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Concurrent Treatment for Substance Use Disorder and Trauma-Related Comorbidities: A Review of Clinical Effectiveness and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

and .

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; .

Context and Policy Issues

Substance use disorder (SUD) is a complex behavioral disorder characterized by preoccupation with obtaining alcohol or other drugs (such as amphetamines, cannabis, cocaine, opioids), excessive consumption of these substances, and loss of control over consumption, resulting in impairment in social and occupational functioning.1 Co-morbidity of SUD with other mental disorders is common.2–4 Mental disorders comprise a wide range of disorders and included among these are posttraumatic stress disorder (PTSD), depression, and anxiety disorders. PTSD involves recurring intrusive recollections of a traumatic event, with recollections beginning within the first six months and lasting over one month.5 Symptoms include nightmares, flashbacks, negative alteration in thoughts and mood, emotional numbness, and hyper-arousal.5,6 PTSD is a global health issue and prevalence rates vary between 1.3% and 37.4%.7 A 2008 report7 mentioned that, in Canada, the prevalence rate of lifetime PTSD was estimated to be 9.2%. Anxiety is periodically experienced by most people, however when it exceeds a certain level and causes dysfunction and undue stress it is considered a disorder.8 Depressive disorders involve severe and persistent sadness which interferes with normal function and frequently results in lack of interest or pleasure in activities.9

In patients diagnosed with PTSD the prevalence of comorbid substance use ranges from 19% to 35% and comorbid alcohol abuse ranges from 36% to 52%.1 These estimates are even higher in certain groups. One estimate showed that 63% of Veterans had comorbid alcohol use disorder and PTSD.10 It is estimated that one-third of patients with major depressive disorder also have SUD.11

SUD and mental disorders are often treated with psychotherapy modalities. These therapies include trauma focused psychological interventions that involve directly addressing thoughts, feelings, or memories of the traumatic event of the patient (e.g. exposure therapy, cognitive therapy); and non-trauma focused psychological interventions, which aim to alleviate the patient’s PTSD symptoms but do not directly target the thoughts and feelings related to the trauma (e.g. relaxation, interpersonal training).12,13 Integrated treatments addressing both comorbidities include concurrent treatment of PTSD and SUD using prolonged exposure therapy (COPE) and “Seeking Safety” (SS).4,14 Anxiety-sensitive therapies have been used to treat comorbid alcohol use disorder and anxiety disorder.15

Comorbidities increase complexity. Individuals with comorbidities have increased risk of other psychiatric conditions, suicidality, and social impairment compared to individuals with one of the conditions.11,13 For patients with comorbid SUD and mental disorder, it is not clear if a treatment approach addressing one disorder could also result in improvement in the second disorder. Some believe that for patients with comorbid SUD and mental disorders, SUD needs to be treated first before implementing interventions for mental disorders.1,16 This sequential treatment approach may lack coordination of care. In recent times, an integrated treatment approach using interventions addressing both disorders at the same time has been considered.1,3,16 However, the comparative clinical effectiveness of these different treatment approaches remains unclear. There appears to be debate regarding optimal treatment approaches for these comorbid conditions.

The purpose of this report is to review treatment options for patients with comorbid SUD and post-traumatic stress disorder, anxiety, or depression by comparing (1) concurrent treatments for SUD and the mental disorders with no treatment, usual care or active treatment for one condition only and (2) treatment for a single condition (SUD or the mental disorders) with no treatment, usual care or active treatment for the second disorder. Additionally, this review aims to review evidence-based guidelines regarding the treatments for patients with these comorbidities.

Research Questions

  1. What is clinical effectiveness of concurrent treatment for patients with substance use disorders and comorbid post-traumatic stress disorder, anxiety, or depression?
  2. What is the clinical effectiveness of the treatment of one condition for the improvement of all symptoms in patients with substance use disorder and comorbid post-traumatic stress disorder, anxiety, or depression?
  3. What are the evidence-based guidelines regarding the treatment of patients with substance use disorders and comorbid post-traumatic stress disorder, anxiety, or depression?

Key Findings

There is a suggestion that integrated treatments offered greater improvement with respect to PTSD symptoms, depression or anxiety compared to no treatment or minimal treatment for patients with comorbid substance use disorder (SUD) and posttraumatic stress syndrome (PTSD), depression or anxiety disorder. However results were not always consistent.

In patients with comorbid SUD and PTSD, there is a suggestion that addiction based interventions were more effective with respect to controlling substance use than control treatments.

One evidence-based guideline recommended an integrated treatment approach for patients with comorbid alcohol use disorder and PTSD, or comorbid alcohol use disorder and anxiety disorder, and cognitive behavioral therapy for comorbid alcohol use disorder and depression.

Methods

Literature Search Methods

A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2012 and July 17, 2017.

Rapid Response reports are organized so that the evidence for each research question is presented separately.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1. Selection Criteria.

Table 1

Selection Criteria.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, or were duplicate publications. Due to large volume of potentially relevant articles identified and time constraints, it was decided that the final selection of articles would be restricted to articles published between 2015 and 2017. Systematic reviews with all studies included in at least one of the selected systematic reviews were excluded. Studies included in a selected systematic review were excluded. Studies on patients with co-morbid SUD and mental illness were excluded, unless the mental illness was specified to be PTSD, depression or anxiety disorder. Studies on pharmacotherapies were excluded. Guidelines with no methods described were excluded.

Critical Appraisal of Individual Studies

The included systematic reviews were critically appraised using AMSTAR,17 randomized clinical trials and non-randomized studies were critically appraised using Downs and Black checklist,18 and guidelines were assessed with the AGREE II instrument.19 Summary scores were not calculated for the included studies; rather, a review of the strengths and limitations of each included study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 316 citations were identified in the literature search. Following screening of titles and abstracts, 282 citations were excluded and 34 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publication was retrieved from the grey literature search. Of these potentially relevant articles, 20 publications were excluded for various reasons, while 14 publications met the inclusion criteria and were included in this report. Five systematic reviews,1,2,16,20,21 seven RCTs,3,4,10,15,22–24 one controlled clinical trial,14 and one guideline25 were selected for inclusion. Appendix 1 describes the PRISMA flowchart of the study selection.

Summary of Study Characteristics

Study characteristics are summarized below and details are presented in Appendix 2, Tables 2 to 5. The term substance use disorder (SUD) is used broadly in the text and includes alcohol use as well as other substance use disorders.

Systematic reviews and clinical studies

Study Design

Of the five included systematic reviews,1,2,16,20,21 four systematic reviews1,16,20,21 included RCTs ranging in number from 3 to 24; and one systematic review2 included two RCTs and one non-randomized study. Seven RCTs3,4,10,15,22–24 and one controlled clinical trial14 were included.

Country of Origin

Of the five included systematic reviews,1,2,16,20,21 four systematic reviews were published from the USA between 2015 and 2017, and one systematic review1 was published by the Cochrane Collaboration in 2016. In two systematic reviews1,20 the RCTs were from Australia or the USA and in three systematic reviews2,16,21 the country for the RCTs was not mentioned.

Of the seven included RCTs,3,4,10,15,22–24 five RCTs4,10,15,22,24 were from the USA (with four RCTs4,10,15,24 published in 2017, and one RCT published in 2016), and two RCTs3,23 were from Australia published in 2016. One included controlled clinical trial14 was published from the USA in 2015.

Population

Three systematic reviews,1,16,21 were on adult patients with co-morbid SUD and PTSD, with the number of patients in the individual included RCTs ranging between 12 and 353 , and the percentage of females in the individual included RCTs ranging between 0% and 100% in two systematic reviews.1,21The proportion of males and females was not reported in one systematic review.16 Two systematic reviews2,20 examined patients with co-morbid SUD and depression, with the number of patients in the individual included RCTs ranging between 18 and 284, and the percentage of females in the individual included RCTs ranging between 8% and 68%. One systematic review20 included adults and in one systematic review22 age was not specified.

Three RCTs4,10,24 and one controlled clinical trial15 were on adult patients with co-morbid SUD and PTSD, with the number of patients ranging between 81 and 179, and percentage females ranging between 0% and 37%. Two RCTs15,22 were on adult patients with co-morbid SUD and anxiety disorder, with numbers of patients ranging between 41 and 247, and percentage females ranging between 37% and 40%. One RCT23 was on adult patients with co-morbid anxiety or depression and included 37 patients of which 46% were females.

Interventions and Comparators

In each of the systematic reviews,1,2,16,20,21 a wide variety of experimental interventions (such as integrated cognitive behavioral therapy [ICBT], interventions targeting both PTSD and SUD, concurrent treatment of PTSD and substance use disorders using prolonged exposure [COPE]) were compared with a wide variety of controls (such as treatment as usual [TAU], waitlist, cognitive behavioral therapy [CBT] for alcohol use disorder [AUD] , behavioral intervention) (details in Appendix 2, Table 2). In addition, in two systematic reviews20,21 findings specifically for addiction based interventions compared with control interventions were also presented separately. TAU was not defined in any of the systematic reviews.

Of the four primary studies4,10,14,24 on comorbid SUD and PTSD, one RCT10 compared a web-based CBT intervention plus TAU with TAU alone, one RCT4 compared COPE with relapse prevention (RP), one RCT24 compared COPE versus RP therapy versus active monitoring control group (AMCG), and one controlled clinical trial14 compared seeking safety (SS) or male trauma recovery empowerment model (M-TREM) with waitlist. Of the two RCTs15,22 on comorbid SUD and anxiety disorder, one RCT22 compared CBT (for drinking and anxiety) with progressive muscle relaxation training (PMRT), and one RCT15 compared anxiety sensitivity (AS) intervention (incorporating substance use and anxiety) plus TAU (not defined) with TAU alone. One RCT3 on co-morbid alcohol use problem and depression, compared the DEAL project (which includes CBT and motivational interviewing) with HealthWatch (an attention control treatment).

Outcomes

Outcomes included substance use,1–4,16,20,21,24 drinking days,10,22,23 abstinent days,15 PTSD symptom change,1,4,10,14,16,21,24 depression,2–4,20,23 anxiety,15,23 adverse events,1 quality of life,10 and self-esteem and proactive coping.14 A variety of were used in the studies and are presented in Appendix 2.

Guideline

The included evidence-based guideline25 was published in 2017 from Germany. It was prepared under the responsibility of the German Association of Psychiatry, Psychotherapy, and Psychosomatics; and the German Association for Addiction Research and Therapy. It had a broad focus and was on patients with co-morbid alcohol use disorder and mental illnesses. However, it presented recommendations separately for patients with co-morbid alcohol use and PTSD, depression or anxiety disorder and recommendations were graded.

