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S T U D Y P R O T O C O L Open Access
A randomized controlled trial of a virtual
reality based, approach-avoidance training
program for alcohol use disorder: a study
protocol
Angelina Isabella Mellentin
1,2,3*
, Anette Søgaard Nielsen
1,2
, Leonie Ascone
4
, Janina Wirtz
4
, Jerzy Samochowiec
5
,
Jolanta Kucharska-Mazur
5
, Friedrich Schadow
4
, Zofia Lebiecka
5
, Tomasz Skoneczny
5
, Nicolai Mistarz
1,2
,
Thomas Bremer
4
and Simone Kühn
4,6,7
Abstract
Background: The approach-avoidance training program (AATP) has shown preliminary promise as an add-on to
standard treatment for alcohol dependence. However, knowledge is lacking as to whether the effectiveness of
AATP can be enhanced further when performed in a typical drinking situation. The main aim of this study is to
investigate whether approach-avoidance training implemented in a virtual reality bar environment is superior to the
classical joystick PC-version of the AATP.
Methods: The study will be implemented as a randomized controlled trial. A total of 204consecutively enrolled
alcohol use disorder (AUD) patients, recruited from alcohol inpatient clinics in Germany, Poland and Denmark, will
be randomized into one of three groups at the start of standard alcohol treatment: group A) stimuli-relevant AATP
+ treatment as usual (TAU); group B) stimuli-relevant AATP in virtual reality + TAU, and group C) TAU only (control
group). Treatment outcomes will be assessed at pre-treatment, post-treatment and 3-month follow-up. Repeated-
measures ANOVA will be applied to compare the trajectories of the groups over time on drinking, craving and
impulsiveness outcomes. It is hypothesized that the two experimental groups will achieve better treatment
outcomes compared to group C and that group B will achieve better outcomes than group A.
(Continued on next page)
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* Correspondence: amellentin@health.sdu.dk
1
Unit for Clinical Alcohol Research, Unit for Psychiatric Research, Department
of Clinical Research, University of Southern Denmark, J. B. Winsløwsvej 18,
5000 Odense Center, Denmark
2
Brain Research-Inter-Disciplinary Guided Excellence (BRIDGE), Department of
Clinical Research, University of Southern Denmark, Odense C, Denmark
Full list of author information is available at the end of the article
Mellentin et al. BMC Psychiatry (2020) 20:340
https://doi.org/10.1186/s12888-020-02739-1
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(Continued from previous page)
Discussion: This study is the first trial examining the effectiveness of stimuli-relevant AATP delivered in a VR
environment. The use of VR has shown promise in enhancing the effectiveness of other psychological treatments
and since AATP has already been shown effective as add-on treatment, it is of interest to investigate whether these
effects can be further enhanced by implementing the program in more ecologically valid environments. If proven
effective, the AATP-VR can, like the AATP, be implemented easily and cheaply as add-on treatment or continued
care to enhance the effectiveness of current evidence-based treatment.
Trial registration: ClinicalTrials.gov ID: NCT04283305
Registration date: 24.02.20
Keywords: Alcohol use disorder, Approach-avoidance training program, Virtual reality
Background
Alcohol use disorders (AUD) are associated with cognitive
dysfunctions such as cognitive biases in the systems pro-
cessing alcohol-related stimuli, which may play an import-
ant role in the maintenance of addictive behavior and
impede the effectiveness of conventional evidence-based
treatments [1–3].
Dual process models suggest that addictive behavior is
influenced by two semi-independent cognitive systems: (1)
a fast and automatic associative “impulsive system”that
automatically evaluates stimuli in terms of motivational
significance and triggers an approach or avoidance re-
sponse based on this evaluation, and (2) a slow and con-
trolled “reflective system”that regulates the automatic and
implicit responses elicited by the impulsive system based
on explicit and controlled higher cognitive processes [4–
7]. It has been proposed that the impulsive system in ad-
dictive behavior is driven by cognitive biases: alcohol cues
automatically capture attention (attentional bias) and elicit
an approach action tendency (approach bias) promoting
alcohol seeking and drinking behavior [8,9]. AUD can be
conceptualized as a dysfunction in both the impulsive and
reflective systems. An over-activated impulsive system is
sensitized and triggers cognitive biases towards alcohol
cues, while a relatively under-activated and weakened re-
flective system is unable to regulate these biases. Because
the impulsive system is partly automatic and implicit,
biases towards alcohol cues in the environment lead to
the maintenance of self-destructive drinking behavior des-
pite explicit knowledge about the consequences generated
by the reflective system [6,7,10].
Conventional evidence-based psychological treatments
for AUD such as cognitive-behavioral therapy (CBT) rely
mainly on the modification of reflective cognitive pro-
cesses, while impulsive cognitive dysfunctions are ad-
dressed to a lesser extent and typically by applying cue
exposure therapy (CET). During CET, patients with AUD
are exposed to alcohol to elicit cravings while refraining
from habitual approach action tendencies, that is, drinking
behavior. With repeated exposure, the sensitization of the
impulsive system is assumed to decrease over time. To
date, CET has shown limited effects on alcohol consump-
tion outcomes [11]. It has been suggested that this con-
ventional method may not be effective because it fails to
provoke cravings and approach biases when delivered in
clinical settings, which is a pre-requisite for desensitizing
the impulsive system [12,13].
