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S T U D Y P R O T O C O L Open Access
Effect of action-based cognitive
remediation on cognition and neural
activity in bipolar disorder: study protocol
for a randomized controlled trial
Caroline V. Ott
1,2
, Maj Vinberg
1
, Christopher R. Bowie
3
, Ellen Margrethe Christensen
1
, Gitte M. Knudsen
4,5
,
Lars V. Kessing
1,5
and Kamilla W. Miskowiak
1,2*
Abstract
Background: Cognitive impairment is present in bipolar disorder (BD) during the acute and remitted phases and
hampers functional recovery. However, there is currently no clinically available treatment with direct and lasting
effects on cognitive impairment in BD. We will examine the effect of a novel form of cognitive remediation,
action-based cognitive remediation (ABCR), on cognitive impairment in patients with BD, and explore the neural
substrates of potential treatment efficacy on cognition.
Methods/design: The trial has a randomized, controlled, parallel-group design. In total, 58 patients with BD in full
or partial remission aged 18–55 years with objective cognitive impairment will be recruited. Participants are
randomized to 10 weeks of ABCR or a control group. Assessments encompassing neuropsychological testing and
mood ratings, and questionnaires on subjective cognitive complaints, psychosocial functioning, and quality of life
are carried out at baseline, after 2 weeks of treatment, after the end of treatment, and at a six-month-follow-up
after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and 2 weeks
into treatment. The primary outcome is a cognitive composite score spanning verbal memory, attention, and
executive function. Two complete data sets for 52 patients will provide a power of 80% to detect a clinically
relevant between-group difference on the primary outcome. Behavioral data will be analyzed using mixed models
in SPSS while MRI data will be analyzed with the FMRIB Expert Analysis Tool (FEAT). Early treatment-related changes
in neural activity from baseline to week 2 will be investigated for the dorsal prefrontal cortex and hippocampus as
the regions of interest and with an exploratory whole-brain analysis.
Discussion: The results will provide insight into whether ABCR has beneficial effects on cognition and functioning in
remitted patients with BD. The results will also provide insight into early changes in neural activity associated with
improvement of cognition, which can aid future treatment development.
Trial registration: Clinicaltrials.gov,NCT03295305. Registered on 26 September 2017.
Keywords: Biomarker, Bipolar disorder, Cognition, Cognitive impairment, Cognitive remediation, Functional magnetic
resonance imaging, Pro-cognitive effect
* Correspondence: kamilla.woznica.miskowiak@regionh.dk
1
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre
Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen,
Denmark
2
Department of Psychology, University of Copenhagen, Copenhagen,
Denmark
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Ott et al. Trials (2018) 19:487
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Background
Persistent moderate to severe cognitive impairment
across several cognitive domains is seen in 30–70% of
patients with bipolar disorder (BD) during periods of
remission [1–3]. The cognitive impairment is directly as-
sociated with reduced functional capacity and poor
occupational outcome [4,5], with the latter being the
greatest economic burden of BD [6]. Despite growing
evidence for negative individual and societal conse-
quences of cognitive impairment associated with BD,
there is currently no available treatments with direct and
lasting effects on cognition [7].
The search for effective treatments for cognitive impair-
ment in BD is adversely related to the lack of a brain-based
biomarker for cognitive improvement [8,9]. In particular,
the development of new treatments targeting the central
nervous system typically rely on pre-clinical studies, which
provide poor prediction of treatment effects in clinical trials
[10]. Consequently, clinical trials investigating the
pro-cognitive effects of candidate cognition treatments have
produced overall disappointing or only preliminary results
[7,11]. However, evidence from a few small open-label,
non-controlled studies suggests that cognitive remediation
(CR)mayhavepro-cognitiveeffectsinpatientswithBD
[12,13], and recent findings from a larger randomized clin-
ical trial of 70 h of computerized CR in remitted patients
with BD type I showed improvements on processing speed,
visual learning, and memory and a cognitive composite
measure [14].
