Mindfulness Based Cognitive Therapy for Bipolar Disorder
Phase: NA
Conditions: Bipolar Disorder
Sponsor: Radboud University Medical Center

 
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL 
Mindfulness Based Cognitive Therapy for Bipolar Disorder 
 
Version 3, d.d. 26 March 2018-04-24  
NTC number: not available yet 
 

NL63319.091.17 / ZonMW dossiernr: 80-84300-98-82003 
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PROTOCOL TITLE  Mindfulness Based Cognitive Therapy for Bipolar Disorder 
 
Protocol ID 
 
Short title 
MBCT for bipolar disorder 
Version 
3 
Date 
26 March 2018 
Coordinating investigator/project 
leader 
 
Dr. Marloes J. Huijbers 
Radboudumc, department of psychiatry 
Reinier Postlaan 4 
6525 GC Nijmegen 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
Prof. Dr. Anne E.M. Speckens 
Radboudumc, department of psychiatry 
Reinier Postlaan 4 
6525 GC Nijmegen 
<Multicenter research: per site> 
 
Pro Persona 
Drs. Marc Lochmann – van Bennekom  
Tarweweg 6 
6534 AM Nijmegen 
Netherlands 
 
Altrecht 
Dr. Eline Regeer 
Lange Nieuwstraat 119 
3512 PG Utrecht 
Netherlands 
Dimence 
Drs. Anja Stevens 
Pikeursbaan 3 
7411 GT Deventer 
Netherlands 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Radboudumc 
Nijmegen, Netherlands 
Tel. +31 (0)24 – 3668456 
Email: mindfulness@radboudumc.nl  
Subsidising party 
ZonMW: The Netherlands Organisation for Health 
Research and Development 
Den Haag, Netherlands 
Tel. +31 (0)70 – 3495111 
Email: info@zonmw.nl 
 
Independent experts 
Radboudumc: Dr. Marleen van Beek, psychiater 
Pro Persona: Dr. Florian Hardeveld, psychiater 
Altrecht: Dr. Aart de Leeuw, psychiater 
Dimence: Drs. Just Wernand, psychiater 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. Aart H. Schene 
Department of Psychiatry  
Radboudumc, Nijmegen  
 
 
 
Principal Investigator: 
Prof. Dr. Anne E.M. Speckens 
Department of Psychiatry, Radboud Center for 
Mindfulnesss  
Radboudumc, Nijmegen  
 
 
 
 
 

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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE ............................................................................................... 7 
2. 
OBJECTIVES .................................................................................................................................. 8 
3. 
STUDY DESIGN .............................................................................................................................. 9 
4. 
STUDY POPULATION .................................................................................................................. 10 
4.1 
Population (base)................................................................................................................... 10 
4.2 
Inclusion criteria ..................................................................................................................... 10 
4.3 
Exclusion criteria.................................................................................................................... 10 
4.4 
Sample size calculation ......................................................................................................... 10 
5. 
TREATMENT OF SUBJECTS ....................................................................................................... 11 
5.1 
Investigational treatment ....................................................................................................... 11 
6. 
METHODS ..................................................................................................................................... 12 
6.1 
Study parameters/endpoints .................................................................................................. 12 
6.1.1 
Main study parameter/endpoint ..................................................................................... 12 
6.1.2 
Secondary study parameters/endpoints ........................................................................ 12 
6.1.3 Other study parameters ............................................................................................................ 14 
6.2 
Randomisation, blinding and treatment allocation ................................................................. 15 
6.3 
Study procedures................................................................................................................... 15 
6.4 
Withdrawal of individual subjects........................................................................................... 17 
6.5 
Replacement of individual subjects after withdrawal ............................................................. 17 
6.6 
Follow-up of subjects withdrawn from treatment ................................................................... 17 
6.7 
Premature termination of the study ....................................................................................... 17 
7. 
SAFETY REPORTING .................................................................................................................. 18 
7.1 
Temporary halt for reasons of subject safety ........................................................................ 18 
7.2 
AEs, SAEs and SUSARs ....................................................................................................... 18 
7.2.1 
Adverse events (AEs) .................................................................................................... 18 
7.2.2 
Serious adverse events (SAEs) ..................................................................................... 18 
7.3 
Follow-up of adverse events .................................................................................................. 19 
7.4 
Data Safety Monitoring Board (DSMB) / Safety Committee .................................................. 19 
8. 
STATISTICAL ANALYSIS ............................................................................................................. 19 
8.1 
Primary study parameter(s) ................................................................................................... 19 
8.2 
Secondary study parameter(s) .............................................................................................. 19 
8.3 
Other study parameters ......................................................................................................... 21 
9. 
ETHICAL CONSIDERATIONS ...................................................................................................... 21 
9.1 
Regulation statement ............................................................................................................. 21 
9.2 
Recruitment and consent ....................................................................................................... 21 
9.3 
Benefits and risks assessment, group relatedness ............................................................... 21 
9.4 
Compensation for injury ......................................................................................................... 21 
9.5 
Incentives (only applicable to the PIT task) ........................................................................... 22 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ....................................... 22 
10.1 
Handling and storage of data and documents ....................................................................... 22 
10.2 
Amendments .......................................................................................................................... 22 
10.3 
Annual progress report .......................................................................................................... 22 
10.4 
Temporary halt and (prematurely) end of study report .......................................................... 22 
10.5 
Public disclosure and publication policy ................................................................................ 22 
11. 
REFERENCES .......................................................................................................................... 23 

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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 
ASRM 
Adverse Reaction 
Altman Self Rating Mania Scale 
BD 
Bipolar Disorder 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CHIME 
Comprehensive Inventory of Mindfulness Experience 
DSMB 
Data Safety Monitoring Board 
FAST 
Functioning Assessment Short Test 
IDS-C 
Inventory of Depressive Symptomatology- clinician rated 
MBCT 
Mindfulness Based Cognitive Therapy 
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
MHC-SF 
Mental Health Continuum – short form 
QIDS-SR 
Quick Inventory of Depressive Symptomatology – Self report 
RPA-NL 
Responses to Positive Affect- Dutch version 
RRS 
Ruminative Response Scale 
(S)AE 
(Serious) Adverse Event  
SCS-SF 
Self-Compasstion Scale – short form 
SCID-I 
Structured Clinical Interview for DSM-IV-TR Axis I Disorders  
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. 
TAU 
Treatment as usual 
TiC-P 
Trimbos/iMTA questionnaire for costs associated with psychiatric illness 
STAI 
State/Trait Anxiety Inventory 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
YMRS 
Young Mania Rating Scale 
 
 

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SUMMARY 
 
Rationale: Persistent and residual depressive symptoms in bipolar disorder (BD) are common and 
have been associated with negative effects on the course of BD. However, limited data are available 
on how to reduce these depressive symptoms, or how to improve outcomes for patients who do not 
benefit sufficiently from available treatments. Mindfulness-Based Cognitive Therapy (MBCT) is an 
innovative intervention that already has been shown effective in reducing depressive symptoms in 
unipolar recurrent depression. Therefore, it is hypothesized that, compared to usual care, MBCT will 
reduce depressive symptoms in BD patients. 
Objective: Outcomes of MBCT for BD patients are examined on a symptomatic level (e.g. depression, 
(hypo)mania, anxiety, risk of relapse/recurrence) and in terms of functioning and mental health/well-
being, including possible working mechanisms such as improvements of mindfulness and self-
compassion skills. 
Study design: A randomized, multicenter, evaluator-blinded, prospective clinical trial with 
assessments at baseline, and 3, 6, 9, 12 and 15 months follow-up. 
Study population: Adult BD type I or BD type II patients (N = 160) who suffered from at least two 
lifetime depressive episodes (either current or in (partial) remission), and having suffered from at least 
one affective episode within the year prior to baseline, without (hypo)manic symptoms within the last 3 
months. 
Intervention: Patients will be randomly assigned to one of two groups: (1) Treatments as usual (TAU): 
Patients continue to receive usual care, typically consisting of pharmacotherapy, psycho-education 
and self-management interventions. (2) TAU + MBCT: Patients will be invited to participate in a 
MBCT-program in addition to their usual care.  
Main study parameters/endpoints: Primary outcome is the severity of depressive symptoms at 3 
months follow-up (T1), assessed with the Inventory of Depressive Symptomatology – Clinician 
administered (IDS-C; Akkerhuis, 1997).  
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: The burden associated with participation in MBCT is relatively high: consisting of 8 
weekly group sessions of 2,5 hours and one silent day (6 hours), and home practice of about 45 
minutes a day. Participation includes 6 research assessments consisting of interviews and 
questionnaires about psychological symptoms, functioning, and quality of life. Before and after the 
intervention the assessment will include computer tasks to assess cognitive control. Although the effort 
requested from patients is high, we expect that practicing mindfulness will be associated with enduring 
changes in patients' coping strategies in daily life, and as a result, can increase participants' autonomy 
and self-efficacy. The risks associated with participation are expected to be low. Although the 
increased awareness of difficult emotions may be confronting or overwhelming for some, this is a 
major topic that will be discussed during MBCT. If participants show a clear increase in symptoms, this 
will be discussed with their responsible clinician and additional guidance will be offered. Participants 
are encouraged to respect their boundaries (both physical and psychological) and are always free to 
suspend or adapt the practice as needed. 
 

