BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.

Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.

Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.

For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.

In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.

Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”

Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.

The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.

BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.

Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.

Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.

For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.

In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.

Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”

Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.

The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.

BOSTON – Veterans were about 13% less likely to die within 5 years of hepatocellular carcinoma diagnosis when multidisciplinary tumor boards managed their care than if they did not, according to a large, multicenter observational study.

Seeing a hepatologist or surgeon within 30 days of diagnosis also significantly improved 5-year overall survival, even after controlling for age, race, Charlson-Deyo comorbidity index, Barcelona Clinic Liver Cancer (BCLC) stage, academic center and geographic region of care, and the distance patients lived from the nearest Veterans Affairs transplant center, Marina Serper, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases. “More studies are needed to understand how to best use multidisciplinary tumor boards to improve the care of patients with hepatocellular carcinoma,” she said.

Outcomes data for hepatocellular carcinoma mostly come from clinical trials; transplant centers; and Surveillance, Epidemiology, and End Results-Medicare analyses, noted Dr. Serper of the University of Pennsylvania in Philadelphia.

For a better look at veterans, she and her associates combined administrative, laboratory, and death data with medical chart reviews and information from the Organ Procurement and Transplantation Network’s Standard Transplant Analysis and Research file. The initial cohort included more than 6,800 veterans whose ICD-9CM diagnosis code indicated a malignant hepatic neoplasm. Excluding patients with neoplasms such as cholangiocarcinoma and those managed outside the VA left 3,989 VA patients with hepatocellular carcinoma.

In the multivariable analysis, use of multidisciplinary tumor boards was associated with a statistically significant 13% improvement in 5-year overall survival (hazard ratio, 0.87; 95% confidence interval, 0.81-0.94; P less than .001). Improved survival also was linked with seeing certain specialists within 30 days of diagnosis, including hepatologists (HR, 0.77; P less than .001) and surgeons (HR, 0.72; P less than .001). Consulting with a hepatologist within 30 days of diagnosis, however, did not improve the chances of receiving curative therapy, such as liver transplantation, resection, local ablation, transarterial chemoembolization, or Y-90 radioembolization.

Care also varied substantially geographically and by academic affiliation, Dr. Serper noted. “Treatment of hepatocellular carcinoma is complex, as it depends as much on liver function as it does on tumor staging,” she emphasized. “Studies to improve multidisciplinary approaches for hepatocellular carcinoma in the community are needed to increase rates of curative therapy and improve clinical outcomes.”

Patients in this study averaged 62 years of age at diagnosis, 54% were white, 36% were within Milan criteria, and 45% had a Child-Turcotte-Pugh score of B or higher. Nearly 18% had macrovascular invasion at diagnosis, and 7% had metastatic disease. Nearly two-thirds of patients were BCLC stage A or B at diagnosis, and more than a third had underlying alcohol misuse and chronic hepatitis C virus infection.

The work was funded by unrestricted grants from Bayer Healthcare Pharmaceuticals and the VA’s HIV, Hepatitis and Public Health Pathogens Programs. The investigators had no relevant financial disclosures.

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

[email protected]

On Twitter @alz_gal

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

[email protected]

On Twitter @alz_gal

WASHINGTON – Certolizumab pegol is not transmitted into human breast milk in any clinically meaningful level, a postmarketing pharmacokinetic study has determined.

While there were individual differences in how much of the TNF inhibitor did cross into milk, none of the 17 women in the study transmitted more than 0.076 mcg/mL in any sample, Megan Clowse, MD, said at the annual meeting of the American College of Rheumatology.

“This is well below even 1% of the expected plasma concentration of a therapeutic dose,” said Dr. Clowse, a rheumatologist and director of the Duke Autoimmunity in Pregnancy Registry at Duke University, Durham, N.C. “Additionally, the mean relative infant dose was 0.125% – also far below the cutoff of less than 10% of the adult dose, the level generally thought to be of little concern for infant well-being.”

©Jupiterimages/Thinkstock

[email protected]

On Twitter @alz_gal

Over the past decade, nationwide attention has focused on mental health conditions associated with military service. Recent legal mandates have led to changes in the DoD, VA, and HHS health systems aimed at increasing access to care, decreasing barriers to care, and expanding research on mental health conditions commonly seen in service members and veterans. On August 31, 2012, President Barack Obama signed the Improving Access to Mental Health Services for Veterans, Service Members, and Military Families executive order, establishing an interagency task force from the VA, DoD, and HHS.¹ The task force was charged with addressing quality of care and provider training in the management of commonly comorbid conditions, including (among other conditions) posttraumatic stress disorder (PTSD) and depression.

Depression and PTSD present major health burdens in both military and veteran cohorts. Overlap in clinical presentation and significant rates of comorbidity complicate effective management of these conditions. This article offers a brief review of the diagnostic and epidemiologic complexities associated with PTSD and depression, a summary of research relevant to these issues, and a description of recent system-level developments within the Military Health System (MHS) designed to improve care through better approaches in identification, management, and research of these conditions.

Diagnostic Uncertainty

Both PTSD and major depressive disorder (MDD) have been recognized as mental health disorders since the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) discarded its previous etiologically based approach to diagnostic classification in 1980 in favor of a system in which diagnosis is based on observable symptoms.^2,3 With the release of DSM-5 in 2013, the diagnostic criteria for PTSD underwent a substantial transformation.⁴ Previously, PTSD was described as an anxiety disorder, and some of its manifestations overlapped descriptively (and in many cases, etiologically) with anxiety and depressive illnesses.⁵

Clinicians also often described shorter-lived, developmental, formes fruste, or otherwise subsyndromal manifestations of trauma associated with PTSD. In DSM-5, PTSD was removed from the anxiety disorders section and placed in a new category of disorders labeled Trauma and Stressor-Related Disorders. This new category also included reactive attachment disorder (in children), acute stress disorder, adjustment disorders, and unspecified or other trauma and stressor-related disorders. Other major changes to the PTSD diagnostic criteria included modification to the DSM-IV-TR (text revision) trauma definition (making the construct more specific), removal of the requirement for explicit subjective emotional reaction to a traumatic event, and greater emphasis on negative cognitions and mood. Debate surrounds the updated symptom criteria with critics questioning whether there is any improvement in the clinical utility of the diagnosis, especially in light of the substantial policy and practice implications the change engenders.⁶

Recently, Hoge and colleagues examined the psychometric implications of the diagnostic changes (between DSM-IV-TR and DSM-5) in the PTSD definition.⁶ The authors found that although the 2 definitions showed nearly identical association with other psychiatric disorders (including depression) and functional impairment, 30% of soldiers who met DSM-IV-TR criteria for PTSD failed to meet criteria in DSM-5, and another 20% met only DSM-5 criteria. Recognizing discordance in PTSD and associated diagnoses, the U.S. Army Medical Command mandated that its clinicians familiarize themselves with the controversies surrounding the discordant diagnoses and coding of subthreshold PTSD.⁷

Adding to the problem of diagnostic uncertainty, the clinical presentation of MDD includes significant overlap with that of PTSD. Specifically, symptoms of guilt, diminished interests, problems with concentration, and sleep disturbances are descriptive of both disorders. Furthermore, the criteria set for several subthreshold forms of MDD evidence considerable overlap with PTSD symptoms. For example, diagnostic criteria for disruptive mood dysregulation disorder include behavioral outbursts and irritability, and diagnostic criteria for dysthymia include sleep disturbances and concentration problems.

Adjustment disorders are categorized as trauma and stressor-related disorders in DSM-5 and hold many emotional and behavioral symptoms in common with PTSD. The “acute” and “chronic” adjustment disorder specifiers contribute to problems in diagnostic certainty for PTSD. In general, issues pertaining to diagnostic uncertainty and overlap likely reflect the limits of using a diagnostic classification system that relies exclusively on observational and subjective reports of psychological symptoms.^8,9

In a treatment environment where a veteran or active-duty patient has presented for care, in the face of these shared symptom sets, clinicians frequently offer initial diagnoses. These diagnoses are often based on perceived etiologic factors derived from patients’ descriptions of stressors encountered during military service. This tendency likely contributes to considerable inconsistencies and potential inaccuracies in diagnoses, and much of the variance can be attributed to the clinicians’ degree of familiarity with military exposures, perceptions of what constitutes trauma, and outside pressure to assign or avoid specific diagnoses.

Importantly, the phenomenologic differences between PTSD and depressive disorders increase the likelihood of poorly aligned and inconsistent treatment plans, and this lack of clarity may, in turn, compromise effective patient care. To address some of these diagnostic challenges, the VA and DoD incorporate military culture training into clinicians’ curriculum to increase provider familiarity with the common stressors and challenges of military life, mandate the use of validated measures to support diagnostic decision making, and regularly review policies that influence diagnostic practices.

