Eran D. Metzger

Antipsychotic and Benzodiazepine Use Among Nursing Home Residents: Findings From the 2004 National Nursing Home Survey

OBJECTIVES To document the extent and appropriateness of use of antipsychotics and benzodiazepines among nursing home residents using a nationally representative survey. METHODS Cross-sectional analysis of the 2004 National Nursing Home Survey. Bivariate and multivariate analyses examined relationships between resident and facility characteristics and antipsychotic and benzodiazepine use by appropriateness classification among residents aged 60 years and older (N = 12,090). Resident diagnoses and information about behavioral problems were used to categorize antipsychotic and benzodiazepine use as appropriate, potentially appropriate, or having no appropriate indication. RESULTS More than one quarter (26%) of nursing home residents used an antipsychotic medication, 40% of whom had no appropriate indication for such use. Among the 13% of residents who took benzodiazepines, 42% had no appropriate indication. In adjusted analyses, the odds of residents taking an antipsychotic without an appropriate indication were highest for residents with diagnoses of depression (odds ratio [OR] = 1.31; 95% confidence interval [CI]: 1.12-1.53), dementia (OR = 1.82; 95% CI: 1.52-2.18), and with behavioral symptoms (OR = 1.97, 95% CI: 1.56-2.50). The odds of potentially inappropriate antipsychotic use increased as the percentage of Medicaid residents in a facility increased (OR = 1.08, 95% CI: 1.02-1.15) and decreased as the percentage of Medicare residents increased (OR = 0.46, 95% CI: 0.25-0.83). The odds of taking a benzodiazepine without an appropriate indication were highest among residents who were female (OR = 1.44; 95% CI: 1.18-1.75), white (OR = 1.95; 95% CI: 1.47-2.60), and had behavioral symptoms (OR = 1.69; 95% CI: 1.41-2.01). CONCLUSION Antipsychotics and benzodiazepines seem to be commonly prescribed to residents lacking an appropriate indication for their use.

Aging, Brain Disease, and Reserve: Implications for Delirium

Cognitive and brain reserve are well studied in the context of age-associated cognitive impairment and dementia. However, there is a paucity of research that examines the role of cognitive or brain reserve in delirium. Indicators (or proxy measures) of cognitive or brain reserve (such as brain size, education, and activities) pose challenges in the context of the long prodromal phase of Alzheimer disease but are diminished in the context of delirium, which is of acute onset. This article provides a review of original articles on cognitive and brain reserve across many conditions affecting the central nervous system, with a focus on delirium. The authors review current definitions of reserve. The authors identify indicators for reserve used in earlier studies and discuss these indicators in the context of delirium. The authors highlight future research directions to move the field ahead. Reserve may be a potentially modifiable characteristic. Studying the role of reserve in delirium can advance prevention strategies for delirium and may advance knowledge of reserve and its role in aging and neuropsychiatric disease generally.

Novel Risk Markers and Long-Term Outcomes of Delirium: The Successful Aging after Elective Surgery (SAGES) Study Design and Methods

OBJECTIVES Delirium, a costly, life-threatening, and potentially preventable condition, is a common complication for older adults following major surgery. Although the basic epidemiology of delirium after surgery has been defined, the contribution of delirium to long term outcomes remains uncertain, and novel biomarkers from plasma and neuroimaging have yet to be examined. This program project was designed to contribute to our understanding of the complex multifactorial syndrome of delirium. DESIGN Long term prospective cohort study. SETTING Three academic medical centers (2 hospitals and 1 coordinating center). PARTICIPANTS Patients without recognized dementia (targeted cohort= 550 patients) age 70 and older scheduled to undergo elective major surgery are assessed at baseline before surgery, daily during their hospital stay, and for 18 to 36 months after discharge. MEASUREMENTS The Successful Aging after Elective Surgery (SAGES) study is an innovative, interdisciplinary study that includes biomarkers, neuroimaging, cognitive reserve markers, and serial neuropsychological testing to examine the contribution of delirium to long term cognitive and functional decline. The primary goal is to examine the contribution of delirium to long term cognitive and functional decline. In addition, novel risk markers for delirium are being examined, including plasma biomarkers (eg, cytokines, proteomics), advanced neuroimaging markers (eg, volumetric, white matter hyperintensity, noncontrast blood flow, and diffusion tensor measures), and cognitive reserve markers (eg, education, occupation, lifetime activities). CONCLUSION Results from this study will contribute to a fuller understanding of the etiology and prognosis of delirium. Ultimately, we hope this project will provide the groundwork for future development of prevention and treatment strategies for delirium, designed to minimize the long term negative impact of delirium in older adults.

3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study.

