Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Leveraging DNA methylation to predict treatment response in major depressive disorder: A critical review.

Major depressive disorder (MDD) is a debilitating and prevalent mental disorder with a high disease burden. Despite a wide array of different treatment options, many patients do not respond to initial treatment attempts. Selection of the most appropriate treatment remains a significant clinical challenge in psychiatry, highlighting the need for the development of biomarkers with predictive utility. Recently, the epigenetic modification DNA methylation (DNAm) has emerged to be of great interest as a potential predictor of MDD treatment outcomes. Here, we review efforts to date that seek to identify DNAm signatures associated with treatment response in individuals with MDD. Searches were conducted in the databases PubMed, Scopus, and Web of Science with the concepts and keywords MDD, DNAm, antidepressants, psychotherapy, cognitive behavior therapy, electroconvulsive therapy, transcranial magnetic stimulation, and brain stimulation therapies. We identified 32 studies implicating DNAm patterns associated with MDD treatment outcomes. The majority of studies (N = 25) are focused on selected target genes exploring treatment outcomes in pharmacological treatments (N = 22) with a few studies assessing treatment response to electroconvulsive therapy (N = 3). Additionally, there are few genome-scale efforts (N = 7) to characterize DNAm patterns associated with treatment outcomes. There is a relative dearth of studies investigating DNAm patterns in relation to psychotherapy, electroconvulsive therapy, or transcranial magnetic stimulation; importantly, most existing studies have limited sample sizes. Given the heterogeneity in both methods and results of studies to date, there is a need for additional studies before existing findings can inform clinical decisions.

Three-dimensional optical imaging of brain activation during transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of the brain is an effective clinical treatment for psychiatric disorders. Noninvasive neuroimaging during rTMS allows visualization of cortical brain activations and responses, and it is a potential tool for investigating the neurophysiological response occurring actively during stimulation. In this paper, we present a fast diffuse optical tomography (DOT) approach for three-dimensional brain mapping of hemodynamics during rTMS. Eight healthy subjects were enrolled in the study. These subjects received 10 Hz stimulation with 80%and 100%of resting motor threshold (rMT), respectively, for 4 seconds for each stimulation. Significant hemodynamic activation was observed in all cases with the strongest response when 100%rMT stimulation was applied. This work demonstrates that fast DOT has the potential to become a powerful tool for noninvasive three-dimensional imaging of the brain during rTMS.

Comparing the effect of the novel ionic cocrystal of lithium salicylate proline (LISPRO) with lithium carbonate and lithium salicylate on memory and behavior in female APPswe/PS1dE9 Alzheimer's mice.

Alzheimer's disease (AD) is characterized by progressive decline of cognition and associated neuropsychiatric signs including weight loss, anxiety, depression, agitation, and aggression, which is particularly pronounced in the female gender. Previously, we have shown that a novel ionic co-crystal of lithium salicylate proline (LISPRO) is an improved lithium formulation compared to the carbonate or salicylate form of lithium in terms of safety and efficacy in reducing AD pathology in Alzheimer's mice. The current study is designed to compare the prophylactic effects of LISPRO, lithium carbonate (LC), and lithium salicylate (LS) on cognitive and noncognitive impairments in female transgenic APPswe/PS1dE9 AD mice. Female APPswe/PS1dE9 mice at 4 months of age were orally treated with low-dose LISPRO, LS, or LC for 9 months at 2.25 mmol lithium/kg/day followed by determination of body weight, growth of internal organs, and cognitive and noncognitive behavior. No significant differences in body or internal organ weight, anxiety or locomotor activity were found between lithium treated and untreated APPswe/PS1dE9 cohorts. LISPRO, LC, and LS prevented spatial cognitive decline, as determined by Morris water maze and depression as determined by tail suspension test. In addition, LISPRO treatment was superior in preventing associative memory decline determined by contextual fear conditioning and reducing irritability determined by touch escape test in comparison with LC and LS. In conclusion, low-dose LISPRO, LC, and LS treatment prevent spatial cognitive decline and depression-like behavior, while LISPRO prevented hippocampal-dependent associative memory decline and irritability in APPswe/PS1dE9 mice.