Summary of Critical Appraisal

The critical appraisal of the included systematic reviews, RCTs, controlled clinical trial, and guideline are presented below and details are available in Appendix 3, Tables 6 to 8.

Systematic reviews and clinical studies

Patients with comorbid SUD and PTSD

Three systematic reviews,1,16,21 three RCTs,4,10,24 and one controlled clinical trial14 were on patients with co-morbid SUD and PTSD.

The three systematic reviews stated the objective and inclusion criteria, conducted a literature search using multiple databases, described the study selection, and reported characteristics of the individual included studies. An excluded articles list was presented in one systematic review1 and not in two systematic reviews.16,21 In one systematic review,1 study selection and data extraction were done in duplicate; quality assessment was conducted and the studies were judged to be of low quality. In one systematic review,21 it was unclear if article selection or data extraction were done in duplicate or if quality assessment was conducted. In one systematic review,16 article selection was done in duplicate, and it was unclear if data extraction was done in duplicate. In this systematic review, quality assessment was conducted and the studies were judged to be of moderate to high quality, however the authors cautioned that there was no consistency in use of the interventions or assessment of outcomes. In two systematic reviews16,21 it was unclear if publication bias was explored and in one systematic review1 it was stated that an examination of publication bias was not feasible as there were few studies per outcome. Meta-analysis was conducted in one systematic review,18 using random effects model. A meta-analysis was not conducted in two systematic reviews.16,21 In two systematic reviews1,16 the authors mentioned there were no conflicts of interest. In one systematic review,21 two authors had no conflicts of interest and one author was associated with industry.

In the four included primary studies4,10,14,24 the objective, inclusion, and exclusion criteria were stated, and the patient characteristics, interventions, and outcomes were described. The method of randomization was not described in two studies,4,10 was unclear in one study24 and one study14 was a controlled clinical trial without full randomization. In two studies4,10 it was unclear if sample size calculation was undertaken, in one study24 sample size was calculated but not met, and in one study14 sample size was calculated and met. Intention-to-treat analysis was conducted in three studies10,14,24 and it was unclear in one study.4 In two studies4,14 withdrawals were not reported and in two studies10,24 withdrawals were high and unequal between the groups. In one study24 the missing data were estimated from the available data but it was unclear if there were any differences in those completing the study and those dropping out, hence it was difficult to judge if this could bias findings. In one study10 it was unclear how missing data were accounted for, hence it is unclear if findings could be biased. In one study4 conflicts of interest were declared and there appeared to be none, in two studies10,24 conflicts of interest were declared and some authors in the group were associated with industry or the publisher of the treatment manual.

Patients with co-morbid SUD and depression

Two systematic reviews2,20 and one RCT3 were on patients with co-morbid SUD and depression.

In the two systematic reviews2,20 the objective and inclusion and exclusion criteria were stated, a literature search was conducted using multiple databases, and study characteristics were described. Neither systematic review presented a list of excluded articles, and it was unclear if data extraction was done in duplicate or if publication bias was explored. Meta-analysis was not conducted. In one systematic review20 study selection was described, article selection was done in duplicate, quality assessment was conducted but results were not consistently presented and conflicts of interest were not presented. In one systematic review2 it was unclear if study selection was done in duplicate or if quality assessment was undertaken; it was mentioned that the authors had no conflicts of interest.

In the included study3 the objective, and inclusion and exclusion criteria were stated, the patient characteristics, interventions and outcomes were described, randomization was described and appeared to be appropriate, the assessor was blinded, and sample size was calculated and appeared to be appropriate. Withdrawals were high and similar in both groups. The investigators conducted a test which indicated that the missing data were random, hence the missing data were unlikely to impact findings. An intention-to-treat analysis was conducted. Conflict of interest was declared and the authors reported being involved with developing the experimental intervention but had no personal or financial benefits from its operation.

Patients with co-morbid SUD and anxiety disorder

The two included studies15,22 were on patients with co-morbid SUD and anxiety disorder. In both studies15,22 the objective and inclusion and exclusion criteria were stated, and the patient characteristics, interventions and outcomes were described. However, the randomization method was not described, it was unclear if there was any blinding, and it was unclear if sample size calculations had been undertaken or if intention-to-treat analysis was conducted. In one study15 withdrawals were high and unequal between the groups, and in one study22 withdrawals were not reported. In one study22 it was mentioned that there were no conflicts of interest and one study15 did not present conflicts of interest.

Patients with co-morbid SUD and depression or anxiety disorder

One included study23 was on patients with co-morbid SUD and depression or anxiety. In the study23 the objective and inclusion and exclusion criteria were stated, the patient characteristics, interventions, and outcomes were described, the outcome assessor was blinded, and a sample size calculation was undertaken and appeared to be appropriate. However, the randomization method was unclear and withdrawals were high and unequal between the groups. It was mentioned that that there were no conflicts of interest.

Guideline

The included guideline25 stated the scope and purpose, the guideline development group had expertise in relevant areas (psychiatry and psychotherapy), a literature search on multiple databases was conducted to identify evidence, recommendations were graded, and the document was externally reviewed. However, details of the evidence identified were lacking and it was unclear how the recommendations were generated. Also, it was unclear if patient views and preferences were considered, if resource implications were considered, or if there was any policy for updating the recommendations. Conflicts of interest were presented and some authors had association with industry.

Summary of Findings

Findings are summarized below and details are available in Appendix 4, Table 9; and Appendix 5, Table 10.

What is clinical effectiveness of concurrent treatment for patients with substance use disorders and comorbid post-traumatic stress disorder, anxiety, or depression?

Patients with comorbid SUD and PTSD

The systematic review by Roberts et al.1 found that compared with TAU or minimal intervention, trauma-focused psychological therapy plus SUD intervention resulted in a statistically significantly greater reduction in PTSD severity post-treatment and up to 7 months follow-up, but reduction in SUD reached statistical significance only at long term follow up (5 to 7 months post treatment). However when trauma-focused psychological therapy was compared with psychological therapy for SUD only no statistically significant between group differences were found with respect to reduction in PTSD severity or substance use. Also, there were no statistically significant between group differences with respect to reduction in PTSD symptoms or substance use for non-trauma based psychological interventions compared to TAU, minimal treatment or treatments for SUD only. Reporting of adverse events was sparse. Limited evidence showed no statistically significant between group differences in adverse events.

The systematic review by Simpson et al.21 investigated three treatment approaches: exposure-based interventions, coping-based interventions, and addiction focused interventions. The exposure based interventions, and coping based interventions are presented in this section and the addiction focused interventions are presented with findings related to Research Question 2. The majority of the studies that compared exposure-based interventions to an active control showed that exposure-based interventions resulted in better PTSD outcomes. No study showed better SUD outcomes with the exposure-based intervention compared to the controls; one study showed better alcohol outcomes in the patients receiving AUD-oriented control interventions. The majority of the studies comparing coping-based interventions (integrating elements addressing both PTSD and SUD) with substance abuse-oriented control treatment, showed a decrease in substance use parameters in both groups; however between group differences were inconsistent. Also there was improvement in PTSD symptoms in both groups; but there was no between group difference.

The systematic review by Gilmore et al.16 showed that the outcomes with technology-based treatments targeting both PTSD and substance use were inconsistent

The RCT by Korte et al.4 showed lower depressive symptoms and PTSD symptoms in the COPE group compared with the relapse prevention group, and reduction in substance use was similar in both groups.

The RCT by Ruglass et al.24 showed that compared with AMCG, COPE and RP therapy resulted in greater reduction in PTSD symptoms. The difference between COPE and RP therapy was not significant in the entire sample (i.e., full and subthreshold PTSD) for PTSD severity, however in the subgroup of patients with full PTSD, there was significantly greater reduction in PTSD severity with COPE compared with RP therapy. Both COPE and RP therapy showed reduction in drinking days.

In the controlled clinical trial by Wolff et al.14 the integrated treatment (SS or M-TREM) showed statistically and clinically significant improvement in PTSD symptom severity over time but the difference in improvement was not statistically significant compared with control (waitlist). On disaggregating the treatment types, it was found that SS outperformed no treatment with respect to mental health symptoms, self-esteem, and proactive coping.

In summary, there is a suggestion that integrated treatments addressing both PTSD and SUD resulted in improvement in PTSD symptoms compared with treatment as usual or minimal treatment however the between group differences were not always statistically significant. Findings with respect to SUD outcomes were inconsistent.

Patients with SUD and depression

The systematic review by Barrett et al.20 showed that, overall, integrated treatments appeared to be more effective than single treatment, however effects were small to moderate.

In the systematic review by Hellem et al.,20 two studies showed improvements in depression with both the experimental and control interventions and one study showed improvements in substance use with both the experimental and control interventions but no statistically significant improvement in depression.

One RCT by Deady et al.3 showed that overall, for young adults with co-occurring depression and alcohol use problems, DEAL produced significant improvements in both depression and alcohol use compared with attention control (HealthWatch) post-treatment. However, the between group differences were no longer significant at the 6-month follow-up point.

In summary, in patients with comorbid SUD and depression, there is a suggestion that integrated treatments are more effective than control treatments or treatments addressing a single condition, but findings were not always consistent.

Patients with SUD and anxiety disorder

The RCT by Anker et al.22 showed that fewer patients relapsed to any drinking in the CBT group compared to the PMRT group. The RCT by Worden et al.15 showed that the nine hour anxiety-sensitivity focused intervention plus TAU led to a short-term benefit over TAU alone, with respect to anxiety sensitivity index but this benefit was not sustained at three months’ follow-up. Also, this RCT showed improvement in percent days abstinent in both groups, but showed no significant between group difference.

Patients with SUD and depression or anxiety disorder

The RCT by Morley et al.23 showed that ICBT appeared to be more effective than usual care with respect to most measures of alcohol consumption but not with respect to improvements in anxiety and depression levels.

What is the clinical effectiveness of the treatment of one condition for the improvement of all symptoms in patients with substance use disorder and comorbid post-traumatic stress disorder, anxiety, or depression?

The systematic review by Simpson et al.21 included six studies that evaluated addiction based interventions. Two studies comparing the experimental contingency management (CM) treatment with control treatment found slightly better early treatment gains with respect to substance use with CM, however the differences did not remain significant in the long term as shown in one study. Results from three studies (other than CM) showed within-group improvement in SUD outcomes over time even for minimal or no treatment. One study showed that the care management program was associated with better alcohol outcomes, but not PTSD outcomes compared to the AUD treatment that patients identified on their own.

