Professional Coalition for Research Progress: 2018 Meeting

On Tuesday, March 20, 2018, the National Institute of Mental Health (NIMH) convened the ninth meeting of the Professional Coalition for Research Progress (Coalition) in Rockville, Maryland. This meeting was an opportunity for NIMH to share information on the latest research advances and related developments at NIMH, to foster dialogue on the future directions of NIMH-funded research, and to hear from Coalition members about their program priorities and concerns associated with the mental health field.

The meeting included presentations and discussions on the drug ketamine, suicide prevention in emergency care settings, and mental health disparities. There was also a member engagement session. To gain perspectives from both the NIMH and the extramural community, a speaker from NIMH and an NIMH-funded researcher presented on each topic. The highlights of the meeting are summarized below. The meeting agenda and participant list are also available for reference.

Ketamine: NIMH Intramural Research Programs Update

Elizabeth Ballard, Ph.D., Director, Experimental Therapeutics and Pathophysiology Branch, Division of Intramural Research Programs, NIMH

Dr. Ballard presented NIMH research on the antidepressant properties of the drug ketamine, and its application in her studies investigating suicide risk. Current antidepressant medications on the market are limited by a lag time of up to 14 weeks before the onset of effects. There are no Food and Drug Administration approved medications to treat acute suicide risk with the exception of clozapine for patients with schizophrenia. Ketamine is a drug that may be able to bridge the treatment gap between acute and chronic suicide risk as a rapid onset intervention.

Ketamine is currently administered intravenously primarily as an analgesic anesthetic for ambulatory surgery and chronic pain. However, it is associated with transient dissociative symptoms and has been abused as a “club drug” under the street name Special K. The Clinical Research Center of the NIMH Intramural Program includes a Mood Disorders Unit that treats patients enrolled in research protocols. The Program recently published the initial results of a ketamine Mechanism of Action clinical trial¹ in which patients with major depressive disorder benefited from a reduction in depressive symptoms after ketamine administration as expected, but healthy controls administered ketamine exhibited a minor increase in depressive symptoms for one day that lasted beyond the initial period of dissociative effects. The results suggest an aspect of homeostatic regulation to ketamine infusions. Researchers in the NIMH Intramural Program have also discovered a ketamine enantiomer that does not produce dissociative effects in a preclinical model in mice. Dr. Ballard then discussed her research on insomnia as a biomarker for suicide risk and the importance of sleep as a therapeutic agent, an electroencephalography sleep study of wakefulness in depressed patients that exposed a normalization of previously disrupted sleep patterns after ketamine infusion. Dr. Jeffrey Lieberman of Columbia University questioned whether Dr. Ballard’s research encompasses individuals with suicidal ideation from other mood disorders besides depression, and those engaging in self-injurious behaviors. Dr. Ballard replied that the NIMH trial is not diagnostic-specific, but they do exclude those for schizophrenia and active substance use. The data suggest that subjects with a history of non-suicidal self-injury and chronic suicidal thoughts may not have as robust of an anti-suicidal response to ketamine as those with an acute risk of suicide.

Ketamine Use in Psychiatric Practice: Clinical and Scientific Perspectives

Sanjay J. Mathew, M.D., Professor, Psychiatry and Behavioral Sciences, Baylor College of Medicine

