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.

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.

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.

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.

Depressed mood and its functional correlates in institutionalized schizophrenia patients.

OBJECTIVE: To determine the frequency of depressed mood in institutionalized schizophrenia patients and its association with illness-related and functional variables. METHODS: Out of 657 institutionalized schizophrenia patients, patients with depressed mood were identified and compared to non-depressed patients, matching for potential confounders. RESULTS: Forty-eight (7.3%) patients had moderate to severe depressed mood. They were younger, more educated and had fewer years since their first hospitalization than non-depressed patients. After matching for these variables, depressed patients showed more positive symptoms and exhibited better social and cognitive functioning. When controlling for negative symptoms, the differences in social and cognitive functioning between the depressed and non-depressed patients disappeared, and depressed patients showed more positive symptoms and more impaired impulse control. CONCLUSIONS: Unlike the negative impact of depressed mood in other populations, this study shows that symptoms of depressed mood may identify a subgroup of institutionalized schizophrenia patients who show better functioning across a variety of indicators. Future studies should determine differential treatment responses and long-term outcomes of these patients.

White matter changes in schizophrenia: evidence for myelin-related dysfunction.

Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.

A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia.

BACKGROUND: Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia. METHODS: Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients. RESULTS: Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo. CONCLUSIONS: It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.

Correlates of change in functional status of institutionalized geriatric schizophrenic patients: focus on medical comorbidity.

OBJECTIVE: Impairment in basic self-care skills is common in patients with schizophrenia and is even more severe in elderly patients with a chronic course of institutional care. While cognitive impairment has proven to be a major predictor of overall functional deficit in schizophrenia, other potential factors, such as medical comorbidity, need to be considered. METHOD: Geriatric institutionalized schizophrenic patients (N=124) were assessed three times over 4 years to determine levels of positive and negative symptoms, impairment in activities of daily living, impairment in cognitive functioning, and medical problems. Path analysis was used to determine which variables best predicted changes in self-care functions. RESULTS: Functional status, negative symptoms, cognitive functions, and health status all significantly worsened during the follow-up. The path analyses showed that change in health status did not predict change in activities of daily living after the analysis accounted for negative symptoms and cognitive functions. DISCUSSION: The results highlight the relative importance of cognitive impairments in the functional impairments of older schizophrenic patients with increased medical burden.

Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists.

RATIONALE: Alterations in the central cholinergic system of patients with schizophrenia such as reduced numbers of muscarinic and nicotinic receptors in the cortex and hippocampus may contribute to the cognitive impairment of schizophrenia. Therefore, pharmacological treatments that enhance central cholinergic function may be useful as cognitive enhancers in schizophrenia. METHODS: Searches were conducted for articles which investigated alterations of central cholinergic systems in patients with schizophrenia. Additional searches were conducted for animal and human trials of potential cognitive enhancing compounds that target the cholinergic system and any preliminary trials conducted with schizophrenic patients. RESULTS: Currently available treatments which are potentially suitable for this purpose include acetylcholinesterase inhibitors, muscarinic agonists, nicotinic agonists, and allosteric potentiators of nicotinic receptor function. Although some open label studies demonstrate modest cognitive improvements of schizophrenic patients treated with donepezil, data from a blinded, placebo controlled study demonstrate no effect. Data from a controlled trial of galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, indicates that this may be an effective alternative. In addition, some preclinical data indicates that selective M(1) muscarinic agonists under development may have potential as cognitive enhancers and antipsychotic treatments for schizophrenic patients. CONCLUSIONS: A cholinergic approach to ameliorating the cognitive dysfunction of schizophrenia appears viable. There is some preliminary data to support the efficacy of combined acetylcholinesterase inhibitors and allosteric potentiators of the nicotinic receptor, whereas future trials are awaited for more specific muscarinic agonists currently under development.

Potential noradrenergic targets for cognitive enhancement in schizophrenia.

Substantial evidence suggests that alterations in noradrenergic function contribute to the cognitive impairments of schizophrenia. Activation of post-junctional alpha 2a-adrenergic receptors in the prefrontal cortex by the alpha 2a-selective agonist guanfacine has demonstrated some preliminary benefit in subjects with schizophrenia treated with atypical antipsychotics. alpha 1-adrenergic receptor activity may be less important in mediating the cognitive impairments of schizophrenia. beta-adrenergic receptors may serve as another potential target for cognitive remediation in schizophrenia. However, the potential increase in memory consolidation in schizophrenia patients produced by beta-adrenergic agonists may be outweighed by the impairment in cognitive flexibility and executive functioning produced by beta-adrenergic agonists. Finally, norepinephrine reuptake inhibitors, such as atomoxetine, hold promise as potential cognitive enhancers in schizophrenia because of their ability to indirectly but selectively increase extracellular dopamine concentrations in the prefrontal cortex.

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.

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.

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.