Elizabeth D. Ballard

Allowing Adolescents and Young Adults to Plan Their End-of-Life Care

OBJECTIVE: The objective of this study was to assess and compare the usefulness, helpfulness, and stress associated with reviewing a previously adapted advance care planning guide, My Thoughts, My Wishes, My Voice, in comparison with the widely used adult document Five Wishes by adolescents and young adults (AYAs) living with a serious illness. METHODS: Fifty-two participants (age 16–28) living with metastatic or recurrent cancer or HIV infection (acquired at birth or early in life) were presented pages randomly from My Thoughts, My Wishes, My Voice and, Five Wishes, and asked to rank 25 items on several factors, including how likely they would be to complete each statement. Participant opinion on suggested changes in content, design, format, and style was obtained and resulted in development of a new document. RESULTS: AYAs living with a life-threatening illness want to be able to choose and record (1) the kind of medical treatment they want and do not want, (2) how they would liked to be cared for, (3) information for their family and friends to know, and (4) how they would like to be remembered. CONCLUSIONS: AYA views of what should be included in an advance care planning guide were incorporated into a new document, Voicing My Choices, that provides youth, families and providers an opportunity to reduce the silence around the dying process by allowing an opportunity to share one’s voice. We provide guidance on how to incorporate this tool into care.

Ask Suicide-Screening Questions (ASQ): A brief instrument for the pediatric emergency department

OBJECTIVE To develop a brief screening instrument to assess the risk for suicide in pediatric emergency department patients. DESIGN A prospective, cross-sectional instrument-development study evaluated 17 candidate screening questions assessing suicide risk in young patients. The Suicidal Ideation Questionnaire served as the criterion standard. SETTING Three urban, pediatric emergency departments associated with tertiary care teaching hospitals. PARTICIPANTS A convenience sample of 524 patients aged 10 to 21 years who presented with either medical/surgical or psychiatric chief concerns to the emergency department between September 10, 2008, and January 5, 2011. MAIN EXPOSURES Participants answered 17 candidate questions followed by the Suicidal Ideation Questionnaire. MAIN OUTCOME MEASURES Sensitivity, specificity, predictive values, likelihood ratios, and area under the receiver operating characteristic curves of the best-fitting combinations of screening questions for detecting elevated risk for suicide. RESULTS A total of 524 patients were screened (344 medical/surgical and 180 psychiatric). Fourteen of the medical/surgical patients (4%) and 84 of the psychiatric patients (47%) were at elevated suicide risk on the Suicidal Ideation Questionnaire. Of the 17 candidate questions, the best-fitting model comprised 4 questions assessing current thoughts of being better off dead, current wish to die, current suicidal ideation, and past suicide attempt. This model had a sensitivity of 96.9% (95% CI, 91.3-99.4), specificity of 87.6% (95% CI, 84.0-90.5), and negative predictive values of 99.7% (95% CI, 98.2-99.9) for medical/surgical patients and 96.9% (95% CI, 89.3-99.6) for psychiatric patients. CONCLUSIONS A 4-question screening instrument, the Ask Suicide-Screening Questions (ASQ), with high sensitivity and negative predictive value, can identify the risk for suicide in patients presenting to pediatric emergency departments.

Improvement in suicidal ideation after ketamine infusion: Relationship to reductions in depression and anxiety *

OBJECTIVE Suicide is a psychiatric emergency. Currently, there are no approved pharmacologic treatments for suicidal ideation. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that rapidly reduces suicidal ideation as well as depression and anxiety, but the dynamic between these symptoms is not known. The aim of this analysis was to evaluate whether ketamine has an impact on suicidal thoughts, independent of depressive and anxiety symptoms. METHODS 133 patients with treatment-resistant depression (major depressive disorder or bipolar I/II disorder) received a single subanesthetic infusion of ketamine (0.5 mg/kg over 40 min). Post-hoc correlations and linear mixed models evaluated the relationship between suicidal ideation and depression and anxiety symptoms using the Hamilton Depression Rating Scale (HAMD), Scale for Suicidal Ideation (SSI), Beck Depression Inventory (BDI), and Hamilton Anxiety Rating Scale (HAMA) focusing on 230 min post-infusion. RESULTS At 230 min post-infusion, correlations between changes in suicidal ideation and depression ranged from 0.23 to 0.44 (p < .05), accounting for up to 19% in the variance of ideation change. Correlations with anxiety ranged from 0.23 to 0.40 (p < .05), accounting for similar levels of variance. Ketamine infusion was associated with significant reductions in suicidal ideation compared to placebo, when controlling for the effects of ketamine on depression (F1,587 = 10.31, p = .001) and anxiety (F1,567 = 8.54, p = .004). CONCLUSIONS Improvements in suicidal ideation after ketamine infusion are related to, but not completely driven by, improvements in depression and anxiety. Investigation of the specific effects of ketamine on suicidal thoughts is warranted.

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine’s clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine’s antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine’s antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

In patients with major depressive disorder or bipolar disorder, abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate and gamma-aminobutyric acid have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic-dose ketamine has led to a collection of studies that have examined neurochemical (e.g., glutamatergic and gamma-aminobutyric acidergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.

Feasibility of Screening Patients With Nonpsychiatric Complaints for Suicide Risk in a Pediatric Emergency Department: A Good Time to Talk?