The systematic review by Gilmore et al.16 included one study comparing technology-based treatment (TAU plus web based intervention targeting alcohol use) with TAU alone, and found decrease in PTSD symptoms; no findings with respect to substance use were reported.

What are the evidence-based guidelines regarding the treatment of patients with substance use disorders and comorbid post-traumatic stress disorder, anxiety, or depression?

One relevant evidence-based guideline25 was identified. For comorbid anxiety and alcohol use disorder or for comorbid PTSD and alcohol use disorder, an integrated approach was recommended (Recommendation grade: CCP i.e. “Clinical consent point”). For comorbid depression and alcohol use disorder, CBT was recommended to improve both depressive symptoms and drinking problems (Recommendation grade B).

Limitations

In two systematic reviews1,21 there was considerable overlap in the studies included, hence the findings are not exclusive. Four systematic reviews2,16,20,21 described findings qualitatively.

In some of the systematic reviews details of the experimental interventions and comparators were lacking. There was considerable variability across studies with respect to both the experimental interventions as well as the comparator control interventions, hence comparison across studies was difficult. Components included in integrated treatments were variable and there appears to be no standard definition of integrated treatment.

Details of what comprised usual care or waitlist were not presented. It was not always possible to determine if the intervention for patients with co-morbid SUD and PTSD, depression or anxiety, solely focused on one condition or addressed both conditions.

No studies comparing treatment designed to address PTSD with treatment designed to address SUD, in patients with co-morbid PTSD and SUD were identified.

Scales used to measure outcomes in the different studies varied and descriptions of clinical significance were often lacking, making it difficult to determine if the magnitude of change was meaningful or not. Also, it was not always clear if a validated outcome measure was used.

Findings from the different studies were not always consistent, hence it is difficult to make definitive conclusions.

Adverse events were rarely reported. Hence harms associated with treatment remain unclear. Long term effects of these treatment modalities are not known as the studies were of short term.

None of the studies were conducted in Canada hence generalizability to the Canadian setting is unclear. However, most of the studies were conducted in USA or Australia where healthcare is probably not too different from that in Canada.

Results need to be interpreted in the light of these limitations.

Conclusions and Implications for Decision or Policy Making

A total of 14 articles comprising five systematic reviews,1,2,16,20,21 seven RCTs,3,4,10,15,22–24 one controlled clinical trial,14 and one guideline25 were selected for inclusion. Three systematic reviews,1,16,21 three RCTs,4,10,24 and one controlled clinical trial14 were on patients with co-morbid SUD and PTSD; two systematic reviews2,20 and one RCT3 were on patients with co-morbid SUD and depression; two RCTs15,22 were on patients with co-morbid SUD and anxiety disorder; one RCT23 was on patients with co-morbid SUD and depression or anxiety; and one guideline presented recommendations for co-morbid SUD and PTSD, depression or anxiety.

In patients with comorbid SUD and PTSD, there is a suggestion that integrated treatments addressing both PTSD and SUD resulted in improvement in PTSD symptoms compared with treatment as usual or minimal treatment however the between group differences were not always statistically significant. Findings with respect to SUD outcomes were inconsistent. In patients with comorbid SUD and depression, there is a suggestion that integrated treatments are more effective than control treatments or treatments addressing a single condition, but findings were not always consistent. In patients with SUD and anxiety disorder, there is a suggestion that integrated treatments were more effective than treatment as usual or minimal treatment but the improvement was not sustained. In patients with SUD and depression or anxiety disorder there is a suggestion that integrated treatment is more effective than usual care with respect to alcohol consumption but not with respect to improvements in anxiety and depression levels.

In patients with comorbid SUD and PTSD, there is a suggestion that addiction based interventions were more effective in controlling substance use than control treatments.

The evidence-based guideline25 recommended an integrated treatment approach for patients with comorbid alcohol use disorder and PTSD, or comorbid alcohol use disorder and anxiety disorder and CBT for alcohol use disorder and depression.

For treatment approaches to be effective, it is likely that not only psychosocial and biological elements need to be considered, but also sociocultural contexts within which such behavior are manifested need to be considered.11 Optimal treatment may require personalizing treatment approaches for this common but heterogeneous population.24

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Abbreviations

ACT

Acceptance and Commitment Therapy

ADS

Alcohol dependence scale

AMCG

active monitoring control group

AnxD

anxiety disorder

AS

anxiety sensitivity

ASI

addiction severity index

AUD

alcohol use disorder

AUDIT

Alcohol Use Disorder Identification Test

BDI

Beck Depression Inventory

BI

behavioral intervention

CAPS

Clinician-Administered PTSD Scale

CBT

Cognitive Behavioral Therapy

CI

confidence interval

CM

contingency management

COPE

Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure

DASS

Depression Anxiety Stress Scale

DEAL

Depression-Alcohol

DTC

drinking to cope

IDS-UE

Index scores for the Unpleasant Emotions

LoE

level of evidence

MD

mean difference

MI

motivational interviewing

MORE

Mindfulness Oriented Recovery Enhancement

MPSS-SR

modified PTSD symptom scale – self report

M-TREM

male trauma recovery empowerment model

OCDS

obsessive compulsive drinking scale

OEF

Operation Enduring Freedom

OIF

Operation Iraqi Freedom

OND

Operation New Dawn

PCL

PTSD Checklist

PCL-M

PTSD Checklist - Military

PHQ-9

Patient Health Questionnaire - 9

PMRT

progressive muscle relaxation training

PTSD

posttraumatic stress disorder

RCT

randomized controlled trial

RP

Relapse Prevention

RPT

relapse prevention therapy

RR

risk ratio

SCID

Structured Clinical Interview for DSM-IV

SD

standard deviation

SE

standard error

SHADE

Self-Help for Alcohol and other drug use and depression

SMD

standardized mean difference

SS

Seeking Safety

SUD

substance use disorder

SUI

substance use inventory

TLFB

Timeline Follow-Back

TOT-AL

quantity and frequency of alcohol use

TSF

12-step facilitated therapy

VA

Veteran’s Administration

Appendix 1. Selection of Included Studies

Image app1f1

Appendix 2. Characteristics of Included Publications

Table 2Characteristics of Included Systematic Reviews

Author, Year, CountryType and Number of Primary Studies Included, AimPopulation CharacteristicsComparisonsOutcome
Barrett,20 2016, USA3 RCTs (published between 2006 to 2009; one from USA and two from Australia)

Setting: community, clinic, or outpatient

Aim: to assess behavioral interventions targeting depression, SUD, and chronic pain.		Adults with depression and hazardous alcohol or cannabis use or SUD.

N = 447 (range: 66 to 284 for individual RCTs)

Age (mean) (years) in the individual studies: 35 to 49

% Female in the individual studies: 8% to 68%
  1. Mindfulness, MI and CBT, and BI versus BI only;
  2. ICBT versus TSF;
  3. MI and CBT, and BI versus BI only
Depression (SCI D, BDI-II, HRSD).

Substance use (AUDIT, TLFB, OTI, SADQ, GAF, PDA, ASI, CIDI)

(Findings: Qualitative description)

Follow up: 12 weeks to 12 months.
Gilmore,16 2016, USA3 RCTs (published in 2013, country not reported)

Aim: To assess technology-based interventions designed to improve mental health outcomes among patients with both trauma symptoms and substance use		Patients with both traumatic stress symptoms and substance use (no psychiatric diagnosis was required).

N = 1604 (range: 167 to 837)

Age: NR

% Female: NR
  1. Technology based intervention targeting alcohol use +TAU versus TAU
  2. Technology based intervention targeting both PTSD and substance use +TAU versus TAU
  3. Technology based intervention targeting both PTSD and substance use versus delayed treatment
PTSD findings, substance use findings

(Findings: Qualitative description)

Follow up: NR
Hellem,2 2015, USA3 studies comprising2 RCT and 1 nonrandomized studies (published between 2005 and 2010; country not stated)

Aim: To assess treatment strategies (psychological as well as pharmacological) for the management of co-occurring depression and methamphetamine use disorders.		Patients with both depression and methamphetamine use disorders.

N = 399 (range: 18 to 214)

Age: NR

Gender: 37% female in one study, 44% female in one study and gay and bisexual males in one study
  1. CBT + motivational interviewing versus control.
  2. CBT versus contingency management versus CBT + contingency management versus gay-specific CBT.
  3. Stepped care approach (CBT and motivational intervention) versus fixed treatment (CBT and motivational intervention)
Depression (BDI, BDI-II) and amphetamine use.

(Findings: Qualitative description)

Follow-up: NR Treatment duration: 16 weeks, 20 weeks and not reported in one study.
Roberts,1 2016, Cochrane Collaboration14 RCTs (published between 2004 and 2013; from Australia [2] USA [12]),

(Of the 14 RCTs, 13 RCTs were analyzed)

Aim: To assess efficacy of psychological therapies for treatment of traumatic stress symptoms, substance misuse symptoms or both in patients with PTSD and SUD compared to control conditions and other psychological therapies		Patients with PTSD and SUD

N = Numbers in the individual studies varied from 43 to 353 in the RCTs on adults, and 33 for the 1 RCT on adolescents-females)

Age (mean) (years): 34 to 55 for 13 RCTs and 16 for one RCT

% Female: 0% to 100%
  1. Trauma focused psychological therapy versus control therapy.
  2. Trauma focused psychological therapy versus active psychological therapy for SUD only.
  3. Non-trauma focused psychological therapy versus control therapy.
  4. Non-trauma focused psychological therapy versus active psychological therapy for SUD only.
PTSD severity, PTSD diagnosis at treatment completion, alcohol or drug use or both, adverse events
Simpson,21 2017, USA24 RCTs (published between 2000 to 2016; country not stated)

Aim: To evaluate behavioral interventions for treatment of individuals with PTSD and SUD		Patients with PTSD and alcohol or drug problems

N (Numbers in the individual studies varied from 12 to 353)

Age: NR

% Female: varied between 0% and 100% for 20 studies and was not reported in 4 studies		Exposure based interventions:
Intervention (such as trauma focused CBT + CBT for AUD; EMDR + TAU; modified prolonged exposure; COPE) versus control (TAU; CBT for AUD; healthy lifestyle; supportive counselling)

Coping based interventions:
Interventions (SS; ICBT) versus control (TAU; addiction counselling + TAU; 12-step facilitation)

Addiction focused interventions:
Interventions (such as contingency management; personalized feedback and motivational interviewing versus control (TAU; personalized feedback only; usual aftercare).		PTSD outcomes, alcohol and drug use outcomes, retention during treatment or follow-up

(Findings: mainly qualitative description, in some cases proportion of patients with certain outcomes were reported)

AUD = alcohol use disorder; AUDIT = Alcohol Use Disorder Identification test; BDI-II = Beck depression Inventory; COPE = Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure ; EMDR = eye movement desensitization and HRSD = Hamilton Rating scale for Depression; PDA = Proportion of days absent; RCT = randomized controlled trial; SCID = Structured Clinical Interview for DSM-IV; SUD = substance use disorder; SS = Seeking Safety; TAU = treatment as usual; TLFB = Time Line Follow Back; TSF = 12 step facilitated therapy.