Epidemiology

The prevalence rates for PTSD are increasing in the military, possibly stemming from the demands on service members engaged in years’ long wars. Despite the increased attention on this phenomenon, research has demonstrated that the majority of service members who deploy do not develop PTSD or significant trauma-related functional impairment.¹⁰ Furthermore, many cases of PTSD diagnosed in the MHS stem from traumatic experiences other than combat exposure, including childhood abuse and neglect, sexual and other assaults, accidents and health care exposures, domestic abuse, and bullying. Depression arguably has received less attention despite comparable prevalence rates in military populations, high co-occurrence of PTSD and depression, and depression being associated with a greater odds ratio for mortality that includes death by suicide in military service members.¹¹

Estimates of the prevalence of PTSD from the U.S. Army suggest that it exists in 3% to 6% of military members who have not deployed and in 6% to 25% of service members with combat deployment histories. The frequency and intensity of combat are strong predictors of risk.⁷ A recent epidemiologic study using inpatient and outpatient encounter records showed that the prevalence of PTSD in the active military component was 2.0% in the middle of calendar year (CY) 2010; a two-thirds increase from 1.2% in CY 2007.¹² The incidence of PTSD

Epidemiologic studies and prevalence/incidence rates derived from administrative data rely on strict case definitions. Consequently, such administrative investigations include data only from service members

PTSD and Depression Treatment

Despite the high rates of PTSD and MDD comorbidity, few treatments have been developed for and tested on an exclusively comorbid sample of patients.¹³ However, psychopharmacologic agents targeting depression have been applied to the treatment of PTSD, and PTSD psychotherapy trials typically include depression response as a secondary outcome. The generalizability of findings to a truly comorbid population may be limited based on study sampling frames and the unique characteristics of patients with comorbid PTSD and depression.^14-16 Several psychopharmacologic treatments for depression have been evaluated as frontline treatments for PTSD. The 3 pharmacologic treatments that demonstrate efficacy in treating PTSD include fluoxetine, paroxetine, and venlafaxine.¹⁷

Although these pharmacologic agents represent good candidate treatments for comorbid patients, the effect size of pharmacologic treatments are generally smaller than those of psychotherapeutic treatments for PTSD.^17,18 This observation, however, is based on indirect comparisons, and a recent systematic review concluded that the evidence was insufficient to determine the comparative effectiveness between psychotherapy and pharmacotherapy for PTSD.¹⁹ Evidence indicates that trauma-focused cognitive behavioral therapies consistently demonstrate efficacy and effectiveness in treating PTSD.^19,20 These treatments also have been shown to significantly reduce depressive symptoms among PTSD samples.²¹

Based on strong bodies of evidence, these pharmacologic and psychological treatments have received the highest level of recommendation in the VA and DoD.^22,23 Accordingly, both agencies have invested considerable resources in large-scale efforts to improve patient access to these particular treatments. Despite these impressive implementation efforts, however, the limitations of relying exclusively on these treatments as frontline approaches within large health care systems have become evident.^24-26

Penetration of Therapies

Penetration of these evidence-based treatments (EBTs) within the DoD and VHA remains limited. For instance, one study showed that VA clinicians in mental health specialty care clinics may provide only about 4 hours of EBT per week.²⁷

Other reports suggest that only about 60% of treatment-seeking patients in PTSD clinics receive any type of evidence-based therapy and that within-session care quality is questionable based on a systematic review of chart notes.^28,29 Attrition in trauma-focused therapy is a recognized limitation, with 1 out of 3 treatment-seeking patients not completing a full dose of evidence-based treatment.^30-33 Large-scale analyses of VHA and DoD utilization data suggest that the majority of PTSD patients do not receive a sufficient number of sessions to be characterized as an adequate dose of EBT, with a majority of dropouts occur- ring after just a few sessions.^34-37

Hoge and colleagues found that < 50% of soldiers meeting criteria for PTSD received any mental health care within the prior 6 months with one-quarter of those patients dropping out of care prematurely.³⁸ Among a large cohort of soldiers engaged in care for the treatment of PTSD, only about 40% received a number of EBT treatment sessions that could qualify as an adequate dose.³⁸ Thus, although major advancements in the development and implementation of effective treatments for PTSD and depression have occurred, the penetration of these treatments is limited, and the majority of patients in need of treatment potentially receive inadequate care.³⁹

System level approaches that integrate behavioral health services into the primary care system have been proposed to address these care gaps for service members and veterans.^40-42 Fundamentally, system-level approaches seek to improve the reach and effectiveness of care through large-scale screening efforts, a greater emphasis on the quality of patient care, and enhanced care continuity across episodes of treatment.

Primary Care

With the primary care setting considered the de facto mental health system, integrated approaches enhance the reach of care by incorporating uniform mental health screening and referral for patients coming through primary care. Specific evidence-based treatments can be integrated into this approach within a stepped-care framework that aims to match patients strategically to the right type of care and leverage specialty care resources as needed. Integrated care approaches for the treatment of PTSD and depression have been developed and evaluated inside and outside of the MHS. Findings indicate that integrated treatment approaches can improve care access, care continuity, patient satisfaction, quality of care,and in several trials, PTSD and depression outcomes.^43-47

Recently, an integrated care approach targeting U.S. Army soldiers who screened positive for PTSD or depression in primary care was evaluated in a multisite effectiveness trial.⁴⁸ Patients randomized to the treatment approach experienced significant improvements in both PTSD and depression symptoms relative to patients in usual care.⁴³ In addition, patients treated in this care model received significantly more mental health services; the patterns of care indicated that patients with comorbid PTSD and depression were more likely to be triaged to specialty care, whereas patients with a single diagnosis were more likely to be managed in primary care.⁴⁹ This trial suggests that integrated care models feasibly can be implemented in the U.S. Army care system, yielding increased uptake of mental health care, more efficiently matched care based on patient comorbidities, and improved PTSD and depression outcomes.

Treatment Research

The MHS supports a large portfolio of research in PTSD and depression through DoD/VA research consortia (eg, the Congressionally Directed Medical Research Program, the Consortium to Alleviate PTSD, the Injury and Traumatic Stress Clinical Consortium). The U.S. Army Medical Research and Materiel Command (USAMRMC) executes and manages the portfolio of research, relying on a joint program committee of DoD and non-DoD experts to make funding recommendations based on identified research priorities, policy guidance, and knowledge translation needs.

Health systems research on PTSD and MDD in federal health care settings is expanding. For example, the RAND Corporation recently evaluated a candidate set of quality measures for PTSD and MDD, using an operational definition of an episode of care.³⁷ This work is intended to inform efforts to measure and improve the quality of care for PTSD and depression across the enterprise.

The DoD Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury is simultaneously completing an inferential assessment of adjunctive mental health care services, many focused on PTSD and depression, throughout the health care enterprise. Along with the substantial resources devoted to research on PTSD and depression, the MHS is implementing strategies to improve the system of care for service members with mental health conditions.

Army Care System Innovations

The U.S. Army is engaged in a variety of strategies to improve the identification of patients with mental health conditions, increase access to mental health services, and enhance the quality of care that soldiers receive for PTSD and depression. To improve the coordination of mental health care, the U.S. Army Medical Command implemented a wide-scale innovative transformation of its mental health care system through the establishment of the Behavioral Health Service Line program management office.

This move eliminated separate departments of psychiatry, psychology, and social work in favor of integrated behavioral health departments that are now responsible for all mental health care delivered to soldiers, including inpatient, outpatient, partial hospitalization, residential, embedded care in garrison, and primary care settings. This transformation ensured coordination of care for soldiers, eliminating potential miscommunication with patients, commands, and other clinicians while clearly defining performance indicators in process (eg, productivity, scheduling, access to care, and patient satisfaction) and outcome measures.⁴⁹ In conjunction with the development of its service line, the U.S. Army created a Behavioral Health Data Portal (BHDP), an electronic and standardized means to assess clinical outcomes for common conditions.

To promote higher quality mental health care, the Office of the Surgeon General of the U.S. Army provided direct guidance on the treatment of PTSD and depression. U.S. Army policy mandates that providers treating mental health conditions adhere to the VA/DoD clinical practice guidelines (CPGs) and that soldiers with PTSD and depression be offered treatments with the highest level of scientific support and that outcome measures be routinely administered. In line with the CPGs, U.S. Army policy also recommends the use of both integrated and embedded mental health care approaches to address PTSD, depression, and other common physical and psychological health conditions.

To reduce stigma and improve mental health care access, the U.S. Army began implementing integrated care approaches in 2007 with its Re-Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil) program, an evidence-based collaborative care model.^51-55 This approach included structured screening and diagnostic procedures, predictable follow-up schedules for patients, and the coordination of the divisions of responsibility among and between primary care providers, paraprofessionals, and behavioral health care providers. From 2007 to 2013, this collaborative care model was rolled out across 96 clinics worldwide and provided PTSD and depression screening to more than 1 million encounters per year.^52,53

More recently, the U.S. Army led DoD in integrating behavioral health personnel in patient centered medical homes (PCMH) in compliance with DoD Instruction 6490.15.⁵⁶ This hybrid integrated care model combines collaborative care elements developed in the RESPECT-Mil program with elements of the U.S. Air Force Behavioral Health Optimization project colocating behavioral health providers in primary care settings to provide brief consultative services.