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1. INTRODUCTION AND RATIONALE 
Bipolar Disorder (BD) is characterized by its severe and chronic course, with patients suffering from 
recurrent depressive, (hypo)manic, and/or mixed episodes, being symptomatic about half of the time 
(Judd et al., 2002). According to the World Health Organization (2008), BD belongs amongst the 
leading causes of years lost due to disability. BD patients typically experience debilitating 
psychological stressors, such as social rejection, internalized stigma, and subjective distress (Davis & 
Kurzban, 2012), and is therefore associated with tremendous economic, social, and occupational 
burden (Dilsaver, 2011; McCrone, Dhanasiri, Patel, Knapp, & Lawton-Smith, 2008; Pini et al., 2005). In 
the Netherlands, BD affects approximately 1.2% of men and 1.4% of women (De Graaf, Ten Have, & 
van Dorsselaer, 2010). Although hospital admissions are more common during manic episodes, it has 
been shown that depressive symptoms substantially predominate over manic symptoms, and that 
illness-related disability is more strongly influenced by depressive episodes (Judd & Akiskal, 2003; 
Judd et al., 2002). It has been estimated that approximately 33 – 50% of BD patients attempt suicide 
at least once in their lifetime, whilst 15 – 20% die due to suicide (Gonda et al., 2012). Since the middle 
of the last century, pharmacological interventions have been the first-line treatment for BD (Vieta & 
Colom, 2004). However, it has become evident that pharmacological interventions alone are 
insufficient, since 60% of patients relapse within two years (Miklowitz et al., 2009; Oud et al., 2016). 
Therefore, augmentation of psychological interventions is required in order to improve symptoms and 
reduce relapse rates (Oud et al., 2016; Vieta & Colom, 2004). Adjunct psychosocial interventions 
appear to improve outcomes as patients learn to adopt behavioural strategies to manage their mood 
instability. However, in spite of these interventions, persistent or residual depressive symptoms remain 
in more than 40% of patients (Samalin, de Chazeron, Vieta, Bellivier, & Llorca, 2016). These 
symptoms are strongly associated with  impairments in interpersonal and occupational functioning 
(Dilsaver, 2011; Samalin et al., 2017), and affect the course of BD and quality of life negatively 
(Gutiérrez‐Rojas et al., 2008). Furthermore, these adjunct psychological interventions seem to become 
less effective in those who suffered more than twelve previous episodes (Scott et al., 2006). Limited 
data are available on how to optimize treatment of persistent or residual depressive symptoms in BD, 
or how to improve outcomes for patients who do not benefit sufficiently from available treatments. 
Furthermore, there is a need for interventions that not only target symptom reduction but also help 
patients to cope with their illness from a wider perspective, i.e. in terms of their personal values, goals, 
and social roles (Farkas, 2007). 
Mindfulness-Based Cognitive Therapy (MBCT), an innovative psychological intervention, has been 
shown effective in reducing depressive symptoms in unipolar recurrent depression (Kuyken et al., 
2016; van Aalderen et al., 2012), and appears to be promising for coping with severe mental illness 
(Davis & Kurzban, 2012). Little is known about the effectiveness of MBCT for BD, with only a number 
of pilot studies showing reductions in depressive symptoms (Miklowitz et al., 2009; Williams et al., 
2008), and one RCT showing a reduction of anxiety symptoms but not of depressive symptoms 
(Perich, Manicavasagar, Mitchell, Ball, & Hadzi-Pavlovic, 2013). The study of Perich et al. (2013), 
however, showed high drop-out rates, which may have compromised the power to detect changes in 
depressive symptoms, especially given the fact that this was an euthymic group at baseline. Thus, 
there is a lack of sufficiently powered RCTs examining the effect of MBCT on BD patients. In addition, 
most studies have included remitted BD patients only, which may have limited the possible range of 
symptom reduction and the clinical representativeness of the studies. The proposed study will be the 
first RCT of MBCT for BD in the Netherlands, providing high-level evidence about the effectiveness of 
MBCT versus TAU for patients with BD. It will be offered in a multi-centre setting and using several 
outcome measures, including cost-effectiveness. If (cost-)effective, MBCT might widen the array of 
psychosocial interventions for patients with BD.  
Growing evidence conceptualizes BD as having difficulties in emotion regulation (Gruber, Eidelman, & 
Harvey, 2008; Gruber, Eidelman, Johnson, Smith, & Harvey, 2011). Rumination of both positive and 
negative affect has been associated with the onset and maintenance of BD (Johnson, 2005; Nolen-
Hoeksema, 1991). Ruminative responses to negative affect appear to create a vicious cycle of 
ruminative thinking, decreased motivation and interest, and loss of positive mood, which intensifies 
symptoms of depression (Johnson, McKenzie, & McMurrich, 2008), whilst rumination of positive affect 

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is associated with goal-directed activity and decreased sleep, which intensifies symptoms of mood 
elevation (Gruber, 2011). According to  Segal, Williams, and Teasdale (2002), training in mindfulness 
should decrease the tendency of depressed patients to enter a vicious cycle of negative ruminative 
thinking. Studies investigating reductions of negative rumination during MBCT are scarce (Michalak, 
Holz, & Teismann, 2010). In a sample of 55 treatment-resistant depressed patients, Eisendrath et al. 
(2008) found significant reductions of negative rumination following MBCT. The study of Deckersbach 
et al. (2012) found a significant decrease of negative rumination after MBCT in a sample of ten BD 
patients. Other studies found statistical trends towards reductions of negative ruminative thinking after 
MBCT in a sample of 19 patients with residual depressive symptoms (Kingston, Dooley, Bates, Lawlor, 
& Malone, 2007), and 95 BD patients (Perich et al., 2013). To our knowledge, no studies to date have 
investigated the effect of MBCT on ruminative responses to positive affect in BD patients. The present 
study will be the first to examine differences in ruminative responses to both positive and negative 
affect following MBCT in BD patients.  
Furthermore, little is known about the potential moderators and working mechanisms of recovery in 
BD. One of the possible moderators of MBCT for patients with recurrent depression is a history of 
childhood traumatic events (CTEs; Williams et al 2014). CTEs also play a major role in BD. For 
example, CTEs are associated with higher risk of developing bipolar disorder and critically with a more 
severe clinical presentation over time (Aas et al., 2016). To find whether CTEs also have an influence 
on the effect of MBCT on BD, another goal of this study is to investigate whether the subgroup of 
patients with CTEs show a differential response to MBCT compared to subjects without CTEs. 
Moreover, CTEs contribute to the development of negative cognitive schemas, a finding that has 
mainly been described in patients with depression (Beck & Haigh, 2014; Gotlib & Joormann, 2010; 
Mathews & MacLeod, 2005). These schemas conceptualized on a cognitive level as a coalescence of 
different cognitive-affective biases (e.g. in attention and memory) leading to a biased view towards the 
self, the future and the environment, sustaining clinical symptoms in depression such as emotion 
dysregulation (Beck, 2008; Beck & Haigh, 2014). Research on cognitive bias in BD is limited and 
results are equivocal (Peckham, Johnson, & Gotlib, 2016). Findings include no attentional bias in 
euthymic BD patients (e.g. Peckham et al., 2016), but critically diminished attention towards positive 
words in mildly depressed BD patients (Jabben, Arts, van Os, & Krabbendam, 2010) and depressive 
mood-related negative recall bias in BD patients (Adams, Shapero, Pendergast, Alloy, & Abramson, 
2014). It seems warranted to investigate whether MBCT results in changes in different forms (e.g. 
attentional memory) of these cognitive-affective biases in BD patients. If so, we will be able to advance 
our insight in the potential cognitive-affective working mechanisms of MBCT in BD.   
In sum, the current study will combine measures of clinical and cost-effectiveness with cognitive 
measures addressing cognitive-affective bias and other psychological processes including rumination, 
mindfulness and self-compassion to assess the potential mechanisms of change in MBCT for bipolar 
disorder.  
 
2. OBJECTIVES 
Primary Objective:  
 
Is MBCT as an adjunctive treatment to TAU more effective in reducing depressive symptoms 
in patients with bipolar disorder, compared to TAU alone? 
 
Secondary Objective(s):  
 
Is MBCT more effective than TAU in reducing levels of (hypo)manic and anxiety symptoms, 
the risk of relapse in depression or (hypo)mania, and ruminative brooding? 
 
Is MBCT equally effective in patients with < 12 mood episodes compared to patients with =/> 
12 episodes?  
 
Is MBCT more effective than TAU in improving mindfulness, self-compassion, functioning, and 
mental health/well-being? 
 
From the viewpoint of the society, is adding MBCT to TAU preferable in terms of societal costs 
and QALYs, compared to TAU alone? 

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Our hypothesis is that participants allocated to MBCT will have fewer depressive, (hypo)manic, and 
anxiety symptoms and experience fewer (hypo)manic or depressive episodes than those allocated to 
TAU over the 15 months study period. In addition, we hypothesize that MBCT will be associated with 
improvement in several areas of functioning and well-being. Furthermore, we expect that positive 
outcomes will be (partially) mediated by a reduction of ruminative thinking, and improvement of 
mindfulness and self-compassion skills. 
 
3. STUDY DESIGN 
A randomized, multicenter, prospective, evaluator-blinded clinical trial of MBCT added to treatment as 
usual (TAU) versus TAU alone. Assessments will be conducted at baseline and at 3, 6, 9, 12, and 15 
months follow-up. At the end of the study period (15 months), the participants in the TAU group will be 
offered MBCT as well. Three external, specialized outpatients clinics for treatment of BD, will be 
participating in the present study. See Figure 1 for a prospective flow chart of the study. 
 
 
Figure 1. Prospective flow chart of the study 

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4. STUDY POPULATION 
4.1 
Population (base)  
BD patients older than 18 years will be recruited from the specialized outpatient clinics of ProPersona, 
Dimence, and Altrecht, and through the Vereniging voor Manisch Depressieven en Betrokkenen 
(VMDB). The psychiatry department of the Canisius Wilhelmina Ziekenhuis (CWZ) will also support 
recruitment by referring potential participants to the Raboudumc. 
4.2 
Inclusion criteria 
In order to be eligible to participate in this study, participants have to meet all of the following criteria: 
 
Confirmed diagnosis of bipolar I or II disorder.  
 
Having suffered at least two lifetime depressive episodes, either current or in (partial) 
remission at baseline (according to SCID-I assessment).  
 
Having suffered at least one affective episode (depressed or (hypo)manic) within the year 
prior to baseline.  
 