We have previously conducted the first randomized,
controlled clinical trial investigating the effect of a
12-week CR program in partially remitted patients with
BD [15]. The treatment showed no effect on objective
cognitive measures (primary outcome), although some
aspects of subjective cognition improved [15]. This lack
of efficacy could reflect a type 2 error, as it was not veri-
fied whether the patients had objectively measured cog-
nitive impairment at enrolment and post hoc
assessments revealed no objective impairment (in the
group as a whole) in the targeted cognition domain (ver-
bal memory), sustained attention, or executive function
[15]. As accumulating evidence indicates that there is
only a weak association between subjective cognitive
complaints and objective cognitive impairment in pa-
tients with BD [16,17], potential cognitive benefits could
have been masked by ceiling effects. However, it is also
conceivable that the CR treatment was not intense
enough and relied too heavily on compensatory strategies
rather than intensive training of cognitive skills. A new
form of CR, action-based cognitive remediation (ABCR),
aims to optimize traditional CR to promote cognitive
flexibility and to transfer skills acquired during
treatment sessions to patients’everyday lives. It involves
individual goal setting, an intense training program
combining computerized training with practical
in-session activities, and cognitively challenging tasks be-
tween sessions, and has shown promising effects [18].
Specifically, Bowie et al. [18] compared ABCR (N=24)
to traditional CR (N= 26) in a patient group with severe
mental illness, including patients with BD. While both
treatments improved cognition, ABCR had a greater ef-
fect on functional capacity than traditional CR [18]. This
converges with a meta-analysis on CR trials in schizo-
phrenia showing that the combination of CR and skills
training had larger effects on patients’functional cap-
acity than CR alone [19]. The adaptation of ABCR to pa-
tients with BD may, therefore, not only improve
cognitive skills but also increase patients’functional cap-
acity, with benefits for quality of life and societal costs.
Patients with BD in remission display aberrant (most
consistently hypo-) activity in areas including the
dorsolateral prefrontal cortex (dlPFC) and the ventro-
lateral prefrontal cortex during cognitive control tasks
like working memory and strategic encoding [20,21].
Changes in neural activity in the dlPFC have been ob-
served in interventions demonstrating possible
pro-cognitive effects in psychiatric disorders. In par-
ticular, a recent meta-analysis assessing the changes in
neural activity following CR treatment in schizophrenia
found increased activity in the lateral and medial pre-
frontal cortex to be the most robust indicator of
treatment-associated cognitive improvement [22]. Our
group has demonstrated changes in neural activity in
dorsal and dorsomedial prefrontal areas during working
memory and learning tasks following 8 weeks of weekly
high-dose erythropoietin (EPO) vs. saline infusions in
patients with affective disorders [23,24]. These findings
indicate that changes in the neural activity in the dorsal
prefrontal cortex may be a possible biomarker for
pro-cognitive effects of interventions targeting
cognition.
Aims and hypotheses
This study aims to assess the effect of ABCR vs. a con-
trol treatment on cognitive improvement in (i) BD pa-
tients in full or partial remission and to (ii) assess early
neural changes indicative of potential treatment benefits
on cognition.
We hypothesize (i) that ABCR vs. a control treatment
has a beneficial effect on cognition in patients with BD
in full or partial remission (the primary hypothesis of
the study). We hypothesize (ii) that this
treatment-associated improvement of cognition trans-
lates into better functional capacity at the 6-months
follow-up assessment (secondary outcome). For the ex-
ploratory analysis of the neuronal underpinnings of these
treatment effects, we hypothesize that ABCR will
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produce an early change in neural activity in the dorsal
prefrontal cortex during working memory and strategic
memory encoding in the direction of the prefrontal ac-
tivity levels seen in a healthy control group (i.e., partial
normalization) and this activity will correlate with
ABCR-associated improvements in cognitive function.
Methods/design
Study design and participants
See Fig. 1for a flow diagram of the trial. The project
has a randomized, controlled, outcome-assessor-blind,
parallel-group design. The trial will include outpatients
with BD in full or partial remission (score ≤14 on the
Hamilton Depression Rating Scale [25]andYoung
Mania Rating Scale [26], respectively). No criteria for
the duration of symptom stability is applied due to the
feasibility of this group-based intervention trial, which
requires starting groups three times per year. However,
current mood symptoms and patients’retrospective
period of symptom stability will be recorded. Recruit-
ment will be carried out through the ongoing Bipolar
Illness Onset study [27], the Copenhagen Affective
Disorder Clinic (Psychiatric Centre Copenhagen,
Rigshospitalet), other mental health centers, consultant
psychiatrists in the Capital Region of Denmark, and
through advertisements on relevant websites.