Context Although delirium is common among hospitalized patients and is associated with adverse outcomes, it often goes unrecognized. A brief and simple means of applying the most widely used diagnostic tool for delirium, the Confusion Assessment Method (CAM), would be helpful in fostering recognition of delirium and its evaluation and treatment. Contribution This study validated a 3-minute version of the CAM (called the 3D-CAM) as a sensitive and specific diagnostic tool in hospitalized patients, including those with and without dementia. Implication Use of the 3D-CAM should aid in the recognition of delirium in hospitalized patients. The Editors Delirium is common, leads to other adverse outcomes, and is costly in hospitalized older persons (13). Despite increasing awareness of its importance, most delirium, particularly hypoactive delirium and delirium superimposed on dementia, still goes unrecognized (13). Prompt recognition of delirium is the first step in appropriate management, which involves careful review for reversible contributors, prevention of complications (including ensuring patient safety), and cognitive and physical rehabilitation (1). Evidence suggests that this approach can shorten the duration of delirium and improve its associated adverse outcomes (1, 3). The Confusion Assessment Method (CAM), developed in 1990 (4), has been widely adopted. A recent comparison of diagnostic methods suggests that the CAM is the best-performing bedside delirium assessment tool (5). Although the CAM is widely used in the literature to define delirium (6), it can be challenging to operationalize in the clinical setting because it requires cognitive assessment and substantial interviewer training. Moreover, application of the CAM varies greatly, which can lead to differential performance in detecting delirium (5). A brief, structured assessment of mental status that operationalizes the CAM algorithm would be extremely helpful to accelerate widespread ascertainment of delirium in high-risk patients (4, 5). Therefore, our overall goal was to develop and validate the 3D-CAM, which is a new 3-minute diagnostic assessment for delirium using the CAM algorithm. Our aims were to create the 3D-CAM using model selection methods to finalize items, determine thresholds for the presence or absence of each of the 4 CAM diagnostic features, and prospectively validate the 3D-CAM by comparing it with a reference standard that included an extensive clinical evaluation in a new population of older general medicine patients with a high burden of baseline cognitive impairment and comorbid conditions. Methods Derivation of the 3D-CAM We started with a data set of 4598 structured delirium assessments from a previously completed multisite trial of the delirium-abatement program conducted in 8 postacute care facilities (7). In previously published work on 3D-CAM derivation, we mapped more than 120 items from this assessment to the 4 CAM diagnostic features (8) and used item response theory (9) to identify the 36 most informative items for the identification of these features (10) (Appendix Table 1). Appendix Table 1. List of Most Informative Items for the 4 CAM Diagnostic Features We further reduced these 36 items using logistic regression and assembled the most useful subset from each of the 4 CAM diagnostic features to create the 3D-CAM. We used regression coefficients to determine the weight of each item and threshold for determining the presence or absence of each of the features: acute change or fluctuating course, inattention, disorganized thinking, and altered level of consciousness. For each feature, the best-performing approach weighted each cognitive testing item, patient symptom question, and interviewer observation equally. Moreover, each feature was rated as present if any one of the items (cognitive test result, reported symptom, or observation item) was rated as present. Once each feature was rated, the presence of delirium was determined by the CAM diagnostic algorithm, which required the presence of features 1 and 2 and either 3 or 4 (Figure 1). For more details, see the Supplement. Figure 1. Overview of the 3D-CAM assessment. The CAM diagnostic algorithm is depicted, with the 3D-CAM items and scoring summarized under each CAM diagnostic feature (4). Supplement 1. Data Supplement Supplement 2. Original Version (PDF) Once we selected the items and defined the scoring algorithm for the 3D-CAM, we made a preliminary assessment of its diagnostic accuracy. From the data set of 4598 assessments, we used only the 3D-CAM items and the aforementioned algorithm to score the CAM algorithm. We then compared the presence or absence of delirium generated from this approach with the results of the full 160-item structured delirium assessment (11). In this initial derivation work, the 3D-CAM achieved 92% sensitivity (95% CI, 90% to 94%) and 93% specificity (CI, 92% to 93%) relative to the full assessment, which met our goal and allowed us to proceed with the prospective validation. Prospective Validation Study Study Population We enrolled participants from a large urban teaching hospital in Boston, Massachusetts. Inclusion criteria were age 75 years or older, admission to general medicine or geriatric medicine services, ability to communicate effectively in English, no terminal conditions, expected hospital stay of 2 days or more, and no previous study participant. Experienced clinicians (clinical psychologists and advanced practice nurses) performed the screening. After approval from the attending physician was obtained, each eligible patient was approached for informed consent. If the patient was unable to provide consent, the designated surrogate decision maker was contacted. Study protocol and informed consent procedures were approved by the institutional review board. Reference Standard Delirium Assessment The operational reference standard diagnosis of delirium was based on an extensive face-to-face interview (45 minutes), medical record review, and input from the patients nurse and available family members. This assessment included the reason for hospital admission and hospital course; presence of cognitive concern before and during the hospitalization; family, social, and functional history; Montreal Cognitive Assessment, a 30-item assessment that takes approximately 20 minutes to administer (12); Geriatric Depression Scale to evaluate for presence of depressive symptoms (13); and medical record review. This review included quantification of comorbid conditions using the Charlson index (14), diagnosis of dementia or mild cognitive impairment (MCI) before hospitalization, determination of functional status using the basic and instrumental activities of daily living scales (15, 16), and a list of psychoactive medications administered. If the assessment indicated potential cognitive impairment (Montreal Cognitive Assessment score 23) (12), the clinical assessor conducted a proxy interview to assist with determining the patients baseline mental status relevant to a possible diagnosis of dementia versus a history of lifelong, developmental, cognitive limitations. The proxy interview included ascertainment of a cognitive concern before and during the hospitalization, ascertainment of whether specific cognitive deficits evident on testing existed before hospitalization, confirmation of functional status obtained from the medical record, and a proxy-based screening questionnaire for dementia (the AD8, which is a brief informant interview to detect dementia) (17). The final delirium diagnoses were adjudicated by a study panel, including the clinical assessor (psychologist or advanced practice nurse), the principal study investigator, a geriatrician, and a board-certified neuropsychologist, using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (18). For patients not meeting delirium criteria, the panel adjudicated the presence or absence of subsyndromal delirium (19), which was defined by the presence of acute change or fluctuating course plus inattention, disorganized thinking, or altered level of consciousness. The panel was blinded to the results of subsequent 3D-CAM testing. A geropsychiatrist subsequently readjudicated a 10% subsample (10 randomly selected participants with delirium and 10 without) blinded to the original results to verify the panel adjudication process. In addition to determining delirium status, the panel adjudicated the presence or absence of cognitive impairment at baseline, including dementia or MCI, using the National Institute on Aging and Alzheimers Association criteria (20, 21). (For details of data used for adjudication of dementia and MCI, see the Supplement.) 3D-CAM Assessments After the reference standard assessment, the 3D-CAM was administered by research assistants (RAs) who were blinded to the results of the reference standard. A total of 8 RAs participated in the validation study, and each evaluated between 4 and 49 participants, based on participant and RA availability. Before the start of the study, each RA had a 1- to 2-hour training session on the use of the 3D-CAM, including practice in administering the instrument to each other and to actual patients. To assess interrater reliability, 50% of the participants were selected to have a second 3D-CAM assessment based on a random-number sequence. The second 3D-CAM assessment was blinded to the reference standard and first 3D-CAM assessments. All 8 RAs, representing 18 distinct pairs of raters, participated in the reliability study. Each pair evaluated between 1 to 19 participants also based on participant and RA availability. To ensure temporal proximity, all assessments (reference standard and first or second 3D-CAM assessment) were completed within a 2-hour period between 11 a.m. and 2 p.m. (Figure 2). Figure 2. Study flow diagram. All assessments were completed within 2 hours of each other, and results