MHS Care Enhancements

Many of the innovations deployed throughout the U.S. Army system of behavioral health care have driven changes across the MHS as a whole. The DoD and the VA have made substantive systemwide policy and practice changes to improve care for beneficiaries with PTSD, depression, and comorbid PTSD and depression. In particular, significant implementation efforts have addressed population screening strategies, outcome monitoring to support measurement-based care, increased access to effective care, and revision of the disability evaluation system.

To improve the identification and referral of soldiers with deployment-related mental health concerns, the DoD implemented a comprehensive program that screens service members prior to deployment, immediately on redeployment, and then again 6 months after returning from deployment. Additionally, annual primary care- based screening requirements have been instituted as part of the DoD PCMH initiative. Both deployment-related and primary care-based screenings include an instrumentation to detect symptoms of PTSD and depression and extend the reach of mental health screening to the entire MHS population.

Building on the success of BHDP, former Assistant Secretary of Defense for Health Affairs Jonathan Woodson mandated BHDP use across the MHS for all patients in DoD behavioral health clinics and the use of outcome measures for the treatment of PTSD, anxiety, depression, and alcohol use disorders.⁵⁷ A DoD-wide requirement to use the PTSD checklist and patient health questionnaire to monitor PTSD and depression symptoms at mental health intakes and regularly at follow-up visits is being implemented. The Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, through its Practice-Based Implementation Network (underwritten by a Joint Incentive Fund managed between DoD and VA), has worked across the MHS and the VA to facilitate the implementation, uptake, and adoption of this initiative.

The DoD established the Center for Deployment Psychology (CDP) in 2006 to promote clinician training in EBTs with the aim of increasing service members’ access to effective psychological treatments. Since its inception, the CDP has provided EBT training to more than 40,000 behavioral health providers. Although the impact of these and other efforts on improving the quality of care that patients receive is unknown, a recent study documented widespread self-reported usage of EBT components in U.S. Army clinics and that providers formally trained in EBTs were more likely to deliver EBTs.⁵⁸

Finally, systemwide changes to the VA Schedule of Ratings for Disability (VASRD) and integration of DoD and VA disability evaluation systems have led to shifts in diagnosis toward PTSD that usually merit a minimum 50% disability rating. Mandates in law require military clinicians to evaluate patients who have deployed for PTSD and TBI prior to taking any actions associated with administrative separation. The practice of attributing PTSD symptoms to character pathology or personality disorders, even when these symptoms did not clearly manifest or worsen with military service, has likely been eliminated from practice in military and veteran populations.

Robust policy changes to limit personality disorder discharges started in fiscal year 2007, when there were 4,127 personality disorder separations across DoD. This number was reduced to 300 within 5 years. Policy changes regarding separation not only seem to have affected discharges, but also may have shaped diagnostic practice. The incidence rate of personality disorder diagnoses declined from 513 per 100,000 person-years in 2007 to 284 per 100,000 person-years by 2011.⁵⁹ The VASRD recognizes chronic adjustment disorder as a disability, and the National Defense Authorization Act of 2008 mandated that DoD follow disability guidelines promulgated by VA.

As stated in the memorandum Clinical Policy Guidance for Assessment and Treatment of Post-Traumatic Stress Disorders (August 24, 2012), DoD recognizes chronic adjustment disorder as an unfitting condition that merits referral to its disability evaluation system.⁶⁰ Acute adjustment disorders may still lead to administrative separations, as many service members manifest emotional symptoms stemming from the failure to adjust to the routine vicissitudes of military life. Finally, many court jurisdictions, including veteran’s courts, military courts, and commanders empowered to adjudicate nonjudicial infractions under the Uniform Code of Military Justice, have recognized PTSD as grounds for the mitigation of penalties associated with a wide array of criminal and administrative infractions.

Conclusion

In response to the increased mental health burden following a decade of war and the associated pressures stemming from federal mandates, the MHS has invested unprecedented resources into improving care for military service members. The U.S. Army has played a prominent role in this endeavor by investing in clinical research efforts to accelerate discovery on the causes and cures for these conditions, enacting policies that mandate best practices, and implementing evidence-based care approaches across the system of care. Despite this progress, however, understanding and effectively treating the most prevalent mental health conditions remain a challenge across the DoD and VHA health care systems. Many service members and veterans still do not receive timely, high-quality care for PTSD, depression, and other common comorbidities associated with military experience, and controversies in diagnostic clarification abound.

In short, great strides have been made, yet there is still a large distance to go. The vision of an effective, efficient, comprehensive care system for mental health conditions will continue to be pursued and achieved through collaborations across key agencies and the scientific community, implementation of health system approaches that support population care, and the sustained efforts of dedicated clinicians, staff, and clinic leaders who deliver the care to our service members and veterans.

Over the past decade, nationwide attention has focused on mental health conditions associated with military service. Recent legal mandates have led to changes in the DoD, VA, and HHS health systems aimed at increasing access to care, decreasing barriers to care, and expanding research on mental health conditions commonly seen in service members and veterans. On August 31, 2012, President Barack Obama signed the Improving Access to Mental Health Services for Veterans, Service Members, and Military Families executive order, establishing an interagency task force from the VA, DoD, and HHS.¹ The task force was charged with addressing quality of care and provider training in the management of commonly comorbid conditions, including (among other conditions) posttraumatic stress disorder (PTSD) and depression.

Depression and PTSD present major health burdens in both military and veteran cohorts. Overlap in clinical presentation and significant rates of comorbidity complicate effective management of these conditions. This article offers a brief review of the diagnostic and epidemiologic complexities associated with PTSD and depression, a summary of research relevant to these issues, and a description of recent system-level developments within the Military Health System (MHS) designed to improve care through better approaches in identification, management, and research of these conditions.

Diagnostic Uncertainty

Both PTSD and major depressive disorder (MDD) have been recognized as mental health disorders since the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) discarded its previous etiologically based approach to diagnostic classification in 1980 in favor of a system in which diagnosis is based on observable symptoms.^2,3 With the release of DSM-5 in 2013, the diagnostic criteria for PTSD underwent a substantial transformation.⁴ Previously, PTSD was described as an anxiety disorder, and some of its manifestations overlapped descriptively (and in many cases, etiologically) with anxiety and depressive illnesses.⁵

Clinicians also often described shorter-lived, developmental, formes fruste, or otherwise subsyndromal manifestations of trauma associated with PTSD. In DSM-5, PTSD was removed from the anxiety disorders section and placed in a new category of disorders labeled Trauma and Stressor-Related Disorders. This new category also included reactive attachment disorder (in children), acute stress disorder, adjustment disorders, and unspecified or other trauma and stressor-related disorders. Other major changes to the PTSD diagnostic criteria included modification to the DSM-IV-TR (text revision) trauma definition (making the construct more specific), removal of the requirement for explicit subjective emotional reaction to a traumatic event, and greater emphasis on negative cognitions and mood. Debate surrounds the updated symptom criteria with critics questioning whether there is any improvement in the clinical utility of the diagnosis, especially in light of the substantial policy and practice implications the change engenders.⁶

Recently, Hoge and colleagues examined the psychometric implications of the diagnostic changes (between DSM-IV-TR and DSM-5) in the PTSD definition.⁶ The authors found that although the 2 definitions showed nearly identical association with other psychiatric disorders (including depression) and functional impairment, 30% of soldiers who met DSM-IV-TR criteria for PTSD failed to meet criteria in DSM-5, and another 20% met only DSM-5 criteria. Recognizing discordance in PTSD and associated diagnoses, the U.S. Army Medical Command mandated that its clinicians familiarize themselves with the controversies surrounding the discordant diagnoses and coding of subthreshold PTSD.⁷

Adding to the problem of diagnostic uncertainty, the clinical presentation of MDD includes significant overlap with that of PTSD. Specifically, symptoms of guilt, diminished interests, problems with concentration, and sleep disturbances are descriptive of both disorders. Furthermore, the criteria set for several subthreshold forms of MDD evidence considerable overlap with PTSD symptoms. For example, diagnostic criteria for disruptive mood dysregulation disorder include behavioral outbursts and irritability, and diagnostic criteria for dysthymia include sleep disturbances and concentration problems.

Adjustment disorders are categorized as trauma and stressor-related disorders in DSM-5 and hold many emotional and behavioral symptoms in common with PTSD. The “acute” and “chronic” adjustment disorder specifiers contribute to problems in diagnostic certainty for PTSD. In general, issues pertaining to diagnostic uncertainty and overlap likely reflect the limits of using a diagnostic classification system that relies exclusively on observational and subjective reports of psychological symptoms.^8,9

In a treatment environment where a veteran or active-duty patient has presented for care, in the face of these shared symptom sets, clinicians frequently offer initial diagnoses. These diagnoses are often based on perceived etiologic factors derived from patients’ descriptions of stressors encountered during military service. This tendency likely contributes to considerable inconsistencies and potential inaccuracies in diagnoses, and much of the variance can be attributed to the clinicians’ degree of familiarity with military exposures, perceptions of what constitutes trauma, and outside pressure to assign or avoid specific diagnoses.

