Treating PTSD in patients with co-occurring substance use disorders: a randomized controlled trial to compare the efficacy of different types and timing of treatment.

Posttraumatic stress disorder (PTSD) and substance use disorder (SUD) often
co-occur, with an estimated prevalence of current PTSD of 25% amongst
individuals with an SUD (Driessen et al., 2008). SUDs are also prevalent
amongst individuals with PTSD. In a large epidemiological study in the United
States, 46% of a PTSD sample met criteria for a substance use disorder
(Pietrzak et al., 2011). Individuals with both disorders have a more severe
clinical profile than those with either disorder alone, with worse physical
health, more interpersonal problems and greater severity of substance use
(Schafer et al., 2007). Furthermore, these patients are more likely to meet
criteria for additional psychiatric disorders, such as depression. Individuals
with co-occurring PTSD and SUD are considered to be more difficult to treat
than individuals with either condition alone, with poorer treatment outcomes,
poorer treatment adherence and shorter periods of abstinence post-treatment
(Roberts et al., 2016). Despite the high prevalence, patients in treatment for
SUD are often not assessed for PTSD or offered PTSD-focused interventions.
Prolonged Exposure therapy (PE) is considered a first line treatment for PTSD.
A recent meta-analysis indicated that PE is an effective treatment for reducing
symptoms of PTSD, achieving remission of PTSD diagnosis and improving
depression symptoms for adults with PTSD (Cusack et al. 2016); 66% more
subjects treated with PE than subjects in waitlist control groups achieved
remission of PTSD diagnosis. PE involves confrontation with distressing stimuli
related to the trauma until anxiety is reduced. It is a manualized
intervention, including both imaginal and in vivo exposure components (Foa et
al., 2007). The aim of both aspects is to extinguish the conditioned emotional
response to traumatic stimuli. Another first line treatment for PTSD is Eye
Movement Desensitization and Reprocessing (EMDR). Evidence supports the
efficacy of EMDR for achieving remission of PTSD diagnosis and improving
depression symptoms (Cusack et al., 2016); 64% more subjects treated with EMDR
recovered from PTSD compared to subjects in waitlist control groups. Both PE
and EMDR are extensively used in clinical practice to treat patients with PTSD.
So far, head-to-head evidence is insufficient to determine the comparative
effectiveness of these treatments (Cusack et al., 2016). Most randomized
controlled trials evaluating PTSD treatments exclude individuals with substance
related problems. In patients suffering from both PTSD and SUD, EMDR has been
studied in only one randomized pilot study with a sample size of 12 patients
(Perez-Dandieu et al., 2014). This pilot study indicated that adding EMDR to
regular addiction treatment leads to a significant reduction of PTSD symptoms.
Prolonged Exposure therapy has been studied more extensively in patients with
co-occurring PTSD/SUD. Several studies and a recent review indicate that PE is
effective in reducing PTSD symptoms in patients with SUDs, when it is added to
regular addiction treatment (see Roberts et al., 2016 for a review). However,
PE is less effective in individuals with PTSD/SUD compared to individuals with
PTSD alone. This may be caused by the finding that, disturbingly, adding PE to
regular addiction treatment leads to higher drop-out rates than regular
addiction treatment only (Roberts et al., 2016). Coffey et al. (2016) tried to
increase treatment completion and effectiveness of PE in patients with PTSD/SUD
by adding a 90-minute trauma-focused motivational enhancement session prior to
PE. Unfortunately, adding this session was not effective in increasing
treatment completion or effectiveness of PE. While valuable advances have been
made towards the treatment of co-occurring PTSD and SUD, it is essential to
conduct head-to-head comparisons of effective treatments to determine the
comparative effectiveness. Furthermore, it is necessary to search for a more
fitting treatment for patients with comorbid PTSD-SUD diagnoses, that leads to
lower drop-out rates. A promising new approach for treating PTSD in patients
with substance use disorders is Imagery Rescripting (ImRs). ImRs is a therapy
that is becoming increasingly popular for treating PTSD and other disorders. It
is a technique that changes the meaning of emotional memories and images (like
intrusions and nightmares). With ImRs the patient is instructed to imagine the
memory (or image) as vividly as possible, as if it is happening in the here and
now, and to imagine that the sequence of events is changed in a direction that
the person desires (Arntz, 2012). A meta-analysis of 19 studies showed that
ImRs is effective in reducing aversive imagery and related psychological
complaints, with large effects obtained in a small number of sessions (Morina
et al., 2017). In chronic PTSD patients, the addition of ImRs to PE led to a
significant reduction of treatment drop-outs and a better effect on anger,
anger control, shame and guilt compared to PE alone (Arntz et al., 2007).
Another study showed that ImRs was highly effective in patients that did not
respond to PE (Grunert et al., 2007). The authors suggest that, when fear is
not the predominant emotion related to the trauma, but emotions like anger,
shame or guilt dominate, ImRs may be a better treatment (Grunert, et al. 2007).
On the other hand, Langkaas et al. (2017) did not find a difference between PE
and ImRs on non-fear emotions in an RCT among inpatients with PTSD. It should
be noted however that the inpatient treatment packages had considerable
overlap, which limits the power of the design. Two RCTs in (complex) PTSD
patients compared ImRs to waitlist and found large effects in favour of ImRs
(Jung & Steil, 2013; Raabe et al., in prep.). The last study also found
ImRs to be much more effective than Cloitre*s stabilization program (Cloitre et
al., 2010), and no evidence that preceding ImRs with the stabilization program
increases effectiveness or reduces dropout (Raabe et al., in prep). The recent
release of the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5;
American Psychiatric Association, 2013) has expanded the scope of criteria of
PTSD beyond a fear-based concept, considering that a traumatic event is also
followed by shame, guilt and/or anger. Trauma-related shame and guilt seem to
play a central role in the maintenance of PTSD symptoms, by contributing to
emotional aversiveness of the trauma memory. PTSD patients with a higher degree
of shame and guilt are more likely to suffer from depression (Aakvaag et al.,
2016) and have higher levels of PTSD symptoms over the course of treatment
(Oktedalen et al., 2015). Reducing the level of nonfear emotions such as shame
and guilt may increase the effectiveness of treatment of PTSD symptoms (Saraiya
& Lopez-Castro, 2016). Holl et al. (2017) found that individuals with a
history of childhood trauma used substances to regulate intense posttraumatic
shame. The authors suggest that shame may have a crucial role in the
development of substance use disorders following a traumatic event. Given its
effectiveness in reducing drop-out and feelings of anger, shame and guilt in
patients with PTSD, Imagery Rescripting is a promising approach for treating
PTSD in patients with substance use disorders (SUDs). In the studies examining
Prolonged Exposure in patients with co-occurring PTSD/SUD, PE and addiction
treatment were delivered simultaneously (Roberts et al., 2016). The
meta-analysisfound that adding PTSD treatment to Treatment As Usual (TAU) was
more effective than TAU in reducing PTSD severity up to seven months follow up.
A study conducted at Jellinek showed that simultaneous treatment can be safely
implemented in inpatient as well as outpatient care without negative effects on
SUD treatment (van Dam, 2013). However, treatment facilities often