Reducing Suicide Risk: Challenges and Opportunities in the Emergency Department.

Emergency departments (ED) are prime locations for identifying individuals at high risk of suicide and for making life-saving interventions. In an ideal scenario, all ED patients at risk of suicide could be identified and connected with effective, feasible interventions, and this would occur in a supportive system not overburdened by screening or assessment requirements. In this review, we focus on challenges to achieving this ideal--along with potential solutions--at the level of patients, providers, the ED environment, and the larger health care system.

Brief Intervention and Follow-Up for Suicidal Patients With Repeat Emergency Department Visits Enhances Treatment Engagement.

We implemented an innovative, brief, easy-to-administer 2-part intervention to enhance coping and treatment engagement. The intervention consisted of safety planning and structured telephone follow-up postdischarge with 95 veterans who had 2 or more emergency department (ED) visits within 6 months for suicide-related concerns (i.e., suicide ideation or behavior). The intervention significantly increased behavioral health treatment attendance 3 months after intervention, compared with treatment attendance in the 3 months after a previous ED visit without intervention. The trend was for a decreasing hospitalization rate.

Older Adults with Mental Disorders: What Factors Distinguish Those Who Present to Emergency Departments for Mental Health Reasons from Those Who Do Not?

OBJECTIVE: To identify among older adults with mental disorders factors associated with those who present to emergency departments (EDs) for mental health reasons versus those who do not. METHODS: The authors conducted a secondary, cross-sectional analysis of the Medical Expenditure Panel Survey (MEPS), which comprises a representative sample of the U.S. civilian noninstitutionalized population. Of the MEPS participants ages 66 and older on December 31 of the survey years 2000-2005, the analysis sample (2,757) included the 177 persons with at least one mental health ED visit and the 2,580 persons with mental disorders without such a visit. The three categories of the Andersen behavioral model for healthcare services utilization-predisposing, enabling, and need factors-were used as the theoretical framework for the independent variables. RESULTS: Logistic regression analysis indicated that four need factors (adjustment disorder [OR: 3.42], psychosis [OR: 2.68], fair perceived physical health status [OR: 2.24], and anxiety disorder [OR: 1.85]) and two predisposing characteristics (widowed and living alone [OR: 1.68] and female [OR: 1.56]) were significantly associated with older adults with mental disorders who present to an ED for mental health reasons. Good perceived mental health status (OR: 0.55) was protective against presenting to an ED. CONCLUSION: EDs that serve populations with higher proportions of older persons that are women, widowed and living alone, with adjustment disorder, psychosis, anxiety disorders, or fair perceived physical health should expect to have a greater likelihood of older persons visiting the ED for mental health reasons.

Impact of the Patient Protection and Affordable Care Act on Emergency Psychiatry.

Emergency psychiatry (EP) is an integral component of comprehensive hospital-based emergency care. EP developed and grew into a medical subspecialty in response to deinstitutionalization and other large-scale forces, resulting in large numbers of psychiatric patients presenting to emergency departments. The Affordable Care Act (ACA) of 2010 contains several features and provisions that are likely to impact the practice of EP. This article reviews and examines the impact of the ACA on psychiatric emergency care to date and anticipated in the near future.

Mental Health Evacuation Rate in USCENTCOM.

