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Background The second generation antipsychotic drugs represent the most common form of pharmacotherapy for schizophrenia disorders. It is now well established that most of the second generation drugs cause metabolic side-effects. Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) are two commonly used antipsychotic drugs with moderate metabolic liability. However, there is a dearth of preclinical data that directly compares the metabolic effects of these two drugs, using sophisticated experimental procedures. The goal of the present study was to compare metabolic effects for each drug versus control animals. Methods Adult female rats were acutely treated with either risperidone (0.1, 0.5, 1, 2, 6 mg/kg), paliperidone (0.1, 0.5, 1, 2, 6 mg/kg) or vehicle and subjected to the glucose tolerance test; plasma was collected to measure insulin levels to measure insulin resistance with HOMA-IR. Separate groups of rats were treated with either risperidone (1, 6 mg/kg), paliperidone (1, 6 mg/kg) or vehicle, and subjected to the hyperinsulinemic euglycemic clamp. Results Fasting glucose levels were increased by all but the lowest dose of risperidone, but only with the highest dose of paliperidone. HOMA-IR increased for both drugs with all but the lowest dose, while the three highest doses decreased glucose tolerance for both drugs. Risperidone and paliperidone both exhibited dose-dependent decreases in the glucose infusion rate in the clamp, reflecting pronounced insulin resistance. Conclusions In preclinical models, both risperidone and paliperidone exhibited notable metabolic side-effects that were dose-dependent. Differences between the two were modest, and most notable as effects on fasting glucose.

Antipsychotic drugs represent the most effective treatment for chronic psychotic disorders. The newer second generation drugs offer the advantage of fewer neurological side-effects compared to prior drugs, but many cause serious metabolic side-effects. The underlying physiology of these side-effects is not well-understood, but evidence exists to indicate that the sympathetic nervous system may play an important role. In order to examine this possibility further, we treated separate groups of adult female rats acutely with either the first generation antipsychotic drug haloperidol (0.1 or 1 mg/kg) or the second generation drugs risperidone (0.25 or 2.5 mg/kg), clozapine (2 or 20 mg/kg), olanzapine (3 or 15 mg/kg) or vehicle by intraperitoneal injection. Blood samples were collected prior to drug and then 30, 60, 120, and 180 mins after treatment. Plasma samples were assayed by HPLC-ED for levels of norepinephrine, epinephrine, and dopamine. Results confirmed that all antipsychotics increased peripheral catecholamines, although this was drug and dose dependent. For norepinephrine, haloperidol caused the smallest maximum increase (+158%], followed by risperidone (+793%), olanzapine (+952%) and clozapine (+1,684%). A similar pattern was observed for increases in epinephrine levels by haloperidol (+143%], olanzapine (+529%), risperidone (+617%) then clozapine (+806%). Dopamine levels increased moderately with olanzapine [+174%], risperidone [+271%], and clozapine [+430%]. Interestingly, levels of the catecholamines did not correlate strongly with each other prior to treatment at baseline, but were increasingly correlated after treatment as time proceeded. The results demonstrate antipsychotics can potently regulate peripheral catecholamines, in a manner consistent with their metabolic liability.

The use of antipsychotics for the treatment of post-operative delirium is often practiced after non-pharmacologic methods of re-orientation have failed. Loxapine is a drug with medium-potency antagonism at dopamine receptors and is used frequently at our institution for delirium. In this small uncontrolled open-label study, we provide early findings that it is effective at reducing the severity and duration of delirium in an older population and may be a reasonable alternative for management. Delirium Rating Scale (DRS-R-98) scores were recorded in 31 older adult surgical patients (mean age 72, 2/3 male). Treating physicians ordered loxapine according to clinical judgment. We monitored for extrapyramidal side-effects, QTc changes, and other adverse events. The mean maximum cumulative loxapine dose per day was 44mg (s.d. 31). DRS-R-98 score after 2 days of treatment (mean 10.19, s.d. 6.61) was significantly reduced compared to DRS-R-98 score at time of diagnosis (mean 18.68, s.d. 4.66) [t(30) = 6.65, p 0.5]. Although there are several limitations to this small uncontrolled open-label study, the findings suggest loxapine is a reasonable alternative in treating delirium in older adult surgical patients.