Table 3Characteristics of Included Clinical Studies

Author, Year, CountryStudy DesignPopulation CharacteristicsComparisonOutcome, Follow-up
Randomized controlled trials
Acosta,10 2017, USARCT

Setting: Patients were recruited from primary care clinics in four Veteran’s Administration (VA) facilities		Adults (Veterans) with co-occurring PTSD or subthreshold PTSD and hazardous substance use.

N = 162 (randomized and analyzed)

Age (mean) (years): 32

% Male: 93%		Primary care treatment as usual (TAU) versus TAU + web-based CBT intervention called “Thinking Forward”

TAU: Tau comprised usual primary care services including medical, behavioral health, pharmacy, weight management, and social work services.

“Thinking Forward”: This is a web-based CBT program and has 24 modules, each module takes approximately 20 minutes. It is designed to teach a variety of cognitive behavioral skills, such as identifying, evaluating, and challenging negative automatic thoughts related to PTSD symptoms and conducting a functional analysis of problematic alcohol or other drug use.		PTSD symptoms (PCL), drinking days (TLFB), QoL (WHOQOL-BREF)

Follow up: 3 months
Anker,22 2016, USARCT
(2 subgroups studied: low IDS-UE, and high IDS-UE. The IDS-UE subscale served as the primary measure of DTC )

Aim: To compare CBT (for reducing DTC and anxiety) with PMRT (for reducing anxiety only)		Adults with co-occurring DTC and anxiety symptoms were selected from a 61-bed, 21-day community-based residential chemical dependency treatment program.

N = 247 of which 218 with complete data were analyzed (110 in low IDS-UE group, and 108 in high IDS-UE group; for low IDS-UE group 43% on CBT and 57% on PMRT; and for high IDS-UE group 51% on CBT and 49% on PMRT

Age (mean) (years): 39.5 (39 in low IDS-UE group, 40 in high IDS-UE group)

% Female: 40% (35% in low IDS-UE group, 45% in high IDS-UE group)		CBT (to reduce DTC and anxiety) versus PMRT program (designed to reduce anxiety)

For both CBT and PMRT: Six daily one-hour sessions. Patients were instructed to practice the newly introduced techniques during their free time between sessions.

CBT comprised three intervention domains: psychoeducation, cognitive restructuring and imagination-based exposure practice. CBT therapy sessions were delivered by a doctoral-level psychologist with supervision provided by a senior person.

PMRT served as active control. It focused on anxiety and stress management without reference to association between anxiety and alcohol use. The PMRT routine was delivered directly from a script by a post-bachelorette research therapist		Drinking days

Follow up: 4 months
Deady,3 2016, AustraliaRCT
Randomization was automated and trial researcher was blinded to randomization.

Recruitment using extensive media coverage such as tertiary radio and newspaper stories, institution flyers, advertisements. On completion of assessments patients received reimbursement for time spent.		Young adults (15 to 25 years) with co-occurring depression (DASS-21-Depression score ≥ 7)and alcohol use problem (AUDITscore ≥ 8).

N = 104 (60 in DEAL, 44 in HealthWatch)

Age (mean) (years): 21.7

% Female: 60%		DEAL project versus HealthWatch

The DEAL project comprises four 1-hour modules to be completed over 4 weeks. It is based on the SHADE program which consists of evidence-based cognitive behavioral therapy and motivational interviewing.

HealthWatch is a 12-module attention-control condition in which participants read information about various health concerns and completed associated surveys. Four modules most relevant for young adults were selected to act as attention control for this study (environmental health, physical and mental activity, nutrition, and relationships..		Depressed mood (PHQ-9), alcohol use (TOT-AL)

Follow-up: 6 months
Korte,4 2017, USARCT

Veterans were recruited by advertisement using flyers placed in local VA and community clinics, newspaper, and internet.

Patients were compensated for participating.		Adults (Veterans) with current diagnosis of PTSD and SUD.
N = 81 (54 in COPE and 27 in RP

Age (mean) (years): 40.4

% Male 90.1%		COPE versus RP.

COPE is a manualized integrated CBT for comorbid PTSD and SUD that consisted of 12 weekly, individual, 90 minute sessions. It includes goal-setting, psychoeducation related to PTSD and SUD, coping methods, and prolonged exposure.

RP is a manualized CBT used for treatment of SUD that consisted of 12 weekly, individual, 90 minute sessions. It focuses on teaching patients a variety of recovery-related skills. It does not include components of treatment for PTSD.		PTSD (PCL-M), substance/ alcohol use
(TLFB),depression (BDI)

Treatment duration: 12 weekly sessions
Morley,23 2016, AustraliaRCT, assessor blinded.

Patients were identified by clinicians at the drug and alcohol unit and by advertisements in GP offices and on line media.

Before randomization there was an initial 3-week alcohol stabilization phase where usual care alcohol support counselling was available.

Setting: Outpatient clinic of Drug Health Services, Royal Prince Alfred Hospital in Australia		Adults with co-occurring alcohol dependence and either anxiety or depressive symptoms.

N = 37 (21 on ICBT, 16 on UC)

Age (mean) (years): 40 in ICBT, 43 in UC.

% Female: 52% in ICBT, 38% in UC		ICBT (for alcohol, anxiety and/or depression) versus UC

ICBT: Trained therapists delivered specific cognitive behavioral therapy based on evidence based treatment manuals for alcohol use, anxiety, and depressive disorders. Cognitive restructuring and behavioral experiments or graded exposure are common CBT approaches for most of these disorders. There were 7 to 10 sessions.

UC: Counselling for treatment of alcohol dependence according to standard practice		Drinking rate, alcohol dependence (ADS), depression, anxiety, or stress (DASS-21)

Follow-up: 12 weeks

(Trial duration: 24 months)
Ruglass,24 2017, USA,RCT, assessor blinded.

Patients were recruited through advertisements and outpatient referrals in New York city		Adults with co-occurring PTSD and SUD.

N = 110 (39 in COPE, 43 in RPT, 28 in AMCG)

Age (mean) (years): 43 in COPE, 44 in RPT, 47 in AMCG.

% Female: 28.2% in COPE, 37.2% in RPT, 46.4 in AMCG		COPE versus RPT versus AMCG

COPE: integrates empirically supported models of PE for PTSD and RPT for SUD.

RPT is a cognitive behavioral SUD intervention and includes coping strategies to manage situations that increase the risk of substance use relapse

Both treatments were administered in 12 weekly sessions

AMCG group met weekly with the research assistants over 12 weeks to complete self report for various outcomemeasures		PTSD symptoms (MPSS-SR, SUI CAPS), addiction (ASI)
Worden,15 2017, USARCT

Patients were recruited from consecutive admissions to two intensive outpatient addiction programs of an urban non-profit hospital’s behavioral network.		Adults with co-occurring SUD and anxiety disorder (anxiety sensitivity index score ≥ 25)

N = 41 (28 in AS+ TAU, 13 in TAU).

Age (mean) (years) 38.7 in AS+ TAU, 38 in TAU

% Female: 46.4% in AS+ TAU, 15.4% in TAU		Anxiety sensitivity intervention (AS) + TAU versus TAU alone

AS: This treatment focused on interoceptive exposures including psychoeducation regarding treatment rationale, relationship between substance use and anxiety, and practice identifying and challenging maladaptive cognitive appraisals of bodily sensations.
The treatment was a manualized protocol comprising 6, 90-minute sessions delivered twice weekly over three weeks.

TAU: This was an addictions intensive outpatient program. The treatment is eclectic drawing from frameworks such as motivational interviewing, 12-step, and cognitive behavioral therapy.
The treatment was tailored to the patient based on need and varied between 9 to 20 hours per week and ranged typically from 3 to 5 weeks.		Anxiety sensitivity index, DASS anxiety subscale, % days abstinent on TLFB,

Follow up: 3 months
Controlled clinical trial
Wolff,14 2015, USACCT
Patients were randomly assigned to treatment (SS or M-TREM) or control (waitlist). Further in the treatment group, patients were either randomly assigned or assigned by preference to one of the treatment groups (SS or M-TREM).

Patients were recruited were incarcerated men housed at a high security prison operated by the Pennsylvania Department of Corrections		Male adults (incarcerated) with co-occurring PTSD and addiction problems.

N = 179 (86 on treatment [42 on SS and 44 on M-TREM] and 93 on waitlist

Age(mean) (years): 46.3 for treatment group and 40.0 for waitlist group.

% Female: 0%		Treatment (SS or M-TREM) versus waitlist

SS and M-TREM are group based integrated treatment for PTSD and addiction disorders.

Groups met for 90-min, twice a week for 14 weeks		PTSD symptom severity, mental health symptom severity, self-esteem, proactive coping.

ADS = alcohol dependence scale; ASI = addiction severity index; AS = anxiety sensitivity intervention; AUDIT = Alcohol Use Disorders Identification Test; AMCG = active monitoring control group; BDI = Beck depression inventory; CAPS = clinician administered PTSD scale; CBT = cognitive behavioral therapy; COPE = Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure; DEAL = Depression-Alcohol; DASS = Depression Anxiety Stress Scale; DTC = drinking to cope; ICBT = integrated cognitive behavioral therapy; IDS-UE = Index scores for the Unpleasant Emotions; MPSS-SR = modified PTSD symptom scale - self report; PHQ-9 = Patient health questionnaire-9; PMRT = progressive muscle relaxation training; RCT = randomized controlled trial; RP = relapse prevention; SHADE = Self-Help for Alcohol and other drug use and depression; SS = Seeking Safety; SUI = substance use inventory; TAU = treatment as usual; TLFB = Timeline follow back; TOT-AL = quantity and frequency of alcohol use; VA = Veteran’s Administration; UC = usual care

Table 4Characteristics of Included Guidelines

First Author/ Group, Year, CountryObjectiveGuideline Development Group, Target UsersMethodology
Preuss,25 2017, GermanyAim: To provide guidelines for treatment approaches including psycho-, pharmaco-, and combination therapies for comorbid mental disease in alcohol use disorderThe guideline development group comprised of individuals in the areas of psychiatry and psychotherapy

Target audience: clinicians		Systematic review was conducted.