Importantly, the phenomenologic differences between PTSD and depressive disorders increase the likelihood of poorly aligned and inconsistent treatment plans, and this lack of clarity may, in turn, compromise effective patient care. To address some of these diagnostic challenges, the VA and DoD incorporate military culture training into clinicians’ curriculum to increase provider familiarity with the common stressors and challenges of military life, mandate the use of validated measures to support diagnostic decision making, and regularly review policies that influence diagnostic practices.

Epidemiology

The prevalence rates for PTSD are increasing in the military, possibly stemming from the demands on service members engaged in years’ long wars. Despite the increased attention on this phenomenon, research has demonstrated that the majority of service members who deploy do not develop PTSD or significant trauma-related functional impairment.¹⁰ Furthermore, many cases of PTSD diagnosed in the MHS stem from traumatic experiences other than combat exposure, including childhood abuse and neglect, sexual and other assaults, accidents and health care exposures, domestic abuse, and bullying. Depression arguably has received less attention despite comparable prevalence rates in military populations, high co-occurrence of PTSD and depression, and depression being associated with a greater odds ratio for mortality that includes death by suicide in military service members.¹¹

Estimates of the prevalence of PTSD from the U.S. Army suggest that it exists in 3% to 6% of military members who have not deployed and in 6% to 25% of service members with combat deployment histories. The frequency and intensity of combat are strong predictors of risk.⁷ A recent epidemiologic study using inpatient and outpatient encounter records showed that the prevalence of PTSD in the active military component was 2.0% in the middle of calendar year (CY) 2010; a two-thirds increase from 1.2% in CY 2007.¹² The incidence of PTSD

Epidemiologic studies and prevalence/incidence rates derived from administrative data rely on strict case definitions. Consequently, such administrative investigations include data only from service members

PTSD and Depression Treatment

Despite the high rates of PTSD and MDD comorbidity, few treatments have been developed for and tested on an exclusively comorbid sample of patients.¹³ However, psychopharmacologic agents targeting depression have been applied to the treatment of PTSD, and PTSD psychotherapy trials typically include depression response as a secondary outcome. The generalizability of findings to a truly comorbid population may be limited based on study sampling frames and the unique characteristics of patients with comorbid PTSD and depression.^14-16 Several psychopharmacologic treatments for depression have been evaluated as frontline treatments for PTSD. The 3 pharmacologic treatments that demonstrate efficacy in treating PTSD include fluoxetine, paroxetine, and venlafaxine.¹⁷

Although these pharmacologic agents represent good candidate treatments for comorbid patients, the effect size of pharmacologic treatments are generally smaller than those of psychotherapeutic treatments for PTSD.^17,18 This observation, however, is based on indirect comparisons, and a recent systematic review concluded that the evidence was insufficient to determine the comparative effectiveness between psychotherapy and pharmacotherapy for PTSD.¹⁹ Evidence indicates that trauma-focused cognitive behavioral therapies consistently demonstrate efficacy and effectiveness in treating PTSD.^19,20 These treatments also have been shown to significantly reduce depressive symptoms among PTSD samples.²¹

Based on strong bodies of evidence, these pharmacologic and psychological treatments have received the highest level of recommendation in the VA and DoD.^22,23 Accordingly, both agencies have invested considerable resources in large-scale efforts to improve patient access to these particular treatments. Despite these impressive implementation efforts, however, the limitations of relying exclusively on these treatments as frontline approaches within large health care systems have become evident.^24-26

Penetration of Therapies

Penetration of these evidence-based treatments (EBTs) within the DoD and VHA remains limited. For instance, one study showed that VA clinicians in mental health specialty care clinics may provide only about 4 hours of EBT per week.²⁷

Other reports suggest that only about 60% of treatment-seeking patients in PTSD clinics receive any type of evidence-based therapy and that within-session care quality is questionable based on a systematic review of chart notes.^28,29 Attrition in trauma-focused therapy is a recognized limitation, with 1 out of 3 treatment-seeking patients not completing a full dose of evidence-based treatment.^30-33 Large-scale analyses of VHA and DoD utilization data suggest that the majority of PTSD patients do not receive a sufficient number of sessions to be characterized as an adequate dose of EBT, with a majority of dropouts occur- ring after just a few sessions.^34-37

Hoge and colleagues found that < 50% of soldiers meeting criteria for PTSD received any mental health care within the prior 6 months with one-quarter of those patients dropping out of care prematurely.³⁸ Among a large cohort of soldiers engaged in care for the treatment of PTSD, only about 40% received a number of EBT treatment sessions that could qualify as an adequate dose.³⁸ Thus, although major advancements in the development and implementation of effective treatments for PTSD and depression have occurred, the penetration of these treatments is limited, and the majority of patients in need of treatment potentially receive inadequate care.³⁹

System level approaches that integrate behavioral health services into the primary care system have been proposed to address these care gaps for service members and veterans.^40-42 Fundamentally, system-level approaches seek to improve the reach and effectiveness of care through large-scale screening efforts, a greater emphasis on the quality of patient care, and enhanced care continuity across episodes of treatment.

Primary Care

With the primary care setting considered the de facto mental health system, integrated approaches enhance the reach of care by incorporating uniform mental health screening and referral for patients coming through primary care. Specific evidence-based treatments can be integrated into this approach within a stepped-care framework that aims to match patients strategically to the right type of care and leverage specialty care resources as needed. Integrated care approaches for the treatment of PTSD and depression have been developed and evaluated inside and outside of the MHS. Findings indicate that integrated treatment approaches can improve care access, care continuity, patient satisfaction, quality of care,and in several trials, PTSD and depression outcomes.^43-47

Recently, an integrated care approach targeting U.S. Army soldiers who screened positive for PTSD or depression in primary care was evaluated in a multisite effectiveness trial.⁴⁸ Patients randomized to the treatment approach experienced significant improvements in both PTSD and depression symptoms relative to patients in usual care.⁴³ In addition, patients treated in this care model received significantly more mental health services; the patterns of care indicated that patients with comorbid PTSD and depression were more likely to be triaged to specialty care, whereas patients with a single diagnosis were more likely to be managed in primary care.⁴⁹ This trial suggests that integrated care models feasibly can be implemented in the U.S. Army care system, yielding increased uptake of mental health care, more efficiently matched care based on patient comorbidities, and improved PTSD and depression outcomes.

Treatment Research

The MHS supports a large portfolio of research in PTSD and depression through DoD/VA research consortia (eg, the Congressionally Directed Medical Research Program, the Consortium to Alleviate PTSD, the Injury and Traumatic Stress Clinical Consortium). The U.S. Army Medical Research and Materiel Command (USAMRMC) executes and manages the portfolio of research, relying on a joint program committee of DoD and non-DoD experts to make funding recommendations based on identified research priorities, policy guidance, and knowledge translation needs.

Health systems research on PTSD and MDD in federal health care settings is expanding. For example, the RAND Corporation recently evaluated a candidate set of quality measures for PTSD and MDD, using an operational definition of an episode of care.³⁷ This work is intended to inform efforts to measure and improve the quality of care for PTSD and depression across the enterprise.

The DoD Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury is simultaneously completing an inferential assessment of adjunctive mental health care services, many focused on PTSD and depression, throughout the health care enterprise. Along with the substantial resources devoted to research on PTSD and depression, the MHS is implementing strategies to improve the system of care for service members with mental health conditions.

Army Care System Innovations

The U.S. Army is engaged in a variety of strategies to improve the identification of patients with mental health conditions, increase access to mental health services, and enhance the quality of care that soldiers receive for PTSD and depression. To improve the coordination of mental health care, the U.S. Army Medical Command implemented a wide-scale innovative transformation of its mental health care system through the establishment of the Behavioral Health Service Line program management office.

This move eliminated separate departments of psychiatry, psychology, and social work in favor of integrated behavioral health departments that are now responsible for all mental health care delivered to soldiers, including inpatient, outpatient, partial hospitalization, residential, embedded care in garrison, and primary care settings. This transformation ensured coordination of care for soldiers, eliminating potential miscommunication with patients, commands, and other clinicians while clearly defining performance indicators in process (eg, productivity, scheduling, access to care, and patient satisfaction) and outcome measures.⁴⁹ In conjunction with the development of its service line, the U.S. Army created a Behavioral Health Data Portal (BHDP), an electronic and standardized means to assess clinical outcomes for common conditions.