Novel psychological treatments targeting the impulsive
system through the modification of cognitive biases are
emerging building on experimental paradigms from clin-
ical neuropsychology [14–16]. One approach targets at-
tentional biases by training attention away from alcoholic
cues and towards non-alcoholic cues [14,15]. Another
method targets approach biases by training approach ac-
tion tendencies towards alcohol to react with avoidance
action tendencies [16]. One treatment that has shown pre-
liminary promise in clinical settings is the approach avoid-
ance training program (AATP). This program builds on
the diagnostic alcohol-approach-avoidance task (alcohol-
AAT) [17,18], which measures approach bias. During the
alcohol- AAT, AUD individuals are requested to react to
pictures of alcoholic drinks using avoidance responses (by
pushing a joystick) and react to pictures of non-alcoholic
drinks using approach responses (by pulling ajoystick).
Approach bias is indicated when reaction times are faster
for approaching alcohol cues than for avoiding them,
whereas the opposite indicates avoidance bias. The AATP
is an attempt to modify approach biases for appetitive al-
cohol cues in sub-clinical and clinical AUD samples [16,
19–21]. During the AATP, patients are typically trained to
‘avoid’alcohol and therefore requested to react to pictures
of alcoholic drinks using avoidance responses (by pushing
a joystick) and react to non-alcoholic drinks using ap-
proach responses (by pulling a joystick).
In contrast to other novel training programs targeting
attentional bias [14,15] and conventional CET methods
[22–24], the AATP is more ‘embodied’in that patients are
requested to actively train action tendencies by reacting
with pull vs. push motor responses (e.g. [25]). The AATP
has shown promise in decreasing reaction times towards
alcohol cues and alcohol consumption in sub-clinical and
clinical AUD samples. In an initial experimental trial
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conducted on a subclinical sample of heavy drinking col-
lege students, it was found that those who were trained to
avoid alcohol cues drank less in a taste test compared to
those who were trained to approach alcohol [16]. In three
subsequent clinical trials, AATP was found to be effective
in retraining AUD patients to avoid rather than approach
alcohol cues, and it was associated with a reduction in re-
lapse rates [8,19,20]. Further, a study examining whether
AATP could be successfully delivered to a sub-clinical
AUD sample via a fully automated web-based delivery
pathway also found a reduction in alcohol consumption
[26]. In addition, it has recently been shown that AATP
may be effective in reducing approach biases even when
treating AUD individuals with major and severe alcohol-
induced cognitive dysfunctions in the reflective system
[27]. Interestingly, functional imaging studies have shown
that the intervention decreases brain activity in neural cor-
relates of automatic and implicit cognitive processing
(mesolimbic brain regions), suggesting that AATP targets
the neural mechanisms behind the maintenance of AUD
[9,21,25,28]. Overall, AATP interventions have to date
shown better effect in reducing alcohol consumption than
conventional methods targeting the impulsive system.
The use of virtual reality (VR) has shown some promise
in enhancing the effectiveness of psychological AUD treat-
ments targeting implicit and automatic cognitive pro-
cesses. In clinical settings, adding VR to CET has been
shown to be potentially more effective than conventional
delivery methods when it comes to inducing cravings [12,
13]. Although AATP interventions have shown more clin-
ical promise than CET in reducing alcohol consumption,
it has been difficult to probe any reductions in craving
levels [8,19,20,26]. Adding VR technology simulates and
enriches real-life situations by exposing AUD individuals
to a wider range of stimuli than possible in clinical set-
tings, which typically only expose AUD individuals to al-
cohol and not associated situations that can cause
cravings and approach responses (e.g. bars and party envi-
ronments) [13]. If conventional methods targeting the im-
pulsive system can be improved using VR, an emerging
question then is whether adding VR to AATP may en-
hance the effectiveness of this approach.
Aims
The objectives of the study are to investigate: 1) whether
AATP as an add-on to CBT increases the effectiveness of
treatment, and 2) whether AATP delivered via VR as an
add-on to CBT is superior compared to conventional
ATTP.
Methods/design
The study is registered according to the Standard Protocol
Items: Recommendations for Interventional Trials (SPIRIT)
guidelines [29] and trial registered: ClinicalTrials.gov ID:
NCT04283305, the 24 of February, 2020 and will be con-
ducted based on the CONSORT guidelines [30]. In there
are any amendments during the trial, it will be registered
on ClinicalTrials.gov.
Design and setting
The study will be conducted as a multi-national, parallel
investigator-blinded randomized controlled trial. Partici-
pating countries include Germany, Poland and Denmark.
A total of 204 consecutively enrolled AUD individuals
(see Statistical analysis section for the power calculation)
will be recruited from inpatient alcohol treatment (68 pa-
tients from each country). In each country, participants
will be recruited at treatment entry from clinics primarily
treating AUD or patients whose primary substance use
disorder is AUD. Participants will be recruited from the
University Clinic in Hamburg-Eppendorf (Germany), the
Pomeranian Medical University Clinic in Szczecin and
West Pomerania (Poland), and the inpatient clinic Ringår-
den in Middelfart, Funen (Denmark).
Treatment as usual at the inpatient alcohol clinics
In all three countries, treatment as usual (TAU) consists
mainly of psychological treatment which in some cases
is combined with pharmacological treatment in accord-
ance with the NICE guidelines [31]. At treatment entry,
the patient is offered detoxification (e.g. diazepam, lor-
azepam, oxazepam or clomethiazole), and other pharma-
cological treatment (e.g. acamprosate, naltrexone or
disulfiram) is provided to support abstinence if needed.
