Lurdes Tse

A parametric study of the acute effects of antipsychotic drugs on glucose sensitivity in an animal model

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 (2mg/kg; 20mg/kg), olanzapine (1.5mg/kg; 15 mg/kg), risperidone (0.5mg/kg; 2.5mg/kg) and haloperidol (0.1mg/kg; 1.0mg/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.

Intermittent treatment with olanzapine causes sensitization of the metabolic side-effects in rats

The second generation antipsychotic drugs are effective treatments for psychotic disorders. Many of these compounds, including the drug olanzapine, have been associated with metabolic side-effects, including weight gain, impaired glucose tolerance and insulin resistance, which increase the risk of developing cardiometabolic disorders. Rodent models of olanzapine-induced metabolic side-effects have been used to study the physiology of these effects, but only at a single time point after drug treatment. The purpose of the present study was to examine longitudinal changes with chronic antipsychotic drug treatment. Adult female rats were treated with either olanzapine (15 mg/kg) or vehicle for five consecutive days each week, followed by a 48 h washout period. Animals were then challenged with either olanzapine (15 mg/kg) or vehicle, and fasting glucose and insulin values were recorded, as well as glucose clearance in the glucose tolerance test. Treatment with olanzapine was continued for 10 weeks, with weekly tests of metabolic indices. Rats treated acutely with olanzapine showed both glucose dysregulation and insulin resistance; for the group treated during the week with olanzapine, these effects did not change by the end of ten weeks of treatment. However, in the group of animals challenged only once per week with olanzapine, the metabolic side-effects markedly intensified with the passage of time, whereby glucose intolerance and insulin resistance increased significantly compared to both baseline values and all other treatment groups. This previously unreported sensitization phenomenon represents a novel finding that may have clinical implications for patients receiving intermittent antipsychotic drug dosing or with variable adherence to treatment.

Differential effects of 3 classes of antidiabetic drugs on olanzapine-induced glucose dysregulation and insulin resistance in female rats

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 antidiabetic 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 metabolic 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 assessment of insulin resistance equation. RESULTS Both doses of olanzapine caused pronounced glucose dysregulation and insulin resistance, 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 antidiabetic treatments. CONCLUSION The present study indicates that oral hypoglycemic drugs that influence hepatic glucose metabolism, 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.

Neuroleptic Malignant Syndrome: A Review from a Clinically Oriented Perspective

Neuroleptic malignant syndrome (NMS) is a rare but potentially life-threatening sideeffect 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.

Pharmacological Risk Factors for Delirium after Cardiac Surgery: A Review

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.

Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension.

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.

Antipsychotic polypharmacy increases metabolic dysregulation in female rats.

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.

Improving metabolic and cardiovascular health at an early psychosis intervention program in vancouver, Canada.

Psychotic disorders most commonly appear during the late teenage years and early adulthood. A focused and rapid clinical response by an integrated health team can help to improve the quality of life of the patient, leading to a better long-term prognosis. The Vancouver Coastal Health early psychosis intervention program covers a catchment area of approximately 800,000 people in the cities of Vancouver and Richmond, Canada. The program provides a multidisciplinary approach to supporting patients under the age of 30 who have recently experienced first-break psychosis. The program addresses the needs of the treatment environment, medication, and psychological therapies. A critical part of this support includes a program to specifically improve patients’ physical health. Physical health needs are addressed through a two-pronged, parallel approach. Patients receive routine metabolic health assessments during their first year in the program, where standard metabolic parameters are recorded. Based on the results of clinical interviews and laboratory tests, specific actionable interventions are recommended. The second key strategy is a program that promotes healthy lifestyle goal development. Patients work closely with occupational therapists to develop goals to improve cardiometabolic health. These programs are supported by an active research environment, where patients are able to engage in studies with a focus on improving their physical health. These studies include a longitudinal evaluation of the effects of integrated health coaching on maintaining cardiometabolic health in patients recently admitted to the program, as well as a clinical study that evaluates the effects of low versus higher metabolic risk antipsychotic drugs on central adiposity. An additional pharmacogenomic study is helping to identify genetic variants that may predict cardiometabolic changes following treatment with antipsychotic drugs.

Incidence and risk factors for impaired mobility in older cardiac surgery patients during the early postoperative period

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.

Loxapine for Management of Delirium in Older Adult Surgical Patients

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.