Eligible participants must be between 18 and 55 years,
be fluent in Danish, and present with objective cognitive
impairment corresponding with a total score below the
cutoff or scores below the cutoff on a minimum of two
out of the five subtests (verbal learning test –immediate,
working memory test, verbal fluency test, verbal learning
test –delayed, and processing speed test) on the Screen
for Cognitive Impairment in Psychiatry—Danish version
(SCIP-D) [17,28]. Patients are eligible if they have an
ICD-10 diagnosis of BD (types I and II) confirmed using
the Schedules for Clinical Assessment in Neuropsych-
iatry interview [29]. Their daily use of benzodiazepines
will be tapered to a maximum dose equivalent to
≤22.5 mg oxazepam or ≤7.5 mg diazepam per day (cut-
offs for doses with limited cognitive side effects). Other
than that, patients are requested to avoid significant
changes to dose and type of any medication prior to or
during the study if possible. Any changes will be re-
corded at treatment completion and at the 6-month
follow-up.
Exclusion criteria are current drug or substance
abuse (up to 3 months prior to inclusion), previous
serious head trauma, neurological illness, schizophre-
nia or schizoaffective disorder, dyslexia, claustropho-
bia, having a pacemaker or other metal implants
inside the body, and electroconvulsive therapy in the
3 months prior to inclusion. Female participants are
not included if they are pregnant. All participants
must provide written informed consent, which in-
cludes consent to collection of biological material and
for data to be used in ancillary studies. See Additional
file 1for a trial protocol checklist.
Procedure
Upon their first visit to the Copenhagen Affective
Disorder Research Center (CADIC), participants are in-
formed about the project and provide written informed
consent after which they undergo an eligibility assess-
ment. The written informed consent will be obtained by
the first author. Upon inclusion, participants are ran-
domized with stratification for gender and age (< or ≥
35 years) to either 10 weeks of ABCR (active treatment)
Fig. 1 Flow diagram
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or patient group (control treatment). When 4–6 partici-
pants have been randomized to a group, baseline assess-
ments will be carried out in the week prior to the first
group session. Deterioration in terms of clinical symp-
toms at the baseline assessment is recorded, but partici-
pants are not excluded if their symptoms worsen. The
baseline assessment is completed over two days, 1–3 days
apart for practical reasons and to avoid attrition.
On day 1, participants’mood is rated with the Hamilton
Depression Rating Scale and Young Mania Rating Scale,
followed by a functional magnetic resonance imaging
(fMRI) scan encompassing spatial and verbal working
memory N-back tasks, a picture encoding task, a resting
state, and a structural scan. On day 2, participants attend
the research center in the morning for a fasting blood test.
A comprehensive neuropsychological test battery is ad-
ministered by a treatment-blinded outcome assessor. Par-
ticipants fill in questionnaires concerning subjective
cognitive complaints, psychosocial functioning, and qual-
ity of life. Functional capacity is assessed using a
clinician-rated interview and a performance-based assess-
ment. Finally, sleep quantity and quality in the past 3 days
is assessed.
After 2 weeks of ABCR or control treatment, the
fMRI, neuropsychological testing, and an assessment
of mood and subjective cognition are repeated to as-
sess whether early task-relevant neural activity
changes—prior to improvement on the behavioral
measures of cognition—correlate with and predict
subsequent cognitive improvement after treatment
completion. The neuropsychological assessments and
questionnaires, as well as assessments of functional
capacity and quality of life, are repeated within 2
weeks after treatment completion (primary outcome
assessment time), and 6 months after treatment com-
pletion. An intermediate clinical mood rating is per-
formed during week 6.
Setting
The ABCR treatment and control treatment will take
place at the outpatient clinic, CADIC, Psychiatric Centre
Copenhagen, Rigshospitalet. Outcome assessments are
performed at CADIC, Psychiatric Centre Copenhagen,
Department O, Rigshospitalet.
Action-based cognitive remediation
ABCR is a manual CR program developed by Professor
Christopher Bowie, Psychology Department, Queen’s
University, Kingston, Ontario, Canada. It is traditionally
carried out on groups of 4–6 participants with two ther-
apists. The program covers the following cognitive do-
mains: meta-cognition, verbal and visual working
memory, memory, attention, and executive functions
(organization, shifting attention, and planning). The pro-
gram is carried out twice a week with each session last-
ing 2 hours. The program duration is 10 weeks,
accompanied by daily computer training at home and
homework assignments consisting of cognitively challen-
ging everyday tasks (e.g. organizing stacks of documents,
reading the newspaper, and making a budget). The com-
puter program, the Danish version of HappyNeuron Pro
(http://www.happyneuronpro.com), is administered on
tablets and includes 28 tasks targeting processing speed,
selective attention, working memory, verbal and visual
learning, reasoning, and problem-solving. The program
has 30 difficulty levels, and participants require an 80%
success rate to advance to a more challenging level.