Young Mania Rating Scale score < 8. 
4.3 
Exclusion criteria 
A potential participant who meets any of the following criteria will be excluded from participation in this 
study: 
 
 
A manic episode within three months before the start of the trial.  
 
Lifetime diagnosis of schizophrenia or schizoaffective disorder, current substance abuse 
disorder, organic brain syndrome, antisocial or borderline personality disorder.  
 
Risk of suicide or aggression.   
 
The presence of a concurrent significant medical condition impeding the ability to participate. 
4.4 
Sample size calculation 
Sample size calculation is based on the estimated change in depressive symptoms form pre- to post-
treatment. As we aim to include patients with all levels of depressive symptoms, we based our 
calculation on a previous study conducted at the Radboudumc Centre for Mindfulness (van Aalderen 
et al., 2012). In this study, levels of depression as assessed with the Inventory of depressive 
symptomatology – self-rated (IDS-SR) decreased in the MBCT+TAU group (n = 102) from 14.9 (± 9.2) to 
10.3 (± 7.8) whereas the TAU group (n = 103) showed no change in depression levels (pretreatment: 
M = 16.2 (± 9.4) and posttreatment: M = 16.2 (± 9.8). This corresponded to an effect size of 0.5 for 
reduction of depressive symptoms in patients with recurrent (unipolar) depression (remitted n = 124, 
currently depressed n = 58). Based on a two-sided test with an alpha of 0.05 and a power of 80%, with 
an estimated effect size of 0.5, including a design factor of 1 – r2 (0.75), and taking account of a 
conservative estimate of 40% loss to follow-up, we intend to recruit N = 160 patients (80 per group). 
  
We anticipate that about 25% of the population will have to be excluded due to (hypo)manic symptoms 
(when exceeding the maximum on the Young Mania Rating Scale) or other exclusion criteria. We 
further expect about 25% of the eligible patients to be interested in the study. 
 
Approximately 690 BD patients are treated in ProPersona, with 518 (75%) meeting the inclusion 
criteria, of whom 130 (25%) would probably be interested to participate. The intended number of 
participants (n = 60) falls comfortably within this estimate. The number of BD patients treated in 
Dimence is about 900, with 675 (75%) meeting the inclusion criteria, of whom 169 (25%) would 
probably be interested to participate. Again, the intended number of participants (n = 50) falls well 
within this estimate. Approximately 650 BD patient are treated in Altrecht, with 100-150 new patients 
per year. About 487 (75%) of BD patients would be meeting the inclusion criteria, of whom 122 (25%) 
would probably be interested. The intended number of participants (n = 50) therefore seems feasible. 
Moreover, we will recruit patients through the patient association Vereniging voor Manisch 
Depressieven en Betrokkenen (VMDB) and the psychiatry department of the Canisius Wilhelmina 

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Ziekenhuis (CWZ). Patients whose attending physician is not affiliated with one of the participating 
centres will be asked permission to inform their attending physician about the patient’s participation in 
the study. 
 
5. TREATMENT OF SUBJECTS 
5.1 
Investigational treatment 
Mindfulness Based Cognitive Therapy (MBCT) + TAU 
This intervention will consist of usual care, with MBCT in adjunct. MBCT is a manualised group skills-
training program (Segal, Williams, & Teasdale, 2012) designed as a relapse prevention programme for 
patients with recurrent depression. The training consists of eight weekly sessions of 2.5 hours, plus 
one day of silent practice. In addition, participants are instructed to practice 45 minutes a day. The 
program includes both formal and informal meditation exercises. Cognitive techniques that are part of 
the program include psychoeducation, monitoring and scheduling of activities, identification of 
negative automatic thoughts and devising a relapse prevention plan. The MBCT intervention offered in 
the current study will be based on the 8-week MBCT course developed by Segal et al. (2012), but will 
be adapted to address the needs of BD patients. A few examples of these adaptations are as follows: 
psychoeducation about manic symptoms in addition to psychoeduction about depression; introducing 
the 3-minute breathing space earlier in the programme and more often during sessions, especially 
when strong emotions are present; repeatedly bringing the focus to self-care; and making use of the 
mindful movement (yoga) exercises more frequently. All group sessions will be conducted at the 
respective mental health sites, with each group comprising 8 - 12 participants.  
 
Mindfulness teachers 
The mindfulness training will be taught by teachers qualifying the advanced criteria of the Association 
of Mindfulness Based Teachers in the Netherlands and Flanders, which include a) a minimum of 150 
hours of education in MBSR/MBCT background and theory, training in teaching formal and informal 
meditation practices, psycho-education and inquiry, supervision and giving an MBSR or MBCT course 
including a reflection report; b) relevant professional training; c) minimum of three years of practicing 
meditation regularly and attending retreats; d) having attended MBSR / MBCT as a participant; e) 
continued training; and f) giving a minimum of two courses per two year. All teachers will receive 
additional training in the study protocol at the start of the project. We will organize peer supervision 
meetings every month during the intervention phase of the trial. Teacher competency will be assessed 
by the Mindfulness-based Interventions - Teacher Assessment Criteria (MBI: TAC, Crane et al., 2012). 
Videotapes of a random selection of sessions will be assessed by assessors who are familiar with this 
mindfulness-based program, are ’proficient’ mindfulness teachers (level 5) and have received training 
in the use of these assessment criteria. An early study of the psychometric properties of the MBI:TAC 
suggests it has good reliability, face validity and promising evidence of validity (Crane et al., 2013).
 
 
Comparator: Treatment as usual (TAU)   
Usual care of BD patients typically consists of pharmacotherapy, psycho-education and self-
management interventions (usually with a psychiatric nurse). According to the guidelines (Trimbos 
Instituut, 2015), these interventions will be or will have been offered to patients prior to participation in 
the current study. It is expected that a large majority of participants receive some form of 
pharmacotherapy. Because of the clinical representativeness, we will not restrict TAU in any way. So 
switching, tapering or augmenting of medication might be part of TAU. We will keep a careful record of 
this in order to examine and control for possible differences between the two groups. However, 
frequent psychological treatments, i.e. fortnightly or more, such as (group-based) CBT, will be an 
exclusion criterion for the current RCT because of practical and methodological reasons. For a 
detailed description of the biological treatment options that are part of TAU, such as several 
pharmacotherapeutic options, electroconvulsive therapy, and heliotherapy, we refer to the clinical 
guidelines "Multidisciplinaire Richtlijn Bipolaire Stoornissen (derde, herziene versie)”, pp 121-167 
(Trimbos Instituut, 2015). Detailed information for each individual pharmacotherapeutic option can be 

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found 
on 
the 
pharmacotherapeutic 
compass: 
https://www.farmacotherapeutischkompas.nl/ 
(Zorginstituut Nederland, 2017). 
 
6. METHODS 
6.1 
Study parameters/endpoints 
Outcome measures will be administered at 6 points in time: baseline (T0) and 3, 6, 9, 12 and 15-
month follow-up (T1 – T5). 
6.1.1 Main study parameter/endpoint 
The primary endpoint of the study is severity of depressive symptoms at 3 months follow-up (T1), 
assessed with the Inventory of Depressive Symptomatology – Clinician administered (IDS-C; 
Akkerhuis, 1997). The IDS-C has good psychometric qualities (Rush, Gullion, Basco, Jarrett, & 
Trivedi, 1996; Trivedi et al., 2004) and will be administered by trained research assistants. 
6.1.2 Secondary study parameters/endpoints  
Clinician-administered measures 
 
Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I; First, Spitzer, Gibbon, & 
Williams, 1996) or its successor for DSM 5 when available, to assess depressive and manic 
relapses. The SCID-I will be used to retrospectively assess possible relapses/recurrences in 
the past 3 months at each time point. The Dutch version of the SCID-I shows good to 
excellent inter-rater reliability (Lobbestael, Leurgans, & Arntz, 2011).  
 
Young Mania Rating Scale (YMRS; Young, Biggs, Ziegler, & Meyer, 1978), Dutch 
translation. The YMRS is an 11-item clinician-administered rating scale to assess the 
severity of (hypo)manic symptoms. It was found to be a reliable, valid, and sensitive 
rating scale to measure the severity of mania (Young et al., 1978).  
 
Functioning Assessment Short Test (FAST;  Rosa et al., 2007), Dutch translation. The FAST is 
a brief instrument designed to assess the main functioning problems experienced by 
psychiatric patients, particularly bipolar patients. It comprises 24 items that assess impairment 
or disability in six specific areas of functioning: autonomy, occupational functioning, cognitive 
functioning, financial issues, interpersonal relationships, and leisure time. It has been shown 
to have strong psychometrics properties in terms of high internal consistency, test-retest 
reliability, and concurrent validity, and its ability to detect differences between euthymic and 
acute BD patients (Rosa et al., 2007). 
 
Self-report measures 
 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR; Rush et al., 
2003). The QIDS-SR is a 16-item self-report version of the IDS-C. The QIDS-SR has good 
psychometric qualities.  
 
Altman self-rating mania scale (ASRM; Altman, Hedeker, Peterson, & Davis, 1997). The 
ASRM is a 5-item self-report questionnaire, with each item representing one of the major 
symptoms of mania, rated in increasing severity from 0 (not present) to 4 (present in 
severe degree). The ASRM has good psychometric properties.  
 
Prospective Life Chart, self-report, Dutch translation (Kupka, Akkerhuis, Nolen, & Honig, 
1997). The Prospective Life Chart documents the course and severity of recurrent affective 
episodes. The current study will use the Life Chart prospectively in order to gain more fine-
grained information about the severity of (hypo)manic or depressive symptoms over time, 
across the entire study period (15 months). The Life Chart has been shown a valid and 
reliable instrument to document the severity of affective episodes (Kupka et al., 1997). 
 
State/Trait Anxiety Inventory (STAI; Spielberger, 1983). The STAI is a self-report measure 
which has been proven reliable and sensitive in the assessment of both state and trait 

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levels of anxiety. It is a standard international measure in anxiety research and its Dutch 
translation has been shown valid (Van der Ploeg, 2000). 
 
