The Evidence Synthesis Program (ESP) Coordinating Center is responding to a request from the Office of Mental Health and Suicide Prevention (OMHSP) for an Evidence Brief on treatment of comorbid mental health conditions, or mental health conditions comorbid with a traumatic brain injury, substance use disorder, or chronic pain among Veterans and military Service members. Findings from this Evidence Brief will be used to inform the development of a clinical provider toolkit, as required by the Commander John Scott Hannon Veterans Mental Health Care Improvement Act (S.785 2019). The toolkit is intended to enhance clinical provider training in delivery of comprehensive care for Veterans and military Service members with comorbid conditions.

PREFACE

The VA Evidence Synthesis Program (ESP) was established in 2007 to provide timely and accurate syntheses of targeted health care topics of importance to clinicians, managers, and policymakers as they work to improve the health and health care of Veterans. These reports help:

• Develop clinical policies informed by evidence;
• Implement effective services to improve patient outcomes and to support VA clinical practice guidelines and performance measures; and
• Set the direction for future research to address gaps in clinical knowledge.

The program comprises three ESP Centers across the US and a Coordinating Center located in Portland, Oregon. Center Directors are VA clinicians and recognized leaders in the field of evidence synthesis with close ties to the AHRQ Evidence-based Practice Center Program. The Coordinating Center was created to manage program operations, ensure methodological consistency and quality of products, interface with stakeholders, and address urgent evidence needs. To ensure responsiveness to the needs of decision-makers, the program is governed by a Steering Committee composed of health system leadership and researchers. The program solicits nominations for review topics several times a year via the program website.

The present report was developed in response to a request from the Office of Mental Health and Suicide Prevention (OMHSP). The scope was further developed with input from Operational Partners (below) and the ESP Coordinating Center review team. Comments on this report are welcome and can be sent to Nicole Floyd, Deputy Director, ESP Coordinating Center at vog.av@dyolF.elociN.

ACKNOWLEDGMENTS

The ESP is grateful to the following individuals for their contributions to this project:

• Operational Partners
  Operational partners are system-level stakeholders who help ensure relevance of the review topic to the VA, contribute to the development of and approve final project scope and timeframe for completion, provide feedback on the draft report, and provide consultation on strategies for dissemination of the report to the field and relevant groups.
• Christopher Loftis, PhD, PMP
  National Director
  VA/DoD Mental Health Collaboration

EXECUTIVE SUMMARY

Psychiatric comorbidity in Veterans and military Service members with a mental health condition, substance use disorder (SUD), traumatic brain injury (TBI), or chronic pain is widespread and is generally associated with a more severe clinical profile, increased clinical complexity, and worse outcomes. Further, therapeutic efficacy may differ with the presence of a comorbid condition. The impact of comorbidity on treatment outcomes is not well understood, and there is debate about the optimal treatment course of these patients. Existing research evaluating the effectiveness of treatments for a primary condition alone often either excludes individuals with comorbid diagnoses or does not measure comorbidity.

The purpose of this review is to identify and synthesize evidence related to the treatment of comorbid conditions, focusing on evidence reported in existing systematic reviews (SRs) that examines whether treatment of a primary condition is impacted by the presence or severity of comorbidities, whether treatment of patients’ primary condition leads to clinical improvement of comorbidities, and the effectiveness of integrated treatment compared to nonintegrated treatment. This review included the following combinations of conditions: adults with PTSD comorbid with anxiety, depression, bipolar disorder, TBI, SUD, or chronic pain; adults with TBI comorbid with anxiety, depression, bipolar disorder, PTSD, SUD, or chronic pain; or adults with anxiety, depression, or bipolar disorder comorbid with SUD or chronic pain.

Due to the complexity and large volume of literature, we prioritized our inclusion to recent SRs. Among 26 prioritized SRs, most were well-conducted but primary studies within the SRs often had methodological limitations, including small sample sizes and moderate-to-high risk of bias. The eligibility criteria of the included SRs did not always line up entirely with our criteria and several of the SRs included studies with populations, comparators, and outcomes not relevant to our review. We focused our synthesis on SRs reporting a synthesis of studies relevant to our criteria (Table ES-1).

Among 6 SRs examining whether response to treatment of a primary condition is impacted by the presence or severity of a comorbid condition, only 1 concluded that the presence of a comorbid condition had a negative impact on treatment outcomes. Based on data from a single study, this SR conducted a trajectory analysis and found that a baseline diagnosis of major depressive disorder (MDD) was a significant predictor of nonresponse to PTSD treatment. The remaining 5 SRs either found that the presence of a comorbid condition had no effect or that the evidence was inconsistent.