Transcatheter aortic valve implantation (TAVI) techniques show favourable survival outcomes in high-risk patients, but the incidence of postoperative delirium is unknown. We conducted a historical cohort study to compare postoperative delirium in retrograde transfemoral (TF) versus anterograde transapical (TA) TAVI procedures. We also sought to identify independent predictors of delirium following TAVI. We performed a retrospective chart review on all patients who underwent TF (n = 77) or TA (n = 45) TAVI during 2008 and 2009 at St. Paul’s Hospital (Vancouver, BC, Canada), the pioneering centre for these procedures. The primary outcome was a documented physician diagnosis of delirium. Abstracted data included information on demographics, medical history, surgical procedure, anesthesia, and postoperative care. We employed a multivariable logistic regression to identify independent predictors of delirium. Delirium occurred in 12% of TF patients vs 53% of TA patients (P

Aim Mobility issues in the early postoperative period result in poor functional outcomes and diminished quality of life for patients of advanced age. We determined the incidence of and risk factors for mobility issues in the early postoperative period in patients receiving open heart cardiac surgery. Methods A retrospective chart review was carried out on 396 patients receiving open heart coronary artery bypass grafts (CABG), valve replacements and combination CABG-valve replacements in a tertiary care hospital. Data on demographics, comorbidities, laboratory values, medications, anesthesia and postoperative care were abstracted. Mobility issues were considered present if they were documented in the medical chart. All pre- and intraoperative variables were entered into logistic regression. Results The mean age was 66.4 ± 11.9 years. In a subset of patients aged 75 years and older, the mean age was 79.8 ± 3.7 years. Mobility issues affected 36.9% of individuals from the total sample, and 47.6% of older patients. Increased age was a weak predictor in the total sample (OR 1.03), but was the only predictor in older adults (OR 1.1). The strongest predictors in the total sample were preoperative COPD (OR 2.7), congestive heart failure (CHF; OR 2.1), renal disease (OR 1.9), and pre-existing physical impairment (OR 1.8). Older patients with mobility issues were more likely to be discharged to acute care facilities, and had higher rates of mortality 3 years after surgery. Conclusions Over one-third of cardiac surgery patients experienced early postoperative mobility issues. Older patients and those with COPD, CHF, renal disease or pre-existing physical impairments might benefit from preoperative consultation with physical therapists. Geriatr Gerontol Int 2015; 15: 276–281.

Antipsychotic polypharmacy refers to the clinical practice of treating a patient with two or more antipsychotic drugs concurrently. There is abundant evidence in the clinical literature that treatment with antipsychotic polypharmacy is associated with an increased prevalence of drug side effects compared with monotherapy. This includes drug-induced metabolic side effects, such as glucose intolerance and insulin resistance. As these metabolic side effects have been accurately modeled in preclinical rodent paradigms using drug monotherapy, the goal of the present study was to determine the metabolic effects of antipsychotic polypharmacy using an established rodent model. In the first experiment, adult female rats were treated with clozapine (5 mg/kg), risperidone (1 mg/kg), vehicle, or clozapine + risperidone. In the second experiment, rats were treated with clozapine (5 mg/kg), haloperidol (0.1 mg/kg), vehicle, or clozapine + haloperidol. Animals were then subjected to a glucose tolerance test. Compared with vehicle-treated control animals, risperidone and haloperidol had no effect on any of the metabolic indices when administered on their own. Addition of risperidone to clozapine significantly increased fasting glucose, fasting insulin, and insulin resistance compared with the clozapine-only group. The addition of haloperidol to clozapine significantly increased fasting insulin levels, insulin resistance, and glucose intolerance compared with clozapine-only rats. These results are consistent with clinical studies and therefore indicate that animal models can successfully be used to study the metabolic side effects of antipsychotic drugs. Future studies related to understanding the physiological mechanisms involved remain a priority.

Purpose: The objective of this review is to evaluate the literature on medications associated with delirium after cardiac surgery and potential prophylactic agents for preventing it. Source: Articles were searched in MEDLINE, Cumulative Index to Nursing and Allied Health, and EMBASE with the MeSH headings: delirium, cardiac surgical procedures, and risk factors, and the keywords: delirium, cardiac surgery, risk factors, and drugs. Principle inclusion criteria include having patient samples receiving cardiac procedures on cardiopulmonary bypass, and using DSM-IV-TR criteria or a standardized tool for the diagnosis of delirium. Principal Findings: Fifteen studies were reviewed. Two single drugs (intraoperative fentanyl and ketamine), and two classes of drugs (preoperative antipsychotics and postoperative inotropes) were identified in the literature as being independently associated with delirium after cardiac surgery. Another seven classes of drugs (preoperative antihypertensives, anticholinergics, antidepressants, benzodiazepines, opioids, and statins, and postoperative opioids) and three single drugs (intraoperative diazepam, and postoperative dexmedetomidine and rivastigmine) have mixed findings. One drug (risperidone) has been shown to prevent delirium when taken immediately upon awakening from cardiac surgery. None of these findings was replicated in the studies reviewed. Conclusion: These studies have shown that drugs taken perioperatively by cardiac surgery patients need to be considered in delirium risk management strategies. While medications with direct neurological actions are clearly important, this review has shown that specific cardiovascular drugs may also require attention. Future studies that are methodologically consistent are required to further validate these findings and improve their utility.