One of the unanswered questions from early ketamine studies is whether participants were effectively blinded considering ketamine’s dissociative effects. Dr. Mathew presented the results of an NIMH-funded Baylor study that compared administration of ketamine with midazolam, which is a short-acting benzodiazepine with negligible antidepressant effects, anxiolytic properties and memory deficit side effects. Both the ketamine- and midazolam-treated patients reported antidepressant effects through Day 7 after administration, highlighting the power of expectancy and the difficulty of developing a reliable control arm in ketamine studies. Dr. Mathew’s team also collaborated with the NIMH Rapidly-Acting Treatments for Treatment-Resistant Depression (TDR) study led by Maurizio Fava, M.D., which addressed issue of the lack of dose response studies via a dose-ranging trial of IV ketamine. They confirmed the standard dose administration of 0.5 mg/kg as ideal, but also obtained rare negative results of ketamine efficacy at a lower test dose of 0.2 mg/kg. There was no correlation between degree of dissociation and antidepressant effects, suggesting that side effects could be mitigated with administration of a low dose of 0.1 mg/kg. Phase III industry sponsored trials are underway in TRD and suicidality, evaluating a low-dose intranasal version of esketamine (the S-isomer of ketamine) to enhance tolerability. Dr. Mathew discussed some of his other ketamine studies, including a comparison to electroconvulsive therapy as well as the impact of global brain connectivity as a proxy for glutamate activity. A recent NIMH Biobehavioral Research Awards for Innovative New Scientists (BRAINS) award led by Rebecca Price, Ph.D. is testing a cognitive training intervention to prolong ketamine’s response. Other researchers are studying sequential therapy with d-cycloserine and/or lurasidone for treatment of suicidal behavior in bipolar disorder. Ketamine has also demonstrated efficacy in studies of suicidal ideation, post- traumatic stress disorder, obsessive compulsive disorder, bipolar disorder, social anxiety disorder, and substance use disorders.

In 2012, the Ketamine Advocacy Network was founded. There are now ketamine clinician organizations, multi-state ketamine treatment centers, and large health care systems covering off-label use. At least 140 ketamine clinics in 30 states are run primarily by psychiatrists, but in some cases are run by anesthesiologists or other medical practitioners. As this is an unregulated practice, the Veteran’s Administration (VA) recently issued national protocol guidance. Likewise, the American Psychiatric Association attempted to address safety issues but ultimately concluded that there was insufficient data to propose evidence-based “practice guidelines” for the off-label use of ketamine. Meeting participants considered how these ketamine clinics could be monitored for safety and how to capture the data generated. Dr. Mathew remarked that states are in the best position to restrict medical privileges for off-label use of ketamine, and the creation of a registry is an essential next step. Dr. Lieberman asked whether researchers were considering how to optimize the therapeutic effect by mode of administration. Dr. Mathew replied that to minimize patient discomfort, slow continuous infusion of ketamine over 40-60 minutes has been the most common protocol. Bolus administration has not been extensively investigated but might be associated with more side effects.

The State of Suicide Prevention in Emergency Care Settings

Jane Pearson, Ph.D., Program Chief, Division of Services and Intervention Research, NIMH

Dr. Jane Pearson stated that suicide prevention is an NIMH priority in which every member of the Coalition has a stake. The Research Prioritization Task Force of the National Action Alliance for Suicide Prevention surveyed many of the Coalition members on aspirational goals to develop a suicide research agenda. Instead of thinking only of demographic risk factors such as age and geographic region, the Task Force came up with an approach that looked for settings where suicide decedents had been identified at risk before death and could have been helped. One of these groups is the estimated 500,000 patients seen in an emergency department (ED) for suicide attempts each year. NIMH funded the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE) study of 1,400 suicidal patients in eight EDs. Three separate phases evaluated ED treatment as usual, the administration of a universal suicide risk screening, and the administration of a universal screening plus brief in ED and telephone follow-up intervention. Suicidal behavior decreased by 30 percent within the 12 months following brief ED screening and follow-up interventions. NIMH staff have estimated benefits of ED interventions through statistical modeling, including ED-SAFE telephone follow up, caring letters, and suicide-focused cognitive behavioral therapy. These efforts are estimated to be cost-effective when incorporated into the ED workflow, and even cost savings in the case of using caring contacts. Dr. Pearson mentioned that a safety-planning intervention, initially developed by NIMH and used by the VA, is being studied in the Suicide Prevention for at-Risk Individuals in Transition (SPIRIT) NIMH study that focuses on high-risk inmates as they are released from jail and prison into the community. Dr. Mark Rapaport of the American Association of Chairs of Departments of Psychiatry asked how the effort was coordinated with the Substance Abuse and Mental Health Services Administration (SAMHSA) and the VA. Dr. Pearson stated that NIMH is frequent contact with VA and SAMHSA staff, and is coordinating with SAMHSA through the Interdepartmental Serious Mental Illness Coordinating Committee. Dr. Gordon added that NIMH has is working with SAMHSA on their Zero Suicide in health systems grants to form a learning collaborative.

