event may 
jeopardize the subject or may require an intervention to prevent one of the 
outcomes listed above). The main reason for this is that all four treatments given 
in the RCTs are evidence-based for at least one of the disorders the patients 
suffer from (PTSD and PD) and patients who will be assigned to the PTSD-
treatment only can given PD-treatment as well after T4 (after 6-12 months) within 
the research design.   
Suicidality or self-injurious behaviour is very common in the study population 
included for this study. It is also known that starting a new treatment, such as 
EMDR or DBT could increase symptoms in the beginning, which can develop into 
suicidal behaviour. SAE’s which will occur during the treatment and for which 
medical care is needed, will be reported to the accredited METC. To monitor the 
SAE’s, patients will be asked to fill in a self-injury questionnaire (Opzettelijk 
zelfverwondend gedrag, Baetens & Claes 2014 based on The Brief Non-Suicidal Self-
Injury Assessment Tool (BNSSI-AT) van Janis Whitlock en Amanda Purington 
(2013)) at the regular assessments. In case of SAE’s for which medical care is 
needed, in between the assessments, therapists will report these incidents to the 
researchers at the weekly consultations, whom will report these to the 
accredited METC.  The sponsor will report SAEs to the accredited METC that 
approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to 
complete the initial preliminary report. All other SAEs will be reported within a 
period of maximum 15 days after the sponsor has first knowledge of the serious 
adverse events.   

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6.2.3. Suspected unexpected serious adverse reactions (SUSARs)  
This part is not applicable to the presented study.  
  
6.3 Annual safety report  
  
 Not applicable (no pharmacological or other agents involved in this study).  
6.4 Follow-up of adverse events  
  
   All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
SAEs will be reported till the end of the study within the Netherlands, as defined in the 
protocol.  
  
6.5 Data Safety Monitoring Board  
  
It has been decided not to engage a Data Safety Monitoring Board in this study, no 
pharmacological or other agents are involved in this study. In addition, no interim 
analyses are planned. In the investigator’s opinion, implementation of a DSMB will not 
have sufficient added value for the current study.  
  
 

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7. STATISTICAL ANALYSIS  
  
Descriptive statistics of continuous outcomes will be presented by disorder category and 
include sample size, mean, median, standard deviation, minimum and maximum. For 
categorical outcomes, the number and percentage of subjects in each category will be 
presented by disorder category. Statistical analyses will be performed using SPSS for 
Windows (version 20) or in R (https://www.r-project.org).   
 
7.1  Primary study parameters  
  
For population description, the CAPS-5, M.I.N.I.-plus, SCID-5-PD, will be used in 
addition to the CTQ, LEC-5, DERS, ITQ, PAI-BOR, STAS, PSQI, DES-II, WAV, RSQ, CPI, 
BDI, AUDIT, WHODAS, EQ5D-5L, and Tic-P will be used (see Table 1). The subgroup of 
patients that underwent MRI will be compared to the rest of the group to test for 
pretreatment differences in PTSD severity and type/severity of PD.   
The primary analysis in the RCTs will be improvement of PTSD symptoms at 3 time 
points. This primary analysis will include trauma symptom scores at T0, T2 and T4 
(CAPS-5, severity score) in a repeated measurements model, a linear mixed model for 
repeated measurements including at least time points, treatment group, the 
interaction between time point and treatment, sex, age and severity as fixed factors, 
baseline score as covariate and subject as random intercept factor. An cAR(1) 
structure will be used to model the residual covariance matrix. Responders will be 
defined as participants with a posttest score at least 1 SD below the pretest score 
(based on Jacobsen and Truax, 1991).  
Secondary analyses will examine whether hormonal and epigenetic factors (5-
HTTLPR, BDNF, cortisol/FKBP5-methylation, oxytocin/OXTR) mediate the treatment 
effects. Mediation analyses will include levels of the aforementioned variables on T0 
and T2 to estimate the direct and indirect paths of casual treatment on the primary 
and secondary study parameters, through the proposed mediators.  
For individual prediction analyses, machine learning techniques (in R: supervised 
and unsupervised techniques, e.g. the random forest model method) will be applied 
to separate treatment responders from non-responders based on clinical and 
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contributing most to classification accuracy, calculating sensitivity, specificity, and 
positive and negative likelihood ratios from the prediction model (Ball et al., 2014). 
Candidate predictors that will be used are:  
- Psychological factors:  Cognitive factors (educational level/IQ, working memory, 
emotion regulation), Affective factors (hyperarousal: anger, sleep; hyperarousal: 
dissociation), and Relational factors (therapeutic alliance, attachment, social 
support);  
- Neurobiological factors:  Neural factors (smaller ACC and hippocampus volume, 
increased right amygdala and ventral ACC activity and de/increased dorsal ACC 
activity), and Hormonal/ epigenetic factors (5-HTTLPR, BDNF, cortisol/FKBP5-
methylation, oxytocin/OXTR).  
  