Prior to the first ABCR session, participants receive an
individual goal setting session, including identification of
cognitive strengths and weaknesses based on the screen-
ing carried out during the eligibility assessment.
The ABCR program begins with an orientation session
about the purpose and structure of the treatment and
provides an opportunity for participants to state their
personal goals to the group. Each session consists of a
short presentation of the theme of the day followed by
related computer activities and a joint discussion of
strategies. Practical everyday-like activities (e.g. planning
a meal and scheduling appointments) are then
role-played keeping in mind the theme of the day and
recently discussed strategies. The everyday-like activities
are a main part of the sessions, and are performed using
props such as food items, planners, city and amusement
park maps etc. to increase the ecological validity of the
activities. Each session ends with a discussion of how
the content is related to each participant’s individual
goal, and by identifying cognitively challenging everyday
tasks for the participants to carry out between sessions.
For four sessions within the program, the usual structure
is replaced by computer training interleaved by 20-min
individual goal setting sessions. Treatment completion is
defined as 80% attendance and individual catch-up ses-
sions are offered for missed sessions, if logistically pos-
sible. Attendance and time spent on the computer
exercises between sessions will be recorded.
Control treatment
The control treatment is a weekly 1-h conversation
group for 10 weeks. The sessions are conducted to con-
trol for the therapeutic effects of group treatment and
are designed to avoid any training of cognitive abilities,
but to remain meaningful for participants. Patients dis-
cuss their experiences of suffering from BD. There is no
set structure in the groups, as relevant themes are sug-
gested by the group leaders but ultimately decided by
the participants. Group leaders primarily have a mediat-
ing function and serve to reinforce the time limit. A
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previous study showed that fewer participants dropped
out of a group with a similar structure than in a psy-
choeducation group, which indicates general satisfaction
with this group format [30].
Treatment retention
All participants will receive feedback on the results of their
neuropsychological results once they have completed the
6-month follow-up assessment. Additionally, participants
randomized to the control group will be offered access to
HappyNeuron Pro (www.happyneuronpro.com) following
the 6-month follow-up-assessment. Participants who are
working will be offered compensation of 100 Danish
crowns an hour for 10 h of fMRI and neuropsychological
assessments. Travel expenses for public transportation will
be reimbursed for all participants.
Randomization and blinding
Pharma Consulting Group carried out block
randomization for each group stratified by gender and
age (< or ≥35 years). Participants are randomized using
a 1:1 allocation ratio. The study is outcome-assessor
blind, and the randomization list and allocation enve-
lopes are sealed in opaque envelopes and will be kept in
a locked filing cabinet to prevent unblinding. The
randomization list will not be opened during the trial
enrolment phase or while the data analyses have not
been completed. Allocation is carried out by the therap-
ist, who will open the envelopes consecutively within
each stratum following each eligibility assessment. Par-
ticipants will be instructed not to disclose any informa-
tion concerning their treatment allocation during
assessments. Under no circumstances will the allocation
be revealed to the outcome assessors.
Outcome assessments
For an overview of outcome assessment frequency and
timing (see Fig. 2). The primary outcome is a broad cog-
nitive composite score, which has been recommended as
a primary outcome in cognition trials by the targeting
cognition task force of the International Society for Bi-
polar Disorders (ISBD) [9]. This composite measure
comprises the following tests assessing verbal memory,
attention, and executive functions: Rey Auditory Verbal
Learning Test (RAVLT) [31], Repeatable Battery for the
Assessment of Neuropsychological Status (RBANS) Cod-
ing [32], verbal fluency with the letter “D”[33],
WAIS-III Letter–Number Sequencing [34], Trail Making
Test B (TMT B) [35], and Rapid Visual Information Pro-
cessing (RVP) from the Cambridge Neuropsychological
Test Automated Battery (CANTAB) (Cambridge Cogni-
tion). The tests in the composite score differ from the
exercises included in HappyNeuron Pro. The composite
score is derived by averaging the six z-transformed test
scores.