MEDICATIONS IN THE TREATMENT OF EATING DISORDERS

Effective planning for medication treatment in patients with bulimia nervosa and anorexia nervosa is based on a comprehensive clinical assessment, including a careful review of comorbid psychiatric disorders and response to treatments for previous episodes of the disorder. Although most patients with bulimia nervosa are offered a trial of psychotherapy, significant results of controlled trials have contributed to an increased role for medications in the treatment of patients with this disorder. Pharmacologic treatment of anorexia nervosa has similarities to that of treatment-resistant depression, with the clinician turning to open trials and clinical reports for clues to rational management. As described in this article, considerations of potential side effects and medical complications are likely to play an important role in guiding the choice of medication used for treatment of patients with eating disorders.

Development of a unidimensional composite measure of neuropsychological functioning in older cardiac surgery patients with good measurement precision

The objective of this analysis was to develop a measure of neuropsychological performance for cardiac surgery and to assess its psychometric properties. Older patients (n = 210) underwent a neuropsychological battery using nine assessments. The number of factors was identified with variable reduction methods. Factor analysis methods based on item response theory were used to evaluate the measure. Modified parallel analysis supported a single factor, and the battery formed an internally consistent set (coefficient alpha = .82). The developed measure provided a reliable, continuous measure (reliability > .90) across a broad range of performance (–1.5 SDs to +1.0 SDs) with minimal ceiling and floor effects.