Questions that will be answered with machine learning in this study are:  
  
1. Does brain activity predict treatment outcome for PTSD and PD (all treatment 
conditions together; N = 80)  
2. Does brain activity predict treatment outcome for PTSD (EMDR and ImRs; N = 40)  
3. Does brain activity predict treatment outcome for integrated PD/PTSD treatment 
(EMDR + DBT and ImRs + SFT, N = 40)  
4. Data from the MRI at T2 can be used to predict relapse after treatment for all 
treatments together (N = 80 if all patients return for a second MRI) or for trauma 
treatment and integrated treatment seperatly (N = 40 for both).  
  
fMRI data will be analysed wit Statistical Parametric Mapping (SPM) software or FMRIB 
Software Library (FSL) to map connectivity in the brain. Standard group comparisons will 
be used to analyse structural and task-related (face recognition) fMRI. First, ANOVA 
analyses will be performed with patients vs. controls for baseline comparison. Second, full 
factorial analyses will be conducted in patients-only, with time (baseline vs. end of 
treatment) and condition (type of treatment) as factors to analyse the effect of 
treatment on (task-related) brain structure, connectivity and activity. Independent 
component analysis (ICA; FSL MELODIC) and dual regression analyses will be used to 
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network, negative affect network, ventral and cognitive control network). Brain areas 
that fluctuate simultaneously over time in blood-oxygen level dependent (BOLD; proxy 
for brain activity) response are automatically assigned to a component per subject. After 
filtering and preprocessing of the components (e.g. components that are caused by 
movement or scanning artefacts), these components are averaged across groups. 
Through non-parametric permutation testing (FSL randomise) we compare functional 
connectivity of these networks between intervention groups and over time (T0 to T2). For 
the whole-brain network analyses, the structural  
MRI will be parcellated into 92 regions of interest (ROIs), based on the Automated 
Anatomical Labeling (AAL) atlas. These parcellations will be transformed to resting-state 
fMRI and time series are extracted for each ROI and correlated to get a whole-brain 
connectivity matrix per subject. The brain connectivity toolbox (BCT) will be used to 
calculate network topological indices (e.g. modularity, betweenness centrality, clustering 
coefficient and efficiency) from these matrices. Network topological indices narrow down 
the large amount of information from the brain scans to a few neurobiologically 
meaningful measures (Rubinov & Sporns, 2010). A more detailed description of these 
topological measures can be found in Bullmore and Sporns (2009). These measures will 
be calculated for every condition and compared through permutation-testing.  
  
 
7.2  Secondary study parameters  
  
Secondary study parameters are quality of life with WHODAS, EQ-5D-5L, and health 
care consumption with Tic-P. The secondary analyses on these continuous measures 
will be similar to the primary analyses.   
  
 
7.3  Other study parameters  
The analyses on other study parameters, including the AUDIT will also be similar to 
the primary and secondary analyses. Safety data: Incidences (number and % of 
subjects with at least one occurrence) of key SAEs and AEs will be presented per 
group. For exploratory purposes, confidence intervals comparing both groups will be 
provided.  
  

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7.4 Interim analysis (if applicable) 
No interim analyses are planned.  
  
  
8. ETHICAL CONSIDERATIONS  
  
 
8.1  Regulation statement  
The study will be conducted in accordance with this protocol as well as the principles 
of the Declaration of Helsinki (64th WMA general assembly; October 2013).  
  
8.2 Recruitment and consent  
Patients diagnosed with PTSD and/or personality disorders will be informed on the 
study with oral and written information of the intaker. The participant will be 
informed about the entire course of the study, potential individual benefits and 
personal risks. Here it must be emphasized that participation is absolutely voluntary. 
Patients are given sufficient time to read all the provided information, counsel 
partners or relatives, and clarify any questions with the investigator (3 days to 2 
weeks). Participation requires written consent before any (screening) procedure 
takes place. This consent can be revoked at any time without citing reasons and 
without any consequences. A copy of the consent form and patient information will 
be given to the participant.  For healthy controls, an extra screening informed 
consent will be used to assess their eligibility.  
  
