A Multi-Phase Quality Improvement Initiative for the Treatment of Active Delirium in Older Persons.

BACKGROUND/OBJECTIVES: The Hospital Elder Life Program emerged 20 years ago as the reference model for delirium prevention in hospitalized older patients. However, implementation has been achieved at only 200 hospitals worldwide over the last 20 years. Among the barriers to implementation for some institutions is an unwillingness of hospital administration to assume the costs associated with implementing programs that service all hospitalized older patients at risk for delirium. Facing such a situation, we implemented a unique and self-evolving model of care of older hospitalized patients who had already developed delirium. DESIGN: Hypothesis testing was carried out using a pretest-posttest design on program administrative data. SETTING: Mount Sinai Hospital, New York, NY, a tertiary-care teaching facility. PARTICIPANTS A total of 9,214 consecutively admitted older patients to non-intensive care (ICU) inpatient units over a 5.5-year period, regardless of the suspected presence of delirium or risk status for developing delirium. INTERVENTION: A delirium intervention program targeting patients in whom delirium has already developed, with a modified delirium team supported by extensive workflow automation with custom tools in our electronic medical records system. MEASUREMENTS: Length of stay (LOS) for delirious and non-delirious patients on units where this program was piloted. Benzodiazepine, opiate, and antipsychotic use on the same units. RESULTS: There was a significant drop in LOS by 1.98 days (95% confidence interval = .24-3.71), a decrease in the average morphine dose equivalents administered from .38 mg to .21 mg per patient hospital day, diazepam dose equivalents from .22 mg to .15 mg per patient hospital day, and quetiapine administered from .17 mg to .14 mg per patient hospital day for delirious patients on the program pilot units. CONCLUSION: Elements of our unique active delirium treatment program may provide some direction to other program developers working on improving the care of older hospitalized delirious patients. However, the supporting evidence presented is limited, and a more rigorous prospective study is needed.

Modifiable factors associated with postoperative delirium after hip fracture repair: An age-stratified retrospective cohort study.

BACKGROUND: Postoperative delirium in hip fracture patients is common and is associated with substantial morbidity and consumption of resources. OBJECTIVE: Using data from the USA, we aimed to examine the relationship between postoperative delirium and (modifiable) peri-operative factors mentioned in the American Geriatrics Society Best Practice Statement on Postoperative Delirium in Older Adults, stratified by 'young old' (<80 years) and 'old-old' (≥80 years) categories. DESIGN: Retrospective cohort study from 2006 to 2016. SETTING: Population-based claims data from the USA. PARTICIPANTS: Patients undergoing 505 152 hip fracture repairs between 2006 and 2016 as recorded in the Premier Healthcare Database. MAIN OUTCOMES AND MEASURES: The main outcome was postoperative delirium; modifiable factors of interest were peri-operative opioid use (high, medium or low; <25th, 25 to 75th or >75th percentile of oral morphine equivalents), anaesthesia type (general, neuraxial, both), use of benzodiazepines (long acting, short acting, both), pethidine, nonbenzodiazepine hypnotics, ketamine, corticosteroids and gabapentinoids. Multilevel models assessed associations between these factors and postoperative delirium, in the full cohort, and separately in those aged less than 80 and at least 80 years. Odds ratios (ORs) and Bonferroni-adjusted 95% confidence intervals (95% CIs) are reported. RESULTS: Overall, postoperative delirium incidence was 15.7% (n = 79 547). After adjustment for relevant covariates, the use of long-acting (OR 1.82, CI 1.74 to 1.89) and combined short and long-acting benzodiazepines (OR 1.56, CI 1.48 to 1.63) and ketamine (OR 1.09, CI 1.03 to 1.15), in particular, was associated with increased odds for postoperative delirium, while neuraxial anaesthesia (OR 0.91 CI 0.85 to 0.98) and opioid use (OR 0.95, CI 0.92 to 0.98 and OR 0.88, CI 0.84 to 0.92 for medium and high dose compared with low dose) were associated with lower odds; all P < 0.05. When analysing data separately by age group, effects of benzodiazepines persisted, while opioid use was only relevant in those aged less than 80 years. CONCLUSION: We identified modifiable factors associated with postoperative delirium incidence among patients undergoing hip fracture repair surgery.

Brain imaging changes associated with risk factors for cardiovascular and cerebrovascular disease in asymptomatic patients.