The psychological treatment consists mainly of CBT ap-
plied during hour-long individual or group sessions. In
Germany, TAU lasts for approximately 1 month,
whereas in Poland it lasts for approximately 2 months
and Denmark it lasts for approximately 3 months. The
inpatient treatment in Germany is shorter due to a
shorter coverage of the health insurance. Although pa-
tients are encouraged to strive for abstinence, the treat-
ment goal for some patients is moderate drinking,
defined as not drinking more than five drinks per occa-
sion. In all countries, the treatment strategy is planned
together with the patient and typically incorporates
psycho-education, functional analysis of drinking situa-
tions, development of coping strategies, problem-solving,
and homework between sessions.
The psychological treatments are delivered by trained
therapists encompassing nurses, social workers and psy-
chologists. Supervision takes place frequently and psy-
chiatrists and clinical psychologists monitor the
treatment course regularly.
Recruitment
After completing detoxification but prior to starting
standard treatment, the patient will be briefly informed
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about the project and asked if he/she is willing to meet
with a research assistant who will provide further infor-
mation. If the patient agrees, the research assistant will
provide him/her with written and oral information about
the study. After obtaining informed consent, a baseline
interview will be carried out. Patients fulfilling the eligi-
bility criteria will be randomized to one of the three
aftercare treatment groups described below.
Randomization
Randomization will occur using computerized
randomization with random numbers. To ensure ad-
equate allocation concealment, the random allocation
sequence was 1.) generated before patient enrollment
begin, and 2.) by a member in the research group (LA)
that is not involved personally with the patients. That is,
is not part of the clinical setting were the study is
implemented.
Eligibility criteria
To be eligible to participate, patients must: 1) agree to
participate in the study and sign written informed con-
sent; 2) be aged between 18 and 65 years; 3) speak the
language of the participating country (German, Polish or
Danish); 4) have completed detoxification (if needed); 5)
have been enrolled within 2 weeks of standard treat-
ment; 6) not have any sensory or motor deficits compli-
cating the provision of AATP (e.g. color-blindness, fine
or gross motor deficits in upper extremities); 7) not fulfil
diagnostic criteria for other substance use disorders; and
8) not have a severe psychiatric or neurological illness
(e.g. psychotic disorders, mental retardation, dementia)
or terminal somatic illness.
Experimental and control groups
A total of 204 (68 patients from each country) fulfilling
the eligibility criteria will be randomized into one of
three groups: (A) AATP + TAU (n= 68); (B) VR-based
AATP + TAU (n= 68), and (C) TAU (n= 68). The mean
optimal effect of AATP among AUD patients is typically
achieved after the sixths training session [32]. Therefore,
group A and group B will receive six sessions (three ses-
sions per week for 2 weeks; duration = 30 mins) of
AATP and VR-based AATP, respectively, in addition to
TAU. Group C will only receive TAU. The two experi-
mental groups will begin treatment approximately 3
weeks before discharge from the inpatient clinics to
measure the add-on effect and to ensure that the add-on
treatment does not extend the treatment period.
Conventional approach- avoidance training program
Since the AATP builds on the experimental neuro-
psychological paradigm, the training is intertwined with
the alcohol-AAT and consists of a pre-test, training, and
post-test session.
In the AAT, patients are instructed to respond to ei-
ther the content or the format of the presented pictures
using a joystick. When responding to the content in the
“stimuli-relevant”trials, they have to pull the joystick to
approach pictures of alcoholic or non-alcoholic drinks
and push the joystick to avoid the pictures. When
responding to the format in the “stimuli-irrelevant”ver-
sion, they must pull or push the joystick based on the
color of the frame around the pictures of the alcoholic
or non-alcoholic drinks. The color of the frame is inter-
changeably reversed (through randomization): a yellow
frame requires a push response and a blue frame re-
quires a pull response. Pulling the joystick increases the
size of the pictures and pushing it decreases the size,
generating a perception of approach and avoidance,
respectively.
The pre-test for the AAT starts with practice trials in
which patients learn to push and pull the joystick. Actual
pre-test trials follow, with patients completing either the
stimuli-irrelevant AAT or the stimuli-relevant version
first in random order. In both versions, the pictures of
alcoholic and non-alcoholic drinks are presented equally
often in push and pull format. Following this, patients
are requested to complete the avoid-alcohol training in
the stimuli-relevant AATP. That is, during the training
the patients are only instructed to respond to the content
of the stimuli. In the training trials, 100% of the alcohol
pictures come in push-format and 0% in pull-format,
with reversed contingencies for pictures of non-alcoholic
drinks. Half of the pictures used in the pre-test will also
be applied in the training, and the half will be different
to allow a test for generalization to untrained pictures.
The post-test for the stimuli-irrelevant/stimuli-relevant
AAT is almost identical to the pre-test: it presents both
trained and untrained pictures of alcoholic (50%) and
non-alcoholic (50%) drinks [19] (see Supplementary
material for further description of the parameters [33]).
Before and after each session, patients will be re-
quested to report their immediate level of cravings on a
VAS scale (see Secondary outcome: cravings, self-
efficacy, impulsivity and depressive severity and Cue-
induced cravings sections for further details).
Approach- avoidance training program in virtual reality
In the VR-based AAT and AATP, patients are situated
in a bar environment where drinks appear on a table in
front of them. Similar to conventional AAT and AATP
(delivered on a computer), the VR-based AATP consists
of a pre-test, training, and post-test session, but patients
are requested to respond to either the content or format
of the presented beverages by pulling or pushing a VR
controller instead of a joystick.