Brooding subscale of the extended version of the Ruminative Response Scale (RRS-EXT; 
Treynor, Gonzalez, & Nolen-Hoeksema 2003). The authors reported adequate internal 
consistency (α = .79) and test–retest stability (α = .62, with a one year time interval) for the 
brooding subscale, which consists of five items. We select the brooding subscale because 
over time, brooding, or rumination, has been more strongly related to levels of depression 
(Treynor et al., 2003). 
 
The Comprehensive Inventory of Mindfulness Experience (CHIME; Bergomi, Tschacher, & 
Kupper, 2014). The CHIME is a 37-item, self-report questionnaire, divided in eight subscales 
measuring eight mindfulness aspects, including inner awareness, outer awareness, acting 
with awareness, acceptance, decentering, openness, relativity, and understanding. The 
CHIME has shown satisfactory to good change sensitivity, internal consistency, and test-
retest reliability (Bergomi et al., 2014; Nila, Holt, Ditzen, & Aguilar-Raab, 2016).   
 
Self-Compassion Scale – short form (SCS-SF; Raes, Pommier, Neff, & Van Gucht, 2011). 
The present study will use the 12-item Dutch short-form version of the SCS-SF to measure 
self-compassion. The scale consists of six components, including self-kindness, self-
judgment, common humanity, isolation, mindfulness and over-identification. The SCS-SF has 
good reliability and validity (Raes et al., 2011). 
 
Mental Health Continuum – short form (MHC-SF; Lamers, Westerhof, Bohlmeijer, ten 
Klooster, & Keyes, 2011). Lamers, 2011). The MHC-SF is a 14-item self-report 
questionnaire that assesses emotional, psychological and social well-being. It has 
adequate psychometric qualities in terms of good internal consistency, (moderate) test-
retest reliability, and good divergent and convergent validity. 
 
Responses to Positive Affect- Dutch Version (RPA-NL; Feldman, Joormann, & 
Johnson, 2008). The RPA is a 17-item questionnaire measuring self-reported levels of 
dampening and rumination in response to positive affect. The RPA-NL shows a 
satisfactory internal consistency (Raes, Daems, Feldman, Johnson, & van Gucht, 
2009). 
 
Childhood Trauma Questionnaire (CTQ; Bernstein et al., 2003). This questionnaire with 28 
intems  assesses five domains of abuse and traumatic experiences during childhood (physical 
abuse, emotional abuse, sexual abuse, physical neglect and emotional neglect). The CTQ 
shows good criterion-related validity (Bernstein et al., 2003).  
 
Treatment Credibility Questionnaire (TCQ; Borkovec and Nau, 1972, adapted version by 
Addis et al. (2004), with one additional item from the Credibility Expectancy Questionnaire 
(Devilly and Borkovec, 2000). The TCQ that will be used in this study consists of 7 items that 
focus on credibility and expectancy of treatment. The TCQ shows good reliability (Borkovec & 
Nau, 1972).   
 
Economic evaluation 
 
EQ-5D-5L (EuroQol Group, 2009). The EQ-5D-5L measures the quality of life by means of 
five dimensions, including mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. In addition it contains a visual analogue scale to determine Quality 
Adjusted Life Years (QALYs). The EQ-5D-5L shows to be a valid instrument (Janssen et al., 
2013).  
 
Trimbos/iMTA questionnaire for costs associated with psychiatric illness (Tic-P; Hakkaart, 
Van Straten, Donker, & Tiemens, 2002). The TiC-P is a 38-item, self-report inventory 
measuring resource use, such as use of care, medication and illness related to work. It 
measures both direct costs, i.e. care consumption of people suffering from psychiatric illness, 
and indirect costs, i.e. costs associated with production loss. The TiC-P shows good reliability 
(Bouwmans et al., 2013).  
 

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Cognitive measures 
 
Stroop Task (Stroop, 1935). Subjects are instructed to name the colour of the printed text on 
the card, not the colour of the word that is written. This tasks measures interference in 
attention.  
 
Emotional Stroop Task (Williams et al., 1996). This is an adapted version of the original 
colour Stroop task. Cards are filled with neutral stimuli (XXXX), negative words (e.g. 
‘sadness’) and positive words (e.g. ‘happy’), reaction time per card is measured.  
 
Breathing Focus Task (Hayes, Hirsch, Krebs, & Matthews, 2010). This task measures state 
rumination. Subjects are instructed to concentrate on their breathing for 5 minutes. The 
computer signals at random points in time, on which the subjects are instructed to tell the 
research assistant whether they focused on breathing or not. Furthermore, they are asked 
to tell whether their thoughts were positive, negative or neutral at the moment of the signal. 
After this, the subjective experience of the breathing task is assessed shortly (Hayes et al., 
2010).  
 
Self Referent Encoding Task (Joormann et al., 2006). This task measures memory bias for 
emotional information. 24 words are presented on a computer screen (12 negative, 12 
positive). Subjects are asked to rate whether or not the word describes them.  After this, 
subjects are distracted for 3 minutes with a trail making task. The trail making task is followed 
by a free recall phase, in which they have to 3 minutes to write down as much words as they 
remember.  
 
Pavlovian to instrumental transfer task (Geurts et al., 2013; Huys et al., 2011). This task 
assesses positive and negative affecte bias on goal-oriented, instrumental behaviour. At 
first, subjects are trained to react to instrumental stimuli with which they can earn small 
amounts of money (5 cents). Next, we show subjects neutral pictures that we then 
associate with monetary wins and losses. By this latter classical (or Pavlovian) conditioning 
procedure these neutral pictures acquire an affective valence and become conditioned 
stimuli (CS) with appetitive and aversive valence respectively. Finally we ask subjects to 
react to the instrumental stimuli again, but now also show them the CS on the background. 
The CS-dependent change in instrumental behaviour then is a measure of Pavlovian 
affective bias. 
 
6.1.3 Other study parameters 
Baseline parameters 
 
Age 
 
Gender 
 
Ethnicity 
 
Level of education 
 
Marital status 
 
Employment status 
 
BD type (bipolar I or II) 
 
Age at onset 
 
Time since last episode of depression or (hypo)mania 
 
Number of previous episodes (manic and depressed, reported separately) 
 
Types and dose of medication being used 
 
Previous treatment with CBT and/or IP(SR)T (yes/no) 
 
Suicide attempt (lifetime; yes/no) 
 
Number of previous hospitalizations due to either manic or depressive episode 
 
Comorbid psychiatric diagnoses 
 
Measures for adherence 
Adherence to mindfulness practice and medication use will be assessed using prospective daily 
registration on the Life Chart.  

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6.2 
Randomisation, blinding and treatment allocation 
Randomisation will be performed within the datamanagement system Castor EDC. This will consist of 
stratified, variable block randomisation with the following stratification variables: Location (site); 
Gender; Depression (current versus remitted); BD type (I versus II); and number of previous episodes 
(<12 versus =/> 12). This system also allows for blinded (concealed) allocation such that research 
assistants on site can be kept blind to condition. MBCT teachers on site will be notified of the 
allocation to MBCT, allowing them to invite the patient to participate and coordinate further 
arrangements. As only assessors will be blind to treatment allocation due to the nature of the 
intervention, no indications for breaking the randomization code are pre-specified. In case of adverse 
reactions, patients are encouraged to discuss this with their MBCT teacher and responsible clinician. 
6.3 
Study procedures 
Figure 2 provides a flowchart of the study procedures from referral to the final assessment. Patients 
will be recruited from several specialized, outpatient clinics in the Netherlands; ProPersona, Dimence, 
and Altrecht, and through the patient association; Vereniging voor Manisch Depressieven en 
Betrokkenen (VMDB). They will receive a letter from their attending clinicans, informing them about the 
study with an included information leaflet. This way, patients are free to choose whether to participate 
in the study, without feeling obligated to their clinicans when asked face-to-face. Interested patients 
are, after verbal consent is obtained, invited for a screening by telephone to assess global eligibility. 
Eligible patients will receive more information and a detailed description of the study procedure.After 
one week, patients will be contacted by telephone to assess whether they are still interested in 
participation. Patients who are still interested to participate will be invited for intake with a research 
assistant, where informed consent is obtained. They are thoroughly screened for in- and exclusion 
criteria with use of the SCID-I and YMRS. Altogether, this will take about 1.5 hours. When patients are 
still eligible and interested, they are invited for baseline assessment (T0), which consists of several 
clinician administered measures ( IDS-C and FAST), which will take about 20 minutes. After a short 
pause, participants are asked to conduct five short computer tasks (Stroop, Emotional Stroop Task, 
Breathing Focus Task, Self Referent Encoding Task, and Attentional Control Scale). This will take 
about onee hour. However, it is possible for participants to do only the first part of these measures, so 
they can skip the computer tasks if necessary. Furthermore, participants are asked to fill in several 
self-report questionnaires at home (STAI, brooding subcale of RRS, CHIME, SCS-SF, MHC-SF, RPA, 
CTQ, TiC-P, and EQ-5D-5L). After baseline assessment, patients are randomised to one of two 
groups: TAU or MBCT + TAU. Participants in the intervention group (MBCT + TAU) will receive an 
eight-week MBCT training, during which they daily have to document mood fluctuations, changes in 
medication, and major life events in the Life Chart. Furthermore, participants are asked to document 
adherence and adverse events in a personal diary. Participants in the comparator group (TAU) will 
receive their treatment as usual, while they daily document in the Life Chart as well. After three 
months (T1), participants are invited for follow-up assessment, during which the clinician administered 
questionnaires (YMRS, IDS-C, FAST, SCID-I) and computer tasks will be conducted again. 
Furthermore, patients are asked to fill out the online self-report questionnaires a second time. More 
follow-up assessments will take place after 6 months (T2), 9 months (T3), 12 months (T4), and 15 
months (T5). During T2, T3, and T4 assessments patients are approached by telephone to assess 
depressive, manic, and anxiety symptoms, and global functioning over the past three months (IDS-C, 
YMRS, FAST, and SCID-I to assess manic and depressive symptoms retrospectively). Furthermore, 
during these assessments patients are asked to fill out the online questionnaires as well.The 
assessment at 15 months follow-up (T5), will consist of the clinician adminstered meassurements 
(IDS-C, YMRS, FAST) and  the online self-report measurements (STAI, brooding subcale of RRS, 
CHIME, SCS-SF, MHC-SF, RPA, TiC-P, EQ-5D-5L). Table 1 provides an overview of the 
assessments. After 15 months of follow-up the study will end, after which participants in the 
comparator group will be given the opportunity to participate in a MBCT-course as well.   
 