Secondary cognitive outcome measures are the One
Touch Stockings of Cambridge (Cambridge Cognition,
CANTAB), which assesses executive functions, and for
assessment of functional capacity, the Functional Assess-
ment Short Test (FAST) [36].
The tertiary (explorative) cognitive outcome measures
are the RAVLT, RBANS Coding, verbal fluency with the
letters “D”and “S”, WAIS-III Letter-Number Sequen-
cing, RBANS Digit Span [32], TMT B and TMT A [35],
RVP, and the Spatial Working Memory (Cambridge Cog-
nition, CANTAB) (cognition). Tertiary (explorative) out-
comes of objective functional capacity, quality of life,
and subjective functioning in daily life are the Brief
Performance-Based Skills Assessment of the University
of California, San Diego (UPSA-B) [37,38], the Sheehan
Disability Scale (SDS) [39], the Assessment of Quality of
Life [40], the World Health Organization's Quality of
Life Assessment (WHOQOL-BREF) [41], Cognitive
Complaints in Bipolar Disorder Rating Assessment
(COBRA) [42], and the Work and Social Adjustment
Scale (WSAS) [43].
The cognition outcomes are in line with the latest rec-
ommendations from the Targeting Cognition Task Force
of the ISBD [44]. Specifically, the recommendations are
to include a cognitive composite score as the primary
outcome, a single intervention-specific cognition meas-
ure as a secondary outcome, and the multiple individual
cognition measures as tertiary (exploratory) outcomes.
The functional outcomes also agree with the Targeting
Cognition Task Force of the ISBD, which recommends
FAST or UPSA-B as secondary outcomes. FAST was
specified as the secondary functional outcome in this
trial since we have previously demonstrated an associ-
ation between objective cognition and functional cap-
acity measures using it [17]. SDS and WSAS were
selected to examine patient-reported outcomes of dis-
ability and work function.
Peripheral and neural biomarkers and genotype
To assess hypothesis (ii), that early changes in neural ac-
tivity in the dlPFC may predict pro-cognitive effects of
ABCR, participants will undergo fMRI scans at baseline
and following 4 weeks of treatment (4 active, twice a
week, ABCR sessions or 2 weekly control group ses-
sions). Blood tests are taken at baseline to investigate
any neurobiological predictors of potential pro-cognitive
effects of ABCR, including high-sensitivity C-reactive
protein (hsCRP), inflammatory and metabolic parame-
ters (lipid status and blood glucose level) [45–49]. These
samples will also be used to assess potential differences
between genotypes of relevance for cognition, such as
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Fig. 2 (See legend on next page.)
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the Catechol-O-methyltransferase (COMT: val158Met)
and Brain-Derived Neurotrophic Factor (BDNF: val66-
Met), relating to treatment-associated improvements in
cognition.
Statistical analyses
Data from the neuropsychological, subjective cognitive
impairment, quality of life, level of functioning, and
psychosocial function assessments will be analyzed
using mixed models. Intention-to-treat analyses will
be performed for missing data. The data will be ana-
lyzed for every participant for all assessments. No in-
terim analyses will be carried out due to the nature
and size of the study.
Functional MRI analyses
fMRI data will be preprocessed and analyzed with the
FMRIB Expert Analysis Tool (FEAT) and the “randomize”
algorithm implemented in the FMRIB Software Library.
Neuropsychological and fMRI data from cognitively intact
healthy controls without prior or current mental illness or
mental illness amongst first-degree relatives from the
Bipolar Illness Onset study will be used for baseline
comparisons.
N-back working memory tasks
fMRI data from the N-back working memory tasks will
be analyzed using a region-of-interest analysis to assess
differences between the ABCR and control groups in
neural activity in the dlPFC after 2 weeks (adjusting for
any differences in neural differences at baseline). In
addition, we will conduct volume-of-interest analyses of
the dorsal prefrontal cortex to examine our hypothesis.
Exploratory whole-brain analyses will be conducted to
investigate any effects in other brain regions.
Strategic picture encoding
We will conduct volume-of-interest analyses of the dor-
sal prefrontal cortex and the hippocampi to assess the
fMRI data from the strategic picture encoding task.
Finally, exploratory whole-brain analyses will be con-
ducted to investigate any effects in other brain regions.