Serotonin Function Following Remission from Bulimia Nervosa

Abnormal serotonergic regulation in bulimia nervosa is thought to contribute to recurrent binge eating, depressed mood, and impulsivity. To follow-up on previous studies showing decreased neuroendocrine responses in symptomatic patients, this study assessed serotonin-mediated prolactin responses in individuals who had remitted from bulimia nervosa. Subjects included 21 women with a history of bulimia nervosa and 21 healthy female controls, as well as an additional comparison group of 19 women with current bulimia nervosa. Placebo-controlled neuroendocrine response studies utilized a single oral dose (60 mg) of the indirect serotonin agonist d,l-fenfluramine. For the bulimia nervosa remitted group, the fenfluramine-stimulated elevation in serum prolactin concentration was not significantly different from the response in healthy controls, but was significantly larger than the response in patients with current bulimia nervosa (p < .01). These findings suggest that diminished serotonergic neuroendocrine responsiveness in bulimia nervosa reflects a state-related abnormality. The results are discussed in relationship to recent reports indicating that some alterations in central nervous system serotonin regulation may persist in symptomatically recovered individuals.

Doing damage in delirium: the hazards of antipsychotic treatment in elderly people

Delirium can be associated with behavioural manifestations such as agitation, inappropriate be haviours, delusions, and hallucinations, which can be distressing to patients and to their families. Moreover, these symptoms can make patients diffi cult to provide care for and are a source of burden and stress for both health-care workers and informal carers. Largely to address these behavioural symptoms, the fi eld of delirium prevention and treatment has come to focus on clinical trials of antipsychotic drugs. 2,3 A search of the PubMed database shows that the annual number of studies of antipsychotic drugs for prevention or treatment of delirium has grown substantially in the past 20 years, from two studies published in 1990 to more than 40 in 2013. This necessitates an urgent call for caution in the use of antipsychotic drugs for the management of patients with delirium. The use of antipsychotics might be regarded as counterintuitive because these drugs can all cause confusion or delirium as side-eff ects. However, powerful incentives in our health-care systems promote prescription of antipsychotics for patients with delirium, and have led to the frequent use of these drugs. Antipsychotics may have appeal as a potential quick fi x compared with non-pharmacological approaches, but clinicians might not fully realise that their attempt to make patients more manageable and less distressed can result in worsened clinical outcomes. In essence, these drugs can be regarded to be a form of chemical restraint, and concern exists that the use of drugs such as haloperidol and atypical antipsychotics for treatment of delirium might often be serving the interests of the providers rather than the patients. The marketing and promotion by the pharmaceutical industry of off -label use of antipsychotics for treatment of agitation in cognitively impaired patients 4

Comparison of the effects of amino acid mixture and placebo on plasma tryptophan to large neutral amino acid ratio.

To assess the possible role of altered central serotonin function in psychiatric disorders, investigators have utilized pharmacological challenge testing with an amino acid mixture to decrease blood tryptophan concentration and, indirectly, brain serotonin levels. The aim of this pilot study was to assess the effectiveness of a modified amino mixture, administered in capsule form, in decreasing plasma tryptophan levels. Studies were conducted in six healthy, medication-free female volunteers. Following double-blind, randomized, cross-over design, subjects received on separate days capsules containing a tryptophan-free amino acid mixture (31.5 grams) or lactose placebo. Over the six hours following amino acid administration, plasma tryptophan concentrations decreased to 21% of baseline values, while the tryptophan/large neutral amino acid ratio decreased to 6% of baseline. Subjects reported minimal symptoms of nausea or other side effects following amino acid administration. The results suggest that the modified amino acid mixture may be useful in assessing behavioral responses to acute tryptophan depletion challenge testing.

ViewpointDoing damage in delirium: the hazards of antipsychotic treatment in elderly people

Delirium can be associated with behavioural manifestations such as agitation, inappropriate be haviours, delusions, and hallucinations, which can be distressing to patients and to their families. Moreover, these symptoms can make patients diffi cult to provide care for and are a source of burden and stress for both health-care workers and informal carers. Largely to address these behavioural symptoms, the fi eld of delirium prevention and treatment has come to focus on clinical trials of antipsychotic drugs. 2,3 A search of the PubMed database shows that the annual number of studies of antipsychotic drugs for prevention or treatment of delirium has grown substantially in the past 20 years, from two studies published in 1990 to more than 40 in 2013. This necessitates an urgent call for caution in the use of antipsychotic drugs for the management of patients with delirium. The use of antipsychotics might be regarded as counterintuitive because these drugs can all cause confusion or delirium as side-eff ects. However, powerful incentives in our health-care systems promote prescription of antipsychotics for patients with delirium, and have led to the frequent use of these drugs. Antipsychotics may have appeal as a potential quick fi x compared with non-pharmacological approaches, but clinicians might not fully realise that their attempt to make patients more manageable and less distressed can result in worsened clinical outcomes. In essence, these drugs can be regarded to be a form of chemical restraint, and concern exists that the use of drugs such as haloperidol and atypical antipsychotics for treatment of delirium might often be serving the interests of the providers rather than the patients. The marketing and promotion by the pharmaceutical industry of off -label use of antipsychotics for treatment of agitation in cognitively impaired patients 4