Among 11 SRs examining whether treatment of a primary condition results in improvements in a comorbid condition, 1 well-conducted SR reported that treatment with antidepressants may result in improvements in certain alcohol outcomes in individuals with comorbid depression and alcohol dependence. Evidence on other comorbid combinations was limited by inconsistent, imprecise, and/or indirect findings.

Six SRs evaluated the effectiveness of integrated treatment of 4 comorbid conditions (PTSD and SUD, PTSD and anxiety/depression, SUD and depression, and SUD and bipolar disorder). Our findings suggest that integrated cognitive-behavioral treatments for PTSD and SUD may be more effective than usual care or treatments for either condition alone. Evidence from 2 SRs on Seeking Safety was limited by inconsistent findings across time points and outcomes. Results on treatments that target the other comorbid conditions were mixed or did not indicate benefit of integrated treatments compared to usual care interventions.

Although comorbidity is widespread and may be associated with worsened outcomes, evidence captured in recent SRs on the treatment of comorbid conditions is sparse and inconsistent. Inconsistent findings across the included SRs may reflect different ways of defining and measuring comorbidity, heterogeneous study samples, and methodological variation across the SRs and their included studies. Given the absence of strong evidence from recent SRs to guide treatment of comorbid conditions, clinicians and policymakers may look to a general pattern of research findings and clinical practice guideline recommendations indicating that: 1) comorbidity should be taken into consideration in the treatment of mental health conditions, substance use, TBI, and chronic pain; and 2) concurrent treatment of comorbid conditions appears to be effective, in particular for the treatment of comorbid PTSD and SUD. There is a need for better-conducted studies on the treatment of comorbid conditions that: 1) appropriately define and measure comorbidity; 2) incorporate appropriate methodology to allow conclusions to be made about the impact of comorbidity on treatment outcomes; and 3) specifically aim to examine the treatment of comorbid conditions. Future systematic reviews of primary literature on individual condition combinations could also benefit the field.

Table ES-1

Summary of Findings.

INTRODUCTION

METHODS

RESULTS

LITERATURE FLOW

The literature flow diagram (Figure 1) summarizes the results of the study selection process (full list of excluded studies available in Appendix C in Supplemental Materials).

Figure 1

Literature Flowchart. Note. Included articles consist of 26 studies in 28 publications. Abbreviations. CDSR=Cochrane Database of Systematic Reviews; SR=systematic review.

LITERATURE OVERVIEW

Our search identified 462 potentially relevant articles. We included 26 SRs in 28 publications. Five SRs met our inclusion criteria but did not synthesize results of the relevant studies, either quantitatively or qualitatively,^42–46 and are not discussed in the detailed synthesis for each KQ.

Eligibility criteria of the 26 SRs are summarized in Table 1 (see Appendix D in Supplemental Materials for full study details). Twelve SRs reviewed evidence related to KQ1,^{33,37,44–53} 16 reviewed evidence related to KQ2,^{37,43,44,50–52,54–63}, and 10 reviewed evidence related to KQ3. Sixteen SRs reviewed evidence on SUDs,^{37,42–44,47,51,54–57,59,61,62,64–66} 15 reviewed evidence on depression,^{33,42,43,49,53–59,61,63,65,66} 13 reviewed evidence on PTSD,^{33,37,42,44,46,48,50–52,59,62,64,67} 7 (in 8 publications) reviewed evidence on anxiety,^{42,45,50,53,56,58,64,66} 5 reviewed evidence on chronic pain,^{43,49,53,60,63} 4 reviewed evidence on TBI,^50,52,60,64 and a single SR reviewed evidence on bipolar disorder.⁴⁷ Figure 2 shows the quantity of SRs included for each potential combination of comorbid conditions by each KQ. We found the largest volume of evidence (5 reviews each) for PTSD comorbid with SUD and for SUD comorbid with depression relevant to KQ2, and for the PTSD and SUD comparison applicable to KQ3. No evidence was identified for the combinations of PTSD and bipolar disorder, PTSD and chronic pain, TBI and bipolar disorder, chronic pain and anxiety, and chronic pain and bipolar disorder.