BACKGROUND: Mental health diagnosis requiring further treatment is one of the top reasons for medical evacuation in the U.S. Central Command (USCENTCOM) area of responsibility (AOR) as of 2022. This study establishes a baseline in which the effectiveness of medical interventions can be measured to determine if they have an impact on the rate of evacuation out of USCENTCOM. MATERIALS AND METHODS: The study period was January 1, 2017 to December 31, 2021. Individual evacuation data including date of initial movement and necessary specialty care requirements originating from the USCENTCOM AOR were acquired via U.S. Transportation Command's Regulating and Command & Control Evacuation System. The base evacuation rate was calculated for each month, and evacuation rates were analyzed for variations. RESULTS: For the entire study period, the mean monthly evacuation rate was 0.44 evacuations per 1,000 people in the AOR (95% CI, 0.41-0.47). There was no statistically significant difference between any monthly evacuation rate (P = .505). There is a statistically significant difference in the mean evacuation rates for calendar years (P = .003). The highest evacuation rate occurred in 2021. CONCLUSIONS: The study establishes a benchmark mental health evacuation rate. This rate will be useful for assessing mental health evacuation reduction initiatives in the USCENTCOM AOR.

Incidence of Suicidal Ideation and Suicide Attempt Based on Time in a Deployed Environment.

INTRODUCTION: Knowing when suicidal ideation (SI) or suicide attempt (SA) is most likely to occur in a deployed environment would aid in focusing prevention efforts. This study aims to determine when evacuation for SA and SI is most likely to occur based on the absolute and relative number of months in a deployed setting. MATERIALS AND METHODS: This is a case-control study of active-duty military personnel evacuated from the U.S. Central Command area of responsibility for SI or an SA between April 1, 2020, and March 30, 2021. The arrival month and expected departure month were identified for all the included evacuees. The month of evacuation and proportion of completed deployment were compared. Secondary outcomes of mental health diagnosis or need for a waiver was also examined. RESULTS: A total of 138 personnel evacuated for SI or attempted suicide during the 12-month study period were included in the analysis. Evacuations occurring during month 3 of deployment were significantly higher (P < .0001) than those during other months. The 30% and 50% completion point of deployment had statistically higher frequencies of evacuations for SI/SA (<.0001). A secondary analysis revealed that 25.4% of the individuals had a documented preexisting behavioral health condition before deployment (P < .0001). CONCLUSION: Specific points along a deployment timeline were significant predictors for being evacuated for SI and SA.

An emergency department-based brief intervention for veterans at risk for suicide (SAFE VET).

Reducing deaths from veteran suicide is a public health priority for veterans who receive their care from the Department of Veterans Affairs (VA) and those who receive services in community settings. Emergency departments frequently function as the primary or sole point of contact with the health care system for suicidal individuals; therefore, they represent an important venue in which to identify and treat veterans who are at risk for suicide. We describe the design, implementation and initial evaluation of a brief behavioral intervention for suicidal veterans seeking care at VA emergency departments. Initial findings of the feasibility and acceptability of the intervention suggest it may be transferable to diverse VA and non-VA settings, including community emergency departments and urgent care centers.

Prevalence, correlates, and symptom profiles of depression among men with a history of military service.

PURPOSE: The purpose of this study was to examine the prevalence, correlates, and symptom profiles of depressive disorders in men with a history of military service. METHODS: Data were obtained from the 2006 Behavioral Risk Factor Surveillance System survey. Multivariable logistic regressions were used to identify correlates of lifetime and current depression. Regularly occurring symptom profiles were identified via cluster analysis. RESULTS: Prevalence of lifetime and current depression was similar in men with and without a history of military service. Younger age was positively, and black minority status, being in a relationship and self-reported good health were negatively associated with a lifetime diagnosis of depression. Other minority status (non-Hispanic, non-black) was positively, and older age, some college, being in a relationship, and self-reported good health were negatively associated with current depression. A cluster of younger men who experience significant depressive symptoms but may not report depressed mood or anhedonia was identified. CONCLUSIONS: Depression is as prevalent in men with a history of military service as it is in men without a history. Research should focus on subpopulations of men with a history of military service in which depression may be more prevalent or burdensome. Younger men with significant depressive symptoms may be missed by standard depression screens and still be at elevated risk for negative outcomes associated with depression.