Antipsychotic drugs (APDs), and the 'atypical' APDs in particular, are commonly associated with metabolic side effects in humans. These include glucose dysregulation, insulin resistance, hyperlipidemia, weight gain and hypertension, which put patients at increased risk of cardiometabolic disorders. The underlying biology of APD-induced side effects in humans is poorly understood, and therefore preclinical rodent models are essential for translational research. With numerous recent studies on the topic, there is an emerging consensus that some symptoms, such as glucose dysregulation and insulin resistance, are more reliably observed than others, such as weight gain and hypertension, but, comparison between preclinical studies is complicated by numerous factors, including drug-specific effects and variables such as diet and treatment regimen. In this paper, we provide a major review of this important and growing field of preclinical study, and address crucial issues for future research.

Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening side-effect that can occur in response to treatment with antipsychotic drugs. Symptoms commonly include hyperpyrexia, muscle rigidity, autonomic dysfunction and altered mental status. In the current review we provide an overview on past and current developments in understanding the causes and treatment of NMS. Studies on the epidemiological incidence of NMS are evaluated, and we provide new data from the Canada Vigilance Adverse Reaction Online database to elaborate on drug-specific and antipsychotic drug polypharmacy instances of NMS reported between 1965 and 2012. Established risk factors are summarized with an emphasis on pharmacological and environmental causes. Leading theories about the etiopathology of NMS are discussed, including the potential contribution of the impact of dopamine receptor blockade and musculoskeletal fiber toxicity. A clinical perspective is provided whereby the clinical presentation and phenomenology of NMS is detailed, while the diagnosis of NMS and its differential is expounded. Current therapeutic strategies are outlined and the role for both pharmacological and non-pharmacological treatment strategies in alleviating the symptoms of NMS are discussed.

Objective Delirium after cardiac surgery is associated with persistent cognitive deficits and increased mortality. The authors’ objective was to determine the incidence of and risk factors for delirium in a mixed cohort of patients undergoing on-pump and off-pump cardiac surgery and transcatheter aortic valve implantations (TAVI) in a Canadian quaternary care center. This study followed a pilot from the same center on patients treated in 2007. Design A retrospective cohort study. Setting A quaternary care center in Vancouver, B.C., Canada. Participants Patients undergoing cardiopulmonary bypass grafts (CABG), conventional valve replacements, combined CABG-valve replacements, transfemoral TAVI, or transapical TAVI in 2008. Interventions Data from 679 charts on demographics, medical history, medications, laboratory results, surgical procedure, and anesthesia were abstracted and analyzed using univariate and multivariate analyses. Nurses screened for delirium using the Confusion Assessment Method, and the final diagnoses were made clinically by physicians. Risk factors were identified using logistic regression and bootstrapping. Measurements and Main Results Delirium occurred in 28% of patients. Delirium was most common in transapical TAVI (47%), and least common in transfemoral TAVI (17%). Delirious patients were older and had greater preoperative cardiac and neurologic burdens than nondelirious patients. Age≥64 years, history of delirium, history of stroke/transient ischemic attack, cognitive impairment, depression, and preoperative use of beta-blocker(s) were associated independently with delirium. Conclusions The incidence of delirium varied greatly with the type of procedure. The authors’ logistic regression model showed that age and certain pre-existing neurologic conditions could predict delirium after cardiac surgery.

Mobility issues in the early postoperative period result in poor functional outcomes and diminished quality of life for patients of advanced age. We determined the incidence of and risk factors for mobility issues in the early postoperative period in patients receiving open heart cardiac surgery.A retrospective chart review was carried out on 396 patients receiving open heart coronary artery bypass grafts (CABG), valve replacements and combination CABG-valve replacements in a tertiary care hospital. Data on demographics, comorbidities, laboratory values, medications, anesthesia and postoperative care were abstracted. Mobility issues were considered present if they were documented in the medical chart. All pre- and intraoperative variables were entered into logistic regression.The mean age was 66.4 ± 11.9 years. In a subset of patients aged 75 years and older, the mean age was 79.8 ± 3.7 years. Mobility issues affected 36.9% of individuals from the total sample, and 47.6% of older patients. Increased age was a weak predictor in the total sample (OR 1.03), but was the only predictor in older adults (OR 1.1). The strongest predictors in the total sample were preoperative COPD (OR 2.7), congestive heart failure (CHF; OR 2.1), renal disease (OR 1.9), and pre-existing physical impairment (OR 1.8). Older patients with mobility issues were more likely to be discharged to acute care facilities, and had higher rates of mortality 3 years after surgery.Over one-third of cardiac surgery patients experienced early postoperative mobility issues. Older patients and those with COPD, CHF, renal disease or pre-existing physical impairments might benefit from preoperative consultation with physical therapists.