Reviews of imaging studies assessing the brain effects of vascular risk factors typically include a substantial number of studies with subjects with a history of symptomatic cardiovascular or cerebrovascular disease and/or events, limiting our ability to disentangle the primary brain effects of vascular risk factors from those of resulting brain and cardiac damage. The objective of this study was to perform a systematic review of brain changes from imaging studies in patients with vascular risk factors but without clinically manifest cardiovascular or cerebrovascular disease or events. The 77 studies included in this review demonstrate that in persons without symptomatic cardiovascular, cerebrovascular, or peripheral vascular disease, the vascular risk factors of hypertension, diabetes mellitus, obesity, hyperlipidemia, and smoking are all independently associated with brain imaging changes before the clinical manifestation of cardiovascular or cerebrovascular disease. We conclude that the identification of brain changes associated with vascular risk factors, before the manifestation of clinically significant cerebrovascular damage, presents a window of opportunity wherein adequate treatment of these modifiable vascular risk factors may prevent the development of irreversible deleterious brain changes and potentially alter patients' clinical course.

Pharmacological treatments of non-substance-withdrawal delirium: a systematic review of prospective trials.

OBJECTIVE: Most reviews of pharmacological strategies for delirium treatment evaluate the effectiveness of these interventions for delirium prevention, reduction in duration and severity of ongoing delirium, and other outcomes that extend beyond the recommendations of expert treatment guidelines. However, little if any attention is given to substantiating the potential benefits of such treatment or addressing the methodological weaknesses that, in part, limit the pharmacological recommendations made by expert treatment guidelines. Therefore, the authors conducted a systematic review to provide the most up-to-date and inclusive review of published prospective trials of potential pharmacological interventions for the prevention and treatment of delirium, and they discuss potential benefits of pharmacological prevention of delirium and/or reduction of ongoing delirium episode duration and severity. METHOD: The analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including prospective randomized and nonrandomized double-blind, single-blind, and open-label clinical trials of any pharmacological agent for the prevention or treatment of delirium and reviewing them systematically for effectiveness on several predefined outcomes. RESULTS: The pharmacological strategies reviewed showed greater success in preventing delirium than in treating it. Significant delirium prevention effects are associated with haloperidol, second-generation antipsychotics, iliac fascia block, gabapentin, melatonin, lower levels of intraoperative propofol sedation, and a single dose of ketamine during anesthetic induction and with dexmedetomidine compared with other sedation strategies for mechanically ventilated patients. CONCLUSIONS: These promising results warrant further study with consideration of the methodological weaknesses and inconsistencies of studies to date.

Novel imaging strategies for assessment of cerebrovascular involvement.

There is an important correlation between vascular risk factors and nonspecific imaging findings in the brain such as white-matter hyperintensities. These vascular risk factors are also associated with dementia and lesser forms of cognitive impairment. One hypothesis is that these vascular risk factors lead to disruption of connective networks in the central nervous system that are supported by myelinated white-matter fibers, which in turn lead to deficits in functional signaling between various brain regions. Another possibility is an alteration of the neurovascular coupling due to vascular risk factors. This reduced functional signaling contributes to the cognitive deficits in persons harboring these vascular risk factors. Lifestyle changes may restore some of these functional deficits through brain plasticity. It is imperative that preclinical diagnostic techniques are developed to identify these early brain changes in persons harboring vascular risk factors, as such efforts may improve primary and secondary prevention efforts. Recently developed imaging techniques may provide objective imaging biomarkers to measure the structural and functional brain changes in persons with vascular risk factors and resulting subclinical atherosclerotic disease. This article reviews a few of these novel imaging techniques.

The effects of hypertension and body mass index on diffusion tensor imaging in schizophrenia.

Recently, the negative effects of hypertension and elevated body mass index on cognitive functioning in schizophrenia have been reported (Friedman et al., 2010). Data suggests that cognitive changes in hypertensive patients from the general population may be mediated, in part, by white matter damage. Therefore, we performed diffusion tensor imaging (DTI) in the same subjects studied by Friedman et al. (2010) to investigate the effects of hypertension and elevated body mass index on the fractional anisotropy (FA) of several major white matter tracts. Significant interactions between a diagnosis of schizophrenia and hypertension on FA in several white matter regions were detected. Hypertension was associated with lower FA in the schizophrenic group and higher FA in the same tracts in the non-schizophrenic subjects. These results suggest hypertension-induced compensatory mechanisms in the brains of non-schizophrenic patients with hypertension which may be impaired in persons with schizophrenia.

Pimozide augmentation of clozapine inpatients with schizophrenia and schizoaffective disorder unresponsive to clozapine monotherapy.

Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.

The effects of hypertension and body mass index on cognition in schizophrenia.