Teaching physicians to assess suicidal youth presenting to the emergency department.

OBJECTIVES: The objective of this study was to determine whether a 5-module self-paced computerized educational program improves residents' skills in assessing and managing youth presenting to the emergency department in acute psychiatric distress. METHODS: The evaluation used a quasi-experimental posttest-only design assessing both knowledge of the educational context of the program and self-rated pretest knowledge of program content with 32 residents recruited from 1 medical center in Cleveland, Ohio. RESULTS: About half of the respondents were female (48%); almost two thirds were white (65%), and few were trained in psychiatric assessment of children/adolescents. On average, residents had significantly higher scores on the posttest compared with the self-rated pretest (6.4 ± 1.1 vs 3.8 ± 2.3; P < 0.001), an effect size of 1.32. Residents responded positively to the modules and rated them highly on educational content (4.2 ± 0.5 on a 5-point scale) and satisfaction with clinical applicability (8.2 ± 1.2 on a 10-point scale) and found the program easy to navigate (8.5 ± 1.9 on a 10-point scale). CONCLUSIONS: A brief, self-administered, Web-based training program shows promise for improving residents' knowledge about suicidal behaviors in youth.

Neuroimaging of depression with diffuse optical tomography during repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and safe treatment for depression; however, its potential has likely been hindered due to non-optimized targeting, unclear ideal stimulation parameters, and lack of information regarding how the brain is physiologically responding during and after stimulation. While neuroimaging is ideal for obtaining such critical information, existing modalities have been limited due to poor resolutions, along with significant noise interference from the electromagnetic spectrum. In this study, we used a novel diffuse optical tomography (DOT) device in order to advance our understanding of the neurophysiological effects of rTMS in depression. Healthy and depressed subjects aged 18-70 were recruited. Treatment parameters were standardized with targeting of the left dorsolateral prefrontal cortex with a magnetic field intensity of 100% of motor threshold, pulse frequency of 10 per second, a 4 s stimulation time and a 26 s rest time. DOT imaging was simultaneously acquired from the contralateral dorsolateral prefrontal cortex. Six healthy and seven depressed subjects were included for final analysis. Hemoglobin changes and volumetric three-dimensional activation patterns were successfully captured. Depressed subjects were observed to have a delayed and less robust response to rTMS with a decreased volume of activation compared to healthy subjects. In this first-in-human study, we demonstrated the ability of DOT to safely and reliably capture and compare cortical response patterns to rTMS in depressed and healthy subjects. We introduced this emerging optical functional imaging modality as a novel approach to investigating targeting, new treatment parameters, and physiological effects of rTMS in depression.

NIH Roundtable on Opportunities to Advance Research on Neurologic and Psychiatric Emergencies.