Most SRs focused on psychosocial interventions (13 SRs in 14 publications),^{33,42–45,47,48,55,58,61,62,65–67} while a smaller number focused on pharmacological interventions (5 SRs)^37,49,54,56 or multiple treatment types (5 SRs in 6 publications).^{50–53,60,64} There was 1 SR each evaluating the effectiveness of deep transcranial magnetic stimulation,⁵⁷ hyperbaric oxygen therapy,⁴⁶ and acupuncture.⁶³ One SR was specifically focused on Veterans and military Service members,⁶⁰ and there were 2 SRs where all relevant studies were conducted with Veterans and/or military Service members.^46,52 Other SRs included some relevant studies with Veteran and/or military Service member samples.^37,51,62,67

Most SRs were rated as low (n = 13) or unclear (n = 7) risk of bias, and 15 SRs included only RCTs or controlled clinical trials. Reviews rated as unclear risk of bias were commonly limited by unclear eligibility criteria and insufficient information on study selection, data abstraction, and/or risk of bias assessment. Reviews rated as high risk of bias were further limited by insufficient efforts to identify studies, inadequate methods of data abstraction and risk of bias assessment, and failure to discuss individual studies’ risk of bias when interpreting results. A range of tools was used to assess study quality and/or risk of bias across the SRs. Generally, the SRs reported some methodological concerns for most of the primary studies, and 2 SRs excluded studies rated as high risk of bias.^33,58

Figure 2

Availability of Evidence from Included Systematic Reviews. Note. Figure represents distribution and quantity of available evidence according to the comorbid pairings examined in this report and does not reflect strength of evidence ratings for each pairing. (more...)

Table 1

Eligibility Criteria of Prioritized Systematic Reviews.

DISCUSSION

This review synthesizes recent evidence from SRs on the impact of psychiatric comorbidities on patient care and the treatment of comorbid conditions. Six SRs synthesized evidence related to whether response to treatment of a primary condition is impacted by the presence or severity of a comorbid condition.^{33,48–50,52,53} These SRs reviewed evidence for 3 combinations of conditions: PTSD and depression, PTSD and TBI, and chronic pain and depression. Only 1 SR⁴⁸ concluded that the presence of a comorbid condition had a negative impact on treatment outcomes. Based on data from a single study, this SR found that a baseline diagnosis of MDD significantly predicted nonresponse to PTSD treatment. Though the other SRs did not find that the presence of a comorbid condition impacts response to treatment, the number of relevant studies identified by these SRs was small, and the evidence was inconsistent.

There was mixed evidence from SRs that treatment of a primary condition leads to clinical improvement of comorbidities. For SRs that evaluated PTSD comorbid with another condition (depression, anxiety, or SUD), only comorbid depression appeared to improve as a result of PTSD treatment. This evidence is limited by indirect and imprecise information from a single SR that included studies of trauma-focused psychotherapy for PTSD. One well-conducted SR on comorbid depression and SUD found that treatment with antidepressants resulted in improvements in certain alcohol outcomes. This finding was not replicated in other SRs evaluating the effect of psychosocial depression treatments on SUD outcomes. Findings from 1 SR suggest that treatment of chronic pain with acupuncture may also result in improvements in depression outcomes, although the included studies were rated as low quality.

The included SRs evaluated integrated treatments for 4 comorbid conditions (PTSD and SUD, SUD and anxiety/depression, SUD and depression, and SUD and bipolar disorder). Our findings suggest that integrated treatments for PTSD/SUD may be more effective than usual care or treatments for either condition alone. There was evidence from 1 SR that integrated cognitive-behavioral interventions were associated with greater improvements in substance use outcomes compared to usual care and single-condition interventions. Evidence from 2 SRs on Seeking Safety was inconsistent across different outcomes and time-points. Results on treatments that target the other comorbid conditions were mixed or did not indicate benefit of integrated treatments compared to usual care interventions.

Of note, multiple recently published trials of COPE with Veterans^68–70 were not included in an SR, including 1 which compared COPE to Seeking Safety.⁷⁰ A literature review that included these trials concluded that COPE is effective for comorbid PTSD and SUD and may be more effective than Seeking Safety for PTSD outcomes.⁹ However, this review did not perform risk of bias assessment and thus did not meet our criteria for inclusion. Additionally, SMART-CPT, a new treatment for comorbid PTSD and history of TBI that integrates components of compensatory cognitive training from the Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) program into cognitive processing therapy (CPT) for PTSD, was evaluated in a recent trial with Veterans.⁷¹ This trial was identified by 1 of our prioritized SRs,⁵² but the trial results are not synthesized by that SR and therefore are not included in our synthesis. This trial found that SMART-CPT resulted in equivalent reductions in PTSD symptoms and greater improvements to cognitive functioning compared to CPT alone.

Inconsistent findings across the included evidence may reflect different ways of defining and measuring comorbidity, heterogeneous study samples, and methodological variation across the SRs and their included studies. Moreover, there was considerable variability across the SRs with respect to their diagnostic requirements for study eligibility. Some SRs only included studies where all participants met full diagnostic criteria for 2 conditions, while others included studies that defined comorbidity in a variety of ways, such as individuals with elevated symptoms on self-report scales or those in treatment. Differences in diagnostic requirements may lead to different conclusions and may affect the ability to generalize results to a truly comorbid population. For example, an SR examining the effect of comorbid depression on PTSD outcomes in trauma-focused psychotherapy found no association between depression and PTSD treatment response when looking at the proportion of the sample meeting a depressive disorder diagnosis, but found that greater pre-treatment depression scores, measured continuously, were associated with attenuated PTSD symptom change.³³ This highlights the importance of defining and measuring comorbidity consistently.