Recommendations were categorized according to specific criteria

Table 5Grade of Recommendations and Level of Evidence for Guidelines

Grade of RecommendationsStrength of Evidence
Preuss,25 2017, Germany
Recommendation grades:
“A “Shall” recommendation: At least one randomized-controlled study of high quality and consistence which directly refers to the respective recommendation and which was not extrapolated (evidence level Ia, Ib, Ic)
B “Should” recommendation: Well implemented clinical (non-randomized) study, directly referring to the recommendation (evidence levels IIa, IIb, IIc) or extrapolation of evidence level I, if reference to specific questioning is lacking
O “Can” or “Open” recommendation: evidence category III, IV, and V. Reports of groups of experts or experts’ opinion and/or clinical experience of acknowledged authorities or extrapolation of evidence levels IIa, IIb or IIc. This categorisation indicates that directly applicable clinical studies of good quality did not exist or were not available
CCP “Clinical consent point”: Recommended as good clinical practice (“Good Clinical Practice Point”) in consent and due to clinical experience of the members of the guideline group as standard in the treatment, for which no experimental scientific exploration is possible or is intended” (Page not numbered)		Evidence levels:
“1a Systematic review (with homogeneity) of randomized-controlled trials (RCTs)
1b Individual RCT (with narrow confidence interval)
1c All or none (all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it)
2a SR (with homogeneity) of cohort studies
2b Individual cohort study (including low-quality RCT; e.g., <80% follow-up)
2c “Outcomes” research; ecological studies
3a SR (with homogeneity) of case-control studies
3b Individual case-control study
4 Case series (and poor quality cohort and case-control studies)
5 Expert opinion without explicit critical appraisal, or based on physiology, bench research, or “first principles” (Page not numbered)

Appendix 3. Critical Appraisal of Included Publications

Table 6Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR

StrengthsLimitations
Barrett,20 2016, USA
  • The objective was clearly stated.
  • The inclusion criteria were stated.
  • The exclusion criteria were stated
  • Multiple databases (such as Medline, PsycInfo, CINAHL) were searched.
  • Study selection was described
  • Flow chart of study selection was provided
  • List of included studies was provided
  • Article selection was done in duplicate
  • Authors reported that the quality assessment was conducted according to the PRISMA quality appraisal score (9-point scale). Of the three relevant included studies two had a score of greater than 7 and were considered by the authors to be of good quality, quality of the third study was not presented.
  • Characteristics of the individual studies were provided
  • List of excluded studies was not provided
  • Unclear id data extraction was done in duplicate
  • Unclear if publication bias was explored
  • Meta-analysis was not conducted. Numerical data from individual studies were not reported. Findings were reported qualitatively.
  • Disclosure of conflict of interest was not presented.
Gilmore,16 2016, USA
  • The objective was clearly stated.
  • The inclusion criteria were stated.
  • The exclusion criteria were stated
  • Multiple databases (such as PubMed, PsycInfo, Cochrane library, Embase) were searched.
  • Study selection was described
  • Flow chart of study selection was provided
  • List of included studies was provided
  • Article selection was done in duplicate
  • Data extraction was done in duplicate
  • Quality assessment of the included studies was reported to have been conducted and was reported to be of moderate to high quality; however the method used was not stated. Furthermore, the authors cautioned that “When considering the quality of the studies overall, it is important to note there was no consistent assessment of trauma symptoms or substance use or consistency in use of technology-based interventions. Therefore, conclusions regarding the research as a whole must be interpreted with this concern regarding the quality of the studies overall” Page4
  • Characteristics of the individual studies were provided but lacked details
  • The authors mentioned there were no conflicts of interest
  • List of excluded studies was not provided
  • Unclear if publication bias was explored
  • Meta-analysis was not conducted. Numerical data from individual studies were not reported. Findings were reported qualitatively.
Hellem,2 2015, USA
  • The objective was clearly stated.
  • The inclusion criteria were stated.
  • The exclusion criteria were stated
  • Multiple databases (such as PubMed, PsycInfo, PubMed, Medline) were searched.
  • List of included studies was provided
  • Characteristics of the individual studies were provided but lacked details
  • The authors mentioned there were no conflicts of interest
  • Study selection was not described
  • Flow chart of study selection was not provided
  • Unclear if article selection was done in duplicate
  • Unclear if data extraction was done in duplicate
  • List of excluded studies was not provided
  • Unclear if quality assessment of the studies was conducted
  • Unclear if publication bias was explored
  • Meta-analysis was not conducted. Numerical data from individual studies were not reported. Findings were reported qualitatively
Roberts,1 2016, Cochrane Collaboration
  • The objective was clearly stated.
  • The inclusion criteria were stated.
  • The exclusion criteria were stated
  • Multiple databases (Medline, Embase, and PsycInfo) were searched. In addition trial registries and databases were searched. Also, key journals, and conference proceedings were hand searched.
  • Study selection was described
  • Flow chart of study selection was provided
  • List of included studies was provided
  • List of excluded studies was provided
  • Article selection was done in duplicate
  • Data extraction was done by three reviewers independently
  • Quality assessment was done using the Cochrane list of bias tool and quality was judges as mostly low to very low quality.
  • Characteristics of the individual studies were provided.
  • Meta-analysis was appropriately conducted. Random effects model was used recognizing the clinical heterogeneity among the included studies.
  • Authors mentioned that publication bias would be explored using Funnel plot if 10 or more studies were available. However, less than 10 trials were available per outcome, hence investigation of publication bias was not feasible.
  • The authors mentioned there were no conflicts of interest
  • There appears to be no major limitations
Simpson,21 2017, USA
  • The objective was clearly stated.
  • The inclusion criteria were stated.
  • Multiple databases (Medline, PubMed, and PsycInfo) were searched.
  • Study selection was described
  • Flow chart of study selection was provided
  • List of included studies was provided
  • Characteristics of the individual studies were provided.
  • It was mentioned that of the three authors, two authors had no conflicts of interest and one author had association with industry.
  • The exclusion criteria were not explicitly stated.
  • List of excluded articles was not presented.
  • Unclear if study selection was done in duplicate
  • Unclear if data extraction was done in duplicate
  • Unclear if quality assessment of the studies were conducted
  • Unclear if publication bias was explored
  • Meta-analysis was not conducted. Findings were reported qualitatively

Table 7Strengths and Limitations of Clinical Studies using Downs and Black checklist

StrengthsLimitations
Randomized controlled trial
Acosta,10 2017, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described. Details of the assessment scales were not always provided.
  • Randomized but randomization method was not described.
  • Lost to follow-up was substantial: 28% in Web-CBT+TAU and 19% in TAU
  • ITT analysis
  • Conflict of interest was presented. One author was associated with business developing the program used in the study
  • Details of randomization were lacking
  • Unclear if there was blinding of the assessor.
  • Unclear if sample size calculation was undertaken
Anker,22 2016, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described.
  • Randomized but randomization method was not described
  • P-values were not always reported
  • The authors mentioned that there was no conflict of interest
  • Details of randomization were lacking
  • Unclear if there was blinding of the assessor.
  • Unclear if sample size calculation was undertaken
  • Does not appear to be ITT analysis
  • Withdrawals were not reported
Deady,3 2016, Australia
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described
  • Randomization was automated and trial researcher was blinded to randomization
  • Sample size calculation was conducted and appeared to be appropriate
  • Lost to follow-up was substantial: 60% in DEAL and 64% in HealthWatch
  • ITT analysis conducted
  • P-values were reported
  • The authors worked on the DEAL project website but derived no personal or financial benefits. Unclear if this could result in bias.
  • Unclear if there was blinding of the assessor.
Korte,4 2017, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described.
  • Randomized but randomization method was not described
  • P-values were reported but not always
  • The authors mentioned that there was no conflict of interest
  • Details of randomization were lacking
  • Unclear if there was blinding of the assessor.
  • Unclear if sample size calculation was undertaken
  • Unclear if there were any withdrawals
  • Unclear if ITT analysis
Morley,23 2016, Australia
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described. Details of scales used not presented
  • Randomized but unclear if method of randomization was appropriate
  • Assessor was blinded
  • Sample size calculation was conducted and appeared to be appropriate
  • Lost to follow-up was reported and was substantial and unequal in the two groups: 52%% in ICBT and 31% in UC
  • ITT analysis conducted
  • P-values were reported but not always
  • The authors mentioned that there was no conflict of interest
  • Lost to follow-up was substantial and unequal in the two groups: 52%% in ICBT and 31% in UC
Ruglass,24 2017, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described. Details of scales used not presented
  • Randomized. An independent biostatistician conducted the random allocation. Unclear if randomization method was appropriate
  • Assessor was blinded
  • Lost to follow-up was reported and was substantial and unequal in the two groups
  • ITT analysis conducted
  • Of the 6 authors, 4authors mentioned that there were no conflicts of interest and two authors mentioned that they had received royalties from the publisher for writing a manual on COPE.
  • Sample size calculation was conducted but the appropriate number ( 50 per group) could not be recruited
  • Lost to follow-up was substantial and unequal in the three groups: 35.9% in COPE, 46.5% in RPT, and 14.3% in AMCG
  • P values were not reported
Worden,15 2017, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described. Details of scales used not always presented.
  • Randomized.
  • Withdrawals were reported and were substantial and unequal in the two groups
  • P-values were reported but not always
  • Details of randomization were lacking
  • Unclear if there was blinding of the assessor.
  • Unclear if sample size calculation was undertaken
  • Withdrawals were substantial and unequal in the two groups: 46% in (AS+TAU), and 23% in TAU
  • Unclear if ITT analysis
  • Disclosure of conflicts of interest was not presented.
Controlled clinical trial
Wolff,14 2015, USA
  • The objective was clearly stated
  • The inclusion and exclusion criteria were stated
  • Patient characteristics, intervention and outcomes were described. Details of scales used not always presented.
  • ITT analysis
  • P-values were reported but not always
  • Partially randomized. Details of randomization were lacking
  • Unclear if there was blinding of the assessor.
  • Withdrawals unclear
  • Disclosure of conflicts of interest was not presented.