Any differences in neural activity will be correlated with
potential changes in the cognitive composite score after
2 weeks of treatment and post-treatment. If there is a sig-
nificant correlation with cognition at post-treatment, mul-
tiple regression analysis will be carried out, adjusting for
mood and demographic characteristics, to assess whether
early changes in neural activity are predictive of
pro-cognitive effects.
Sample size and power calculation
The power calculation was carried out by Pharma
Consulting Group (Uppsala, Sweden) (http://www.phar-
maconsultinggroup.com) using SAS, based on findings
from a previous randomized controlled trial run by our
group assessing the effect of 8 weeks of EPO treatment
on the same cognitive composite score [50]. The differ-
ence between the EPO and saline-treated groups re-
garding changes on the cognitive composite score was
0.5 standard deviations (SD) from baseline. In this trial,
a clinically relevant difference between the ABCR and
the control groups following 10 weeks of treatment is
assumed to be 0.4 SD (corresponding to a medium ef-
fect size) on the primary outcome, with a mean change
in the cognitive composite score of 0.5 SD. The power
calculation assumes normally distributed data and uses
two-sided sample t-tests. With these assumptions, we
will achieve a power of >80% to detect a clinically rele-
vant difference between the treatment groups at an
alpha level of 0.05 with 26 participants in both the
ABCR and control groups, respectively. Assuming a
10% drop-out rate from baseline to treatment comple-
tion, we will recruit up to 58 participants to achieve
complete data sets for 52 participants.
Data management and monitoring
Personal information is obtained during the eligibility as-
sessment, and information from patient records is
accessed only if patients are unable to provide the neces-
sary information. Signed consent forms are kept in a
locked filing cabinet. Pseudo-anonymized data from
neuropsychological tests, questionnaires, demographic
assessments, and interviews will be entered into the Re-
search Electronic Data Capture Database (REDCap).
REDCap meets the good clinical practice requirements for
data management and storage. The password-protected
list matching participant IDs and personal information
(See figure on previous page.)
Fig. 2 Schedule of enrolment, interventions, and assessments. OTS One Touch Stockings of Cambridge, FAST Functional Assessment Short Test,
SWM spatial working memory, RVP Rapid Visual Information Processing, RAVLT Rey Auditory Verbal Learning Test, RBANS Repeatable Battery for
the Assessment of Neuropsychological Status, WAIS-III LNS Wechsler Adult Intelligence Scale Version III Letter–Number Sequencing, TMT-A Trail
Making Test A, TMT-B Trail Making Test B, UPSA-B Brief Performance-Based Skills Assessment of the University of California, San Diego, SDS
Sheehan Disability Scale, AQoL Assessment of Quality of Life, WHOQOL-BREF World Health Organization's Quality of Life Assessment, COBRA
Cognitive Complaints in Bipolar Disorder Rating Assessment, WSAS Work and Social Adjustment Scale, WHODAS World Health Organization
Disability Assessment Schedule, DART Danish Adult Reading Test, CTQ Child Trauma Questionnaire, SCIP-D Screen for Cognitive Impairment in
Psychiatry—Danish version
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will be kept separate from the pseudo-anonymized data.
Data quality is promoted, as the first author will verify the
data entered by the outcome assessors into the REDCap
database, and by having range restrictions on values from
neuropsychological tests and questionnaires. REDCap fea-
tures a substantial logging module, which tracks all en-
tered data. The list matching participants IDs and
personal information will be deleted and consent forms
will be shredded 10 years after study completion, after
which the data will be completely anonymized. The entire
project group will have access to the final data sets. The
Danish Data Protection Agency can conduct inspections
to ensure that data management is handled in agreement
with the legislation. The Danish Data Protection
Agency operates independently of the study. If a par-
ticipant is excluded or withdraws from the study, the
exclusion reason will be recorded, including specifica-
tion of any adverse events.
Discussion
The present study investigates the effect of ABCR on
cognitive improvement in clinically stable BD patients. It
also explores early treatment effects on dorsal prefrontal
activity to examine neurocircuitry target engagement. This
will contribute to the broader aim of identifying a neuro-
circuitry biomarker model for pro-cognitive effects.