In addition to differences in diagnostic requirements, there was considerable heterogeneity among studies included in SRs in study samples, experimental interventions and comparators, and outcome measurement, making comparison across studies difficult. Strength of evidence was rated as low to insufficient across all but 1 outcome for this review. This is not surprising given that few methodologically rigorous studies have been designed and conducted to explicitly evaluate the Key Questions. As such, our conclusions, and those of the included SRs, generally rely on indirect, imprecise, and inconsistent information. However, they do provide an overview of knowledge on treatment of comorbid conditions.

Despite the absence of strong evidence from recent SRs to guide treatment of comorbid conditions, there is an emerging pattern of research findings and clinical practice guideline recommendations indicating that: 1) comorbidity should be taken into consideration in the treatment of mental health conditions, substance use, TBI, and chronic pain; and 2) concurrent treatment of comorbid conditions appears to be effective, in particular for the treatment of comorbid PTSD and SUD.³⁵ Current Veterans Affairs/Department of Defense (VA/DoD) clinical practice guidelines (CPGs) advise that comorbid conditions can modify treatment priorities, selection of interventions, and care setting.⁷² The 2017 VA/DoD CPG for the management of PTSD recommends that the presence of co-occurring disorders should not prevent patients from receiving VA/DoD guideline-recommended treatments for PTSD and recommends VA/DoD guideline-based treatments for PTSD in the presence of co-occurring SUD.⁷² The 2021 VA/DoD CPG for the treatment of SUD also states that use of a substance should not automatically preclude treatment for a co-occurring condition, and recommends providers address comorbid conditions concurrently with PTSD symptoms.⁷³ Moreover, recognition by clinicians that individuals with comorbid conditions have unique treatment needs has led to increased interest in fully integrated treatment, as evidenced by recent randomized clinical trials of novel treatment approaches that incorporate evidence-based components targeting multiple comorbid conditions and that can be delivered by a single provider (eg, COPE and SMART-CPT).⁷⁴

REFERENCES

1.

Commander John Scott Hannon Veterans Mental Health Care Improvement Act of 2019, S.785 — 116th Congress (2019–2020), (2020).

2.

Feinstein AR. The pre-therapeutic classification of co-morbidity in chronic disease. Journal of chronic diseases. 1970;23(7):455–468. [PubMed: 26309916]

3.

Bosco MA, Gallinati JL, Clark ME. Conceptualizing and treating comorbid chronic pain and PTSD. Pain research and treatment. 2013;2013. [PMC free article: PMC3684116] [PubMed: 23819047]

4.

CDC. Health Status Of Vietnam Veterans: Volume Iv -Psychological And Neuropsychological Evaluation. Centers for Disease Control;1998.

5.

Lew HL, Otis JD, Tun C, Kerns RD, Clark ME, Cifu DX. Prevalence of chronic pain, posttraumatic stress disorder, and persistent postconcussive symptoms in OIF/OEF veterans: polytrauma clinical triad. Journal of Rehabilitation Research & Development. 2009;46(6). [PubMed: 20104399]

6.

Marmar CR, Schlenger W, Henn-Haase C, et al. Course of posttraumatic stress disorder 40 years after the Vietnam War: Findings from the National Vietnam Veterans Longitudinal Study. JAMA Psychiatry. 2015;72(9):875–881. [PubMed: 26201054]

7.

Richardson JD, Ketcheson F, King L, et al. Psychiatric comorbidity pattern in treatment-seeking veterans. Psychiatry Res. 2017;258:488–493. [PubMed: 28899613]

8.

Yurgil KA, Barkauskas DA, Vasterling JJ, et al. Association between traumatic brain injury and risk of posttraumatic stress disorder in active-duty Marines. JAMA Psychiatry. 2014;71(2):149–157. [PubMed: 24337530]

9.

Pedersen ER, Bouskill KE, Holliday SB, et al. Improving Substance Use Care: Addressing Barriers to Expanding Integrated Treatment Options for Post-9/11 Veterans. Santa Monica, CA: RAND Corporation; 2020.

10.

Drag LL, Spencer RJ, Walker SJ, Pangilinan PH, Bieliauskas LA. The Contributions of Self-reported Injury Characteristics and Psychiatric Symptoms to Cognitive Functioning in OEF/OIF Veterans with Mild Traumatic Brain Injury. J Int Neuropsychol Soc. 2012;18(3):576–584. [PubMed: 22390876]

11.