Table 8Strengths and Limitations of Guidelines using AGREE II

StrengthsLimitations
Preuss,25 2017, Germany
  • The scope and purpose were clearly stated.
  • The authors had expertise in relevant areas(psychiatry and psychotherapy)
  • A systematic review was conducted using PubMed and the Cochrane library
  • The evidence was categorized as various levels
  • Recommendations were assigned grades
  • The document was externally reviewed
  • Conflicts of interest of the authors were declared. Some authors had association with industry.
  • Unclear if patient views and preferences were considered
  • Unclear if resource implications and organizational barriers were considered
  • Unclear if there was any policy for updating of the recommendations

Appendix 4. Main Study Findings and Author’s Conclusions

Table 9Summary of Findings of Included Studies

Main Study FindingsAuthor’s Conclusion
Systematic Reviews
Barrett,20 2016, USA
For patients with both depression and hazardous alcohol or cannabis use or substance use disorder.
One study compared ICBT with 12-step facilitation (TSF) in patients with depression and SUD, and found both groups had improvements in depression and SUD during treatment. However by three and six months there was increase in depressive mood in the TSF group whereas the ICBT group maintained a stable decreased depressed mood up to 12 months.
One study compared CBT+MI+BI with BI alone in patients with depression and hazardous alcohol or cannabis use problems, and found response in both groups but the response was greater in the CBT+MI+BI group.
One study compared integrated treatment (mindfulness +CBT+MI+BI) with BI alone in patients with depression and hazardous alcohol use problems, and found that the integrated treatment seemed to reduce and depression and drinking occasions of alcohol but not the amount consumed per drinking occasion.

Summary: Overall, integrated treatments appeared to be more effective than single treatment, however effects were small to moderate.		“MORE, ACT, and CBT combined with mindfulness and Motivational Interviewing had the most promising results for treating chronic pain, depression, and SUD in various combinations in primary care settings.” Page 345
Gilmore,16 2016, USA
For patients with both substance use and trauma symptoms
One study compared technology based treatment (TAU +web based intervention targeting alcohol use) with TAU alone, and found decrease in PTSD symptoms; no findings with respect to substance use was reported.
One study compared technology based treatment (TAU + biweekly telephone monitoring and support targeting PTSD and alcohol and drug use) with TAU alone, and found no differences in PTSD or substance use findings.
One study compared technology based treatment targeting PTSD and alcohol use with delayed treatment, and found decreases in both PTSD symptoms and alcohol use and related problems.

Summary: Results with technology based treatments targeting both PTSD and substance use were inconsistent.		“This review suggests that technology-based interventions for co-occurring trauma symptoms and substance use are feasible, but more work is needed to assess efficacy using scientifically rigorous studies.” Page 1
Hellem,2 2015, USA
For patients with both depression and methamphetamine use disorders.
One study (RCT) compared CBT + motivational interviewing with control, and found that there was a statistically significant improvement in depression rating scores between pre- and post-treatments (P < 0.001)and also between pre-treatment and 6-months follow-up (P <0.001), but no differences in scores between post-treatment and 6-months follow-up.
One study (RCT) compared four treatment modalities: CBT, contingency management, CBT + contingency management, and gay-specific CBT, and found a 75% decrease in methamphetamine use across all four groups but no statistically significant changes with respect to depression.
One non-randomized study compared stepped care approach incorporating CBT and motivational intervention with fixed treatment incorporating CBT and motivational intervention and found a 53% decrease in depression rating scores in the stepped care group and 48% decrease in the control group; however the authors cautioned that these findings need further investigation in a large sample.

Summary: There appeared to be some improvements with the various treatment modalities investigated but it was unclear which treatment modalities were optimal.		“No clear treatment model exists to suggest how to optimally manage co-occurring depression and MA use disorders [....] High-quality studies of co-occurring depression and MA use disorders are required for building a more expansive foundation of evidence-based practice to guide clinical and research recommendations.” Page 9
Roberts,1 2016, Cochrane Collaboration
For patients with both PTSD and SUD

Trauma-focused psychological therapy versus control therapy		“We assessed the evidence in this review as mostly low to very low quality. Evidence showed that individual trauma-focused psychological therapy delivered alongside SUD therapy did better than TAU/minimal intervention in reducing PTSD severity post-treatment and at long-term follow-up, but only reduced SUD at long-term follow-up. All effects were small, and follow-up periods were generally quite short. There was evidence that fewer participants receiving trauma-focused therapy completed treatment. There was very little evidence to support use of non-trauma-focused individual-or group-based integrated therapies. Individuals with more severe and complex presentations (e.g. serious mental illness, individuals with cognitive impairment, and suicidal individuals) were excluded from most studies in this review, and so the findings from this review are not generalisable to such individuals. Some studies suffered from significant methodological problems and some were underpowered, limiting the conclusions that can be drawn. Further research is needed in this area.” Page2
OutcomeNo. of studiesNo. of patientsEffect measureEffect size,
PTSD severity at treatment completion4405SMD (95% CI)-0.41 (-0.72 to -0.10)
PTSD severity 3 to 4 months post-treatment1120MD (95% CI)-9.83 (-17.11 to -2.55)
PTSD severity 5 to 7 months post-treatment3388SMD (95% CI)-0.34 (-0.58 to -0.10)
Drug, or alcohol use or both at treatment completion3388SMD (95% CI)-0.13 (-0.41 to 0.15)
Drug, or alcohol use or both 3 to 4 months post-treatment1120MD (95% CI)-2.33 (-12.87 to 8.21)
Drug, or alcohol use or both 5 to 7 months post-treatment3388SMD (95% CI)-0.28 (-0.48 to -0.07)
Treatment completers3316RR (95% CI)0.78 (0.64 to 0.96)
PTSD diagnosis at treatment completion1120RR (95% CI)0.71 (0.51 to 1.00)
Adverse events2268RR (95% CI)0.81 (0.34 to 1.90)
Trauma-focused psychological therapy versus psychological therapy for SUD only
OutcomeNo. of studiesNo. of patientsEffect measureEffect size,
PTSD severity at treatment completion146MD (95% CI)-3.91 ( -19.16 to 11.34 )
PTSD severity 5 to 7 months post-treatment145MD (95% CI)-9.32 ( -22.89 to 4.25 )
PTSD severity 8 to 10 months post-treatment147MD (95% CI)2.11 ( -16.10 to 20.32 )
Drug, or alcohol use or both at treatment completion146MD (95% CI)-1.27 ( -5.76 to 3.22 )
Drug, or alcohol use or both 5 to 7 months posttreatment145MD (95% CI)1.90 ( -1.65 to 5.45 )
Drug, or alcohol use or both 8 to 10 months post-treatment147MD (95% CI)-0.93 ( -4.04 to 2.18 )
Treatment completers162RR (95% CI)1.00 ( 0.74 to 1.36 )
PTSD diagnosis at treatment completion162RR (95% CI)1.04 (0.67 to 1.62)
SUD diagnosis at treatment completion162RR (95% CI)1.16 (0.83 to 1.60)
Non-trauma-focused psychological therapy versus control therapy
OutcomeNo. of studiesNo. of patientsEffect measureEffect size,
PTSD severity at treatment completion4513SMD (95% CI)-0.02 (-0.19 to 0.16)
PTSD severity 3 to 4 months post-treatment4499SMD (95% CI)0.00 (-0.17 to 0.18)
PTSD severity 5 to 7 months post-treatment4566SMD (95% CI)-0.14 (-0.31 to 0.03)
PTSD severity 12 months post-treatment2518SMD (95% CI)-0.07 (-0.25 to 0.10)
Drug, or alcohol use or both at treatment completion3564SMD (95% CI)-0.41 (-0.97 to 0.14)
Drug, or alcohol use or both 3 to 4 months post-treatment4499SMD (95% CI)-0.08 (-0.40 to 0.23)
Drug, or alcohol use or both 5 to 7 months post-treatment4572SMD (95% CI)-0.06 (-0.23 to 0.11)
Drug, or alcohol use or both 12 months post-treatment2528SMD (SUD diagnosis 95% CI)0.02 (-0.15 to 0.20)
Treatment completers2381RR (95% CI)1.18 (0.88 to 1.45)
PTSD diagnosis at treatment completion277RR (95% CI)1.01 (0.66 to 1.54)
Adverse events1353RR (95% CI)1.03 (0.71 to 1.50)
Non-trauma-focused psychological therapy versus active psychological treatment for SUD only
OutcomeNo. of studiesNo. of patientsEffect measureEffect size,
PTSD severity at treatment completion2128SMD (95% CI)-0.26 [-1.29, 0.77]
PTSD severity 3 to 4 months post-treatment2128SMD (95% CI)0.12 [-0.31, 0.55]
PTSD severity 5 to 7 months post-treatment175MD (95% CI)7.52 (-3.78 to 18.82)
Drug, or alcohol use or both at treatment completion2128SMD (95% CI)0.22 [-0.13, 0.57]
Drug, or alcohol use or both 3 to 4 months post-treatment2128SMD (95% CI)0.18 [-0.18, 0.53]
Drug, or alcohol use or both 5 to 7 months post-treatment175MD (95% CI)0.10 (-0.20 to 0.40)
Treatment completers2128RR (95% CI)0.91 [0.68, 1.20]
PTSD diagnosis at treatment completion153MD (95% CI)0.94 (0.68 to 1.30)
Note: Control therapy includes usual care, waiting list, or no treatment
Simpson,21 2017, USA
For patients with co-occurring PTSD and alcohol or drug problems

Exposure based approaches:
Seven RCTs evaluated exposure based interventions. Of the 7 studies, 6 studies found positive within-subject changes in PTSD and SUD outcomes for both experimental and control conditions. Of the 6 studies that compared exposure-based intervention to an active control, five studies found that exposure-based intervention resulted in better PTSD outcomes. No study found better SUD outcomes with the exposure-based intervention compared to the controls; one study found better alcohol outcomes in the patients receiving AUD-oriented control.

Coping based interventions:
Eleven RCTs evaluated coping based interventions. Three RCTs comparing SS with control treatment found no between group difference with respect to either SUD or PTSD outcomes. In the three studies, there was decreased PTSD in both treatment and control groups. Of the nine coping based studies that included a substance abuse-oriented control treatment, eight studies showed decrease in substance use parameters, and one study showed no difference. Three studies investigating alcohol and drug outcomes separately, found between group differences favoring the experimental treatment on drug use but not on alcohol use. Though PTSD is generally not directly addressed in usual SUD interventions, findings indicate that such treatments are not significantly different from coping based treatments that were designed for treating both PTSD and SUD, with respect to PTSD outcomes.