Primary objectives:
1). Compare efficacy of Prolonged Exposure therapy (PE), Eye Movement
Desensitization and Reprocessing (EMDR), and Imagery Rescripting (ImRs) with a
3-month waitlist condition (WL) in reducing posttraumatic stress disorder
(PTSD) symptoms in patients with co-occurring PTSD and substance use disorder
(SUD).
Hypothesis: We expect that at 3-month follow-up, all trauma-focused therapies
will have led to a stronger reduction of PTSD symptoms than the waitlist
condition.

2). Compare effectiveness of simultaneous SUD/PTSD treatment with sequential
SUD/PTSD treatment in reducing PTSD symptoms in patients with co-occurring
PTSD/SUD.
Hypothesis: We expect a greater reduction of PTSD symptoms in the simultaneous
treatment condition compared to the sequential treatment condition across the
whole follow-up period.

3). Explore differential efficacy between active treatments (PE vs EMDR; PE vs
ImRs; EMDR vs ImRs) in reducing PTSD symptoms in patients with co-occurring
PTSD/SUD.

Secondary objectives:
- Compare PE, EMDR, ImRs and waitlist in terms of secondary outcome measures,
e.g. treatment completion, patient satisfaction, intensity of trauma related
emotions.
- Compare simultaneous and sequential treatment in terms of secondary outcome
measures.
- Compare differential cost-effectiveness between the active treatment arms and
between simultaneous versus sequential treatment.
- Determine which treatment is most effective for which patient, by examining
whether specific predominant trauma-related emotions (fear, anger, shame or
guilt) predict and moderate treatment effectiveness.

Current amendment:

Primary objective:

1) Identify risk and protective factors for revictimization in patients that
received treatment for PTSD/SUD

Secondary objectives:

2) Compare effectiveness of simultaneous SUD/PTSD treatment with sequential
SUD/PTSD treatment in reducing PTSD symptoms at 48-month
follow-up in patients with co-occurring PTSD/SUD

3) Gain insight into context characteristics of revictimization incidents
in patients who have been treated for PTSD/SUD.