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Figure 2. Flowchart of the study procedures 
 
 
 Recruitment via mental health professionals’ referrals or self-referrals. 
Interested individuals screened by telephone to assess global eligibility after verbal consent is 
obtained.  
Does patient (probably) meet inclusion (and not exclusion criteria? 
Yes 
No 
Exclude  
Study procedure explained in detail and study information is provided. Patients get one week (or 
longer if needed) to decide whether or not to participate. 
Patient still interested in participation? 
No 
Exclude 
Patient is invited for the research interview, in which the in- and exclusion criteria are 
assessed in detail. Informed consent is collected. 
Eligible and informed consent obtained? 
Randomization (stratification variables: research centre; gender; depression status (current 
versus remitted); type of Bipolar Disorder; number of previous episodes (<12 versus =/> 12).  
TAU + MBCT  
TAU 
Yes 
No 
Exclude 
Yes 
-MBCT intervention (8 
weeks)  
T2 assessment (6 months) 
T3 assessment (9 months) 
T4 assessment (12 months) 
T5 assessment (15 months) 
T1 assessment (3 months) 
T0 assessment (baseline) 

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Table 1.  Overview assessments 
Interviews: 
T0 
MBCT 
T1 
T2 
T3 
T4 
T5 
SCID-1 (Full) 
* 
 
 
 
 
 
 
SCID-1 (depression / mania) 
 
 
* 
* 
* 
* 
* 
IDS-C 
* 
 
* 
* 
* 
* 
* 
YMRS 
* 
 
* 
* 
* 
* 
* 
FAST 
* 
 
* 
* 
* 
* 
* 
Self-report questionnaires: 
T0 
MBCT 
T1 
T2 
T3 
T4 
T5 
CTQ 
* 
 
 
 
 
 
 
TCQ 
* 
 
 
 
 
 
 
STAI 
* 
 
* 
* 
* 
* 
* 
MHC-SF 
* 
 
* 
* 
* 
* 
* 
RRS-Br 
* 
* 
* 
* 
* 
* 
* 
SCS-SF 
* 
* 
* 
* 
* 
* 
* 
Q-IDS - SR 
 
* 
 
 
 
 
 
ASRM 
 
* 
 
 
 
 
 
CHIME 
* 
* 
* 
* 
* 
* 
* 
RPA-NL 
* 
* 
* 
* 
* 
* 
* 
EQ-5D-5L 
* 
 
* 
* 
* 
* 
* 
TiC-P 
* 
 
* 
* 
* 
* 
* 
Life CHART (incl medication 
adherence) 
* 
Mfn adherence + Adverse events 
* 
Cognitive measures: 
T0 
MBCT 
T1 
T2 
T3 
T4 
T5 
 
self-referent encoding task and 
trail making task (distraction) 
 
breathing focus task 
 
emotional stroop task 
 
colour stroop task 
 
Pavlovian instrumental transfer  
 
 
Visual-analogue scale (mood 
rating; after breathing focus 
task) 
* 
 
* 
 
 
 
 
 
6.4 
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 investigator can decide to withdraw a subject from the study for urgent medical 
reasons. 
6.5 
Replacement of individual subjects after withdrawal 
 After withdrawal, individual participants will not be replaced. 
6.6 
Follow-up of subjects withdrawn from treatment 
 Dropouts will be contacted by phone and asked to fill out the remaining questionnaires to supply the 
researchers with a post measurement and follow-up. Dropouts will be reminded that they are free to 
refuse. 
6.7 Premature termination of the study 
There are no criteria for premature termination of the study.  

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7. SAFETY REPORTING 
7.1 
Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is 
sufficient ground that continuation of the study will jeopardise subject health or safety.  The sponsor 
will notify the accredited METC without undue delay of a temporary halt including the reason for such 
an action. The study will be suspended pending a further positive decision by the accredited METC. 
The investigator will take care that all subjects are kept informed.  
 
7.2 
AEs, SAEs and SUSARs 
7.2.1 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 mindfulness training. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
7.2.2 Serious adverse events (SAEs) 
  
A serious adverse event is 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 inpatients’ hospitalisation; 
 
Results in persistent or significant disability or incapacity; 
 
Is a congenital anomaly or birth defect, or; 
 
Any other important medical event that did not result in any of the outcomes listed above due 
to medical or surgical intervention but could have been based upon appropriate judgement by 
the investigator. 
 
We expect the number of (S)AE’s during the intervention to be minimal, as the intervention is non-
invasive. Adverse events or reactions that may occur during the study will be examined at each 
assessment by explicitly asking if people may have noticed unpleasant effects that appear to be 
causally related to the MBCT training. Reported adverse events related to meditation could be 
relaxation-induced anxiety and panic, paradoxical increases in tension, impaired reality testing, 
confusion, disorientation, dissociation, feeling addicted to meditation and grandiosity (Dobkin, Irving, & 
Amar, 2012; Shapiro, 1992). Furthermore, we will  be watchful for posttraumatic stress symptoms that 
might arise as a result of the MBCT training, such as re-experiencing. The principal investigators will 
check the questionnaires on signs of (S)AE’s as well. All adverse events reported spontaneously by 
the participant or observed by the principal investigator or his/her staff will be recorded and reported 
through the web portal ToetsingOnline 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. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining knowledge of 
the events, except for the following SAEs:   
 
An elective hospital admission.  
 
Relapse into a (hypo)manic or depressive episode, which is an expected event in this specific 
population, since 60% of BD patients relapse within two years (Miklowitz et al., 2009; Oud et 
al., 2016). The study of Perich et al. (2013), who conducted a RCT of MBCT for BD, found that 
59% of participants in the MBCT condition and 48% in the TAU condition reported a 
(hypo)manic episode, while 59% in the MBCT condition and 68% in TAU reported a 
depressive episode over a 12 month follow-up period. In that study, the median time to 

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(hypo)mania relapse was 130 days for MBCT and 143 for TAU. Median time to depressive 
relapse was 53 days for MBCT and 46 days for TAU.  
7.3 
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 need to be reported till end of study within the 
Netherlands, as defined in the protocol. 
7.4 
Data Safety Monitoring Board (DSMB) / Safety Committee 
It is estimated that the risk of harm is not increased when participating in this study. With regard to 
NFU-classification the risk is negligible. Therefore a DSMB is not needed for this study. 
 
8. STATISTICAL ANALYSIS 
Multilevel analysis will be used to account for the cluster-randomized design and therefore the 
hierarchical structure of the data, with outcome variables at the pre- and postmeasurements at the 
lowest level, nested within individuals, nested within treatment groups (for the intervention condition), 
and nested within condition (MCBT + TAU vs TAU). Any baseline parameters that may be 
inadvertently unequally distributed between the conditions are included as covariates. Multilevel 
logistic regression will be performed for dichotomous outcomes and multilevel regression analysis for 
normally distributed continuous outcomes. The clinical outcome data will be analysed and reported 
according to the CONSORT guidelines, i.e. on intention-to-treat basis. Given the anticipated drop-out, 
we will also analyze and report on the per-protocol group, and discuss possible differences between 
the two analysis sets. 
 
Additional analyses will be performed within subgroups with and without a current depressive episode. 
To account for possible differences between therapy groups, we will add a random group effect. 
Sensitivity analyses will be conducted with different scenarios of imputed data sets, in case of missing 
data, to examine the influence of missing data on the pattern of outcomes. 
8.1 
Primary study parameter(s) 
The primary analysis is aimed at comparing the effects of MBCT + TAU on depressive symptoms. The 
primary outcome parameter will be the total scores on the IDS-C. In order to investigate consolidation 
of treatment effect, we will follow-up participants for another 15 months. We will use a multilevel 
regression model for repeated measures to analyse differences between baseline, 3 months, 6 
months, 9 months, 12 months, and 15 months follow-up measurements. 
 
8.2 
Secondary study parameter(s)  
The secondary analysis is aimed at comparing the effects of MBCT + TAU on (hypo)manic and 
anxiety symptoms, quality of life, rumination, mindfulness and self-compassion skills. The secondary 
outcome parameters will be the total scores on the YMRS, FAST, STAI, RPA, MHC-SF, SCS-SF, 
CHIME, and the brooding subscale of the RRS. In order to investigate consolidation of treatment 
effect, we will follow-up participants for another 15 months. We will use a multilevel regression model 
for repeated measures to analyse differences between baseline, 3 months, 6 months, 9 months, 12 
months, and 15 months follow-up measurements. 
 
Furthermore, cost-effectiveness evaluation is carried out from a societal perspective considering direct 
as well as indirect costs. Data on resource use (health care uptake) and productivity losses will be 
collected with the Tic-P. Total costs for each patient will be obtained by multiplying these data with 
standard costs, based on the Dutch guideline for costing research (Hakkaart et al., 2002). Overall 
mean and median costs will be compared across the conditions and where relevant, differences will be 
calculated inclusive of 95% confidence intervals. 

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Cost-effectiveness and cost-utility analysis 
For these analyses we will use SPSS statistical software and Excel (for the Bootstraps). Respondents 
for whom at least 75% of the data per measurement instrument are available will be included in the 
analysis. Missing cost and outcome data will be imputed using multiple imputation (MI) methods and 
last-observation carried forward (LOCF), for intention to treat (ITT) analysis following Dutch guidelines  
(Zorginstituut Nederland 2016). 
 