Addiction based interventions:
Six studies evaluated addiction based interventions. Two studies comparing the experimental contingency management (CM) treatment with control treatment found slightly better early treatment gains with CM, however the differences did not remain significant in the long term as shown in one study. Results from three studies (other than CM) showed within-group improvement in SUD outcomes over time even for minimal or no treatment. One study showed that the care management program was associated with better alcohol outcomes, but not PTSD outcomes compared to the AUD treatment that patients identified on their own.		“In conclusion, the majority of RCTs found significant within-group improvements across outcomes and across conditions and few consistent between-group differences. We believe these findings suggest there are no wrong doors through which to enter treatment, and individuals with comorbid SUD/PTSD can benefit from available treatments, including manualized SUD care, which is more widely available than SUD/PTSD-oriented care and does not require that providers be cross-trained to specifically address PTSD concerns.” Page 700
Randomized controlled trial
Acosta,10 2017, USA
For patients with co-occurring PTSD and SUD

Comparison between TAU and (TAU + “Thinking Forward”) using generalized mixed-effects piecewise regression analysis.		“The current study examined the efficacy of a web-based CBT intervention for OEF/OIF/OND veterans who presented in VA primary care with diagnostic or subthreshold PTSD and hazardous drinking or drug use. Our results show that the Thinking Forward intervention significantly reduced alcohol use (including heavy drinking) among recently returned combat veterans but did not change self-reported levels of PTSD or quality of life.” Page 272

“Future research is needed to investigate if adding professional support to web-based treatments may boost their effectiveness in treating PTSD and to determine which aspects of the current treatment are essential to generate the desired improvements in PTSD and substance use outcomes.” Page 273
OutcomeTreatment effecta, estimate (SE)
In-treatment periodBetween in- and post-treatment periods
Percent of drinking days-0.93 (1.12)1.67 (1.84)
Percent of heavy drinking days-1.80 (0.79)b1.89 (1.33)
Percent of drug use days-0.27 (0.25)-0.06 (0.49)
PTSD severity - mean PCL score-0.09 (0.50)0.40 (0.82)
QOL - Physical domain0.75 (0.52)-0.51 (0.91)
QOL - Psychological domain0.77 (0.58)-0.88 (0.94)
QOL - Social domain1.27 (1.02)-2.00 (1.72)
QOL - Environment domain0.13 (0.61)0.15 (1.02)
Comparison between TAU and (TAU + “Thinking Forward”) with rest to clinically meaningful effect
OutcomeTime pointPercentage patients with clinically significant improvementComment
TAU+ “Thinking Forward”TAU
Clinically significant in PTSD symptoms on PCL (i.e., > 10-point decrease)12 weeks41.0%31.3%Chi-square analyses did not indicate significant differences between the two groups
3-month post-treatment37.5%29.7%
Change from clinically significant distress on PCL (i.e., > 50) to no clinical levels of distress12 weeks22.2%17.9%
3-month post-treatment23.4%17.9%
Anker,22 2016, USA
For patients with co-occurring anxiety disorder and problematic alcohol use

Comparison between CBT and PMRT		“These findings establish a meaningful clinical distinction among those with co-occurring AUD-AnxD based on the degree to which the symptoms of the two disorders are functionally linked through DTC. Those whose cooccurring AUD-AnxD is more versus less strongly linked via DTC are especially likely to benefit from standard AUD treatment that is augmented by a brief CBT designed to disrupt this functional link.” Page 1
OutcomeSubgroupTreatment
CBTPMRT
Relapse to any drinkingLow IDS-UE38.3%50.8%
High IDS-UE43.6%60.4%
In the high IDS-UE group, the patients receiving CBT had substantially fewer binge days after 4 months following treatment compared with those receiving PMRT, however this difference in binge days was much smaller in the low IDS-UE group.

In the high IDS-UE group, patients receiving CBT reported to have substantially fewer drinks over the 4-month follow-up period compared with those receiving PMRT, however this difference was much smaller in the low IDS-UE group.
Deady,3 2016, Australia
For young adult patients with co-occurring depression and problematic alcohol use

Comparison between DEAL and HealthWatch with respect to PHQ-9 scores		“Overall, the DEAL Project was associated with more rapid improvement in both depression symptoms and alcohol use outcomes in young people with these co-occurring conditions relative to an attention-control condition. However, long-term outcomes are less clear.” Page 1
Time pointDEALHealthWatchBetween group difference
Value at time point, mean (95% CI)Change from T0 (95% CI), P valueValue at time point, mean (95% CI)Change from T0 (95% CI), P valueChange from T0 (95% CI), P value
T016.58 (15.42, 17.75)NA15.95 (14.36 to 17.54)NANA
T110.64 (8.31, 12.97)-5.94 (-8.18 to -3.70), P < 0.00114.53 (12.33 to, 16.73)-1.43 (-3.46 to 0.60), P = 0.174.51 (1.49 to 7.54), P = 0.003
T210.65 (7.99, 13.31)–5.93 (– 8.53 to –3.37), P < 0.00111.75 (8.76 to 14.74)–4.21 (– 7.27 to –1.15), P = 0.01–1.73 (– 5.74 to 2.29), P = 0.40
T39.05 (6.21, 11.90)–7.53 (– 10.51 to –4.55), P < 0.00111.14 (7.82 to 14.45)–4.82 (– 8.28 to 1.36), P = 0.01–2.71 (– 7.28 to 1.86), P = 0.24
Comparison between DEAL and HealthWatch with respect to drinks per week using TOT-AL
Time pointDEALHealthWatchBetween group difference
Value at time point, mean (95% CI)RRa (95% CI), P valueValue at time point, mean (95% CI)RRa (95% CI), P valueRRa (95% CI), P value
T025.65 (19.52 to 33.71)NA19.43 (14.02 26.93)NANA
T111.72 (8.11 16.93)0.46 (0.32 to 0.65), P <0.00118.89 (14.00 to 25.52)0.97 (0.67 to 1.41) P = 0.882.13 (1.28 to 3.54), P =0.02
T29.79(4.66- 20.54)0.38 (0.19 to 0.76), P = 0.00612.96 (7.65 to 21.96)0.67 (0.37 to 1.22) P = 0.191.75 (0.70 to 4.73), P = .23
T315.81 (9.89- 25.27)0.62 (0.41 to 0.93), P = 0.0215.97 (9.87 to 25.84)0.82 (0.47 to 1.42), P = 0.481.33 (0.67 to 2.65), P =0.41
Comparison between DEAL and HealthWatch with respect to drinking days per week using TOT-AL
Time pointDEALHealthWatchBetween group difference
Value at time point, mean (95% CI)RRa (95% CI), P valueValue at time point, mean (95% CI)RRa (95% CI), P valueRRa (95% CI), P value
T03.00 (2.49 to3.60)NA2.64 (2.05 ti3.41)NANA
T11.56 (1.18 to 2.07)0.52 (0.41to 0.67), P < 0.0012.48 (1.89 to3.25)0.93 (0.69 to 1.26), P = 0.021.79 (1.22 to 2.64), P = 0.003
T21.59 (1.07 to 2.34)0.53 (0.37 to 0.76), P = 0.0011.90 (1.15 to 3.13)0.72 (0.42 to 1.24), P = 0.581.35 (0.70 to 2.61), P = 0.36
T32.07 (1.46 to 3.13)0.69 (0.50 to 0.96), P =0.032.67 (1.71 to 4.15)1.01 (0.64 to 1.59), P = 0.381.46 (0.83 to 2.55) P = 0.19
Note: T0 = baseline, T1 = at post-treatment (5 weeks), T2 = follow-up 3 months post baseline, and T3 = follow-up 6 months post baseline
Korte,4 2017, USA
For Veterans with co-occurring PTSD and SUD

Comparison of COPE with RP with respect to various outcome measures		“Results revealed significantly lower depressive symptoms at post-treatment in the COPE group, as compared to the relapse prevention group.” Page1

“[…] the present study demonstrated temporal precedence of the change in PTSD symptoms at mid-treatment mediating the change in depressive symptoms at post-treatment. In contrast, the midtreatment change in substance use symptoms did not mediate the change in post-treatment depressive symptoms, thereby further bolstering the significance of these findings and the benefits of integrated PTSD/SUD treatment on depression.” Page 6
Outcome measureTime pointEffect, mean (SD)
COPE (n = 54)RP (n = 27)
BDIBaseline29.2 (12.3)29.6 (9.7)
Session 619.5 (11.7)26.2 (13.7)
Session 1213.0 (11.0)19.4 (12.3)
PCLBaseline62.2 (11.1)64.3 (8.9)
Session 645.5 (15.6)58.0 (18.5)
TLFBBaseline0.47 (0.36)0.50 (0.34)
Session 60.21 (0.26)0.29 (0.30)
Mediators of change in depression:
The authors investigated the effect of the treatment group on symptoms of depression at treatment session 12, considering the changes in PTSD symptoms and substance use at session 6. “PTSD symptoms were a significant mediator of the effect of the treatment group on depressive symptoms (standardized estimate: 0.165, 95% CI: 0.004-0.326, p < 0.05). This finding indicates that (1) individuals who received RP endorsed more severe PTSD symptoms at session 6 compared to individuals who received COPE; and (2) individuals with more severe PTSD symptoms at session 6 reported more severe depressive symptoms at session 12 […]. However, substance use was not a significant mediator of the effect of the treatment group on depressive symptoms (standardized estimate: 0.013, 95% CI: -0.027 -0.053, NS; […]). Individuals in both treatments evidenced similar levels of reduction in substance use, and reduction in substance use during treatment did not influence later depressive symptoms.” Page 6
Morley,23 2016, Australia
For adults with co-occurring alcohol dependence and anxiety or depression

Comparison between ICBT with UC with respect to various outcomes		“For the main efficacy drinking outcomes, there was support for integrated care to be more effective than usual care for most measures of alcohol consumption.” Page 407

“There was little support for the hypothesis that integrated care would result in significantly greater improvements in anxiety and depression levels relative to usual care.” Page 407
Outcome measureEffect, mean ± SDP value
ICBT (n = 21)UC (n =16)
Primary outcomes
-Days abstinent (%)80.69 ± 10.7849.97 ± 11.00< 0.05
-Drinks per drinking day6.17 ± 1.587.12 ± 1.58NR
-Heavy drinking days (%)12.39 ± 7.2422.10 ± 8.50NR
-Days until lapse post 21 day stabilization period42.75 ± 10.067.80 ± 2.16< 0.01
-Days until relapse post 21 day stabilization period46.50 ± 10.8814.20 ± 8.38< 0.05
Secondary outcomes
-ADS11.82 ± 3.0712.28 ± 3.07NR
-DASS-21 depression16.83 ± 4.018.63 ± 4.17NR
-DASS-21 anxiety8.83 ± 1.818.00 ± 1.89NR
-DASS-21 stress15.00 ± 2.7614.36 ± 2.86NR
-OCDS obsessive6.45 ± 1.455.40 ± 1.52NR
-OCDS compulsive11.91 ± 2.1011.10 ± 2.20NR
Ruglass,24 2017, USA
For adults with co-occurring PTSD and SUD