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The pre-test for the VR-based AAT starts with prac-
tice trials in which patients learn to use the VR control-
ler. This is followed by actual pre-test trials: patients
complete the stimuli-irrelevant AAT first followed by
the stimuli-relevant AAT. In the stimuli-irrelevant AAT,
there is a colored outline around the beverages which
patients must respond to. The colored outline is inter-
changeable reversed (via randomization), with a yellow
outline requiring a push response and a blue outline re-
quiring a pull response. In the stimuli-relevant AAT, pa-
tients must respond to the content of the bottles. Both
versions present alcoholic and non-alcoholic drinks
equally often in push and pull format. Patients are then
requested to complete the avoid-alcohol training and re-
spond to the content in the stimuli-relevant VR-based
AATP. In the training trials, 100% of the alcoholic bev-
erages come in push-format and 0% in pull-format. The
contingencies are reversed for non-alcoholic drinks. Half
of the beverages used in the pre-test will also be applied
in the training, and the other half will be different to
allow a test for generalization to untrained alcoholic.
Similar to the conventional ATT, the post-test for the
stimuli-irrelevant/stimuli-relevant VR-based ATT is al-
most identical to the pre-test.
In the VR-based AATP, pulling the VR controller will
approximate the drink (will bring the drink closer) and
pushing it will distance the drink, which we anticipate
generates a more real perception of approach and avoid-
ance, respectively, relative to the zooming feature in the
conventional AATP. Further, the VR-based AATP will
prompt patients to exercise more realistic movements
compared to the conventional AATP, and the virtual bar
context may make the setting appear more like real life.
Also, a bar tender will be placing the alcoholic beverages
onto the bar counter, which may enhance the amount of
effort used to avoid and push drinks away. Patients will
be seated on a bar stool in VR, and the alcoholic and
non-alcoholic beverages will be depicted as high-poly
objects to make the experience as realistic as possible
(see Supplementary material for further description of
the parameters [33]).
Similar to the conventional AATP, patients will be
asked to rate state craving on a VAS scale before and
after training.
Treatment as usual
The control group will not receive any add-on sham-
training since prior studies testing the AATP did not
find any difference between AATP-sham-training and
no-training [19]. Patients in this group will be randomly
assigned to complete the stimuli-relevant and stimuli-
irrelevant AAT on either the PC- or VR-based bias as-
sessment and will only be assessed at baseline and post-
treatment (see Measures section). The conventional and
VR-based AATP will be delivered by a trained research
assistant.
Measures
Socio-demographic factors, AUD diagnoses and severity,
prior AUD treatment, psychiatric comorbidity, medica-
tion, behavioral inhibition and treatment goal will be
assessed in the baseline interview (T1). Clinical outcome
measures relating to alcohol consumption and cravings
will be assessed at baseline, post-treatment, and 3-month
follow-up (T1, T2, and T3). Additionally, experimental
outcomes, including approach biases, cue-induced crav-
ings and a response inhibition task, will be assessed at
baseline and post-treatment (T1 and T2) (See Fig. 1for an
overview of the assessment and intervention timeline
across countries). Finally, the patients will be assessed for
concomitant treatment between the post-treatment and
3-month follow-up at the 3-month follow-up assessment
(T3). The assessments will, like the interventions, be car-
ried out by trained research assistants.
Baseline assessment instruments
The Mini-International Neuro-psychiatric Interview
(MINI) for DSM-5 is a structured interview probing the
17 most common psychiatric diagnoses using dichotom-
ous questions that ask for a yes/no response. The MINI
will be used to establish the severity of AUD diagnoses
as well as to screen patients for eligibility and detect psy-
chiatric comorbidity diagnoses [34,35].
The European version of the Addiction Severity Index
(EUROP-ASI) is a semi-structured interview assessing
sociodemographic variables as well as AUD severity and
seven potential problem areas (alcohol use, drugs use,
medical problems, psychiatric problems, family prob-
lems, employment/economy problems, and legal prob-
lems) [36,37]. The EUROP-ASI will be applied to
standardize the assessment of sociodemographic data
and AUD severity across all sites.
Clinical outcome measures
Primary outcome: alcohol consumption Alcohol con-
sumption measures will be derived from the Timeline
Followback (TLFB). The TLFB method involves using a
calendar to identify alcohol consumption patterns in
terms of number of drinks per day during the last 30
days [38,39]. One drink is defined as 12 g of ethanol.
Secondary outcome: cravings, self-efficacy, impulsivity
and depressive severity The Visual Analogue Scale
(VAS) comprises single-items used to measure the de-
gree of alcohol cravings on scales ranging from 0 to 100,
with 0 representing no cravings and 100 an extreme de-
gree of cravings. The scale is presented visually on a
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ruler, and the individual will be requested to report the
mean level and the peak level of cravings experienced
during the last 30 days [40,41].
The 14-item obsessive-compulsive drinking scale
(OCDS) measures the degree of cravings experienced
during the last 7 days. Items are rated on scales ranging
from 0 to 4. The higher the score, the more pronounced
the cravings. The scale has two subscales: obsessive crav-
ings score and compulsive cravings score. A total score
is calculated based on these subscales, and it is possible
to calculate a resistance/impairment and interference
subscale score [42].