To promote higher quality mental health care, the Office of the Surgeon General of the U.S. Army provided direct guidance on the treatment of PTSD and depression. U.S. Army policy mandates that providers treating mental health conditions adhere to the VA/DoD clinical practice guidelines (CPGs) and that soldiers with PTSD and depression be offered treatments with the highest level of scientific support and that outcome measures be routinely administered. In line with the CPGs, U.S. Army policy also recommends the use of both integrated and embedded mental health care approaches to address PTSD, depression, and other common physical and psychological health conditions.

To reduce stigma and improve mental health care access, the U.S. Army began implementing integrated care approaches in 2007 with its Re-Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil) program, an evidence-based collaborative care model.^51-55 This approach included structured screening and diagnostic procedures, predictable follow-up schedules for patients, and the coordination of the divisions of responsibility among and between primary care providers, paraprofessionals, and behavioral health care providers. From 2007 to 2013, this collaborative care model was rolled out across 96 clinics worldwide and provided PTSD and depression screening to more than 1 million encounters per year.^52,53

More recently, the U.S. Army led DoD in integrating behavioral health personnel in patient centered medical homes (PCMH) in compliance with DoD Instruction 6490.15.⁵⁶ This hybrid integrated care model combines collaborative care elements developed in the RESPECT-Mil program with elements of the U.S. Air Force Behavioral Health Optimization project colocating behavioral health providers in primary care settings to provide brief consultative services.

MHS Care Enhancements

Many of the innovations deployed throughout the U.S. Army system of behavioral health care have driven changes across the MHS as a whole. The DoD and the VA have made substantive systemwide policy and practice changes to improve care for beneficiaries with PTSD, depression, and comorbid PTSD and depression. In particular, significant implementation efforts have addressed population screening strategies, outcome monitoring to support measurement-based care, increased access to effective care, and revision of the disability evaluation system.

To improve the identification and referral of soldiers with deployment-related mental health concerns, the DoD implemented a comprehensive program that screens service members prior to deployment, immediately on redeployment, and then again 6 months after returning from deployment. Additionally, annual primary care- based screening requirements have been instituted as part of the DoD PCMH initiative. Both deployment-related and primary care-based screenings include an instrumentation to detect symptoms of PTSD and depression and extend the reach of mental health screening to the entire MHS population.

Building on the success of BHDP, former Assistant Secretary of Defense for Health Affairs Jonathan Woodson mandated BHDP use across the MHS for all patients in DoD behavioral health clinics and the use of outcome measures for the treatment of PTSD, anxiety, depression, and alcohol use disorders.⁵⁷ A DoD-wide requirement to use the PTSD checklist and patient health questionnaire to monitor PTSD and depression symptoms at mental health intakes and regularly at follow-up visits is being implemented. The Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, through its Practice-Based Implementation Network (underwritten by a Joint Incentive Fund managed between DoD and VA), has worked across the MHS and the VA to facilitate the implementation, uptake, and adoption of this initiative.

The DoD established the Center for Deployment Psychology (CDP) in 2006 to promote clinician training in EBTs with the aim of increasing service members’ access to effective psychological treatments. Since its inception, the CDP has provided EBT training to more than 40,000 behavioral health providers. Although the impact of these and other efforts on improving the quality of care that patients receive is unknown, a recent study documented widespread self-reported usage of EBT components in U.S. Army clinics and that providers formally trained in EBTs were more likely to deliver EBTs.⁵⁸

Finally, systemwide changes to the VA Schedule of Ratings for Disability (VASRD) and integration of DoD and VA disability evaluation systems have led to shifts in diagnosis toward PTSD that usually merit a minimum 50% disability rating. Mandates in law require military clinicians to evaluate patients who have deployed for PTSD and TBI prior to taking any actions associated with administrative separation. The practice of attributing PTSD symptoms to character pathology or personality disorders, even when these symptoms did not clearly manifest or worsen with military service, has likely been eliminated from practice in military and veteran populations.

Robust policy changes to limit personality disorder discharges started in fiscal year 2007, when there were 4,127 personality disorder separations across DoD. This number was reduced to 300 within 5 years. Policy changes regarding separation not only seem to have affected discharges, but also may have shaped diagnostic practice. The incidence rate of personality disorder diagnoses declined from 513 per 100,000 person-years in 2007 to 284 per 100,000 person-years by 2011.⁵⁹ The VASRD recognizes chronic adjustment disorder as a disability, and the National Defense Authorization Act of 2008 mandated that DoD follow disability guidelines promulgated by VA.

As stated in the memorandum Clinical Policy Guidance for Assessment and Treatment of Post-Traumatic Stress Disorders (August 24, 2012), DoD recognizes chronic adjustment disorder as an unfitting condition that merits referral to its disability evaluation system.⁶⁰ Acute adjustment disorders may still lead to administrative separations, as many service members manifest emotional symptoms stemming from the failure to adjust to the routine vicissitudes of military life. Finally, many court jurisdictions, including veteran’s courts, military courts, and commanders empowered to adjudicate nonjudicial infractions under the Uniform Code of Military Justice, have recognized PTSD as grounds for the mitigation of penalties associated with a wide array of criminal and administrative infractions.

Conclusion

In response to the increased mental health burden following a decade of war and the associated pressures stemming from federal mandates, the MHS has invested unprecedented resources into improving care for military service members. The U.S. Army has played a prominent role in this endeavor by investing in clinical research efforts to accelerate discovery on the causes and cures for these conditions, enacting policies that mandate best practices, and implementing evidence-based care approaches across the system of care. Despite this progress, however, understanding and effectively treating the most prevalent mental health conditions remain a challenge across the DoD and VHA health care systems. Many service members and veterans still do not receive timely, high-quality care for PTSD, depression, and other common comorbidities associated with military experience, and controversies in diagnostic clarification abound.

In short, great strides have been made, yet there is still a large distance to go. The vision of an effective, efficient, comprehensive care system for mental health conditions will continue to be pursued and achieved through collaborations across key agencies and the scientific community, implementation of health system approaches that support population care, and the sustained efforts of dedicated clinicians, staff, and clinic leaders who deliver the care to our service members and veterans.

Over the past decade, nationwide attention has focused on mental health conditions associated with military service. Recent legal mandates have led to changes in the DoD, VA, and HHS health systems aimed at increasing access to care, decreasing barriers to care, and expanding research on mental health conditions commonly seen in service members and veterans. On August 31, 2012, President Barack Obama signed the Improving Access to Mental Health Services for Veterans, Service Members, and Military Families executive order, establishing an interagency task force from the VA, DoD, and HHS.¹ The task force was charged with addressing quality of care and provider training in the management of commonly comorbid conditions, including (among other conditions) posttraumatic stress disorder (PTSD) and depression.

Depression and PTSD present major health burdens in both military and veteran cohorts. Overlap in clinical presentation and significant rates of comorbidity complicate effective management of these conditions. This article offers a brief review of the diagnostic and epidemiologic complexities associated with PTSD and depression, a summary of research relevant to these issues, and a description of recent system-level developments within the Military Health System (MHS) designed to improve care through better approaches in identification, management, and research of these conditions.

Diagnostic Uncertainty

Both PTSD and major depressive disorder (MDD) have been recognized as mental health disorders since the American Psychiatric Association’s Diagnostic and Statistical Manual (DSM) discarded its previous etiologically based approach to diagnostic classification in 1980 in favor of a system in which diagnosis is based on observable symptoms.^2,3 With the release of DSM-5 in 2013, the diagnostic criteria for PTSD underwent a substantial transformation.⁴ Previously, PTSD was described as an anxiety disorder, and some of its manifestations overlapped descriptively (and in many cases, etiologically) with anxiety and depressive illnesses.⁵

Clinicians also often described shorter-lived, developmental, formes fruste, or otherwise subsyndromal manifestations of trauma associated with PTSD. In DSM-5, PTSD was removed from the anxiety disorders section and placed in a new category of disorders labeled Trauma and Stressor-Related Disorders. This new category also included reactive attachment disorder (in children), acute stress disorder, adjustment disorders, and unspecified or other trauma and stressor-related disorders. Other major changes to the PTSD diagnostic criteria included modification to the DSM-IV-TR (text revision) trauma definition (making the construct more specific), removal of the requirement for explicit subjective emotional reaction to a traumatic event, and greater emphasis on negative cognitions and mood. Debate surrounds the updated symptom criteria with critics questioning whether there is any improvement in the clinical utility of the diagnosis, especially in light of the substantial policy and practice implications the change engenders.⁶

Recently, Hoge and colleagues examined the psychometric implications of the diagnostic changes (between DSM-IV-TR and DSM-5) in the PTSD definition.⁶ The authors found that although the 2 definitions showed nearly identical association with other psychiatric disorders (including depression) and functional impairment, 30% of soldiers who met DSM-IV-TR criteria for PTSD failed to meet criteria in DSM-5, and another 20% met only DSM-5 criteria. Recognizing discordance in PTSD and associated diagnoses, the U.S. Army Medical Command mandated that its clinicians familiarize themselves with the controversies surrounding the discordant diagnoses and coding of subthreshold PTSD.⁷

Adding to the problem of diagnostic uncertainty, the clinical presentation of MDD includes significant overlap with that of PTSD. Specifically, symptoms of guilt, diminished interests, problems with concentration, and sleep disturbances are descriptive of both disorders. Furthermore, the criteria set for several subthreshold forms of MDD evidence considerable overlap with PTSD symptoms. For example, diagnostic criteria for disruptive mood dysregulation disorder include behavioral outbursts and irritability, and diagnostic criteria for dysthymia include sleep disturbances and concentration problems.