OBJECTIVE: In recent years there has been a greater appreciation of the elevated prevalence of cardiovascular risk factors in the schizophrenia population and the liability some treatments have for their development. These vascular risk factors are in turn important risk factors in the development of dementia and more subtle cognitive impairments. However, their impact on the cognitive functions of patients with schizophrenia remains underexplored. The authors investigated whether vascular risk factors influence the cognitive impairments of schizophrenia and whether their effects on cognition in schizophrenia are different from those observed in nonpsychiatric comparison subjects. METHOD: The authors compared 100 patients with schizophrenia and 53 comparison subjects on cognitive test performance in 2×2 matrices composed of individual vascular risk factors and group (schizophrenia patients and comparison subjects). RESULTS: Hypertension exerted a significant negative effect on immediate delayed and recognition memory in both groups. Patients with schizophrenia and hypertension were adversely affected in recognition memory, whereas comparison subjects were not. A body mass index above 25 was associated with negative effects on delayed memory in both groups, although the association fell short of statistical significance. CONCLUSIONS: Given that patients with schizophrenia have a higher prevalence of vascular risk factors than the general population and are undertreated for them, treatment of these risk factors may significantly improve cognitive outcome in schizophrenia.

Strong synaptic transmission impact by copy number variations in schizophrenia.

Schizophrenia is a psychiatric disorder with onset in late adolescence and unclear etiology characterized by both positive and negative symptoms, as well as cognitive deficits. To identify copy number variations (CNVs) that increase the risk of schizophrenia, we performed a whole-genome CNV analysis on a cohort of 977 schizophrenia cases and 2,000 healthy adults of European ancestry who were genotyped with 1.7 million probes. Positive findings were evaluated in an independent cohort of 758 schizophrenia cases and 1,485 controls. The Gene Ontology synaptic transmission family of genes was notably enriched for CNVs in the cases (P = 1.5 x 10(-7)). Among these, CACNA1B and DOC2A, both calcium-signaling genes responsible for neuronal excitation, were deleted in 16 cases and duplicated in 10 cases, respectively. In addition, RET and RIT2, both ras-related genes important for neural crest development, were significantly affected by CNVs. RET deletion was exclusive to seven cases, and RIT2 deletions were overrepresented common variant CNVs in the schizophrenia cases. Our results suggest that novel variations involving the processes of synaptic transmission contribute to the genetic susceptibility of schizophrenia.

Temporal characteristics of tract-specific anisotropy abnormalities in schizophrenia.

White matter abnormalities have been detected using diffusion tensor imaging in a variety of locations in the brains of patients with schizophrenia. Studies that included first-episode patients report less severe or no abnormalities but more pronounced deficits in chronic patients. Here, we investigated these abnormalities in a very large group of patients with schizophrenia who had both large ranges in age and in duration of illness. A highly reproducible diffusion tensor imaging tractography technique was used to quantify the fractional anisotropy of the genu and splenium of the corpus callosum as well as the bilateral pyramidal tracts. We found a decline in fractional anisotropy that correlated with the duration of illness in the genu and splenium of the corpus callosum but not in the pyramidal tracts. The findings suggest that there are white matter tract-specific degenerative mechanisms that may be present at the point of illness onset and may progress throughout the illness.

Diffusion tensor imaging findings in first-episode and chronic schizophrenia patients.

OBJECTIVE: Comparisons of diffusion tensor imaging (DTI) data between first-episode and chronic schizophrenia patients assessed in different studies have led to the suggestion that the decreased fractional anisotropy observed in chronic schizophrenia patients is less pronounced in first-episode patients. However, such comparisons of imaging data generated across studies are susceptible to numerous confounders, which may limit the interpretation of any differences. In order to address these issues and determine whether the DTI abnormalities of chronic schizophrenia are present at illness onset, the authors conducted a DTI investigation of the largest cohort of first-episode schizophrenia patients yet reported in conjunction with a group of chronic schizophrenia patients and healthy subjects for comparison. METHOD: Fractional anisotropy data generated by diffusion tensor imaging with a 3-T Siemens Allegra head-dedicated MRI system were compared between 40 first-episode schizophrenia patients and 39 age- and gender-matched healthy comparison subjects and between 40 chronic schizophrenia patients and 40 age- and gender-matched healthy comparison subjects. The following regions of interest were assessed: forceps minor (bilaterally), forceps major (bilaterally), inferior longitudinal fasciculus (bilaterally), and the genu and splenium of the corpus callosum. RESULTS: In most regions, chronic schizophrenia patients showed significant or trend-level lower fractional anisotropy than healthy comparison subjects, whereas the first-episode schizophrenia patients showed only trend-level lower fractional anisotropy in the inferior longitudinal fasciculus. CONCLUSIONS: The cross-sectional data reported here suggest less widespread changes in white matter at illness onset in schizophrenia which progress in more chronic states. More definitive conclusions will require follow-up imaging of first-episode schizophrenia patients.