The 40-item Alcohol Abstinence Self-Efficacy Scale
(AASE) measures current level of temptation to drink al-
cohol and self-efficacy to abstain from drinking. The
scale applies 20 situations representing typical drinking
cues. Twenty items pertain to temptation levels, the
other 20 items to self-efficacy. Items are rated on scales
ranging from not at all (0) to extremely (4). The measure
comprises the following sub-scales: (1) negative affect;
(2) social interaction and positive states; (3) physical and
other concerns; and (4) withdrawal and urges [43].
The 30-item Barratt impulsiveness scale (BIS, Patton,
Stanford, & Barratt, 1995) assesses dimensions of impul-
sivity using three subscales: (1) attentional (attention
and cognitive instability), (2) motor (motor and perse-
verance); and (3) non-planning (self-control and cogni-
tive complexity). Items are rated on 4-point Likert scales
ranging from 1 = very true for me to 4 = very false for
me [44].
The Beck Depression Inventory-II (BDI-II; Beck et a.,
1996) is a 21-item multiple-choice instrument that mea-
sures the severity of depression. Each item is rated on a
4-point scale ranging from 0 to 3 based on severity [45].
Experimental outcomes
AAT and diagnostic-AAT-VR The conventional AAT
will be applied as described in Conventional approach-
avoidance training program section. The application of
the VR-based AATP will be described in Approach-
avoidance training program in virtual reality section.
The TAU group will be randomized to either the PC or
VR AAT bias assessments as described in Treatment as
usual. The stimuli in the AAT and AATP stimuli consist
in known brands or stimuli that are easily recognized
(see Supplementary material for further description and
pictures of the stimuli [33]).
Cue-induced cravings Cravings will be assessed for all
alcoholic and non-alcoholic beverages from the stimuli-
relevant conventional and VR-based AATP. The pictures
will be rated on the VAS scale ranging from 0 to 100 ac-
cording to the immediate level of craving induced to
examine their potential to elicit cue-induced cravings.
1
Response inhibition Response inhibition towards alco-
hol cues will be recorded using a modified version of the
classical Go/No-Go Task [46,47]. The modification in-
volves the use of alcohol-related and neutral pictures to
specifically test inhibition capacities towards alcohol-
related cues. Pictures of alcoholic and non-alcoholic
drinks from the conventional and VR-based AAT as well
Fig. 1 Overview of the study design across assessment sites (countries). Abbreviations: AATP: approach-avoidance training programme; PC:
personal computer; T1: baseline assessment; T2: post-treatment assessment; T3: 3month follow-up; VR: virtual reality. * Both add-on experimental
AATP interventions starts 3 weeks before discharge
1
In addition, patients randomized to the experimental groups will be
requested to report their immediate level of cravings on the VAS scale
at the beginning and at the end of the AATP session to test for
immediate pre- and post-training effects (see Conventional approach-
avoidance training program and Approach- avoidance training pro-
gram in virtual reality sections).
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as new pictures will be included in the task. Patients will
be instructed to respond as fast as possible, and without
errors, by pressing a response button when they see a
non-alcoholic drink (i.e. “Go”signals) but to withhold
their response when an alcoholic drink is presented (i.e.
“NoGo”signals) (see Supplementary material for further
description of the parameters [33]).
Data management
All data collected in the study will be treated as strictly
confidential and the data collected by research assistants
will be entered in a secure database. Before extraction or
transferring data across sites, data will be anonymized
(person sensitive data) and encrypted (group allocation)
by an external data manager and transmitted through se-
cure pathways. Researchers responsible for reporting the
results will not have access to the data and will receive
the analysis in their final form for reporting. All proce-
dures are approved by the research ethics committee in
each of the participating countries (see Ethics section).
Statistical analysis
Descriptive statistics will be calculated to summarize
socio-demographic factors, AUD diagnosis and psychiatric
comorbidity as well as primary and secondary measures at
baseline. Categorical variables will be described using fre-
quencies and percentages. Normally distributed numeric
variables will be described using the mean/standard devi-
ation (SD), non-normally distributed numerical variables
using the median/interquartile range (IQR).
The main analyses will be conducted with a repeated
measures ANOVA, with group as the between-subjects
factor and drinks per day the last 30 days at each assess-
ment time-point as the within-subjects factor, to test the
effectiveness of the intervention across the assessment
points, which would be indicated by a significant Time X
Study Group interaction. If there is an overall significant
interaction effect between any one time-point and group,
we will examine whether the change over time differs be-
tween the groups and the time-point using contrasts. Sec-
ondary analysis of continuous outcomes will be conducted
with repeated measures ANOVA models, with group as
the between-subjects factor and other alcohol consump-
tion- (drinking days and drinks per drinking day), crav-
ing-, impulsivity- and depressive symptom outcomes as
the within-subjects factor. In the case of unbalanced attri-
tion in the randomization groups, mixed models will be
applied instead of repeated measures ANOVA. Secondary
analysis of dichotomous outcomes (e.g. relapse) will be
conducted using mixed model logistic regressions. The
analyses will be adjusted for the randomization stratifica-
tion variable, site, as well as for the outcome values at
baseline [48]. Since the study is a randomized controlled
trial, other covariates are expected to be balanced across
the randomization groups. Missing data will be handled
using multiple imputation with changed equation (MICE)
methods applying the non-parametric predicted mean
matching (PMM) methods [49].
All analyses will be conducted as intention to treat as
well as per protocol, and subgroup analyses will be con-
ducted on patients who were successfully treated with
conventional or VR-based AATP, defined as completing
all six sessions. Further, moderation analyses of ap-
proach bias and using anti-craving medication on the
treatment effect will be conducted for the primary and
secondary outcomes.