Objective: Screening children for suicide risk when they present to the emergency department (ED) with nonpsychiatric complaints could lead to better identification and treatment of high-risk youth. Before suicide screening protocols can be implemented for nonpsychiatric patients in pediatric EDs, it is essential to determine whether such efforts are feasible. Methods: As part of an instrument validation study, ED patients (10-21 years old) with both psychiatric and nonpsychiatric presenting complaints were recruited to take part in suicide screening. Clinically significant suicidal thoughts, as measured by the Suicidal Ideation Questionnaire, and suicidal behaviors were assessed, as well as patient opinions about suicide screening. Recruitment rates for the study as well as impact on length of stay were assessed. Results: Of the 266 patients and parents approached for the study, 159 (60%) agreed to participate. For patients entering the ED for nonpsychiatric reasons (n = 106), 5.7% (n = 6) reported previous suicidal behavior, and 5.7% (n = 6) reported clinically significant suicidal ideation. There were no significant differences for mean length of stay in the ED for nonpsychiatric patients with positive triggers and those who screened negative (means, 382 [SD, 198] and 393 [SD, 166] minutes, respectively; P = 0.80). Ninety-six percent of participants agreed that suicide screening should occur in the ED. Conclusions: Suicide screening of nonpsychiatric patients in the ED is feasible in terms of acceptability to parents, prevalence of suicidal thoughts and behaviors, practicality to ED flow, and patient opinion. Future endeavors should address brief screening tools validated on nonpsychiatric populations.

Suicide risk in youth with intellectual disabilities: the challenges of screening.

Children and adolescents with intellectual disabilities (IDs), often diagnosed with comorbid psychiatric disorders, are a vulnerable population who may be at risk for developing suicidal thoughts and behaviors. Previous research has demonstrated that direct suicide screening can rapidly and effectively detect suicide risk and facilitate further clinical evaluation and management. Currently, there are no measures that screen for suicide risk designed specifically for individuals with ID. A review of the literature was conducted to (1) estimate the prevalence of suicidal thoughts, behaviors, and deaths by suicide in children and adolescents with ID; (2) describe associations between youth with ID and suicide risk; and (3) identify the limitations of commonly used suicide screening measures developed for non-ID youth. The literature review confirms that suicide risk exists in this population; youth with ID think about, attempt, and die by suicide. Standardized suicide risk screening is challenged by the lack of measures developed for this population. A summary of the findings is followed by a discussion of the practical clinical considerations surrounding the assessment of suicide risk in youth with ID.

Suicide in the Medical Setting

BACKGROUND Little is known about suicide in the hospital setting. Although suicide is a major public health concern, the literature on suicide in the medical setting is limited, and accurate data on hospital-based suicides are unavailable. Consequently, the prevalence, demographic characteristics, and risk factors for suicide in this population are unknown. The literature on completed suicides in medical or surgical wards of a general hospital was summarized to generate hypotheses for further investigation regarding in-hospital suicides. METHODS MEDLINE, PsycINFO, IndexCat, and Scopus were queried for English-language articles on inpatient suicides in a general hospital. These data were compared with reports of suicide by psychiatric inpatients and the annual suicide statistics from the U.S. general population. RESULTS Twelve articles detailing 335 suicides in the medical setting were included. Published data on hospital-based suicides are limited by selection bias, incomplete reporting, and a small number of completed suicides. Consequently, no significant setting-specific findings emerge from the existing literature. Reported cases suggest that inpatients who commit suicide in the medical setting may have a different demographic profile and employ different methods of suicide in comparison with individuals who commit suicide in psychiatric settings or the general population. DISCUSSION Given the absence of systematic data collection and the highly variable nature of reported suicides, it could not be determined if clinically relevant distinctions exist between suicides in different health care settings. Prospective and more detailed data collection are needed because a more complete characterization of suicide in medical inpatients may be useful in both prevention approaches and institutional policies with respect to hospital-based suicides.

The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis

OBJECTIVE Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation. METHOD Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration. RESULTS Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohens d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamines effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms. CONCLUSIONS Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamines effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamines long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Therapeutic Modulation of Glutamate Receptors in Major Depressive Disorder

Current pharmacotherapies for major depressive disorder (MDD) have a distinct lag of onset that can prolong distress and impairment for patients, and real-world effectiveness trials further suggest that antidepressant efficacy is limited in many patients. All currently approved antidepressant medications for MDD act primarily through monoaminergic mechanisms, e.g., receptor/reuptake agonists or antagonists with varying affinities for serotonin, norepinephrine, or dopamine. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors are implicated in the pathophysiology of MDD, as well as in the development of novel therapeutics for this disorder. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in MDD. These have been associated with relatively modest antidepressant effects compared to ketamine, but some have shown more favorable characteristics with increased potential in clinical practice (for instance, oral administration, decreased dissociative and/or psychotomimetic effects, and reduced abuse/diversion liability). This article reviews the clinical evidence supporting the use of glutamate receptor modulators with direct affinity for cognate receptors: 1) non-competitive NMDA receptor antagonists (ketamine, memantine, dextromethorphan, AZD6765); 2) subunit (NR2B)-specific NMDA receptor antagonists (CP-101,606/traxoprodil, MK-0657); 3) NMDA receptor glycine-site partial agonists (D-cycloserine, GLYX-13); and 4) metabotropic glutamate receptor (mGluR) modulators (AZD2066, RO4917523/basimglurant). Several other theoretical glutamate receptor targets with preclinical antidepressant-like efficacy, but that have yet to be studied clinically, are also briefly discussed; these include α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA) agonists, mGluR2/3 negative allosteric modulators, and mGluR7 agonists.