Emergency Department Screen for Teens at Risk for Suicide (ED-STARS) Update

Cheryl A. King, Ph.D., Professor, Departments of Psychiatry and Psychology, University of Michigan

Dr. King thanked Dr. Pearson for her introduction to NIMH’s ED suicide prevention research. Suicide is now the second leading cause of death among adolescents. Many of these youths have no history of mental health services and for about half of them, their first attempt is fatal. Youth screening is therefore critical to identify at-risk individuals and intervene to prevent morbidity and mortality. ED-STARS is designed to address current challenges with existing screening instruments and the prevalence of youth who deny or conceal suicidal thoughts. A total of 15 Pediatric Emergency Care Applied Research Network (PECARN) EDs as well as the Whiteriver PHS Indian Hospital ED administered a Computerized Adaptive Screen (CAS) to compare to the standard Ask Suicide-Screening Questions (ASQ). They screened approximately 6,500 youth aged 12 to 17 and then measured the outcomes of a high-risk subset of 3,000 youth for three and six months. The initial goal to develop a CAS with sufficient sensitivity and improved specificity was met. The second part of the study has now begun to validate the CAS with a new sample of youth. This sample is enriched for youth at elevated suicide risk as approximately 40 percent of the sample presented to the ED with psychiatric chief complaints. Dr. King added that she and her team of colleagues recently launched an associated study to identify 24-hour warning signs for suicide in 1,800 high-risk youth from the ED-STARS sample. As the evidence-base is scant, the study is employing a case crossover design where each youth functions as their own control. A case control design will also be used to match three youth who did not make a suicide attempt to each youth who did. The selected youth will be followed for an additional 18 months after ED-STARS via an incentivized text messaging survey to report attempted suicide events. Dr. Lieberman asked whether any similar interventions were being considered for primary care settings and schools. Dr. King replied that the advantages of ED screening are that high-risk youth are better represented than in primary care (higher proportion of males), screening is relatively easy to administer in ED waiting rooms due to common waiting times, youth are usually accompanied by a parent, and there seems to be a relatively high acceptability for being asked personal questions. Dr. Sara Kim of the Asian American Psychological Association expressed her concern with the use of technological interventions when social media use has been implicated as a risk factor. Dr. King replied that she has consulted with technology experts and that her study only sends text messages to youth every two weeks as a means of screening them rather than intervening with them.