Comparison of COPE, RPT and AMCG with respect to various outcome measures		“COPE and RPT reduced PTSD and SUD severity in participants with PTSD + SUD. Findings suggest that among those with full PTSD, COPE improves PTSD symptoms more than a SUD-only treatment. The use of PE for PTSD was associated with significant decreases in PTSD symptoms without worsening of substance use.” Page 150
Outcome measureTime pointEffect, mean (SD
COPE (n= 39)RPT (n = 43)AMCG (n = 28)
Self-reported measures
MPSS-SR (past 7 days of PTSD severity)Baseline54.26 (24.60) (n = 39)57.49 (24.33) (n = 43)50.21 (23.58) (n = 28)
End-of- treatmenta19.40 (17.70) (n = 10)26.80 (20.87) (n = 10)40.00 (28.10) (n = 19)
SUI (past 7 days of primary substance use)Baseline3.90 (2.69) (n = 39)4.05 (2.35) (n = 43)3.79 (2.27) (n = 28)
End-of- treatmenta1.60 (2.46) (n = 10)0.40 (0.52) (n = 102.85 (2.48) (n = 20)
Clinician administered measures
CAPS (past 30 days of PTSD severity)Baseline55.38 (16.40) (n = 39)57.70 (20.80) (n = 43)46.39 (11.07) (n = 28)
Post-treatmentb37.63 (23.76) (n = 19)30.79 (27.54) (n = 24)41.89 (24.52) (n = 18)
1-month FU29.50 (27.88) (n = 20)29.00 (22.99) (n = 29)NA
2-month FU29.77 (26.14) (n = 22)30.40 (22.83) (n = 25)NA
3-month FU28.40 (23.09) (n = 25)28.91 (22.91) (n = 23)NA
ASI (past 30 days of primary substance use)Baseline18.23 (10.55) (n = 39)18.16 (10.31) (n = 42)21.79 (8.36) (n = 28)
Post-treatmentb11.60 (10.30) (n = 20)4.21 (6.47) (n = 24)13.74 (9.74 (n = 19)
1-month FU8.65 (11.34) (n = 20)3.45 (5.64) (n = 29)NA
2-month FU10.82 (11.85) (n = 22)4.21 (7.33) (n = 24)NA
3-month FU8.08 (9.95) (n = 26)3.88 (7.38 (n = 24)NA
Primary substance use:
Compared to baseline values, both COPE and RPT showed significantly greater decrease in primary substance use at both 1-month follow-up and 3-month follow-up (P <0.001 in all comparisons). There was no evidence of differential treatment effects based on the lack of a group-by-time interaction and the lack of between group differences in primary substance use at follow-ups.
Abstinence rates:
Time pointAbstinence rate
COPERPTAMCG
End-of-treatment (past 7 days)12.8%14%14.3%
3-month follow-up (past 30 days)20.5%27.9%NR
Findings according to baseline PTSD diagnostic status (full or subthreshold):
Regardless of PTSD status, both COPE and RPT showed significantly greater decrease in MPSS-SR scores compared with AMCG.
For patients with full PTSD status, COPE showed significantly greater decrease in MPSS-SR scores compared with RPT, mean difference (-21.32 and 95% CI, -42.37 to -o.28, P = 0.047). For patients with subthreshold PTSD status, comparison between COPE and RPT showed no statistically significant between group difference in MPSS-SR scores.
Worden,15 2017, USA
For adults with co-occurring SUD and anxiety disorders

Comparison of (AS+TAU) versus TAU alone with respect to various outcomes Anxiety sensitivity index: Both groups improved significantly over time, however at post-treatment, greater improvement was found in the (AS+ TAU) group than in the control (TAU alone) group; P =0.001; between group difference (Cohen’s d = 1.01). The difference between the groups, however was no longer statistically significant at 3-months follow up (P = 0.74; between group difference Cohen’s d = -0.23).

Timeline Follow Back (TLFB): Both the (AS+TAU) and TAU groups improved significantly over time with respect to percent days abstinent (PDA) on the TLFB. In both groups, the overall differences between baseline and post-treatment and between baseline and follow-up were statistically significant (P < 0.0001 and P = 0.01, respectively). However, there was no significant difference between the two groups at any of the time points; between group Cohen’s d -0.22 at post treatment and 0.27 at 3-months follow-up.

DASS anxiety subscale score: Both the (AS+TAU) and TAU groups improved significantly over time with respect to DASS anxiety scores. In both groups, the overall differences between baseline and post-treatment and between baseline and follow-up were statistically significant (P = 0.0003 and P = 0.003, respectively). However, there was no significant difference between the two groups at any of the time points; between group Cohen’s d 0.14 at post treatment and 0.26 at 3-months follow-up.		“Results suggest that the ninehour AS-focused intervention led to a short-term benefit over TAU alone, but this benefit was not sustained at three months’ follow-up. Future AS interventions may need to target specific subconstructs of AS for selected populations, or target emotional distress tolerance more broadly.” Page 1

(AS = anxiety sensitivity)
Controlled clinical trial
Wolff,14 2015, USA
For adults (incarcerated men) with co-morbid PTSD and addiction problems

“Overall, study results modestly support the effectiveness of SS and M-TREM for incarcerated males. In terms of absolute effectiveness (waitlist comparison), participants receiving integrated treatment (SS or M-TREM) showed statistically and clinically significant improvement in PTSD symptom severity over time, although the difference in improvements was not statistically significant compared to the waitlist group (controlling for baseline differences) and the effect size was small.” Page 16

On disaggregating the treatment types, it was found that SS outperformed no treatment with respect to three outcomes: mental health symptoms, self-esteem, and proactive coping.

Regression analysis using hierarchical linear modelling (HLM) showed significant improvements in PTSD symptom severity over time and in mental health symptom severity as well as self-esteem, proactive coping, and self-efficacy for both SS and M-TREM, compared to no treatment. HLM regression maximizes the use of longitudinal data (increasing power) and controls for the nesting of data within individuals and groups.		“Findings cautiously support implementing either Seeking Safety or M-TREM to treat incarcerated men with co-morbid PTSD and addiction problems.” Page 1

ACT = Acceptance and Commitment Therapy; Anx-D = anxiety disorder; AUD = alcohol use disorder; ADS = alcohol dependence scale; BDI = Beck Depression Inventory; CBT = Cognitive Behavioral Therapy; CI = confidence interval; COPE = Concurrent Treatment of PTSD and Substance Use Disorder Using Prolonged Exposure; MD = mean difference; MORE = Mindfulness Oriented recovery Enhancement; NA = not applicable; NR = not reported; OCDS = obsessive-compulsive drinking scale; OEF = Operation Enduring Freedom; OIF = Operation Iraqi Freedom; OND = Operation New Dawn; PCL = PTSD Checklist; PTSD = posttraumatic stress disorder; QoL = quality of life; RP = Relapse Prevention; RR = risk ratio; SD = standard deviation; SE = standard error; SMD = standardized mean difference; SUD = substance use disorder;

a

The difference between “Thinking Forward” and TAU in rate of improvement

b

P < 0.05

There was no statistically significant difference between the groups for PHQ-9 scores at baseline, T0 (P = 0.53)

a

with respect to T0.

There was no difference between the groups for drinks per week at baseline, T0

a

with respect to T0.

There was no statistically significant difference between the groups for drinking days per week at baseline, T0 (P = 0.43)

a

End of treatment outcomes indicate symptom levels over the last week or last month of treatment.

b

Post treatment interviews were conducted 1 week after session 12 for the active treatment groups and during the 12 week visit for the control group (AMCG).

Appendix 5. Summary of Guideline Recommendations

Table 10Recommendations

EvidenceRecommendations
Preuss,25 2017, Germany
Literature search was conducted to identify systematic reviews and RCTs. Specific details of the evidence used were not presentedRecommendations with respect to psychotherapies for co-morbid depression and alcohol use disorders:

“Psychotherapy in comorbid depression and alcohol use disorders Cognitive (behavioral) therapy (CBT) shall be offered to treat individuals with comorbid disorders to improve depressive symptoms and drinking patterns. Recommendations for other forms of psychotherapy cannot be given due to insufficient data.
GRADE B
LoE: 2b” Supplement 3

“Combination of psycho- and pharmacotherapy in comorbid depression and alcohol dependence: A combination of CBT and antidepressant medication should be offered for treatment of alcohol use disorders and (moderate to severe) depression
GRADE A
LoE: 1a” Supplement 3

“Insufficient efficacy of sole treatments of comorbid depression and alcohol dependence: If sole treatment with psychotherapy or antidepressant medication is insufficient, CBT, SSRI (antidepressants) and Naltrexon can be combined.
GRADE CCP
LoE: n. a.” Supplement 3

Recommendations with respect to psychotherapies for co-morbid anxiety and alcohol use disorders:

“Both disorders should be treated in an integrated setting. If this integrated setting is not possible, treatment approaches for both disorders should be coordinated appropriately.
GRADE CCP
LoE: n. a.” Supplement 3

“Anxiety-specific CBT shall be employed to alleviate anxiety symptoms.
GRADE A
LoE: 1a” Supplement 3

Recommendations with respect to psychotherapies for co-morbid PTSD and alcohol use disorders:

“Both disorders should be treated in an integrated setting which includes interventions for PTSD as well as alcohol use disorders.
GRADE CCP
LoE: n. a.” Supplement 3

“To alleviate PTSD symptoms, PTSD-specific CBT approaches shall be employed in comorbid individuals with alcohol use disorders.
GRADE A
LoE: 1b” Supplement 3

Stabilizing integrated CBT approaches shall be offered for comorbid PTBS and alcohol use disorder individuals.
GRADE A
LoE: 1a” Supplement 3

“Exposition-based interventions shall be offered for PTBS symptoms in comorbid individuals, if alcohol use has been reduced to a low stable level or abstinence has been achieved.
GRADE CCP
LoE: n. a.” Supplement 3

CBT = cognitive behavioral therapy; CM = contingency management; LoE = level of evidence;

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal
ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

Suggested citation:

Concurrent treatment for substance use disorder and trauma-related comorbidities: a review of clinical effectiveness and guidelines. Ottawa: CADTH; 2017 Aug. (CADTH rapid response report: summary with critical appraisal).

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Bookshelf ID: NBK525683PMID: 30226696

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