A pilot study of adjunctive atomoxetine treatment to second-generation antipsychotics for cognitive impairment in schizophrenia.

Relationships between altered prefrontal cortical dopamine, norepinephrine, and some of the cognitive impairments of schizophrenia support an approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine. Atomoxetine, a selective norepinephrine reuptake inhibitor, produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine. Given this, we evaluated atomoxetine's cognitive effects in a pilot placebo-controlled trial in patients with schizophrenia. Moreover, a functional magnetic resonance imaging investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine. Twenty participants with schizophrenia were randomized to treatment with placebo or atomoxetine 80 mg daily for an 8-week parallel-designed treatment trial. Cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia. No significant cognitive improvement was associated with atomoxetine treatment. However, atomoxetine treatment was associated with significantly greater increases in working memory-related activation of the left dorsolateral prefrontal and left posterior cingulate cortices. The negative results of this study conflict with the effectiveness of amphetamine in enhancing the cognitive abilities of schizophrenic patients and may be related to the differential pattern of cortical activation and deactivation produced by amphetamine.

Long-term outcomes in chronically hospitalized geriatric patients with schizophrenia: retrospective comparison of first generation and second generation antipsychotics.

INTRODUCTION: Some groups have reported the longitudinal course of elderly poor outcome schizophrenic patients to be characterized by progressive decline in cognitive functions and functional capacity. Although many of these patients experience minimal reduction of psychotic symptoms, there may be beneficial effects of antipsychotic treatments on cognitive functions and functional capacity. METHODS: This naturalistic study compared the longitudinal course of psychotic symptoms, cognitive functions and functional impairment in geriatric schizophrenic patients treated with first generation (N=97) or second generation (N=78) antipsychotic medications. Mixed effects linear regression analyses were used to examine the effects of treatment (first generation vs. second generation antipsychotic), time and treatment x time. RESULTS: Cognitive functions (Mini Mental State Examination time effect estimate=-.41, p<.001; ADAS-L Cog time effect estimate=.64, p<.001) and self-care skills (ADAS-L Self-Care time effect estimate=.65, p<.001) declined over time for the subject group as a whole and this decline was not modified by treatment with second generation antipsychotics relative to first generation antipsychotics. Similarly, second generation antipsychotic treatment produced no effect on the progressive worsening of negative symptom over time. CONCLUSION: This long-term naturalistic study of poor outcome geriatric patients with schizophrenia did not find atypical antipsychotics to produce any differential protective effect relative to typical antipsychotics on the long-term manifestations of symptoms, cognition and self-care in poor outcome geriatric schizophrenic patients.

RETRACTED: The Relationships Between White Matter Cerebral Metabolites and Clinical Manifestations in Geriatric Patients with Schizophrenia: A 4 Tesla Proton Magnetic Resonance Spectroscopy Study.

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Validity and stability of performance-based estimates of premorbid educational functioning in older patients with schizophrenia.

This paper presents the results of two studies of the validity of word-recognition reading as an indicator of premorbid functioning in schizophrenia. The first examined the stability over a 6-year follow-up period of word recognition reading compared to other aspects of cognitive functioning, including verbal learning and delayed recall, verbal fluency, constructional skills, and naming ability. The second study examined the relative predictive power of indicators of premorbid functioning as compared to current cognitive functioning for the prediction of current social and self-care skills. In the first study 218 patients with chronic schizophrenia participated. For the second study, 231 male veterans with schizophrenia were assessed for cognitive functioning, indicators of premorbid adjustment, and current functional status. Analyses of the differences between correlations indicated that word recognition reading ability was significantly more stable than other aspects of cognitive functioning over a six-year period during which decline in some other aspects of performance was found. In the second study, premorbid educational and social attainment, word recognition reading skill, and current cognitive functioning were all significantly related to current functional status, defined by correlations with ratings of current functional status. Path analyses indicated, however, that current cognitive functioning was the only significant predictor of current functional status when the intercorrelations of the variables were considered. In sum, Premorbid functioning estimated with word-recognition reading was stable over time (study 1) and correlated with both current cognitive and functional status (study 2). The results of these two studies suggest that word-recognition reading skills are useful screening instruments to estimate premorbid functioning even in deteriorated patients with schizophrenia.