Second-generation antipsychotics (SGAs) are associated with significant comorbid metabolic abnormalities. Adjunct medications may be prescribed to treat these metabolic side effects, but the evidence supporting this practice (especially for the management of antipsychotic-associated dyslipidemia and hypertension) is limited. The purpose of this review was to evaluate the effects of adjunct medications on triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein, and blood pressure levels in participants taking SGAs for psychosis. Studies were systematically searched and evaluated. Studies were included for review if participants were taking SGAs and if lipid and/or blood pressure levels were included as outcome measures. Statins, conventional lipid-lowering agents, fluvoxamine, ramelteon, topiramate, valsartan, telmisartan, omega-3 fatty acids, metformin (including both immediate-release and extended-release formulations), and a combination of metformin-sibutramine seemed to have beneficial effects on lipid levels. Valsartan, telmisartan, and topiramate appeared to be effective for controlling increases in blood pressure. The literature on adjunct medications for the treatment of antipsychotic-associated dyslipidemia and hypertension is not exhaustive, and long-term randomized-controlled trials would offer valuable results.

Background: The second-generation antipsychotic drug olanzapine is an effective pharmacological treatment for psychosis. However, use of the drug is commonly associated with a range of metabolic side effects, including glucose intolerance and insulin resistance. These symptoms have been accurately modelled in rodents. Methods: We compared the effects of 3 distinct classes of anti dia betic drugs, metformin (100 and 500 mg/kg, oral), rosiglitazone (6 and 30 mg/kg, oral) and glyburide (2 and 10 mg/kg, oral), on olanzapineinduced metab olic dysregulation. After acutely treating female rats with lower (7.5 mg/kg) or higher (15 mg/kg) doses of olanzapine, we assessed glucose intolerance using the glucose tolerance test and measured insulin resistance using the homeostatic model assess ment of insulin resist ance equation. Results: Both doses of olanzapine caused pronounced glucose dysregulation and insulin resist ance, which were significantly reduced by treatment with metformin and rosiglitazone; however, glucose tolerance did not fully return to control levels. In contrast, glyburide failed to reverse the glucose intolerance caused by olanzapine despite increasing insulin levels. Limitations: We evaluated a single antipsychotic drug, and it is unknown whether other antipsychotic drugs are similarly affected by anti diabetic treatments. Conclusion: The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metab olism, such as metformin and rosiglitazone, are more effective in regulating olanzapine-induced glucose dysregulation than drugs primarily affecting insulin release, such as glyburide. The current model may be used to better understand the biological basis of glucose dysregulation caused by olanzapine and how it can be reversed.

The therapeutic use of atypical antipsychotics is associated with a high incidence of metabolic side-effects. In the present study we examined the acute effects of both high and low-dose atypical antipsychotic drugs and one typical drug on alterations in glucose and insulin parameters using a rodent model. The effects of administration of clozapine (2 mg/kg; 20 mg/kg), olanzapine (1.5 mg/kg; 15 mg/kg), risperidone (0.5 mg/kg; 2.5 mg/kg) and haloperidol (0.1 mg/kg; 1.0 mg/kg) on glucose sensitivity and insulin resistance were determined through HOMA-IR values in fasted rats and glucose clearance during a glucose tolerance test. Acute effects were determined 60, 180 or 360 min following drug administration. The atypical antipsychotics produced significant dose and time dependent effects on fasting plasma glucose and insulin concentrations, HOMA-IR values, insulin resistance and glucose intolerance. The greatest effect on glucose dysregulation was noted primarily with clozapine and olanzapine; however, all four treatments caused significant increases in fasting glucose and/or insulin levels with the high dose, 60 min post-drug administration. Together, these findings indicate that acute administration of antipsychotic drugs has potent effects on metabolic regulation of glucose and insulin sensitivities, which may contribute to metabolic side-effects seen in humans.