Director’s Update

Joshua A. Gordon, M.D., Ph.D., Director, NIMH

Dr. Gordon stated that he planned to update the participants on the latest legislative, budget, and leadership news as well as NIMH initiatives and the balance of NIMH’s portfolio investments. His discussions with congressional representatives across the country have revealed their interest in research that can have an immediate impact, especially with regards to the opioid epidemic. He has made an effort to connect the opioid crisis to the increasing rates of substance use, depression, and suicide in the United States. In terms of the budget, an increase in 2017 allowed NIMH to keep pace with inflation and maintain a trend of funding rates at or above 20 percent. Dr. Gordon highlighted the Online Partnership to Accelerate Research (OnPAR) with Leidos Health’s Life Sciences Division to match excellent scoring, unfunded NIH applications with private biomedical foundations and/or industries seeking to fund promising research. Dr. Gordon then noted changes in leadership. Elinore McCance-Katz has been named the Assistant Secretary for Mental Health and Substance Abuse, a position that replaces the former Director of SAMHSA. At NIMH, Pamela Collins, former Director of the Office for Research on Disparities and Global Mental Health (ORDGMH) has returned to work in academia. The Interagency Autism Coordinating Committee has released several publications including a research portfolio analysis report of the autism research being conducted across multiple government agencies. A total of 110 FY17 Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative® awards were granted to over 178 investigators at 56 institutions. NIMH plans to engage participants in the All of Us Research Program in various Research Domain Criteria (RDoC) endeavors to develop much needed bottom-up, data driven approaches to advance therapeutics. Dr. Gordon then review a few NIMH science highlights. A conglomerate of 11 health care systems in the Mental Health Research Network have agreed to share data on over 39 million patients and address questions on racial-ethnic differences in psychiatric diagnoses and treatment. Finally, Dr. Gordon commented on the shift to long-term research investments in the NIMH research portfolio over the past few years. Funding opportunity announcements with set asides for clinical trials as well as services and implementation research have been released to help stabilize this trend. Dr. Rapaport questioned where NIMH stood in terms of creating a learning health system. Dr. Gordon remarked that NIMH’s Early Psychosis Intervention Network (EPINET) is an effort to encourage early psychosis treatment clinics to agree to certain data reporting requirements and engage with academic investigators with the goal of developing a learning healthcare system. Dr. Paula Skedsvold of the Federation of Associations in Behavioral and Brain Scientists asked how NIMH was responding to the recent school shootings. Dr. Gordon stated that NIMH is open to support research on gun violence and has funded a number of studies looking at the relationship between mental health and violence in the past.

NIMH Coalition Engagement Session: Group Discussion

Joshua A. Gordon, M.D., Ph.D., Director, NIMH

Dr. Gordon stated the purpose of the meeting engagement session was to understand the ways in which being a Coalition member provides value to the Coalition organizations and how well the Coalition meetings serve that purpose. Dr. Rapaport proposed prototyping activities to maintain ongoing dialogue and feedback from members such as surveys. Other participants suggested inviting other Federal partners (e.g., Department of Housing and Urban Development) and organizations that are not normally represented in the mental health field (e.g., the National Association of Secondary School Principals) to future Coalition meetings to expand upon the translational applications of the research. Members also responded positively to a suggestion by Dr. Gordon to convene the Coalition meeting alongside the Alliance for Research Progress advocacy group meeting every couple of years. Dr. Lieberman asked whether NIMH would welcome more proactive stakeholder engagement in public advocacy, and if NIMH had a role to play in harmonizing diverse stakeholder positions. Dr. Gordon replied that members can help spread the message of the importance of NIMH research, but it is not within NIMH’s purview to promote certain positions over others. He noted that Ms. Phyllis Ampofo, Legislative Director, is the person to contact with regards to interacting with legislators and encouraged the participants to inform her of any legislative initiatives in which their organizations are involved. Coalition members representing underrepresented populations expressed their concern that little progress has been made in disparities research. Dr. Gordon acknowledged the need to strengthen the disparities research. Dr Gordon remarked that the NIMH experimental therapeutics initiative was designed to address gaps in NIMH investments. NIMH hopes to fill the role of the ORDGMH Director with an individual experienced in the application of novel approaches. In response to questions as to how they could provide input earlier in the research development process, Dr. Gordon remarked that Coalition members could be represented in the workshops and consultations with the extramural community that are used to develop funding opportunity announcements. Ms. Carmen, Head of the American Academy of Child and Adolescent Psychiatry, applauded the number of awards NIMH has granted to early career investigators and mentioned that her organization also has an extensive awards portfolio for these applicants.

Research and Partnerships: A Pathway to Reduce Disparities in Mental Health

Andrea Horvath Marques, M.D., Ph.D., M.P.H., Program Chief, Office of Research on Disparities and Global Mental Health, NIMH