All participants are required to present with objective
cognitive impairment to be enrolled in the study. The
criteria are based on findings from our previous EPO tri-
als, showing that patients with worse objective cognitive
functioning at baseline have the greatest chance of
achieving treatment efficacy [50] and on the subsequent
methodological recommendations for cognition trials in
BD by the Targeting Cognition Task Force of the ISBD
[44]. The criteria will serve to ensure that the sample is
enriched for cognitive impairment, which will enhance
the chances of detecting treatment-associated cognitive
improvement [9]. However, it could cause a recruitment
challenge since it is estimated that 30–70% of euthymic
patients with BD show clinically relevant objective cog-
nitive impairment [1–3]. As the study will recruit up to
58 patients with BD in full or partial remission to ensure
complete data sets for 52 patients, multiple recruitment
channels have been identified: psychiatric centers run by
Mental Health Services in the Capital Region of
Copenhagen, consultant psychiatrists, advertisements,
and the Copenhagen Affective Disorder Clinic in Rig-
shospitalet. A break will interleave the fifth and sixth
session in the ABCR program with sessions occurring
twice a week, to ensure that all ABCR participants are
assessed with fMRI and neuropsychological tests follow-
ing 2 weeks (four sessions) of treatment.
There are no known direct risks associated with par-
ticipation in the study. All participants are covered by
public insurance provided by the Patient Compensation
Association. The use of a control group, where partici-
pants are not offered treatment targeting cognitive im-
pairment, will control for non-specific therapeutic
effects of being in a group setting, which may increase
participants’quality of life and functional capacity. The
use of a control group is also rendered necessary, as
there is currently no effective treatment for cognitive
impairment with direct and lasting effects [9].
Trial status and dissemination
A pilot trial was conducted in the autumn and winter of
2016, with minor modifications of some of the practical
everyday-like activities to promote feasibility and cul-
tural adaptation. The pilot trial was conducted as a feasi-
bility study and objective cognition was assessed using
the SCIP-D rather than a full neuropsychological battery.
Objective cognitive impairment was not a requirement.
However, three of the five patients included presented
with objective cognitive impairment at baseline. All
three patients improved numerically on the total SCIP-D
score (M= 10 and SD = 7), providing some preliminary
indications of treatment effect, although the improve-
ment could also be a result of repeated testing given the
lack of a control pilot group.
Recruitment will commence in summer 2017 and will
complete in the spring of 2019. The final data from the
6-month follow-up will be collected in the autumn/win-
ter of 2019. The results will be disseminated in
peer-reviewed scientific journals and at scientific confer-
ences. Author eligibility will be assessed using the Van-
couver Convention, and no professional writers will be
used. After the follow-up assessment, all participants will
receive feedback on their neuropsychological test per-
formance at baseline and after treatment completion.
Additional file
Additional file 1: SPIRIT 2013 Checklist: Recommended items to address
in a clinical trial protocol and related documents. (DOC 122 kb)
Abbreviations
ABCR: Action-based cognitive remediation; AQoL: Assessment of quality of
life; BD: Bipolar disorder; CADIC: Copenhagen Affective Disorder Research
Center; COBRA: Cognitive Complaints in Bipolar Disorder Rating Assessment;
CTQ: Child Trauma Questionnaire; CR: Cognitive remediation; DART: Danish
Adult Reading Test; dlPFC: Dorsolateral prefrontal cortex; EPO: Erythropoietin;
FAST: Functional Assessment Short Test; FEAT: FMRIB Expert Analysis Tool;
fMRI: Functional magnetic resonance imaging; hsCRP: High-sensitivity C-
reactive protein; ISBD: International Society for Bipolar Disorders; OTS: One
Touch Stockings of Cambridge; RAVLT: Rey Auditory Verbal Learning Test;
RBANS: Repeatable Battery for the Assessment of Neuropsychological Status;
REDCap: Research Electronic Data Capture Database; RVP: Rapid Visual
Information Processing; SCIP-D: Screen for Cognitive Impairment in
Psychiatry—Danish version; SD: Standard deviation; SDS: Sheehan Disability
Scale; SWM: Spatial working memory; TMT: Trail making test; UPSA-B: Brief
Performance-Based Skills Assessment of the University of California, San
Diego; WAIS-III LNS: Wechsler Adult Intelligence Scale Version III Letter–
Ott et al. Trials (2018) 19:487 Page 8 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Number Sequencing; WHODAS: World Health Organization Disability
Assessment Schedule; WHOQOL: World Health Organization's Quality of Life
Assessment; WSAS: Work and Social Adjustment Scale
Acknowledgements
The authors wish to thank the Copenhagen Affective Disorder Clinic,
Rigshospitalet, Copenhagen, Denmark, in particular, the specialist in
psychotherapy Nanna Tuxen, for her input during development of the
treatment program, recruitment, and for carrying out the intervention.