Hefner K, Rosenheck R. Multimorbidity among Veterans diagnosed with PTSD in the Veterans Health Administration nationally. Psychiatric Quarterly. 2019;90(2):275–291. [PubMed: 30847694]

12.

Nichter B, Norman S, Haller M, Pietrzak RH. Psychological burden of PTSD, depression, and their comorbidity in the US veteran population: suicidality, functioning, and service utilization. J Affect Disord. 2019;256:633–640. [PubMed: 31299445]

13.

Outcalt SD, Kroenke K, Krebs EE, et al. Chronic pain and comorbid mental health conditions: independent associations of posttraumatic stress disorder and depression with pain, disability, and quality of life. Journal of Behavioral Medicine. 2015;38(3):535–543. [PubMed: 25786741]

14.

Schneiderman AI, Braver ER, Kang HK. Understanding sequelae of injury mechanisms and mild traumatic brain injury incurred during the conflicts in Iraq and Afghanistan: persistent postconcussive symptoms and posttraumatic stress disorder. American Journal of Epidemiology. 2008;167(12):1446–1452. [PubMed: 18424429]

15.

Arnow BA, Hunkeler EM, Blasey CM, et al. Comorbid depression, chronic pain, and disability in primary care. Psychosom Med. 2006;68(2):262–268. [PubMed: 16554392]

16.

Bedard-Gilligan M, Duax Jakob JM, Doane LS, et al. An investigation of depression, trauma history, and symptom severity in individuals enrolled in a treatment trial for chronic PTSD. J Clin Psychol. 2015;71(7):725–740. [PMC free article: PMC4461449] [PubMed: 25900026]

17.

Blanco C, Xu Y, Brady K, Pérez-Fuentes G, Okuda M, Wang S. Comorbidity of posttraumatic stress disorder with alcohol dependence among US adults: Results from National Epidemiological Survey on Alcohol and Related Conditions. Drug and Alcohol Dependence. 2013;132(3):630–638. [PMC free article: PMC3770804] [PubMed: 23702490]

18.

Drapkin ML, Yusko D, Yasinski C, Oslin D, Hembree EA, Foa EB. Baseline functioning among individuals with posttraumatic stress disorder and alcohol dependence. J Subst Abuse Treat. 2011;41(2):186–192. [PMC free article: PMC3144264] [PubMed: 21546205]

19.

Ouimette P, Goodwin E, Brown PJ. Health and well being of substance use disorder patients with and without posttraumatic stress disorder. Addict Behav. 2006;31(8):1415–1423. [PubMed: 16380217]

20.

Saladin ME, Brady KT, Dansky BS, Kilpatrick DG. Understanding comorbidity between PTSD and substance use disorders: Two preliminary investigations. Addict Behav. 1995;20(5):643–655. [PubMed: 8712061]

21.

Schäfer I, Najavits LM. Clinical challenges in the treatment of patients with posttraumatic stress disorder and substance abuse. Curr Opin Psychiatry. 2007;20(6):614–618. [PubMed: 17921765]

22.

Steinert C, Hofmann M, Leichsenring F, Kruse J. The course of PTSD in naturalistic long-term studies: high variability of outcomes. A systematic review. Nord J Psychiatry. 2015;69(7):483–496. [PubMed: 25733025]

23.

Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7(4):357–363. [PMC free article: PMC2713155] [PubMed: 19597174]

24.

Krawczyk N, Feder KA, Saloner B, Crum RM, Kealhofer M, Mojtabai R. The association of psychiatric comorbidity with treatment completion among clients admitted to substance use treatment programs in a U.S. national sample. Drug and Alcohol Dependence. 2017;175:157–163. [PMC free article: PMC5490486] [PubMed: 28432939]

25.

Hunter G, Yoon J, Blonigen DM, Asch SM, Zulman DM. Health care utilization patterns among high-cost VA patients with mental health conditions. Psychiatr Serv. 2015;66(9):952–958. [PubMed: 25930040]

26.

Yu W, Ravelo A, Wagner TH, et al. Prevalence and costs of chronic conditions in the VA health care system. Medical Care Research and Review. 2003;60(3_suppl):146S–167S. [PubMed: 15095551]

27.

Mills KL, Lynskey M, Teesson M, Ross J, Darke S. Post-traumatic stress disorder among people with heroin dependence in the Australian treatment outcome study (ATOS): prevalence and correlates. Drug and Alcohol Dependence. 2005;77(3):243–249. [PubMed: 15734224]

28.