Adjustment disorders are categorized as trauma and stressor-related disorders in DSM-5 and hold many emotional and behavioral symptoms in common with PTSD. The “acute” and “chronic” adjustment disorder specifiers contribute to problems in diagnostic certainty for PTSD. In general, issues pertaining to diagnostic uncertainty and overlap likely reflect the limits of using a diagnostic classification system that relies exclusively on observational and subjective reports of psychological symptoms.^8,9

In a treatment environment where a veteran or active-duty patient has presented for care, in the face of these shared symptom sets, clinicians frequently offer initial diagnoses. These diagnoses are often based on perceived etiologic factors derived from patients’ descriptions of stressors encountered during military service. This tendency likely contributes to considerable inconsistencies and potential inaccuracies in diagnoses, and much of the variance can be attributed to the clinicians’ degree of familiarity with military exposures, perceptions of what constitutes trauma, and outside pressure to assign or avoid specific diagnoses.

Importantly, the phenomenologic differences between PTSD and depressive disorders increase the likelihood of poorly aligned and inconsistent treatment plans, and this lack of clarity may, in turn, compromise effective patient care. To address some of these diagnostic challenges, the VA and DoD incorporate military culture training into clinicians’ curriculum to increase provider familiarity with the common stressors and challenges of military life, mandate the use of validated measures to support diagnostic decision making, and regularly review policies that influence diagnostic practices.

Epidemiology

The prevalence rates for PTSD are increasing in the military, possibly stemming from the demands on service members engaged in years’ long wars. Despite the increased attention on this phenomenon, research has demonstrated that the majority of service members who deploy do not develop PTSD or significant trauma-related functional impairment.¹⁰ Furthermore, many cases of PTSD diagnosed in the MHS stem from traumatic experiences other than combat exposure, including childhood abuse and neglect, sexual and other assaults, accidents and health care exposures, domestic abuse, and bullying. Depression arguably has received less attention despite comparable prevalence rates in military populations, high co-occurrence of PTSD and depression, and depression being associated with a greater odds ratio for mortality that includes death by suicide in military service members.¹¹

Estimates of the prevalence of PTSD from the U.S. Army suggest that it exists in 3% to 6% of military members who have not deployed and in 6% to 25% of service members with combat deployment histories. The frequency and intensity of combat are strong predictors of risk.⁷ A recent epidemiologic study using inpatient and outpatient encounter records showed that the prevalence of PTSD in the active military component was 2.0% in the middle of calendar year (CY) 2010; a two-thirds increase from 1.2% in CY 2007.¹² The incidence of PTSD

Epidemiologic studies and prevalence/incidence rates derived from administrative data rely on strict case definitions. Consequently, such administrative investigations include data only from service members

PTSD and Depression Treatment

Despite the high rates of PTSD and MDD comorbidity, few treatments have been developed for and tested on an exclusively comorbid sample of patients.¹³ However, psychopharmacologic agents targeting depression have been applied to the treatment of PTSD, and PTSD psychotherapy trials typically include depression response as a secondary outcome. The generalizability of findings to a truly comorbid population may be limited based on study sampling frames and the unique characteristics of patients with comorbid PTSD and depression.^14-16 Several psychopharmacologic treatments for depression have been evaluated as frontline treatments for PTSD. The 3 pharmacologic treatments that demonstrate efficacy in treating PTSD include fluoxetine, paroxetine, and venlafaxine.¹⁷

Although these pharmacologic agents represent good candidate treatments for comorbid patients, the effect size of pharmacologic treatments are generally smaller than those of psychotherapeutic treatments for PTSD.^17,18 This observation, however, is based on indirect comparisons, and a recent systematic review concluded that the evidence was insufficient to determine the comparative effectiveness between psychotherapy and pharmacotherapy for PTSD.¹⁹ Evidence indicates that trauma-focused cognitive behavioral therapies consistently demonstrate efficacy and effectiveness in treating PTSD.^19,20 These treatments also have been shown to significantly reduce depressive symptoms among PTSD samples.²¹

Based on strong bodies of evidence, these pharmacologic and psychological treatments have received the highest level of recommendation in the VA and DoD.^22,23 Accordingly, both agencies have invested considerable resources in large-scale efforts to improve patient access to these particular treatments. Despite these impressive implementation efforts, however, the limitations of relying exclusively on these treatments as frontline approaches within large health care systems have become evident.^24-26

Penetration of Therapies

Penetration of these evidence-based treatments (EBTs) within the DoD and VHA remains limited. For instance, one study showed that VA clinicians in mental health specialty care clinics may provide only about 4 hours of EBT per week.²⁷

Other reports suggest that only about 60% of treatment-seeking patients in PTSD clinics receive any type of evidence-based therapy and that within-session care quality is questionable based on a systematic review of chart notes.^28,29 Attrition in trauma-focused therapy is a recognized limitation, with 1 out of 3 treatment-seeking patients not completing a full dose of evidence-based treatment.^30-33 Large-scale analyses of VHA and DoD utilization data suggest that the majority of PTSD patients do not receive a sufficient number of sessions to be characterized as an adequate dose of EBT, with a majority of dropouts occur- ring after just a few sessions.^34-37

Hoge and colleagues found that < 50% of soldiers meeting criteria for PTSD received any mental health care within the prior 6 months with one-quarter of those patients dropping out of care prematurely.³⁸ Among a large cohort of soldiers engaged in care for the treatment of PTSD, only about 40% received a number of EBT treatment sessions that could qualify as an adequate dose.³⁸ Thus, although major advancements in the development and implementation of effective treatments for PTSD and depression have occurred, the penetration of these treatments is limited, and the majority of patients in need of treatment potentially receive inadequate care.³⁹

System level approaches that integrate behavioral health services into the primary care system have been proposed to address these care gaps for service members and veterans.^40-42 Fundamentally, system-level approaches seek to improve the reach and effectiveness of care through large-scale screening efforts, a greater emphasis on the quality of patient care, and enhanced care continuity across episodes of treatment.

Primary Care

With the primary care setting considered the de facto mental health system, integrated approaches enhance the reach of care by incorporating uniform mental health screening and referral for patients coming through primary care. Specific evidence-based treatments can be integrated into this approach within a stepped-care framework that aims to match patients strategically to the right type of care and leverage specialty care resources as needed. Integrated care approaches for the treatment of PTSD and depression have been developed and evaluated inside and outside of the MHS. Findings indicate that integrated treatment approaches can improve care access, care continuity, patient satisfaction, quality of care,and in several trials, PTSD and depression outcomes.^43-47

Recently, an integrated care approach targeting U.S. Army soldiers who screened positive for PTSD or depression in primary care was evaluated in a multisite effectiveness trial.⁴⁸ Patients randomized to the treatment approach experienced significant improvements in both PTSD and depression symptoms relative to patients in usual care.⁴³ In addition, patients treated in this care model received significantly more mental health services; the patterns of care indicated that patients with comorbid PTSD and depression were more likely to be triaged to specialty care, whereas patients with a single diagnosis were more likely to be managed in primary care.⁴⁹ This trial suggests that integrated care models feasibly can be implemented in the U.S. Army care system, yielding increased uptake of mental health care, more efficiently matched care based on patient comorbidities, and improved PTSD and depression outcomes.

Treatment Research

The MHS supports a large portfolio of research in PTSD and depression through DoD/VA research consortia (eg, the Congressionally Directed Medical Research Program, the Consortium to Alleviate PTSD, the Injury and Traumatic Stress Clinical Consortium). The U.S. Army Medical Research and Materiel Command (USAMRMC) executes and manages the portfolio of research, relying on a joint program committee of DoD and non-DoD experts to make funding recommendations based on identified research priorities, policy guidance, and knowledge translation needs.

Health systems research on PTSD and MDD in federal health care settings is expanding. For example, the RAND Corporation recently evaluated a candidate set of quality measures for PTSD and MDD, using an operational definition of an episode of care.³⁷ This work is intended to inform efforts to measure and improve the quality of care for PTSD and depression across the enterprise.

The DoD Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury is simultaneously completing an inferential assessment of adjunctive mental health care services, many focused on PTSD and depression, throughout the health care enterprise. Along with the substantial resources devoted to research on PTSD and depression, the MHS is implementing strategies to improve the system of care for service members with mental health conditions.

Army Care System Innovations

The U.S. Army is engaged in a variety of strategies to improve the identification of patients with mental health conditions, increase access to mental health services, and enhance the quality of care that soldiers receive for PTSD and depression. To improve the coordination of mental health care, the U.S. Army Medical Command implemented a wide-scale innovative transformation of its mental health care system through the establishment of the Behavioral Health Service Line program management office.