A baseline analysis will be performed to examine the comparability of groups at baseline for both costs 
and outcomes. If necessary methods will be applied to control for differences in baseline (Manca, 
Hawkins, & Sculpher, 2005). To investigate whether data are normally distributed a Kolmogorov-
Smirnov test will be performed. Despite the usual skewness in the distribution of costs, the arithmetic 
means will be generally considered the most appropriate measures to describe cost data (Barber & 
Thompson, 2000; Ramsey et al., 2005). Therefore arithmetic means (and standard deviations) will be 
presented. In case of skewness of the cost data, non-parametric bootstrapping will be used to test for 
statistical differences in costs between the intervention and control group. Non-parametric 
bootstrapping is a method based on random sampling with replacement based on individual data of 
the participants (A. H. Briggs, Wonderling, & Mooney, 1997). The bootstrap replications will be used to 
calculate 95% confidence intervals around the costs (95% CI), based on the 2.5th and 97.5th 
percentiles. If cost data are distributed normally, t-tests will be used. 
The Incremental cost-effectiveness ratio (ICER) will be determined on the basis of incremental costs 
and effects of MBCT compared to TAU. The cost-effectiveness ratio will be stated in terms of costs 
per outcome rate (IDS-C), the cost-utility ratio will focus on the cost per QALY gained. 
 
The ICER will be calculated as follows. ICER = (Ci – Cc) / (Ei – Ec), where Ci is the total cost of the 
MCBT group, Cc is the total cost of the TAU group, Ei is the effect at 12 months follow-up for the 
MCBT group and Ec is the effect at 12 months follow-up  for the TAU group. 
 
Sensitivity analysis 
Stochastic uncertainty of the ICER will be handled using 2,500 non-parametric bootstraps and by 
plotting the simulated ICERs on the ICER plane. Bootstrap simulations will be conducted in order to 
quantify the uncertainty around the ICER, yielding information about the joint distribution of cost and 
effect differences. The bootstrapped cost-effectiveness ratios will be subsequently plotted in a cost-
effectiveness plane, in which the vertical line reflects the difference in costs and the horizontal line 
reflects the difference in effectiveness. The choice of treatment depends on the maximum amount of 
money that society is prepared to pay for a gain in effectiveness, which is called the willingness-to-
pay (WTP) ceiling ratio. For decision-making purposes, the ICER acceptability curve will be plotted for 
various WTP) ceilings for making judgments whether discontinuation offers good value for money 
relative to routine medical care. Deterministic one-way sensitivity analyses directed at uncertainty in 
the main effects and main cost drivers will be performed to assess the robustness of our findings. 
Additionally, a multi-way sensitivity (scenario-) analyses will be performed. In the sensitivity analysis 
uncertain factors of assumptions in the base case analysis will recalculated in order to assess whether 
the assumptions have influenced the incremental cost-effectiveness ratio (ICER), for example by 
varying cost-prices and volumes between minimum and maximum (A. H. Briggs et al., 1997). 
 
Budget-impact analysis 
The budget impact analysis (BIA) will be conducted as outlined by the ISPOR Task Group (i.e. 
Mauskopf et al., 2007; Sullivan et al., 2014) to assess how health care budgets change when MCBT is 
offered over a range of implementation levels. The BIA will be conducted from various perspectives: 
(1) the societal perspective, i.e. including productivity losses; (2) the perspective of the public purse (in 
Dutch: netto Budgettair Kader Zorg); and (3) the perspective of the health care insurer. In each 
perspective the following scenarios will be assessed: a scenario in which the intervention is offered to 
40%, 60% and 80% of the target group and an extreme scenario in which 100% of the target group 
will be receiving the MCBT intervention. These scenarios will be compared with a base-case scenario 

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where 0% of the target group is offered MCBT (reflecting treatment as usual (TAU). The BIA will be 
based on a health-economic simulation excel model, based on modelling techniques outlined in 
Briggs, Claxton, & Sculpher (2006) and following ISPOR modeling guidelines (Caro, Briggs, Siebert, & 
Kuntz, 2012). The BIA will be conducted according Dutch guidelines (Zorginstituut Nederland, 2016), 
taking into account the complexity and dynamics of clinical practice and specific characteristics of the 
Dutch health care system. Cost data will be extracted from the trial and are based on the Dutch 
manual of costing (Tan, Bouwmans-Frijters, & Hakkaart-van Roijen, 2012). Costs will be modelled out 
over the short term (12 months) and longer-term (36 months) as required by the Dutch guideline for 
health-economic evaluation (Zorginstituut Nederland, 2016). Long-term costs will be discounted 
according to the Dutch guidelines. The impact of MBCT on budgets is furthermore depending on 
(changes in) the prevalence of BD. Sensitivity analyses on the main input parameters will be 
conducted to assess the robustness of the outcomes. 
8.3 
Other study parameters 
The potential effects of CTEs on MBCT treatment effect will be assessed by moderation analysis. 
Furthermore, we will assess whether MBCT induces change in the acquired cognitive-affective bias 
measures. In addition, mediation analysis will be used to study the effect of MBCT on cognitive control 
measures (cognitive-affective bias, rumination) in the MBCT + TAU versus the TAU group. Mediation 
and moderation analyses will be carried out using the PROCESS tool (Hayes, 2012). With PROCESS, 
estimates of mediation/moderation effects were computed using bootstrapping methods.  
 
9. ETHICAL CONSIDERATIONS 
9.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (6th edition, 
2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO). 
9.2 
Recruitment and consent 
A description of recruitment and informed consent procedures are appointed in the study procedures 
on page 15 of this study protocol.  
9.3 
Benefits and risks assessment, group relatedness 
This study involves capacitated adults and examines a therapeutic intervention that already is adopted 
as a treatment option in the ‘Multidisciplinaire Richtlijn Bipolaire Stoornissen’ (Trimbos, 2015). 
Participation is free of charge. We believe that the risks of participation are negligible. However, 
because of this vulnerable patient group, we will be extra watchful for adverse reactions to the MBCT 
training, such as slight feelings of disorientation, confusion, dissociation, impaired reality testing, and 
grandiosity. If patients show a clear increase in symptoms, additional guidance will be offered. 
Participants are encouraged to respect their boundaries (both physical and psychological) and are 
always free to suspend or adapt the practice as needed. The burden associated with participation in 
MBCT is relatively high: consisting of 8 weekly group sessions of 2,5 hours and one silent day (6 
hours), and home practice of about 45 minutes a day. Participation includes 6 research assessments 
consisting of interviews and questionnaires about psychological symptoms, functioning, and quality of 
life. Although the effort requested from patients is high, we expect that practicing mindfulness will be 
associated with enduring changes in patients' coping strategies in daily life, and as a result, can 
increase participants' autonomy and self-efficacy.  
9.4 
Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the WMO. 
  
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects through 
injury or death caused by the study. 

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The insurance applies to the damage that becomes apparent during the study or within 4 years after 
the end of the study. 
  
9.5 
Incentives (only applicable to the PIT task) 
The Pavlovian instrumental transfer task (see section 6.1.2.) relies on reinforcement learning and 
previous studies with these tasks have used monetary incentives as reinforcement (Geurts et al. 2014, 
Huys et al 2011, Huys et al 2016). We will tell participants they will receive monetary reinforcement 
calculated based on their performance after the second time they participate in the task. We will inform 
them that the amount of money earned generally will amount to 5-6 euro. All participants involved will 
receive a gift-card of 5 euro with (depending on their performance) another 10-90 cents of money.  
 
10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
10.1 Handling and storage of data and documents 
All data will securely be stored for 15 years after the study, until November 2036. All data will be kept 
and stored according to the Personal Data Protection Act (in Dutch: De Wet Bescherming 
Persoonsgevens). After signing up and randomisation, participants will be linked to a unique number. 
Data which leads to the contact details (such as name, telephone number, and e-mail address) of the 
participant will be stored in a separate dataset from the dataset in which all other research data will be 
stored during the study. Only via the unique number, contact details can be linked to research data. 
Access to the code that couples the study data to the participants contact details is limited to the 
principal investigators and research assistant(s). 
10.2 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited METC 
has been given. All amendments will be notified to the METC that gave a favourable opinion. All 
substantial amendments will be notified to the METC and to the competent authority. Non-substantial 
amendments will not be notified to the accredited METC and the competent authority, but will be 
recorded and filed by the sponsor. 
10.3 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
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 trial, serious adverse events/ 
serious adverse reactions, other problems, and amendments.  
10.4 Temporary halt and (prematurely) end of study report 
The investigator will notify the accredited METC of the end of the study within a period of 8 weeks. The 
end of the study is defined as the last participant’s follow-up T5 questionnaires are finished. In case 
the study is ended prematurely, the investigator will notify the accredited METC 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 METC. 
10.5 Public disclosure and publication policy 
This study follows the basic principles of the CCMO’s position on the disclosure/publication of 
research results obtained from studies involving human participants. Results of scientific research 
involving human participants will be disclosed unreservedly.   
 