4) Explore the role of fear of sexuality in characterizing differences
between revictimized and non-rectivimized patients that were treated for
PTSD/SUD

5) Compare treatment arms in terms of secondary outcome measures at
48-month follow-up, such as residual SUD symptoms, health care
consumption, quality of life, and emotional abuse

6) Determine predictors of severity of PTSD symptoms at 48-month follow-up.

This study is a single blind 6-arm randomized controlled trial comparing
simultaneous SUD/PTSD treatment to sequential SUD/PTSD treatment, whilst also
comparing Prolonged Exposure, Eye Movement Desensitization and Reprocessing,
Imagery Rescripting, to only SUD treatment in patients with SUD/PTSD. Study
population: Study participants will be patients (18 years of age or older) who
applied for treatment of a substance use disorder at Jellinek Amsterdam,
Utrecht for whom treatment of co-occurring PTSD is indicated.

The flow chart of the study design is depicted in Figure 1. After a baseline
assessment, patients will be randomly assigned to PE, EMDR, ImRs or waitlist
(each 25% chance). All patients will receive SUD treatment directly after the
baseline assessment. Patients allocated to PE, EMDR or ImRs will receive PTSD
and SUD treatment simultaneously (75% of the sample), whereas patients in the
3-month waitlist condition will receive PTSD treatment after completing 3
months SUD treatment (25% of the sample). After the first follow-up measure,
patients in the waitlist condition will be randomly allocated to either PE (33%
chance), EMDR (33% chance) or ImRs (33% chance) and start with the PTSD
treatment. The waitlist condition is necessary to enable a comparison between
SUD treatment plus PTSD treatment vs. SUD treatment only; and additionally
enable a comparison between simultaneous and sequential treatment of PTSD and
SUD. This is important, since currently it is unknown which timing of PTSD
treatment is most effective. Follow-up assessments will take place at 3, 6 and
9 months after the baseline assessment.

The study will be conducted at Jellinek Amsterdam and Jellinek Utrecht. The
duration of the study will be 3.5 years, from inclusion of the first
participant until the last follow-up measure of the final participant. The
trial will be registered in the Netherlands Trial Register (NTR).

Current amendment:

Alle deelnemers die geïncludeerd zijn in de TOPA studie en voldoen aan de
inclusie criteria worden telefonisch benaderd voor de aanvullende
vervolgmeting. Er is een minimale periode van zeven dagen tussen het benaderen
van deelnemers en de vervolgmeting. De meting kan of online (via beeldbellen)
of in persoon (bij een Arkin locatie) afgenomen worden.

All treatments will be provided by trained therapists working at Jellinek and
will consist of twelve 90-minute sessions conducted twice per week.

Intervention 1: Prolonged Exposure (PE): PE involves confrontation with
distressing stimuli related to the trauma until anxiety is reduced. It is a
manualized intervention including both imaginal and in vivo exposure components
(Foa et al., 2007). Imaginal exposure uses confrontation to trauma memories
through imagination, whereas in vivo exposure involves confronting real life
situations that provoke anxiety and are avoided because of their association
with the traumatic event. The aim of both is to extinguish the conditioned
emotional response to traumatic stimuli.

Intervention 2: Eye Movement Desensitization and Reprocessing (EMDR): EMDR is a
manualized intervention in which the patient is asked to hold the distressing
image in mind, along with the associated negative cognitions and bodily
sensations, while engaging in saccadic eye movements. After approximately 20
seconds, the therapist asks the patient to *blank it out*, take a deep breath
and note any changes occurring in the image, sensations, thoughts or emotions.
This process is repeated until desensitization has occurred.

Intervention 3: Imagery Rescripting (ImRs): With ImRs the individual is
instructed to imagine the trauma memory as vividly as possible, as if it is
happening in the here and now, and to imagine that the sequence of events is
changed in a direction that the person desires (Arntz, 2012). The procedure
aims to correct dysfunctional meanings attached to trauma memories and restore
perceived control.

Current amendment:
not applicable

Patients suffering from a substance use disorder are at high risk of suffering
from a co-occurring post-traumatic stress disorder. With this study, we can
investigate the efficacy of interventions aimed at reducing PTSD symptoms.
Participants are expected to benefit from the investigated interventions since
it is hypothesized that all three interventions will lead to a reduction of
PTSD symptoms. The PTSD treatment Prolonged Exposure is currently already
offered to participants as part of regular treatment at Jellinek. In order to
participate, participants will have to invest four times 60 to 90 minutes to
complete the assessments. Apart from the investment of time, there is no
additional burden for participants. Participants in all trial arms will be
provided with the same amount of therapy and the same amount of assessments. We
see no risks associated with participating in this study.

Current amendment
We expect that the burden voor participation is minimal. Participants will
invest 90-120 minutes of their time for the assessment. There are no risks
associated with the participation in the follow-up assessment.