Psychology PhD student Jeff Z. Petersen is acknowledged for his
contribution in terms of recruitment and treatment delivery. Psychology PhD
student Hanne Lie Kjærstad and senior researchers Julian Macoveanu and
Patrick Fisher are acknowledged for help in setting up the fMRI paradigms.
Hanne Lie Kjærstad MD, PhD student Klara Coello, and PhD student Sharleny
Stanislaus MD are acknowledged for their assistance with the recruitment of
participants from the Bipolar Illness Onset study. Finally, we are grateful to all
the private psychiatrists and mental health centers in the Capital Region of
Denmark for their assistance with the recruitment of participants, in
particular Mia Greisen Søndergaard MD, Lioudmila Kosenkova MD, Shashi
Kant Jha MD, and Claudio Csillag MD PhD.
Funding
The study is supported by the Lundbeck Foundation (grant R215–20154121).
The Lundbeck Foundation has not been involved in writing the present
manuscript or in the design of the study, nor will the Lundbeck Foundation
be involved in the data collection, analysis, or interpretation of data.
Availability of data and materials
The data sets used and analyzed during the current study are available from
the corresponding author on reasonable request.
Authors’contributions
KWM conceived the study together with LVK. MV contributed to the study
design. KWM wrote the study protocol and obtained the required funding
for the study. LVK and MV contributed to revising the study protocol. GMK
and KWM set up the fMRI paradigms. CRB developed the ABCR intervention,
and trained CVO, EMC, and KWM in delivering the treatment. CRB will act as
a consultant throughout the trial and supervise the ABCR intervention to
ensure adherence with the ABCR methodology. CRB and CVO will be
responsible for the fidelity analyses of the ABCR treatment. CVO is
responsible for recruitment, enrolment, and carrying out the treatments with
assistance from clinical psychologists and nurses at the Copenhagen
Affective Disorder Clinic. CVO has the primary responsible for data collection,
data analysis, and interpretation of the data under supervision of KWM. EMC
and MV are involved in recruitment. CVO, EMC, LVK, and KWM tailored the
ABCR treatment to the participant group. All authors have read and
approved the present manuscript.
Ethics approval and consent to participate
The study has been approved by the Ethics Committee in the Capital Region
of Denmark (protocol H-16043480) and the Danish Data Protection Agency
(2012-58-0004). It was retrospectively registered at Clinicaltrials.gov
(NCT03295305) on 26 September 2017 (https://clinicaltrials.gov/ct2/show/
NCT03295305?term=NCT03295305&rank=1). Written informed consent will
be obtained from all participants. Any important changes in the protocol will
be reported to the Ethics Committee in the Capital Region of Denmark and
the Danish Data Protection Agency.
Consent for publication
Not applicable.
Competing interests
KWM has received consultant fees from H. Lundbeck and Allergan. MV has
received consultancy fees from H. Lundbeck and Astra Zeneca within the last
3 years. LVK has been a consultant for H. Lundbeck, AstraZeneca, and Sunovion
within the last 3 years. EMC has received honoraria from H. Lundbeck within
the last 3 years. CRB has received honoraria from Boehringer Ingelheim,
Lundbeck, Otsuka, and Abbie. CVO has no competing interests. GMK has not
received any honoraria from pharmaceutical companies within the last 3 years.
The computer software used in the ABCR group is provided free of charge by
HappyNeuron Pro (www.happyneuronpro.com).
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Copenhagen Affective Disorder Research Center (CADIC), Psychiatric Centre
Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen,
Denmark.
2
Department of Psychology, University of Copenhagen,
Copenhagen, Denmark.
3
Psychology Department, Queen’s University,
Kingston, ON, Canada.
4
Neurobiology Research Unit and Center for
Experimental Medicine Neuropharmacology, Rigshospitalet, Copenhagen,
Denmark.
5
Faculty of Health and Medical Sciences, University of
Copenhagen, Copenhagen, Denmark.
Received: 2 October 2017 Accepted: 13 August 2018
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