This move eliminated separate departments of psychiatry, psychology, and social work in favor of integrated behavioral health departments that are now responsible for all mental health care delivered to soldiers, including inpatient, outpatient, partial hospitalization, residential, embedded care in garrison, and primary care settings. This transformation ensured coordination of care for soldiers, eliminating potential miscommunication with patients, commands, and other clinicians while clearly defining performance indicators in process (eg, productivity, scheduling, access to care, and patient satisfaction) and outcome measures.⁴⁹ In conjunction with the development of its service line, the U.S. Army created a Behavioral Health Data Portal (BHDP), an electronic and standardized means to assess clinical outcomes for common conditions.

To promote higher quality mental health care, the Office of the Surgeon General of the U.S. Army provided direct guidance on the treatment of PTSD and depression. U.S. Army policy mandates that providers treating mental health conditions adhere to the VA/DoD clinical practice guidelines (CPGs) and that soldiers with PTSD and depression be offered treatments with the highest level of scientific support and that outcome measures be routinely administered. In line with the CPGs, U.S. Army policy also recommends the use of both integrated and embedded mental health care approaches to address PTSD, depression, and other common physical and psychological health conditions.

To reduce stigma and improve mental health care access, the U.S. Army began implementing integrated care approaches in 2007 with its Re-Engineering Systems of Primary Care Treatment in the Military (RESPECT-Mil) program, an evidence-based collaborative care model.^51-55 This approach included structured screening and diagnostic procedures, predictable follow-up schedules for patients, and the coordination of the divisions of responsibility among and between primary care providers, paraprofessionals, and behavioral health care providers. From 2007 to 2013, this collaborative care model was rolled out across 96 clinics worldwide and provided PTSD and depression screening to more than 1 million encounters per year.^52,53

More recently, the U.S. Army led DoD in integrating behavioral health personnel in patient centered medical homes (PCMH) in compliance with DoD Instruction 6490.15.⁵⁶ This hybrid integrated care model combines collaborative care elements developed in the RESPECT-Mil program with elements of the U.S. Air Force Behavioral Health Optimization project colocating behavioral health providers in primary care settings to provide brief consultative services.

MHS Care Enhancements

Many of the innovations deployed throughout the U.S. Army system of behavioral health care have driven changes across the MHS as a whole. The DoD and the VA have made substantive systemwide policy and practice changes to improve care for beneficiaries with PTSD, depression, and comorbid PTSD and depression. In particular, significant implementation efforts have addressed population screening strategies, outcome monitoring to support measurement-based care, increased access to effective care, and revision of the disability evaluation system.

To improve the identification and referral of soldiers with deployment-related mental health concerns, the DoD implemented a comprehensive program that screens service members prior to deployment, immediately on redeployment, and then again 6 months after returning from deployment. Additionally, annual primary care- based screening requirements have been instituted as part of the DoD PCMH initiative. Both deployment-related and primary care-based screenings include an instrumentation to detect symptoms of PTSD and depression and extend the reach of mental health screening to the entire MHS population.

Building on the success of BHDP, former Assistant Secretary of Defense for Health Affairs Jonathan Woodson mandated BHDP use across the MHS for all patients in DoD behavioral health clinics and the use of outcome measures for the treatment of PTSD, anxiety, depression, and alcohol use disorders.⁵⁷ A DoD-wide requirement to use the PTSD checklist and patient health questionnaire to monitor PTSD and depression symptoms at mental health intakes and regularly at follow-up visits is being implemented. The Defense Centers of Excellence for Psychological Health and Traumatic Brain Injury, through its Practice-Based Implementation Network (underwritten by a Joint Incentive Fund managed between DoD and VA), has worked across the MHS and the VA to facilitate the implementation, uptake, and adoption of this initiative.

The DoD established the Center for Deployment Psychology (CDP) in 2006 to promote clinician training in EBTs with the aim of increasing service members’ access to effective psychological treatments. Since its inception, the CDP has provided EBT training to more than 40,000 behavioral health providers. Although the impact of these and other efforts on improving the quality of care that patients receive is unknown, a recent study documented widespread self-reported usage of EBT components in U.S. Army clinics and that providers formally trained in EBTs were more likely to deliver EBTs.⁵⁸

Finally, systemwide changes to the VA Schedule of Ratings for Disability (VASRD) and integration of DoD and VA disability evaluation systems have led to shifts in diagnosis toward PTSD that usually merit a minimum 50% disability rating. Mandates in law require military clinicians to evaluate patients who have deployed for PTSD and TBI prior to taking any actions associated with administrative separation. The practice of attributing PTSD symptoms to character pathology or personality disorders, even when these symptoms did not clearly manifest or worsen with military service, has likely been eliminated from practice in military and veteran populations.

Robust policy changes to limit personality disorder discharges started in fiscal year 2007, when there were 4,127 personality disorder separations across DoD. This number was reduced to 300 within 5 years. Policy changes regarding separation not only seem to have affected discharges, but also may have shaped diagnostic practice. The incidence rate of personality disorder diagnoses declined from 513 per 100,000 person-years in 2007 to 284 per 100,000 person-years by 2011.⁵⁹ The VASRD recognizes chronic adjustment disorder as a disability, and the National Defense Authorization Act of 2008 mandated that DoD follow disability guidelines promulgated by VA.

As stated in the memorandum Clinical Policy Guidance for Assessment and Treatment of Post-Traumatic Stress Disorders (August 24, 2012), DoD recognizes chronic adjustment disorder as an unfitting condition that merits referral to its disability evaluation system.⁶⁰ Acute adjustment disorders may still lead to administrative separations, as many service members manifest emotional symptoms stemming from the failure to adjust to the routine vicissitudes of military life. Finally, many court jurisdictions, including veteran’s courts, military courts, and commanders empowered to adjudicate nonjudicial infractions under the Uniform Code of Military Justice, have recognized PTSD as grounds for the mitigation of penalties associated with a wide array of criminal and administrative infractions.

Conclusion

In response to the increased mental health burden following a decade of war and the associated pressures stemming from federal mandates, the MHS has invested unprecedented resources into improving care for military service members. The U.S. Army has played a prominent role in this endeavor by investing in clinical research efforts to accelerate discovery on the causes and cures for these conditions, enacting policies that mandate best practices, and implementing evidence-based care approaches across the system of care. Despite this progress, however, understanding and effectively treating the most prevalent mental health conditions remain a challenge across the DoD and VHA health care systems. Many service members and veterans still do not receive timely, high-quality care for PTSD, depression, and other common comorbidities associated with military experience, and controversies in diagnostic clarification abound.

In short, great strides have been made, yet there is still a large distance to go. The vision of an effective, efficient, comprehensive care system for mental health conditions will continue to be pursued and achieved through collaborations across key agencies and the scientific community, implementation of health system approaches that support population care, and the sustained efforts of dedicated clinicians, staff, and clinic leaders who deliver the care to our service members and veterans.

Micrograph showing MM

The National Comprehensive Cancer Network (NCCN) has revised its clinical practice guidelines on multiple myeloma (MM) to include response criteria developed by the International Myeloma Working Group (IMWG) and testing for minimal residual disease (MRD).

The NCCN develops practice guidelines to help physicians in making informed treatment decisions.

Its recommendations can facilitate reimbursement for testing or treatment.

“The NCCN’s action represents a further step toward broad use of MRD testing,” said Brian Durie, MD, chairman of the International Myeloma Foundation (IMF).

The importance of first identifying and then eliminating MRD is the key principle of the IMF’s Black Swan Research Initiative®, a collaborative effort launched in 2012 to cure MM.

“We’ve long believed early intervention with highly effective treatments is the pathway to curing myeloma, and we are currently testing this in clinical trials,” Dr Durie said.

Through the Black Swan Research Initiative, the IMF helped develop next-generation flow cytometry, 1 of 2 tests recommended by the NCCN to assess the presence of MRD in MM patients. The second test is next-generation sequencing.

The new MM response criteria, on which the NCCN based its most recent revision to the guidelines, were developed and agreed upon by the more than 200 members of the IMWG.

The new response criteria spell out exact definitions of “MRD negative” by next-generation flow cytometry or next-generation sequencing.

“We are pleased that the 2016 IMWG response criteria were adopted in full in the new NCCN recommendations,” said Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota.

The 2016 IMWG response criteria were published in The Lancet Oncology in August.

Micrograph showing MM

The National Comprehensive Cancer Network (NCCN) has revised its clinical practice guidelines on multiple myeloma (MM) to include response criteria developed by the International Myeloma Working Group (IMWG) and testing for minimal residual disease (MRD).

The NCCN develops practice guidelines to help physicians in making informed treatment decisions.

Its recommendations can facilitate reimbursement for testing or treatment.