Read JP, Brown PJ, Kahler CW. Substance use and posttraumatic stress disorders: Symptom interplay and effects on outcome. Addict Behav. 2004;29(8):1665–1672. [PubMed: 15451135]

29.

VA/DoD. VA/DoD Clinical Practice Guidelines. https://www​.healthquality​.va.gov/guidelines/. Published 2021. Accessed 09/21/21, 2021.

30.

Clarkin JF, Kendall PC. Comorbidity and treatment planning: summary and future directions. 1992. [PubMed: 1460151]

31.

Angelakis S, Nixon RD. The comorbidity of PTSD and MDD: Implications for clinical practice and future research. Behaviour Change. 2015;32(1):1–25.

32.

Flory JD, Yehuda R. Comorbidity between post-traumatic stress disorder and major depressive disorder: alternative explanations and treatment considerations. Dialogues in clinical neuroscience. 2015;17(2):141. [PMC free article: PMC4518698] [PubMed: 26246789]

33.

Kline AC, Cooper AA, Rytwinski NK, Feeny NC. The Effect of Concurrent Depression on PTSD Outcomes in Trauma-Focused Psychotherapy: A Meta-Analysis of Randomized Controlled Trials. Behav. 2021;52(1):250–266. [PMC free article: PMC7826446] [PubMed: 33483121]

34.

Cook JM, Dinnen S, Simiola V, Thompson R, Schnurr PP. VA residential provider perceptions of dissuading factors to the use of two evidence-based PTSD treatments. Professional Psychology: Research and Practice. 2014;45(2):136. [PMC free article: PMC4193802] [PubMed: 25309031]

35.

Norman SB, Hamblen JL. Promising directions for treating comorbid PTSD and substance use disorder. 2017. [PubMed: 28181264]

36.

Capehart B, Bass D. Managing posttraumatic stress disorder in combat veterans with comorbid traumatic brain injury. Journal of Rehabilitation Research & Development. 2012;49(5). [PubMed: 23015586]

37.

Petrakis IL, Simpson TL. Posttraumatic Stress Disorder and Alcohol Use Disorder: A Critical Review of Pharmacologic Treatments. Alcohol Clin Exp Res. 2017;41(2):226–237. [PMC free article: PMC5375032] [PubMed: 28102573]

38.

Petrillo LA, Ritchie CS. The challenges of symptom management for patients with multimorbidity in research and practice: a thematic review. Progress in palliative care. 2016;24(5):262–267. [PMC free article: PMC5613670] [PubMed: 28959091]

39.

Robinson KA, Brunnhuber K, Ciliska D, et al. Evidence-Based Research Series-Paper 1: What Evidence-Based Research is and why is it important? J Clin Epidemiol. 2021;129:151–157. [PubMed: 32979491]

40.

Whiting P, Savović J, Higgins JP, et al. ROBIS: a new tool to assess risk of bias in systematic reviews was developed. J Clin Epidemiol. 2016;69:225–234. [PMC free article: PMC4687950] [PubMed: 26092286]

41.

Berkman ND, Lohr KN, Ansari MT, et al. Grading the strength of a body of evidence when assessing health care interventions: an EPC update. J Clin Epidemiol. 2015;68(11):1312–1324. [PubMed: 25721570]

42.

Banerjee S SC. Concurrent treatment for substance use disorder and trauma-related comorbidities: A review of clinical effectiveness and guidelines. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. 2017. [PubMed: 30226696]

43.

Barrett K, Chang YP. Behavioral Interventions Targeting Chronic Pain, Depression, and Substance Use Disorder in Primary Care. J Nurs Scholarsh. 2016;48(4):345–353. [PubMed: 27149578]

44.

Meshberg-Cohen S, Ross MacLean R, Schnakenberg Martin AM, Sofuoglu M, Petrakis IL. Treatment outcomes in individuals diagnosed with comorbid opioid use disorder and Posttraumatic stress disorder: A review. Addict Behav. 2021;122:107026. [PubMed: 34182307]

45.

Oliveira LM, Bermudez MB, Macedo MJA, Passos IC. Comorbid social anxiety disorder in patients with alcohol use disorder: A systematic review. J Psychiatr Res. 2018;106:8–14. [PubMed: 30236640]

46.

Parr NJ, Anderson J, Veazie S. Evidence brief: Hyperbaric oxygen therapy for traumatic brain injury and/or post-traumatic stress disorder. Washington DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. 2021(#09-199).

47.

Crowe M, Eggleston K, Douglas K, Porter RJ. Effects of psychotherapy on comorbid bipolar disorder and substance use disorder: A systematic review. Bipolar Disord. 2021;23(2):141–151. [PubMed: 32615028]

48.