STUDY OBJECTIVE: The Institute of Medicine Committee on the Future of Emergency Care in the United States Health System (2003) identified a need to enhance the research base for emergency care. As a result, a National Institutes of Health (NIH) Task Force on Research in Emergency Medicine was formed to enhance NIH support for emergency care research. Members of the NIH Task Force and academic leaders in emergency care participated in 3 Roundtable discussions to prioritize current opportunities for enhancing and conducting emergency care research. We identify key research questions essential to advancing the science of emergency care and discuss the barriers and strategies to advance research by exploring the collaboration between NIH and the emergency care community. METHODS: Experts from emergency medicine, neurology, psychiatry, and public health assembled to review critical areas in need of investigation, current gaps in knowledge, barriers, and opportunities. Neurologic emergencies included cerebral resuscitation, pain, stroke, syncope, traumatic brain injury, and pregnancy. Mental health topics included suicide, agitation and delirium, substances, posttraumatic stress, violence, and bereavement. RESULTS: Presentations and group discussion firmly established the need for translational research to bring basic science concepts into the clinical arena. A coordinated continuum of the health care system that ensures rapid identification and stabilization and extends through discharge is necessary to maximize overall patient outcomes. There is a paucity of well-designed, focused research on diagnostic testing, clinical decisionmaking, and treatments in the emergency setting. Barriers include the limited number of experienced researchers in emergency medicine, limited dedicated research funding, and difficulties of conducting research in chaotic emergency environments stressed by crowding and limited resources. Several themes emerged during the course of the roundtable discussion, including the need for development of (1) a research infrastructure for the rapid identification, consent, and tracking of research subjects that incorporates innovative informatics technologies, essential for future research; (2) diagnostic strategies and tools necessary to understand key populations and the process of medical decisionmaking, including the investigation of the pathobiology of symptoms and symptom-oriented therapies; (3) collaborative research networks to provide unique opportunities to form partnerships, leverage patient cohorts and clinical and financial resources, and share data; (4) formal research training programs integral for creating new knowledge and advancing the science and practice of emergency medicine; and (5) recognition that emergency care is part of an integrated system from emergency medical services dispatch to discharge. The NIH Roundtable "Opportunities to Advance Research on Neurological and Psychiatric Emergencies" created a framework to guide future emergency medicine-based research initiatives. CONCLUSION: Emergency departments provide the portal of access to the health care system for most patients with acute neurologic and psychiatric illness. Emergency physicians and colleagues are primed to investigate neurologic and psychiatric emergencies that will directly improve the delivery of care and patient outcomes.

A Research Agenda for Assessment and Management of Psychosis in Emergency Department Patients.

INTRODUCTION: Emergency departments (ED) manage a wide variety of critical medical presentations. Traumatic, neurologic, and cardiac crises are among the most prevalent types of emergencies treated in an ED setting. The high volume of presentations has led to collaborative partnerships in research and process development between experts in emergency medicine (EM) and other disciplines. While psychosis is a medical emergency frequently treated in the ED, there remains a paucity of evidence-based literature highlighting best practices for management of psychotic presentations in the ED. In the absence of collaborative research, development of best practice guidelines cannot begin. A working group convened to develop a set of high-priority research questions to address the knowledge gaps in the care of psychotic patients in the ED. This article is the product of a subgroup considering "Special Populations: Psychotic Spectrum Disorders," from the 2016 Coalition on Psychiatric Emergencies first Research Consensus Conference on Acute Mental Illness. METHODS: Participants were identified with expertise in psychosis from EM, emergency psychiatry, emergency psychology, clinical research, governmental agencies, and patient advocacy groups. Background literature reviews were performed prior to the in-person meeting. A nominal group technique was employed to develop group consensus on the highest priority research gaps. Following the nominal group technique, input was solicited from all participants during the meeting, questions were iteratively focused and revised, voted on, and then ranked by importance. RESULTS: The group developed 28 separate questions. After clarification and voting, the group identified six high-priority research areas. These questions signify the perceived gaps in psychosis research in emergency settings. Questions were further grouped into two topic areas: screening and identification; and intervention and management strategies. CONCLUSION: While psychosis has become a more common presentation in the ED, standardized screening, intervention, and outcome measurement for psychosis has not moved beyond attention to agitation management. As improved outpatient-intervention protocols are developed for treatment of psychosis, it is imperative that parallel protocols are developed for delivery in the ED setting.

Predictive Validity of the Columbia-Suicide Severity Rating Scale among a Cohort of At-risk Veterans.