When performing the descriptive and inferential ana-
lysis, the researchers will be blinded to the experimental
and control groups, and an external statistician will con-
duct the analysis. The significance level in the models
will be set at 5%, and two-sided analyses will be con-
ducted. Effect sizes will be reported in accordance with
the statistical modelling. All analyses will be conducted
using Stata 16.
Power analysis
The present study is the first to focus exclusively on
stimuli-relevant AATP training in addition to TAU in
clinical AUD patients, and only one prior study has ex-
amined the stimuli-relevant AATP training [26]. This
prior study was conducted among subclinical AUD indi-
viduals and used a continuous drinking (drinks per day)
measure as an evaluation of a stand-alone stimuli-
relevant AATP over the web. A small effect at post-
treatment (f = 0.17) and close to a medium effect at 3-
month follow-up (f = 0.22) was identified [26]. Since our
study is targeting a clinical sample with a higher degree
of alcohol consumption, it may be easier to detect an ef-
fect than in a subclinical AUD sample, however, the
AATP training in our study is provided as an add-on to
TAU which could dilute the treatment effect compared
to the prior study. To be conservative, we only aim to
achieve a small additive effect at 3-months follow-up.
Since pre- and post-treatment assessments of our inter-
vention are conducted in an inpatient setting rather than
over the web, attrition is mainly an issue at the 3-
months follow-up assessment. Therefore, we collect only
the clinical outcomes that can be measured in a variety
of settings (e.g. at treatment, at home, over the phone or
through a link on the web). An attrition rate of 30% at
3-month follow-up is assumed.
Based on this, a power analysis (PA) [50,51] was con-
ducted using G*Power for a repeated-measures ANOVA
with α= 0.05; effect size (ES) of f = 0.17; power = 0.80;
groups k = 3; time-points measurements = 3; correlations
among repeated measures = 0.40; and nonsphericity cor-
rection E = 0.60, resulting in a sample size of n= 123 par-
ticipants. To allow for adjustment of the stratification
Mellentin et al. BMC Psychiatry (2020) 20:340 Page 7 of 12
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
variable, site, an extra 20 patients are required for the final
analysis (total n= 143). Finally, to account for an attrition
rate of 30%, the required sample size is 204 (= 143/(1–
0.3)) patients, corresponding to 68 patients in each group.
Ethics
The patients in this study will receive standard treat-
ment at the inpatient clinics and although 66% will re-
ceive additional treatment, all patients will be well-
treated with evidence-based AUD treatment. Thus, we
find no ethical problems with not offering the interven-
tion to the entire sample. However, a critical ethical
question is whether using the AATP may encourage pa-
tients in the experimental groups to consume alcohol in-
stead of discouraging it. This concern relates to the fact
that AAT and AATP involve in vivo exposure to alcohol.
However, in European culture, all patients will be ex-
posed to alcohol, both during and after treatment, and
they will be unable to avoid this since large-scale alcohol
advertisements are on display in the public space, in mag-
azines and on television. Also, alcohol is available, highly
visible and easy to buy around the clock in all supermar-
kets, delicatessens, kiosks and gas stations. Therefore, we
consider exposure to alcohol pictures in the experimental
groups to be no riskier for the patients than their exposure
in everyday life. On the contrary, in the experimental
groups, the patients will be trained to avoid alcohol cues
and to approach non-alcoholic drinks when exposed in
real life. Another ethical question worth considering is
whether the VR-based AATP may cause discomfort such
as motion sickness (dizziness, nausea, dry eyes etc.). How-
ever, patients will not be moving freely around in the VR,
which is what usually causes motion sickness. Moreover,
the treatment will be performed by healthcare profes-
sionals and if any discomfort is experienced, the treatment
will be interrupted, and the discomfort alleviated before
the end of the training session. Further, we expect the
benefits of the VR training to outweigh potential episodes
of minor discomfort.
The study protocol has been approved by the research
ethics committee in each of the participating countries.
In Germany by the local psychological ethical committee
at University Medical Center Hamburg-Eppendorf (pro-
ject-ID: LPEK-0088. In Poland by the Ethical Committee
at Pomeranian Medical University in Szczecin (project-
ID: KB-0012/162/19). In Denmark by the Regional Sci-
entific Ethical Committees for Southern Denmark (pro-
ject-ID: S-20190136).
Discussion
The main aim of this study is to investigate whether
stimuli-relevant AATP as an add-on increases the effect-
iveness of standard treatment and whether stimuli-
relevant VR-based AATP is superior compared to the
classical joystick PC-version of the AATP.
It is important to emphasize that both the conven-
tional AAT and AATP can be delivered in a stimuli-
relevant”and “stimuli-irrelevant”version. In the former
version, patients are instructed to focus on the content
of the picture (e.g. approach soda, avoid alcohol),
whereas in the latter version they are instructed to focus
on the format of the picture (e.g. approach horizontal,
avoid vertical). Hence, the main difference between the
two versions has to do with where the patients’attention
is directed, that is, towards either picture content or an
image-irrelevant feature like the picture format. The ma-
jority of AAT studies examining AUD and other sub-
stance use disorder samples have applied the SI version,
even though a recent meta-analysis showed that the
stimuli-relevant AAT produces much stronger approach
bias measures than the stimuli-irrelevant AAT [52]. Fur-
ther, alcohol consumption has been found to correlate
positively with automatic approach biases in an AUD
sample –but only in the stimuli-relevant AAT –sug-
gesting that the stimuli-irrelevant AAT is not a reliable
and valid measure of action tendencies in AUD samples
[53].