8.3 Benefits and risks assessment, group relatedness  
All treatments given in our center are evidence-based and delivered by specialized 
health care professionals with continuing supervision. The safety and efficacy of the 
treatments are well established. The number of patient visits will be limited. The 
additional questionnaires for research purposes require an additional time, which can 
be completed at home if the patient has access to the Internet.   
Potential benefits of this study for the patients is that outcome monitoring will be 
better implemented and that patients can be better informed on improvements and 
eventual deteriorations so as to adapt treatment plans. Patients are not withheld any 
standard treatment. Furthermore, routine care consists of less extensive monitoring 

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of symptom change and functioning compared to the current study, so all patients 
may benefit from the thorough examinations during study participation.   
In the face of the limited additional burden for the patient when participating in the 
current study as compared to routine treatment, and the possible positive outcome 
for future treatment, offering participation to selected patients appears to be 
justified.  
  
 8.4  
Compensation for injury  
The sponsor/investigator has a liability insurance and a trial insurance, which is in 
accordance with article 7, sub-section 6 of the WMO.   
  
 8.5  
Incentives  
Participants will receive a monetary reward: 10 euro for the assessments for which 
they have to visit the Sinai centrum. (at T0, T2 and T4). The subgroup that participates 
in the MRI research will receive 20 euro per scan session plus travel costs. Participants 
will receive the amount of money in “VVV-bonnen”.  
  
 

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9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION   
  
 
9.1.  
Handling and storage of data and documents  
  
Privacy laws and regulations will be adhered to during the complete study. The 
collection and processing of participants’ personal information will be limited to what 
is necessary to ensure the study’s scientific practicability, the evaluation of efficacy 
and adherence. Information collected about participants during this clinical 
investigation will be treated confidentially.  At inclusion into this study, a unique 
project number will be allocated to each subject. For the PTSS-BPD RCT numbers will 
begin with 45 (year of liberation after WW-II), followed by number 001 resulting in 
45001, 45002, etc.. For the PTSS-CPD RCT numbers will begin with 46, resulting in 
46001, 46002, etc.. Healthy controls will be numbered with 47001, 47002, etc..  
The key of these project numbers will only be available to the principal investigators 
and datamanagers (maximum of 3) of the project. All (paper and digital) 
questionnaires and data will be stored and handled de-identified using this project 
number. Study outcomes will be reported anonymously. Storage of data will be 
supervised by the principal investigator and complies with the Dutch Personal Data 
Protection Act (in Dutch: De Wet Bescherming Persoonsgegevens, Wbp). All the data 
will be stored for 15 years.   
  
 
9.2.  
Monitoring and Quality Assurance  
  
Associated investigators will be carefully selected and comprehensively informed and 
trained regarding Good Clinical Practice (GCP), all study procedures and the required 
examinations and documentation.  
  
 
9.3.  
Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the ERB 
application, or to the protocol or any other supporting documentation, that is likely to 
affect to a significant degree:  

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- The safety or physical or mental integrity of the subjects of the study;  
- The scientific value of the study;  
- The conduct or management of the study; or  
- The quality or safety of any intervention used in the study.  
  
All substantial amendments will be submitted for approval to the ERB and to the 
competent authority. For non-substantial amendments, only a notification will be 
send to the accredited ERB, which will be recorded and filed by the sponsor.   
  
 
9.4.  
Annual progress report  
The sponsor/investigator will submit a summary of the progress of the study to the 
accredited ERB once a year. Information will be provided on the date of inclusion of 
the first subject, numbers of subjects included and numbers of subjects that have 
completed the study, serious adverse events/ serious adverse reactions, and other 
problems. The investigators will inform the METC about the start of the study and any 
amendments.   
  
 
9.5.  
End of study report  
The sponsor will notify the accredited ERB and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last 
patient’s last visit.   
  
In case the study is ended prematurely, the sponsor will notify the accredited ERB and 
the competent authority within 15 days, including the reasons for the premature 
termination.  
  
Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the 
study, to the accredited ERB and the Competent Authority.   
  

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9.6.  
Public disclosure and publication policy  
The results of the study will be submitted for publication in an international peer-
reviewed journal adhering to applicable privacy laws and regulations. The principal 
investigator will determine publication strategy. No treatment group information will 
be made available until after study completion.   
   
  
  
  
10. STRUCTURED RISK ANALYSIS  
  
10.1 Potential issues of concern  
  
No additional concerns.  
  
Pharmacokinetic interactions  
Not applicable.  
  
10.2 Synthesis  
Not applicable  
  
 

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