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11. REFERENCES 
 
Aas, M., Henry, C., Andreassen, O. A., Bellivier, F., Melle, I., & Etain, B. (2016). The role of childhood 
trauma in bipolar disorders. International journal of bipolar disorders, 4(1), 2. 
doi:10.1186/s40345-015-0042-0 
Adams, A. M., Shapero, B. G., Pendergast, L. H., Alloy, L. B., & Abramson, L. Y. (2014). Self-referent 
information processing in individuals with bipolar spectrum disorders. J Affect Disord, 152, 
483-490. doi:https://doi.org/10.1016/j.jad.2013.07.039 
Akkerhuis, G. W. (1997). Vertaling IDS. Utrecht, The Netherlands: H.C. Rümke Groep. 
Altman, G., Hedeker, D., Peterson, J. L., & Davis, J. M. (1997). The Altman Self-Rating Mania Scale. 
Society of Biological Psychiatry, 42, 948-955.  
Barber, J. A., & Thompson, S. G. (2000). Analysis of cost data in randomized trials: an application of 
the non‐parametric bootstrap. Statistics in medicine, 19(23), 3219-3236.  
Beck, A. T. (2008). The evolution of the cognitive model of depression and its neurobiological 
correlates. American Journal of Psychiatry, 165(8), 969-977. 
doi:https://doi.org/10.1176/appi.ajp.2008.08050721  
Beck, A. T., & Haigh, E. A. P. (2014). Advances in cognitive theory and therapy: the generic cognitive 
model. Annual review of clinical psychology, 10, 1-24. doi:https://doi.org/10.1146/annurev-
clinpsy-032813-153734 
Bergomi, C., Tschacher, W., & Kupper, Z. (2014). Konstruktion und erste Validierung eines 
Fragebogens zur umfassenden Erfassung von Achtsamkeit. Das Comprehensive Inventory of 
Mindfulness Experiences. Diagnostica, 60, 111-125. doi:http: 
//dx.doi.org/10.1026/0012-1924/a000109. 
Bouwmans, C., de Jong, K., Timman, R., Zijlstra-Vlasveld, M., van der Feltz-Cornelis, C., Swan Tan, 
S., & Hakkaart-van Roijen, L. (2013). Feasibility, reliability and validity of a questionnaire on 
healthcare consumption and productivity loss in patients with a pscyhiatric disorder (TiC-P). 
BMC Health Services Research, 13, 1-9. doi:1472-6963/13/217 
Briggs, A. H., Claxton, K., & Sculpher, M. J. (2006). Decision modelling for health economic 
evaluation. Oxford: Handbooks in Health Economic  
Briggs, A. H., Wonderling, D. E., & Mooney, C. Z. (1997). Pulling cost‐effectiveness analysis up by its 
bootstraps: A non‐parametric approach to confidence interval estimation. Health economics, 
6(4), 327-340.  
Caro, J. J., Briggs, A. H., Siebert, U., & Kuntz, K. M. (2012). ISPOR-SMDM Modeling Good Research 
Practices Task Force. Modeling good research practices--overview: a report of the ISPOR-
SMDM Modeling Good Research Practices Task Force--1. Value Health, 15(6), 796-803.  
Crane, R. S., Eames, C., Kuyken, W., Hastings, R. P., Williams, J. M. G., Bartley, T., . . . Surawy, C. 
(2013). Development and Validation of the Mindfulness-Based Interventions–Teaching 
Assessment Criteria (MBI:TAC). Assessment, 20(6), 681-688. 
doi:10.1177/1073191113490790 
Davis, L., & Kurzban, S. (2012). Mindfulness-Based Treatment for People With Severe Mental Illness: 
A Literature Review. American Journal of Psychiatric Rehabilitation, 15(2), 202-232. 
doi:10.1080/15487768.2012.679578 
De Graaf, R., Ten Have, M., & van Dorsselaer, S. (2010). De psychische gezondheid van de 
Nederlandse bevolking. Nemesis-2: Opzet en eerste resultaten, Trimbos-Instituut, Utrecht.  
Deckersbach, T., Holzel, B. K., Eisner, L. R., Stange, J. P., Peckham, A. D., Dougherty, D. D., . . . 
Nierenberg, A. A. (2012). Mindfulness-based cognitive therapy for nonremitted patients with 
bipolar disorder. CNS Neurosci Ther, 18(2), 133-141. doi:10.1111/j.1755-5949.2011.00236.x 
Dilsaver, S. C. (2011). An estimate of the minimum economic burden of bipolar I and II disorders in the 
United States: 2009. J Affect Disord, 129(1-3), 79-83. 
doi:https://doi.org/10.1016/j.jad.2010.08.030 
Dobkin, P. L., Irving, J. A., & Amar, S. (2012). For Whom May Participation in a Mindfulness-Based 
Stress Reduction Program be Contraindicated? . Mindfulness, 3, 44-50. doi:DOI 
10.1007/s12671-011-0079-9 
Eisendrath, S. J., Delucchi, K., Bitner, R., Fenimore, P., Smit, M., & McLane, M. (2008). Mindfulness-
based cognitive therapy for treatment-resistant depression: a pilot study. 
Psychother.Psychosom., 77(5), 319-320.  
EuroQol Group (Producer). (2009). EQ-5D-5L. Retrieved from https://euroqol.org/eq-5d-
instruments/eq-5d-5l-about/ 

NL63319.091.17 / ZonMW dossiernr: 80-84300-98-82003 
    MBCT for BD 
Version 3, 24-4-2018 
 
24 of 26 
Farkas, M. (2007). The vision of recovery today: what it is and what it means for services. World 
Psychiatry, 6(2), 68-74.  
Feldman, G. C., Joormann, J., & Johnson, S. L. (2008). Responses to Positive Affect: A Self Report 
Measure of Rumination and Dampening. Cognitive Therapy and Research, 32(4), 507-525. 
doi:doi:10.1007/s10608-006-9083-0 
First, M. B., Spitzer, R. L., Gibbon, M., & Williams, J. B. W. (1996). Structured Clinical Interview for the 
DSM-IV Axis I Disorders (SCID-I). New York: Biometric Research. 
Gonda, X., Pompili, M., Serafini, G., Montebovi, F., Campi, S., Dome, P., . . . Rihmer, Z. (2012). 
Suicidal behavior in bipolar disorder: epidemiology, characteristics and major risk factors. J 
Affect Disord, 143(1), 16-26. doi:https://doi.org/10.1016/j.jad.2012.04.041 
Gotlib, I. H., & Joormann, J. (2010). Cognition and depression: current status and future directions. 
Annual review of clinical psychology, 6, 285-312. 
doi:https://doi.org/10.1146/annurev.clinpsy.121208.131305  
Gruber, J. (2011). Can Feeling Too Good be Bad? Positive Emotion Persistence (PEP) in Bipolar 
Disorder. Current Directions in Psychology, 20(4), 217-221. doi:10.1177/0963721411414632 
Gruber, J., Eidelman, P., & Harvey, A. G. (2008). Transdiagnostic emotion regulation processes in 
bipolar disorder and insomnia. Behaviour research and therapy, 46(9), 1096-1100. 
doi:https://doi.org/10.1016/j.brat.2008.05.004 
Gruber, J., Eidelman, P., Johnson, S. L., Smith, B., & Harvey, A. G. (2011). Hooked on a Feeling: 
Rumination About Positive and Negative Emotion in Inter-Episode Bipolar Disorder. Journal of 
Abnormal Psychology, 120(4), 956-961. doi:10.1037/a0023667. 
Gutiérrez‐Rojas, L., Gurpegui, M., Ayuso‐Mateos, J. L., Gutiérrez‐Ariza, J. A., Ruiz‐Veguilla, M., & 
Jurado, D. (2008). Quality of life in bipolar disorder patients: a comparison with a general 
population sample. Bipolar Disord, 10(5), 625-634. doi:10.1111/j.1399-5618.2008.00604.x 
Hakkaart, v. R., L., Van Straten, A., Donker, M., & Tiemens, B. (2002). Trimbos/iMTA questionnaire for 
costs associated with psychiatric illness (TIC-P). Institute for Medical Technology Assessment, 
Erasmus University Rotterdam. Trimbos.  
Jabben, N., Arts, B., van Os, J., & Krabbendam, L. (2010). Neurocognitive functioning as intermediary 
phenotype and predictor of psychosocial functioning across the psychosis continuum: studies 
in schizophrenia and bipolar disorder. Journal of Clinical Psychiatry, 71(6), 764.  
Janssen, M. F., Pickard, A. S., Golicki, D., Gudex, C., Niewada, M., Scalone, L., . . . Busschbach, J. 
(2013). Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight 
patient groups: a multi-country study. Quality of Life Research, 22(7), 1717-1727.  
Johnson, S. L. (2005). Mania and dysregulation in goal pursuit: A review. Clinical psychology review, 
25(2), 241-262. doi:https://doi.org/10.1016/j.cpr.2004.11.002 
Johnson, S. L., McKenzie, G., & McMurrich, S. (2008). Ruminative responses to negative and positive 
affect among students diagnosed with bipolar disorder and major depressive disorder. 
Cognitive Therapy and Research, 32(5), 702-713. doi:10.1007/s10608-007-9158-6 
Judd, L. L., & Akiskal, H. S. (2003). Depressive episodes and symptoms dominate the longitudinal 
course of bipolar disorder. Current psychiatry reports, 5(6), 417-418.  
Judd, L. L., Akiskal, H. S., Schettler, P. J., Endicott, J., Maser, J., Solomon, D. A., . . . Keller, M. B. 
(2002). The long-term natural history of the weekly symptomatic status of bipolar I disorder. 
Arch Gen Psychiatry, 59(6), 530-537.  
Kingston, T., Dooley, B., Bates, A., Lawlor, E., & Malone, K. (2007). Mindfulness-based cognitive 
therapy for residual depressive symptoms. Psychol.Psychother., 80(Pt 2), 193-203.  
Kupka, R. W., Akkerhuis, G. W., Nolen, W. A., & Honig, A. (1997). De life-chartmethode voor de 
manisch-depressieve stoornis. Tijdschrift voor Psychiatrie, 39(3), 232-239.  
Kuyken, W., Warren, F., Taylor, R. S., Whalley, B., Crane, C., Bondolfi, G., . . . Dalgleish, T. (2016). 
Efficacy and moderators of mindfulness-based cognitive therapy (MBCT) in prevention of 
depressive relapse: An individual patient data meta-analysis from randomized trials. JAMA 
Psychiatry, 73(6), 565-574.  
Lamers, S., Westerhof, G. J., Bohlmeijer, E. T., ten Klooster, P. M., & Keyes, C. L. M. (2011). 
Evaluating the psychometric properties of the mental health continuum‐short form (MHC‐SF). 
Journal of clinical psychology, 67(1), 99-110. doi:10.1002/jclp.20741 
Lobbestael, J., Leurgans, M., & Arntz, A. (2011). Inter-rater reliability of the Structured Clinical 
Interview for DSM-IV Axis I Disorders (SCID I) and Axis II Disorders (SCID II). Clin Psychol 
Psychother, 18(1), 75-79. doi:10.1002/cpp.693 