In line with research applying the conventional AAT,
only two trials so far have compared the stimuli-relevant
and stimuli-irrelevant versions of the AATP in AUD
samples [19,26], whereas other studies have focused ex-
clusively on the stimuli-irrelevant AATP [8,16,20]. The
first study found the stimuli-relevant AATP to be
equivalent to the stimuli-irrelevant version in increasing
abstinence rates when delivered as add-on treatment in
a clinical AUD sample [19]. The second study demon-
strated a superior effect of stimuli-relevant AATP on al-
cohol consumption compared to the stimuli-irrelevant
version in a sub-clinical community sample of AUD in-
dividuals [26]. It should be highlighted that none of the
AATP studies targeting alcohol approach bias have ap-
plied a stimuli-relevant AAT, and this upcoming study is
the first to examine whether both stimuli-related and
stimuli-irrelevant AAT can be modified by a stimuli-
relevant AATP and whether they moderate the effect on
clinical outcomes. Studies investigating the effect of
AATP on other addictive behavior than AUD have ex-
clusively applied the stimuli-irrelevant version [54–56],
which is why it is not possible to draw any inferences
from this parallel line of research.
Since the stimuli-relevant AAT and AATP have shown
promise in AUD samples, this approach seems particu-
larly suitable for implementation in a VR format, which
may be more challenging when directing attention to-
wards image-irrelevant features in natural drinking envi-
ronments without interfering with its authenticity. To
date, VR has primarily been used in attempts to enhance
Mellentin et al. BMC Psychiatry (2020) 20:340 Page 8 of 12
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
the effectiveness of CET interventions though the induc-
tion of cravings. Traditional methods of inducing crav-
ings rely on presenting alcohol in vivo either by placing
real alcohol or pictures and videos of alcohol in front of
the patient. Although these cues have been shown to in-
duce cravings in some studies [57], and cravings have
been shown to predict relapses among AUD patients
[58,59], it has been more difficult to demonstrate a sim-
ultaneous decrease in cravings and alcohol consumption
in CET trials [11]. Therefore, it has been suggested that,
overall, CET interventions may have limited effectiveness
because they fail to induce cravings in clinical settings,
which is a prerequisite for desensitizing the impulsive sys-
tem [12,13]. It has been suggested that integrating alcohol
and associated cues in natural drinking environments (e.g.
bars, party’s)maybemorerelevanttoinducemorecravings
than CET, and that VR-based CET may then represent an
improvement to CET in that AUD individuals can be taken
out of the laboratory or clinical context and placed in an
environment with the capacity to induce greater cravings,
which in turn might prompt the generalization of treatment
to real world activities [12,60–62].
In sub-clinical and clinical AUD samples, a number of
studies have applied VR as an assessment tool to explore
alcohol cravings and have found it highly effective in indu-
cing cravings [63–67]. Furthermore, studies examining
other drugs of abuse have found that virtual conditions in-
duced more cravings than pictures (e.g. [68–70]. Also,
some studies have examined VR-based CET for reducing
alcohol-related cravings in AUD samples and found the
intervention to be effective in reducing cravings for alco-
hol [12,71–73]. The results of assessment and interven-
tion studies are relatively consistent and indicate that if
induction of cravings in more alcoholic environments is a
major challenge, VR-based CET shows promise for enhan-
cing the treatment of AUD [13].
Cognitive biases and cravings should share a reciprocal
relationship, where increases in cravings will make alco-
hol and associated cues more salient and as these cues
become the focus of attention and activate action ten-
dencies they will elicit further increases in subjective
craving [74,75]. Moreover, the association between crav-
ing and attentional bias appears to be larger when the
strength of craving is relatively high than when it is low
at the time of assessment [75], and although this re-
mains to be investigated among substance (ab) users,
similar findings have been found between food-craving
and approach bias among binge eaters [76].
AATP interventions have to date somehow shown
more promise than conventional CET in reducing alco-
hol consumption but, like with CET, it has been more
difficult to prove simultaneous reductions in craving
levels and alcohol consumption [8,19–21]. However,
since AAT and AATP also involve in vivo exposure
through alcohol pictures, it is plausible that these cues
in drinking-related environments may also induce a
higher cravings level and cognitive bias, which in turn
may improve alcohol consumption measures. In addition
to being easier to implement in VR, the stimuli-relevant
AATP may have the potential to induce more cravings
than the stimuli-irrelevant version because the patients
are, like in CET, requested to focus attention on alcohol
and associated stimuli [52,53]. Indeed, it has been sug-
gested that the stimuli-irrelevant AATP may in some
cases fail to induce bias because patients totally ignore
the content of the picture and only respond to the
stimuli-irrelevant content (the format of the picture) due
to limits in attention span [77–79]. While assessment
tools and interventions targeting attentional biases have
exclusively applied stimuli-irrelevant versions (e.g. [14,
15]), in sub-clinical and clinical samples suffering from a
wide range of psychiatric disorders, those targeting ap-
proach biases can be used in both stimuli-irrelevant and
stimuli-relevant versions making them more suitable for
VR, where stimuli-relevant versions may be better fitted.
