British Columbia Mental Health and Addictions Research Institute

Vancouver, Canada

British Columbia Mental Health and Addictions Research Institute

Vancouver, Canada
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Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute
Current neuropharmacology | Year: 2017

Chronic prescription of antipsychotics seems to lose its therapeutic benefits in the prevention of recurring psychotic symptoms. In many instances, the occurrence of relapse from initial remission is followed by an increase in dose of the prescribed antipsychotic. The current understanding of why this occurs is still in its infancy, but a controversial idea that has regained attention recently is the notion of iatrogenic dopamine supersensitivity. Studies on cell cultures and animal models have shown that long-term antipsychotic use is linked to both an upregulation of dopamine D2-receptors in the striatum and the emergence of enhanced receptor affinity to endogenous dopamine. These findings have been hypothesized to contribute to the phenomenon known as dopamine supersensitivity psychosis (DSP), which has been clinically typified as the foundation of rebound psychosis, drug tolerance, and tardive dyskinesia. The focus of this review is the update of evidence behind the classification of antipsychotic induced DSP and an investigation of its relationship to treatment resistance. Since antipsychotics are the foundation of illness management, a greater understanding of DSP and its prevention may greatly affect patient outcomes.


Boyda H.N.,University of British Columbia | Tse L.,University of British Columbia | Procyshyn R.M.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | And 4 more authors.
Trends in Pharmacological Sciences | Year: 2010

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. © 2010 Elsevier Ltd.


Boyda H.N.,University of British Columbia | Procyshyn R.M.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | Pang C.C.Y.,University of British Columbia | And 2 more authors.
Journal of Neuroendocrinology | Year: 2013

It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and β-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α2A and β2), skeletal muscle (α1A and β2), liver (α1A & B and β2) and adipose tissue (α1A and β1 & 3) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α1, α2, and β-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism. © 2012 British Society for Neuroendocrinology.


This systematic review examines treatment guidelines, efficacy/effectiveness, and tolerability regarding the use of antipsychotics concurrently with psychostimulants in treating aggression and hyperactivity in children and adolescents. Articles examining the concurrent use of antipsychotics and psychostimulants to treat comorbid attention deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs) were identified and their results were summarized and critically analyzed. Antipsychotic and stimulant combination therapy is recommended by some guidelines, but only as a third-line treatment following stimulant monotherapy and stimulants combined with behavioral interventions to treat aggression in patients with ADHD. Some studies suggest efficacy/effectiveness for an antipsychotic and stimulant combination in the treatment of aggression and hyperactivity in children and adolescents. However, the data do not clearly demonstrate superiority compared to antipsychotic or psychostimulant monotherapy. Most studies were performed over short time periods, several lacked blinding, few studies used any placebo control, and no comparisons were made with behavioral interventions. There are concerns about the tolerability of combination therapy, but data do not suggest significantly worse adverse effects for combination compared to either antipsychotic or stimulant monotherapy. Conversely, and contrary to speculation, use of a stimulant does not significantly reduce metabolic effects of antipsychotics. Combination treatment with antipsychotics and psychostimulants is used frequently, and increasingly more often. Few studies have directly examined this combination for the treatment of ADHD and DBDs. Further studies are necessary to confirm the efficacy and tolerability of the concurrent use of antipsychotics and psychostimulants in children and adolescents.


Leung J.Y.T.,University of British Columbia | Barr A.M.,University of British Columbia | Barr A.M.,British Columbia Mental Health and Addictions Research Institute | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | And 4 more authors.
Pharmacology and Therapeutics | Year: 2012

Cardiovascular disease is the leading cause of death in people with severe mental disorders, and rates are proportionally greater than for other diseases such as cancer. Reports of sudden death in patients receiving antipsychotic treatment have raised concerns about the safety of antipsychotic drugs, leading to a number of recent changes in how such drugs are advertised and marketed. The majority of second generation antipsychotic drugs also have significant metabolic side-effects, such as weight gain, insulin resistance and hyperlipidemia, which may contribute indirectly to cardiovascular complications. As the use of antipsychotic drugs continues to expand into new indications and populations such as children and adolescents, a better understanding is needed of how antipsychotic drugs affect the cardiovascular system. Antipsychotic drugs interact with numerous receptors both centrally and peripherally, including monoamine receptors. The direct, non-specific pharmacological actions of antipsychotic drugs can lead to adverse cardiovascular effects, including orthostatic hypotension, tachycardia and ventricular arrhythmias. The mechanisms responsible for these antipsychotic-induced cardiovascular abnormalities have not been fully elucidated, but likely involve blockade of adrenergic or cholinergic receptors and hERG channels, in addition to impaired autonomic function. The direct and indirect effects of antipsychotic drugs on the cardiovascular system and their possible mechanisms of action are discussed in this review, where both preclinical and clinical findings are integrated. © 2012 Elsevier Inc. All rights reserved.