Dewar M, Paradis A, Fortin CA. Identifying Trajectories and Predictors of Response to Psychotherapy for Post-Traumatic Stress Disorder in Adults: A Systematic Review of Literature. Can J Psychiatry. 2020;65(2):71–86. [PMC free article: PMC6997973] [PubMed: 31535576]

49.

Forte ML, Butler M, Andrade KE, Vincent A, Schousboe JT, Kane RL. Treatments for Fibromyalgia in Adult Subgroups. Agency for Healthcare Research and Quality (US). 2015:01. [PubMed: 25719189]

50.

Greer N, Ackland R, Sayer N, et al. Relationship of deployment-related mild traumatic brain injury to posttraumatic stress disorder, depressive disorders, substance use disorders, suicidal ideation, and anxiety disorders: A systematic review. Washington DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. 2019(#09-009). [PubMed: 31116544]

51.

Hoffman V, Middleton JC, Feltner C, et al. Psychological and pharmacological treatments for adults with posttraumatic stress disorder: A systematic review update. Agency for Healthcare Research and Quality (US). 2018;Comparative Effectiveness Review No. 207(Publication No. 18-EHC011). [PubMed: 30204376]

52.

Mikolic A, Polinder S, Retel Helmrich IRA, Haagsma JA, Cnossen MC. Treatment for posttraumatic stress disorder in patients with a history of traumatic brain injury: A systematic review. Clin Psychol Rev. 2019;73:101776. [PubMed: 31707182]

53.

Skelly AC, Chou R, Dettori JR, et al. Noninvasive nonpharmalogical treatment for chronic pain: A systematic review update. Agency for Healthcare Research and Quality (US). 2020(Publication No. 20-EHC009). [PubMed: 32338846]

54.

Agabio R, Trogu E, Pani PP. Antidepressants for the treatment of people with co-occurring depression and alcohol dependence. Cochrane Database Syst Rev. 2018;4:CD008581. [PMC free article: PMC6494437] [PubMed: 29688573]

55.

Hides L, Quinn C, Stoyanov S, Kavanagh D, Baker A. Psychological interventions for co-occurring depression and substance use disorders. Cochrane Database Syst Rev. 2019;11(11):26. [PMC free article: PMC6953216] [PubMed: 31769015]

56.

Ipser JC, Wilson D, Akindipe TO, Sager C, Stein DJ. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev. 2015;1:CD007505. [PMC free article: PMC8931612] [PubMed: 25601826]

57.

Kedzior KK, Gerkensmeier I, Schuchinsky M. Can deep transcranial magnetic stimulation (DTMS) be used to treat substance use disorders (SUD)? A systematic review. BMC Psychiatry. 2018;18(1):137. [PMC free article: PMC5960210] [PubMed: 29776355]

58.

Larsen SE, Bellmore A, Gobin RL, Holens P, Lawrence KA, Pacella-LaBarbara ML. An initial review of residual symptoms after empirically supported trauma-focused cognitive behavioral psychological treatment. J Anxiety Disord. 2019;63:26–35. [PubMed: 30825720]

59.

Li J, Wang H, Li M, et al. Efficacy of pharmacotherapeutics for patients comorbid with alcohol use disorders and depressive symptoms-A bayesian network meta-analysis. CNS Neurosci Ther. 2020;26(11):1185–1197. [PMC free article: PMC7564195] [PubMed: 32686291]

60.

O’Neil ME, Carlson KF, Holmer HK, et al. Chronic Pain in Veterans and Servicemembers with a History of Mild Traumatic Brain Injury: A Systematic Review. Department of Veterans Affairs (US). 2020;08:08. [PubMed: 33400450]

61.

Pott SL, Delgadillo J, Kellett S. Is behavioral activation an effective and acceptable treatment for co-occurring depression and substance use disorders? A meta-analysis of randomized controlled trials. J Subst Abuse Treat. 2021;132:108478. [PubMed: 34146994]

62.

Roberts NP, Roberts PA, Jones N, Bisson JI. Psychological therapies for post-traumatic stress disorder and comorbid substance use disorder. Cochrane Database Syst Rev. 2016;4:CD010204. [PMC free article: PMC8782594] [PubMed: 27040448]

63.

Yan B, Zhu S, Wang Y, Da G, Tian G. Effect of Acupuncture on Chronic Pain with Depression: A Systematic Review. Evid Based Complement Alternat Med. 2020;2020:7479459. [PMC free article: PMC7334776] [PubMed: 32714417]

64.

Ackland PE, Greer N, Sayer NA, et al. Effectiveness and harms of mental health treatments in service members and veterans with deployment-related mild traumatic brain injury. J Affect Disord. 2019;252:493–501. [PubMed: 31028994]

65.