However, in this context it is of relevance to notice that
a few studies have applied alternate versions of atten-
tional bias modification programs with stimuli-relevant
instructions in non-clinical samples to train attentional
negative emotional and affective bias. These studies have
consistently shown greater or a similar reduction of at-
tentional bias compared to traditional stimuli-irrelevant
versions [80–82], which suggests that cognitive bias re-
training programs might in general show promise in
content relevant versions and be easily implementable in
VR formats in the future. Although AATP is already
regarded as the most embodied of the cognitive bias re-
training programs, the VR format has the potential to
make the paradigm even more so. This is because pa-
tients are not just requested to actively train action ten-
dencies by reacting with pull vs. push motor responses,
but they can navigate in a relatively interactive environ-
ment and approach or avoid the alcohol and related
stimuli in a wider sense.
In the realm of the available evidence from prior
AATP studies it is hypothesized that the two experi-
mental groups will achieve better treatment outcomes
(i.e. significantly lower drinking, cravings and impul-
sivity) compared to the control group, and that the
VR-based AATP will achieve better outcomes than
conventional AATP at tree month follow-up. The
current study will provide important knowledge about
the effectiveness of stimuli-relevant AATP and
whether its potential effectiveness can be further
enhanced by implementing it in a VR bar. If proven
effective, future studies should examine the effect of
VR-based AATP in the longer term as well as its
cost-effectiveness as adjunctive treatment.
Mellentin et al. BMC Psychiatry (2020) 20:340 Page 9 of 12
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Combining psychological treatments that address
AUD-related cognitive dysfunctions in the reflective and
impulsive systems might better prepare patients for their
inevitable confrontation with alcohol in their natural en-
vironment and increase the probability of preventing re-
lapses in the longer term. The stimuli-relevant VR-based
AATP can, like the stimuli-relevant conventional AATP,
be implemented easily and cheaply as add-on treatment
or continued care to enhance the effectiveness of current
evidence-based treatment.
Supplementary information
Supplementary information accompanies this paper at https://doi.org/10.
1186/s12888-020-02739-1.
Additional file 1.
Abbreviations
AASE: Alcohol abstinence self-efficacy scale; AUD: Alcohol use disorder;
AAT: Approach avoidance task; AATP: Approach avoidance training program;
BDI: Beck depression inventory; BIS: Barratt impulsiveness scale;
CBT: Cognitive behavior therapy; CET: Cue exposure therapy;
OCDS: Obsessive-compulsive drinking scale; TAU: Treatment as usual;
TLFB: Timeline followback; VR: Virtual reality
Acknowledgements
Not applicable.
Authors’contributions
SK, AIM, ASN, LA, FS, JW, JS and JKM designed the study. FS and TB designed
the stimuli for the AAT and AATP as well as VR-based AAT and AATP. SK, LA,
AIM, JW, ASN, JS, JKM, ZL, TS and NM will collect and manage data. SK, AIM,
ASN, LA, JW, JS, JKM, ZL, TS and NM will analyze, interpret the data and write
up reports and SK will have the ultimate authority over any of these activ-
ities. AIM and LA wrote the draft of the manuscript, and all authors contrib-
uted to and approved the final manuscript.
Funding
The study is unconditionally funded by the “Baltic Game Industry -
Empowering a Booster for Regional Development “(BGI) grant, which is part
of the Interreg Baltic Sea Region (BSR), supported by the European Union’s
Regional Development fund. Contact information: Christine Sauter, Tel: + 49
(030) 809 94 113, bgi@bgz-berlin.de. BGI/BSR have neither reviewed our
protocol in its present form nor has the funding partner imposed any
specific constraint or requirements for our study. We are granted full
scientific authority to design and conduct this study, and BGI/BSR will not
have any not be involved in the interpretation, reporting or publishing the
results.
Availability of data and materials
The datasets pertaining to the study are available on request from the
authors, provided this is compliant with national legislations and with the
decisions of the ethical committees of the respective countries.
Ethics approval and consent to participate
The study protocol has been approved by the research ethics committee in
each of the participating countries. In Germany by the local psychological
ethical committee at University Medical Center Hamburg-Eppendorf (project-
ID: LPEK-0088. In Poland by the Ethical Committee at Pomeranian Medical
University in Szczecin (project-ID: KB-0012/162/19). In Denmark by The Re-
gional Scientific Ethical Committees for Southern Denmark (project-ID: S-
20190136). All participants are provided oral and written information about
the study and sign written informed consent before enrollment in the study.
The protocol is registered on Clinical Trials (ClinicalTrials.gov, XXX). No
significant deviations from the protocol will be implemented without prior
review and approval from the research ethics committee in each of the
participating countries. Any amendment made to the protocol is to be
submitted as an update of the Clinical Trials account.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Unit for Clinical Alcohol Research, Unit for Psychiatric Research, Department
of Clinical Research, University of Southern Denmark, J. B. Winsløwsvej 18,
5000 Odense Center, Denmark.
2
Brain Research-Inter-Disciplinary Guided
Excellence (BRIDGE), Department of Clinical Research, University of Southern
Denmark, Odense C, Denmark.
3
Tele-Psychiatric Center, Region of Southern
Denmark, Odense C, Denmark.
4
Neuroplasticity Research Group, Department
of Psychiatry and Psychotherapy, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
5
Department of Psychiatry
Pomeranian Medical University in Szczecin Poland, Szczecin, Poland.
6
Lise
Meitner Group for Environmental Neuroscience, Max Planck Institute for
Human Development, Berlin, Germany.
7
Physikalisch-Technische
Bundesanstalt Braunschweig, Braunschweig, Germany.
Received: 14 February 2020 Accepted: 15 June 2020
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