Boyda H.N.,University of British Columbia | Procyshyn R.M.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | Tse L.,University of British Columbia | And 7 more authors.
Journal of Psychiatry and Neuroscience | Year: 2012

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 assessment of insulin resist ance 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 anti diabetic 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. © 2012 Canadian Medical Association.


Lang D.J.,University of British Columbia | Barr A.M.,British Columbia Mental Health and Addictions Research Institute | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute
Current Cardiovascular Risk Reports | Year: 2013

Severe psychotic disorders, which on their own may be a risk factor for metabolic disorder and cardiovascular illness, are clinically compounded by the significant adverse side effects of antipsychotic medications. The majority of patients with severe psychotic disorders (i.e., schizophrenia, bipolar disorder, mania, and depression) must take antipsychotic medications to treat their psychoses and, subsequently, will require efficacious interventions to manage the metabolic consequences of pharmacologic treatment to mitigate excessive mortality associated with cardiovascular illness. We have reviewed the metabolic consequences of antipsychotic treatment and discussed pilot findings from a new nonpharmacologic intervention study looking at the clinical benefits of regular exercise as a management tool for the cardiometabolic risk factors in a cohort with severe mental illness. © 2013 The Author(s).


Boyda H.N.,University of British Columbia | Procyshyn R.M.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | Tse L.,University of British Columbia | And 6 more authors.
Neuropharmacology | Year: 2012

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. This article is part of a Special Issue entitled 'Schizophrenia'. © 2011 Elsevier Ltd. All rights reserved.


Leung J.Y.T.,University of British Columbia | Pang C.C.Y.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | Barr A.M.,University of British Columbia | Barr A.M.,British Columbia Mental Health and Addictions Research Institute
Vascular Pharmacology | Year: 2014

Treatment with antipsychotics is associated with adverse cardiovascular effects such as orthostatic hypotension and arrhythmias. Despite the higher prevalence of cardiovascular complications in patients with schizophrenia, the effects of antipsychotic drugs on vascular tone and cardiac contractility have received little attention. In order to better understand the cardiovascular effects of antipsychotic drugs, we investigated if the atypical antipsychotic olanzapine alters in vivo cardiovascular function in rats. Male Sprague-Dawley rats were prepared with indwelling catheters. After 4 h of recovery from surgery, the mean arterial pressure (MAP), mean circulatory filling pressure (MCFP; index of body venous tone), heart rate, left ventricular peak systolic pressure (LVP) and cardiac contractility (± dP/dt) were measured in conscious, unrestrained rats for 60 min after a single injection of olanzapine (3 or 15 mg/kg, i.p.) or vehicle. Cardiovascular measurements were not altered at any time points in the vehicle-treated rats. Olanzapine did not affect heart rate, but dose-dependently decreased MAP, MCFP, LVP and + dP/dt. Acute olanzapine treatment in rats thus reduced blood pressure and venous tone, as well as cardiac contractile function. Decreased venous tone may be a contributing factor to orthostatic hypotension commonly observed in patients during initiation of antipsychotic therapy. © 2014 Elsevier Inc. All rights reserved.


Panenka W.J.,University of British Columbia | Procyshyn R.M.,University of British Columbia | Procyshyn R.M.,British Columbia Mental Health and Addictions Research Institute | Lecomte T.,University of Montréal | And 6 more authors.
Drug and Alcohol Dependence | Year: 2013

Methamphetamine (MA) is a highly addictive psychostimulant drug that principally affects the monoamine neurotransmitter systems of the brain and results in feelings of alertness, increased energy and euphoria. The drug is particularly popular with young adults, due to its wide availability, relatively low cost, and long duration of psychoactive effects. Extended use of MA is associated with many health problems that are not limited to the central nervous system, and contribute to increased morbidity and mortality in drug users. Numerous studies, using complementary techniques, have provided evidence that chronic MA use is associated with substantial neurotoxicity and cognitive impairment. These pathological effects of the drug, combined with the addictive properties of MA, contribute to a spectrum of psychosocial issues that include medical and legal problems, at-risk behaviors and high societal costs, such as public health consequences, loss of family support and housing instability. Treatment options include pharmacological, psychological or combination therapies. The present review summarizes the key findings in the literature spanning from molecular through to clinical effects. © 2012 Elsevier Ireland Ltd.

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