Hobden B, Bryant J, Carey M, et al. Finding the optimal treatment model: A systematic review of treatment for co-occurring alcohol misuse and depression. Aust N Z J Psychiatry. 2018;52(8):737–750. [PubMed: 29466868]

66.

Mehta K, Hoadley A, Ray LA, Kiluk BD, Carroll KM, Magill M. Cognitive-Behavioral Interventions Targeting Alcohol or Other Drug Use and Co-Occurring Mental Health Disorders: A Meta-Analysis. Alcohol Alcohol. 2021;29:29. [PMC free article: PMC8406071] [PubMed: 33778869]

67.

Roberts NP, Roberts PA, Jones N, Bisson JI. Psychological interventions for post-traumatic stress disorder and comorbid substance use disorder: A systematic review and meta-analysis. Clin Psychol Rev. 2015;38:25–38. [PubMed: 25792193]

68.

Back SE, Killeen T, Badour CL, et al. Concurrent treatment of substance use disorders and PTSD using prolonged exposure: A randomized clinical trial in military veterans. Addict Behav. 2019;90:369–377. [PMC free article: PMC6488423] [PubMed: 30529244]

69.

Lancaster CL, Gros DF, Mullarkey MC, et al. Does trauma-focused exposure therapy exacerbate symptoms among patients with comorbid PTSD and substance use disorders? Behavioural and Cognitive Psychotherapy. 2020;48(1):38–53. [PMC free article: PMC6832765] [PubMed: 31010449]

70.

Norman SB, Trim R, Haller M, et al. Efficacy of integrated exposure therapy vs integrated coping skills therapy for comorbid posttraumatic stress disorder and alcohol use disorder: A randomized clinical trial. JAMA Psychiatry. 2019;76(8):791–799. [PMC free article: PMC6487906] [PubMed: 31017639]

71.

Jak AJ, Jurick S, Crocker LD, et al. SMART-CPT for veterans with comorbid post-traumatic stress disorder and history of traumatic brain injury: a randomised controlled trial. J Neurol Neurosurg Psychiatry. 2019;90(3):333–341. [PubMed: 30554135]

72.

VA/DoD. VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. Washington, DC: Department of Veteran Affairs, Department of Defense;2017.

73.

VA/DoD. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Washington, DC: Department of Veteran Affairs, Department of Defense;2021.

74.

Simpson TL, Lehavot K, Petrakis IL. No Wrong Doors: Findings from a Critical Review of Behavioral Randomized Clinical Trials for Individuals with Co-Occurring Alcohol/Drug Problems and Posttraumatic Stress Disorder. Alcohol Clin Exp Res. 2017;41(4):681–702. [PubMed: 28055143]

75.

DeRubeis RJ, Gelfand LA, German RE, Fournier JC, Forand NR. Understanding processes of change: How some patients reveal more than others—and some groups of therapists less—about what matters in psychotherapy. Psychother. 2014;24(3):419–428. [PMC free article: PMC4210369] [PubMed: 24219275]

76.

Van Bavel JJ, Mende-Siedlecki P, Brady WJ, Reinero DA. Contextual sensitivity in scientific reproducibility. Proceedings of the National Academy of Sciences. 2016;113(23):6454–6459. [PMC free article: PMC4988618] [PubMed: 27217556]

77.

Vujanovic AA, Meyer TD, Heads AM, Stotts AL, Villarreal YR, Schmitz JM. Cognitive-behavioral therapies for depression and substance use disorders: An overview of traditional, third-wave, and transdiagnostic approaches. American Journal of Drug and Alcohol Abuse. 2017;43(4):402–415. [PubMed: 27494547]

78.

Bisson JI, Roberts NP, Andrew M, Cooper R, Lewis C. Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults. Cochrane Database Syst Rev. 2013(12). [PMC free article: PMC6991463] [PubMed: 24338345]

Supplemental Materials

Suggested citation:

Beech EH, Rahman B, Ward R, Anderson J, Belsher BE, Parr NJ. Evidence Brief: Treatment of Comorbid Conditions. Washington, DC: Evidence Synthesis Program, Health Services Research and Development Service, Office of Research and Development, Department of Veterans Affairs. VA ESP Project #09-203; 2021.

This report was prepared by the Evidence Synthesis Program Coordinating Center located at the VA Portland Health Care System, directed by Mark Helfand, MD, MPH, MS and funded by the Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development.

The findings and conclusions in this document are those of the author(s) who are responsible for its contents and do not necessarily represent the views of the Department of Veterans Affairs or the United States government. Therefore, no statement in this article should be construed as an official position of the Department of Veterans Affairs. No investigators have any affiliations or financial involvement (eg, employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in the report.