Dr. Horvath Marques introduced herself as the Chief of the Mental Health Disparities Research Program at ORDGMH that aims to reduce mental health disparities in the United States and around the globe. The prevalence of mental health disorders in racial and ethnic minorities varies. However, these groups are less likely to have access to mental health services and a lower quality of care when services are available. To address these challenges, NIMH has developed policies as well as research and partnership initiatives. In 2015 the NIMH Strategic Plan for Research designated mental health disparities as a cross-cutting research theme and required the enrollment of minorities in NIMH research. Dr. Horvath Marques stated that NIMH recognizes the mental health workforce shortage is most pronounced in rural areas, resulting in unequal access to care. NIMH has partnered with other institutes and convened a workshop on how to train the next generation of implementation researchers for health equity. In addition, a Federal Interagency Health Equity Team meets on a monthly basis to identify opportunities for federal collaboration, partnership to advance health equity. Dr. Horvath Marques noted that the results of a recent study using a simulation test of NIMH and Social Security Administration datasets showed the importance of addressing social determinants of health (e.g., increasing employment) for improving mental and physical health among people with mental disorders. In September 2017, NIMH partnered with the Health Resource Service Administration to implement a collaborative care model with 11 safety net clinics that treat approximately 250,000 patients annually across the country. Dr. Horvath Marques concluded by describing how ORDGMH, in partnership with the National Institute on Minority Health and Health Disparities, is translating the “hub model” applied in low and middle-income countries to populations of American Indian and Alaska Native youth in the United States to reduce suicide and promote resilience. Hubs are defined as multidisciplinary research teams and their collaborators focused on a common research topic.

Mental Health Disparities and Strengths-based Approaches for Vulnerable Populations

Mary Cwik, Ph.D., Associate Scientist, Johns Hopkins Bloomberg School of Public Health

Dr. Cwik presented on a long-term partnership between the Johns Hopkins Center for American Indian Health and the White Mountain Apache Tribe, an autonomous nation in eastern Arizona consisting of approximately 17,500 enrolled tribal members. The rate of youth suicide in the Apache reservation spiked beginning in the 1980’s. In 2001, a tribal resolution was passed mandating that all community members were responsible for reporting individuals at risk for self-injurious behavior. The community-based system has produced a significant amount of data, insight into the underlying motivations for suicide, and connected at-risk individuals to care. The benefits of a program utilizing trained community health professionals include flexibility in service delivery and understanding of the language and culture. Tribal sovereignty provides a unique opportunity to develop creative solutions attributable to the Apache belief in the sacredness of life, strong family networks, and respect for cultural identity and traditions. Research findings included a close ratio between male and female suicide attempts, hanging as the primary suicide method, and conflict with partner or close relative, loss of a loved one, and substance use as common motivators. Johns Hopkins in partnership with the tribe also obtained several SAMHSA grants to develop comprehensive prevention methods, including community-wide education, early identification and triage of high-risk youth, and an intensive intervention for youth who made suicide attempts and their families. One hypothesis for the rising suicide rate is that younger generations are losing their sense of tribal identity. This has prompted Apache Elders to engage with youth as mentors in elementary school workshops and field trips, as well as develop a middle school curriculum. This comprehensive program has successfully decreased the suicide death rate in Apache youth from 40 to 24 percent as last reported in 2012. The program was awarded one of the three ORDGMH-sponsored hubs for American Indian youth suicide prevention that will allow for dissemination of the Apache model to other tribes. Future surveillance will include CommCare machine learning algorithms to predict suicide risk. They are now planning to conduct a Sequential Multiple Assignment Randomized Trial examining the effects of the evidence-based intervention New Hope and an Elders’ Resiliency curriculum. Initial pilot data reveals that New Hope has decreased youth ED visits for suicide risk. Ms. Head asked whether there were any publications on their community based participatory (CBPR) approach. Dr. Cwik replied that a paper is currently being written, but their primary method of dissemination of the CBPR model is via week-long training courses at Johns Hopkins.

FINAL DISCUSSION AND WRAP-UP

NIMH staff confirmed that the presentation slides will be distributed to attendees through an electronic platform. The moderator thanked members for their participation and encouraged them to provide feedback on the meeting in the evaluation forms and to be in contact with NIMH in the upcoming year. The Coalition meeting adjourned at 3:50 P.M.

REFERENCE

¹ Nugent AC et al., Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects., Mol. Psychiatry. Feb. 2018.

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Professional Coalition for Research Progress: 2018 Meeting

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