NL63319.091.17 / ZonMW dossiernr: 80-84300-98-82003 
    MBCT for BD 
Version 3, 24-4-2018 
 
25 of 26 
Manca, A., Hawkins, N., & Sculpher, M. J. (2005). Estimating mean QALYs in trial‐based 
cost‐effectiveness analysis: the importance of controlling for baseline utility. Health 
economics, 14(5), 487-496.  
Mathews, A., & MacLeod, C. (2005). Cognitive vulnerability to emotional disorders. Annu. Rev. Clin. 
Psychol., 1, 167-195. doi:https://doi.org/10.1146/annurev.clinpsy.1.102803.143916  
McCrone, P., Dhanasiri, S., Patel, A., Knapp, M., & Lawton-Smith, S. (2008). Paying the price. The 
cost of mental health care in England to 2026. King's Fund. 
Michalak, J., Holz, A., & Teismann, T. (2010). Rumination as a predictor of relapse in mindfulness-
based cognitive therapy for depression. Psychol.Psychother.  
Miklowitz, D. J., Alatiq, Y., Goodwin, G. M., Geddes, J. R., Fennell, M. J. V., Dimidjian, S., . . . 
Williams, J. M. G. (2009). A Pilot Study of Mindfulness-Based Cognitive Therapy for Bipolar 
Disorder. International Association for Cognitive Psychotherapy, 2(4), 373-382. 
doi:https://doi.org/10.1521/ijct.2009.2.4.373  
Nila, K., Holt, D. V., Ditzen, B., & Aguilar-Raab, C. (2016). Mindfulness-based stress reduction 
(MBSR) enhances distress tolerance and resilience through changes in mindfulness. Mental 
Health & Prevention, 4, 36-41. doi:http://dx.doi.org/10.1016/j.mhp.2016.01.001 
Nolen-Hoeksema, S. (1991). Responses to depression and their effects on the duration of depressive 
episodes. Journal of Abnormal Psychology, 100(4), 569. doi:http://dx.doi.org/10.1037/0021-
843X.100.4.569  
Oud, M., Mayo-Wilson, E., Braidwood, R., Schulte, P., Jones, S. H., Morriss, R., . . . Kendall, T. 
(2016). Psychological interventions for adults with bipolar disorder: systematic review and 
meta-analysis. The British Journal of Psychiatry, 208(3), 213-222. doi:DOI: 
10.1192/bjp.bp.114.157123 
 
Peckham, A. D., Johnson, S. L., & Gotlib, I. H. (2016). Attentional bias in euthymic bipolar I disorder. 
Cognition and Emotion, 30(3), 472-487. doi: https://doi.org/10.1080/02699931.2015.1014313 
Perich, T., Manicavasagar, V., Mitchell, P. B., Ball, J. R., & Hadzi-Pavlovic, D. (2013). A randomized 
controlled trial of mindfulness-based cognitive therapy for bipolar disorder. Acta Psychiatr 
Scand, 127(5), 333-343. doi:10.1111/acps.12033 
Pini, S., de Queiroz, V., Pagnin, D., Pezawas, L., Angst, J., Cassano, G. B., & Wittchen, H.-U. (2005). 
Prevalence and burden of bipolar disorders in European countries. European 
Neuropsychopharmacology, 15(4), 425-434. 
doi:https://doi.org/10.1016/j.euroneuro.2005.04.011 
Raes, F., Daems, K., Feldman, G. C., Johnson, S. L., & van Gucht, D. (2009). A psychometric 
evaluation of the dutch version of the responses to positive affect questionnaire. Psychologica 
Belgica, 49(4), 293-310. doi:10.5334/pb-49-4-293 
Raes, F., Pommier, E., Neff, K. D., & Van Gucht, D. (2011). Construction and factorial validation of a 
short form of the Self-Compassion Scale. Clin Psychol Psychother, 18(3), 250-255. 
doi:10.1002/cpp.702 
Ramsey, S., Willke, R., Briggs, A., Brown, R., Buxton, M., Chawla, A., . . . Petitti, D. (2005). Good 
research practices for cost-effectiveness analysis alongside clinical trials: the ISPOR RCT-
CEA Task Force report. Value in health, 8(5), 521-533.  
Rosa, A. R., Martínez-Aran, A., Torrent, C., Vieta, E., Kapczinski, F., Colom, F., . . . Reinares, M. 
(2007). Validity and reliability of the Functioning Assessment Short Test (FAST) in bipolar 
disorder. Clinical Practice and Epidemiology in Mental Health, 3(1), 5. 
doi:https://doi.org/10.1186/1745-0179-3-5 
Rush, A. J., Gullion, C. M., Basco, M. R., Jarrett, R. B., & Trivedi, M. H. (1996). The Inventory of 
Depressive Symptomatology (IDS): Psychometric properties. Psychol Med, 26(3), 477-486.  
Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. N., . . . Keller, M. B. 
(2003). The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating 
(QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major 
depression. Biol Psychiatry, 54(5), 573-583.  
Samalin, L., Boyer, L., Murru, A., Pacchiarotti, I., Reinares, M., Bonnin, C. M., . . . Vieta, E. (2017). 
Residual depressive symptoms, sleep disturbance and perceived cognitive impairment as 
determinants of functioning in patients with bipolar disorder. J Affect Disord, 210, 280-286. 
doi:10.1016/j.jad.2016.12.054 

NL63319.091.17 / ZonMW dossiernr: 80-84300-98-82003 
    MBCT for BD 
Version 3, 24-4-2018 
 
26 of 26 
Samalin, L., de Chazeron, I., Vieta, E., Bellivier, F., & Llorca, P. M. (2016). Residual symptoms and 
specific functional impairments in euthymic patients with bipolar disorder. Bipolar Disord, 
18(2), 164-173. doi:10.1111/bdi.12376 
Scott, J., Paykel, E., Morriss, R., Bentall, R., Kinderman, P., Johnson, T., . . . Hayhurst, H. (2006). 
Cognitive–behavioural therapy for severe and recurrent bipolar disorders. The British Journal 
of Psychiatry, 188(4), 313-320. doi:10.1192/bjp.188.4.313  
Segal, Z. V., Williams, J. M. G., & Teasdale, J. D. (2002). Mindfulness-based cognitive therapy for 
depression: A new approach to relapse prevention. New York: Guilford Press. 
Segal, Z. V., Williams, J. M. G., & Teasdale, J. D. (2012). Mindfulness-Based Cognitive Therapy for 
Depression (2nd ed.). New York: Guilford Press. 
Shapiro, D. H. (1992). Adverse effects of meditation: a preliminary investigation of long-term 
mediators. International Journal of Psychosomatics, 39(1-4), 62-67.  
Spielberger, C. D. (1983). Manual for the State-Trait Anxiety Inventory Palo Alto, CA: Consulting 
Psychologists Press. 
Tan, S. S., Bouwmans-Frijters, C. A. M., & Hakkaart-van Roijen, L. (2012). Handleiding voor 
kostenonderzoek: methoden en referentieprijzen voor economische evaluaties in de 
gezondheidszorg. Tijdschrift voor gezondheidswetenschappen, 90(6), 367-372.  
Treynor, W., Gonzalez, R., & Nolen-Hoeksema, S. (2003). Rumination reconsidered: A psychometric 
analysis. Cognitive Therapy and Research, 27, 247-259.  
Trimbos Instituut. (2015). Multidisciplinaire richtlijn bipolaire stoornissen (derde, herziene versie). 
Utrecht: De Tijdstroom.  
Trivedi, M. H., Rush, A. J., Ibrahim, H. M., Carmody, T. J., Biggs, M. M., Suppes, T., . . . Kashner, T. 
M. (2004). The Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-
Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, Clinician Rating 
(QIDS-C) and Self-Report (QIDS-SR) in public sector patients with mood disorders: a 
psychometric evaluation. Psychol Med, 34(1), 73-82.  
van Aalderen, J. R., Donders, A. R., Giommi, F., Spinhoven, P., Barendregt, H. P., & Speckens, A. E. 
(2012). The efficacy of mindfulness-based cognitive therapy in recurrent depressed patients 
with and without a current depressive episode: a randomized controlled trial. Psychol Med, 
42(5), 989-1001. doi:10.1017/S0033291711002054 
S0033291711002054 [pii] 
Van der Ploeg, H. (2000). Een Nederlandse bewerking van de Spielberger State-Trait Anxiety 
Inventory: Lisse, the Netherlands: Swets & Zeitlinger. 
Vieta, E., & Colom, F. (2004). Psychological interventions in bipolar disorder: From wishful thinking to 
an evidence-based approach. Acta Psychiatrica Scandinavica, 110(422), 34-38. 
doi:10.1111/j.1600-0447.2004.00411.x 
Williams, J. M., Alatiq, Y., Crane, C., Barnhofer, T., Fennell, M. J., Duggan, D. S., . . . Goodwin, G. M. 
(2008). Mindfulness-based Cognitive Therapy (MBCT) in bipolar disorder: preliminary 
evaluation of immediate effects on between-episode functioning. J.Affect.Disord., 107(1-3), 
275-279.  
World Health Organization. (2008). The global burden of disease: 2004 update. (978 92 4 156371 0). 
Young, R. C., Biggs, J. T., Ziegler, V. E., & Meyer, D. A. (1978). A rating scale for mania: reliability, 
validity and sensitivity The British Journal of Psychiatry, 133(5), 429-435.  
Zorginstituut Nederland (Producer). (2017). Farmacotherapeutisch Kompas. Retrieved from 
https://www.farmacotherapeutischkompas.nl/