OBJECTIVE: To examine the psychometric properties of the Columbia- Suicide Severity Rating Scale (C-SSRS) among a cohort of veterans identified to be at risk for suicide. METHOD: Convergent, divergent, and predictive validity of the C-SSRS were examined using secondary data from a study of veterans who presented to the psychiatric emergency room (n = 237). Data were collected 1 week, 1 month, 3 months, and 6 months following emergency room discharge. RESULTS: Results demonstrated good evidence for convergent and divergent validity. Baseline intensity subscale scores predicted actual and interrupted attempts, and any behavior for all available data and for the subsample who had 6-month follow-up data, and also predicted preparatory behavior in the full sample. Baseline severity subscale scores predicted preparatory behavior and any behavior for the full sample and for those with 6 months of follow-up, and actual attempts for the full sample. Severity of ideation cutoff scores was significantly associated with actual attempts and any behavior in both samples. Adding a prior behavior criterion demonstrated similar results. CONCLUSIONS: Findings suggest that the C-SSRS is a psychometrically sound measure that can be used to augment suicide risk assessment with veterans who are already identified to be at risk for suicide.

Psychiatric emergency services for the U.S. elderly: 2008 and beyond.

In 2011 the oldest baby boomers will turn age 65. Although healthcare researchers have started to examine the future preparedness of the healthcare system for the elderly, psychiatric emergency services (PES) have been widely overlooked. Research is needed to address PES need and demand by older patients, assess the consequences of this need or demand, and establish recommendations to guide PES planning and practice. The authors examined journal articles, review articles, textbooks, and electronic databases related to these topics. The authors outline the current PES environment in terms of facilities, characteristics, and visits, and discuss current geriatric patient PES use. Factors expected to impact future use are examined, including sociodemographic characteristics, psychiatric illness prevalence, cohort effects, medical comorbidity, mental healthcare resources and utilization, and stigma. Consequences of these on future psychiatric care and well-being of the elderly are then explored, specifically, greater acute services need, more suicide, strained delivery systems, increased hospitalization, and greater costs. The following are proposed to address likely future PES shortcomings: enhance service delivery, increase training, standardize and improve PES, prioritize finances, and promote research. The degree to which the geriatric mental healthcare "crisis" develops will be inversely related to the current system's response to predictable future needs.

Do geographic regions with higher suicide rates also have higher rates of nonfatal intentional self-harm?

Fatal and nonfatal intentional self-harm events in eight U.S. states were compared using emergency department, hospital, and vital statistics data. Nonfatal event rates increased by an estimated 24.20% over 6 years. Case fatality ratios varied widely, but two northeastern states' total event rates (fatal plus nonfatal) were very high (New Hampshire 206.5/100,000 person years; Massachusetts 166.7/100,000). Geographic context did not uniformly impact the likelihood of self-harm across event types. The state-level public health burden posed by such acts cannot, therefore, be accurately estimated from either mortality or morbidity data alone.

Suicidal Behavior and Non-Suicidal Self-Injury in Emergency Departments Underestimated by Administrative Claims Data.

BACKGROUND: External causes of injury codes (E-codes) are used in administrative and claims databases for billing and often employed to estimate the number of self-injury visits to emergency departments (EDs). AIMS: This study assessed the accuracy of E-codes using standardized, independently administered research assessments at the time of ED visits. METHOD: We recruited 254 patients at three psychiatric emergency departments in the United States between 2007 and 2011, who completed research assessments after presenting for suicide-related concerns and were classified as suicide attempters (50.4%, n = 128), nonsuicidal self-injurers (11.8%, n = 30), psychiatric controls (29.9%, n = 76), or interrupted suicide attempters (7.8%, n = 20). These classifications were compared with their E-code classifications. RESULTS: Of the participants, 21.7% (55/254) received an E-code. In all, 36.7% of research-classified suicide attempters and 26.7% of research-classified nonsuicidal self-injurers received self-inflicted injury E-codes. Those who did not receive an E-code but should have based on the research assessments had more severe psychopathology, more Axis I diagnoses, more suicide attempts, and greater suicidal ideation. LIMITATIONS: The sample came from three large academic medical centers and these findings may not be generalizable to all EDs. CONCLUSION: The frequency of ED visits for self-inflicted injury is much greater than current figures indicate and should be increased threefold.