“The NCCN’s action represents a further step toward broad use of MRD testing,” said Brian Durie, MD, chairman of the International Myeloma Foundation (IMF).

The importance of first identifying and then eliminating MRD is the key principle of the IMF’s Black Swan Research Initiative®, a collaborative effort launched in 2012 to cure MM.

“We’ve long believed early intervention with highly effective treatments is the pathway to curing myeloma, and we are currently testing this in clinical trials,” Dr Durie said.

Through the Black Swan Research Initiative, the IMF helped develop next-generation flow cytometry, 1 of 2 tests recommended by the NCCN to assess the presence of MRD in MM patients. The second test is next-generation sequencing.

The new MM response criteria, on which the NCCN based its most recent revision to the guidelines, were developed and agreed upon by the more than 200 members of the IMWG.

The new response criteria spell out exact definitions of “MRD negative” by next-generation flow cytometry or next-generation sequencing.

“We are pleased that the 2016 IMWG response criteria were adopted in full in the new NCCN recommendations,” said Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota.

The 2016 IMWG response criteria were published in The Lancet Oncology in August.

Micrograph showing MM

The National Comprehensive Cancer Network (NCCN) has revised its clinical practice guidelines on multiple myeloma (MM) to include response criteria developed by the International Myeloma Working Group (IMWG) and testing for minimal residual disease (MRD).

The NCCN develops practice guidelines to help physicians in making informed treatment decisions.

Its recommendations can facilitate reimbursement for testing or treatment.

“The NCCN’s action represents a further step toward broad use of MRD testing,” said Brian Durie, MD, chairman of the International Myeloma Foundation (IMF).

The importance of first identifying and then eliminating MRD is the key principle of the IMF’s Black Swan Research Initiative®, a collaborative effort launched in 2012 to cure MM.

“We’ve long believed early intervention with highly effective treatments is the pathway to curing myeloma, and we are currently testing this in clinical trials,” Dr Durie said.

Through the Black Swan Research Initiative, the IMF helped develop next-generation flow cytometry, 1 of 2 tests recommended by the NCCN to assess the presence of MRD in MM patients. The second test is next-generation sequencing.

The new MM response criteria, on which the NCCN based its most recent revision to the guidelines, were developed and agreed upon by the more than 200 members of the IMWG.

The new response criteria spell out exact definitions of “MRD negative” by next-generation flow cytometry or next-generation sequencing.

“We are pleased that the 2016 IMWG response criteria were adopted in full in the new NCCN recommendations,” said Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota.

The 2016 IMWG response criteria were published in The Lancet Oncology in August.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

Neil Osterweil/Frontline Medical News

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

Neil Osterweil/Frontline Medical News

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

NATIONAL HARBOR, MD. – Sex difference in immune regulatory responses may drive the poorer responses to treatment with immune checkpoint inhibitors targeted against programmed death–1 (PD-1 inhibitors) seen in women with advanced melanoma, investigators report.

Among patients with advanced melanoma treated with either pembrolizumab (Keytruda) or nivolumab (Opdivo) monotherapy in four clinical trials, the median objective response rate (ORR) among women was 33.1%, compared with 54.6% among men. Median progression-free survival (PFS), respectively, was 5.5 months vs. 18 months, reported Katy K. Tsai, MD, a clinical instructor in cutaneous oncology at the University of California, San Francisco.

Neil Osterweil/Frontline Medical News

Response prediction model

Dr. Tsai and her colleagues had previously reported on a validated clinical scoring model for predicting response to anti–PD-1 therapy. In that study, they found that female sex was associated with a lower response rate with an odds ratio of 0.36 (95% confidence interval, 0.19-0.67).

In a separate study, they reported that relative abundance in tumors of a partially exhausted T-cell phenotype (PD-1^high/CTLA-4–positive CD8 cells) was predictive of response to anti–PD-1 therapy.

In the current study, they looked at data on 118 women and 218 men who had advanced cutaneous melanoma and were treated in one of four clinical trials of pembrolizumab or nivolumab as monotherapy or in combination with an anti-CTLA4 agent such as ipilimumab (Yervoy) (NCT01295827, NCT01704287, NCT01721746, and NCT02156804).

On flow-cytometry analysis of pre-treatment tumor samples, women had a significantly lower proportion of PD-1^high/CTLA-4–positive CD8 cells as compared with men (mean, 16.9% vs. 26%; P = .008).

“The mechanisms of this [discrepancy] may have an immunologic basis given the difference in pre-treatment T-cell profiles between women and men. Sex-related differences in tumor immunity and immunotherapy responses warrant further investigation,” the investigators wrote in a poster presentation.

The study was internally funded. Dr. Tsai and her colleagues reported no relevant disclosures.

CHICAGO – Adjustment for fluid balance increased the detection rate of acute kidney injury, more accurately staged the kidney damage, and distinguished false-positive cases in critically ill children, based on a secondary analysis of the Study of the Prediction of Acute Kidney Injury in Children Using Risk Stratification and Biomarkers (AKI-CHERUB).

Fluid overload can mask acute kidney injury (AKI) in critically ill children. “The failure to correct serum creatinine measure for fluid overload dilutes the impact of AKI on outcomes,” David T. Selewski, MD, of the University of Michigan, Ann Arbor, said at the annual meeting sponsored by the American Society for Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Adjustment for fluid balance increased the detection rate of acute kidney injury, more accurately staged the kidney damage, and distinguished false-positive cases in critically ill children, based on a secondary analysis of the Study of the Prediction of Acute Kidney Injury in Children Using Risk Stratification and Biomarkers (AKI-CHERUB).

Fluid overload can mask acute kidney injury (AKI) in critically ill children. “The failure to correct serum creatinine measure for fluid overload dilutes the impact of AKI on outcomes,” David T. Selewski, MD, of the University of Michigan, Ann Arbor, said at the annual meeting sponsored by the American Society for Nephrology.

Brian Hoyle/Frontline Medical News

CHICAGO – Adjustment for fluid balance increased the detection rate of acute kidney injury, more accurately staged the kidney damage, and distinguished false-positive cases in critically ill children, based on a secondary analysis of the Study of the Prediction of Acute Kidney Injury in Children Using Risk Stratification and Biomarkers (AKI-CHERUB).

Fluid overload can mask acute kidney injury (AKI) in critically ill children. “The failure to correct serum creatinine measure for fluid overload dilutes the impact of AKI on outcomes,” David T. Selewski, MD, of the University of Michigan, Ann Arbor, said at the annual meeting sponsored by the American Society for Nephrology.

Brian Hoyle/Frontline Medical News

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

WASHINGTON – Data from the first randomized trial of switching from an originator biologic to a biosimilar of the originator indicate that the infliximab biosimilar Remsima is no different from the infliximab originator Remicade in the rate of disease worsening over 1 year across a combination of all its approved indications.

The outcomes of the Norwegian, double-blind, noninferiority trial, called NOR-SWITCH, indicate similar rates of disease worsening across patients switched to Remsima and those who stayed on Remicade. However, exploratory group analyses conducted on the different disease subgroups in the trial (Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis) showed a potentially concerning level of disease worsening among Crohn’s disease patients on Remsima with a confidence interval that nearly fell entirely within the range favoring Remicade.

In the United States, Remsima, also known as CT-P13, is marketed by Pfizer as Inflectra.

NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.

The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.

Bruce Jancin/Frontline Medical News

NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.

The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.

Bruce Jancin/Frontline Medical News

NEW ORLEANS – An investigational synthetic natriuretic peptide given early during hospitalization for acute decompensated heart failure didn’t produce any of the hoped-for intermediate- or long-term clinical benefits in the phase III TRUE-AHF study, Milton Packer, MD, reported at the American Heart Association scientific sessions.

The failure of this investigational vasodilator, ularitide, to influence downstream cardiovascular mortality or early readmission for heart failure closes the door on the once-promising hypothesis that myocardial microinjury occurring during ADHF is due to ventricular distension, observed Dr. Packer, the Distinguished Scholar in Cardiovascular Science at Baylor University Medical Center, Dallas. “Ularitide did exactly what we expected it to do while we were giving it: we caused intravascular decompression, we reduced cardiac wall stress, but we did not affect cardiac microinjury, and we didn’t change long-term cardiovascular mortality or any of our secondary endpoints, including and in particular the 30-day risk of rehospitalization for heart failure,” he said.

Bruce Jancin/Frontline Medical News

ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.

“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).

Bruce Jancin/Frontline Medical News

ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.

“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).

Bruce Jancin/Frontline Medical News

ROME – Cardiac rehabilitation programs have a previously unappreciated benefit: participants enjoy a 60% reduction in the risk of stroke, Gijs van Halewijn, MD, reported at the annual congress of the European Society of Cardiology.

“I think cardiologists are really focused on cardiovascular deaths, especially from MI. But we’ve shown that cardiac rehabilitation also has an effect on cerebrovascular events,” said Dr. van Halewijn of Erasmus University in Rotterdam (the Netherlands).

Bruce Jancin/Frontline Medical News