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3/9/2010 DISCLAIMER CARDIOTOXICITY, HYPERGLYCEMIA AND ANTIPSYCHOTIC MEDICATIONS AMIT VASHIST, MD PGY III INTERNAL MEDICINE/PSYCHIATRY NEITHER THE PUBLISHER NOR THE AUTHORS ASSUME ANY LIABILITY FOR ANY INJURY AND OR DAMAGE TO PERSONS OR PROPERTY ARISING FROM THIS WEBSITE AND ITS CONTENT. Case Presentation 1 Mr. A, a 61 61--yearyear-old man with CAD and COPD, was admitted to the ICU for respiratory failure. He was intubated on admission to the hospital; fortunately, his pulmonary function improved, and he was extubated on the third hospital day. Following extubation, he became agitated, and psychiatric consultation was requested. Delirium was diagnosed and IV haloperidol was recommended. Case Presentation 1 (Contd.) Despite knowing that Mr. A's EKG revealed a normal rate and rhythm, that his QTc was 440 ms, and that the rest of his cardiac intervals were normal, the medical resident was uncomfortable with the recommendation. The resident noted that he had seen “lots of problems” with IV haloperidol and that he would rather not use it to treat Mr. A since he had CAD. 1 3/9/2010 Case Presentation 2 A 4646-yearyear-old man was brought to the ER by his wife after she noticed some apparent seizure seizure--like activity lasting one to two minutes, and included tongue biting and urinary incontinence. His PMH included bipolar d/o, DM, HTN and dyslipidemia. His medications included metformin, lantus insulin, simvastatin, lisinopril, paroxetine, lamotrigine and had not changed for many months except for the recent addition of paliperidone four days before his arrival to the ER. EKG revealed A. fib., QTc of 461 ms and no acute ST--T wave changes. ST Risk factors for cardiovascular/metabolic disease: Considerations for patients with schizophrenia Modifiable risk factors Non-modifiable risk factors Case Presentation 2 (Contd.) The pt. had no chest pain, and all other labs and vital signs were normal. He was admitted for evaluation and given IV diltiazem with resultant conversion to NSR NSR, after which his heart rate and QTc interval normalized. He was discharged after one day. Cardiovascular health status and mortality rates associated with schizophrenia Obesity Gender Dyslipidemia Family history Diabetes Hypertension Cardiovascular Disease Personal history Age Smoking ATP III. JAMA. 2001;285:2486-2497. Nearly 60% of the patients are obese. Risk of developing diabetes is more than two times higher than the general population. 70--80% smoke versus 25% in the general 70 population. population Approx. two times higher incidence of cardiovascular disease mortality than general population. Sedentary lifestyle, poor dietary habits and inadequate access to healthcare worsen the situation. Theisen FM et al. J Psychiatr Res. 2001;35:3392001;35:339-345. Herrán A et al. Schizophr Res. 2000;41:3732000;41:373-381. Allebeck P. Schizophr Bull. 1989;15:811989;15:81-89. 2 3/9/2010 Risk of cardiovascular and metabolic events in patients with schizophrenia and in the general population Cardiac complications associated with antipsychotics Weight gain Adverse lipid profile Orthostatic hypotension Myocarditis Cardiomyopathy Torsades de Pointes (TdP) V. fib. other than TdP Enger et al, J Nerv Ment Dis (2004) Consequences of Dyslipidemias Elevated cholesterol and LDL increase risk for cardiovascular disease (CVD)1 Increased triglycerides1 I d Independent d t risk i k factor f t for f CVD Lowering lipids by 10% decreases cardiovascular risk by 20%20%-30%2 Consequences of Diabetes Increased risk of cardiovascular disease Macrovascular complications due to high levels of cholesterol and triglycerides Microvascular i l effects ff 1. Wirshing et al. J Clin Psychiatry. 2002;63:856. 2. Sacks et al. N Engl J Med. 1996;335:1001. Retinopathies blindness Nephropathies kidney failure Peripheral neuropathies physical pain Lindenmayer et al. J Clin Psychiatry. 2001;62(suppl 23):30. 3 3/9/2010 Survival of Diabetics Without a History of MI Is Similar to That of Nondiabetics Who Are PostPost-MI CV mortaliity (%) 50 No prior MI Obesity and mortality risk Mortality 2.5 ratio 2.0 42 Prior MI 40 15.9 20 10 1.0 15.4 n= 69 1304 Nondiabetic 169 890 0.0 Diabetic Olanzapine, clozapine and quetiapine have been associated with increases in serum triglycerides, modest increases in total cholesterol but limited impact on LDL. Recent switch data also suggest that there may be direct, adipocyte--independent effects of metabolically offending adipocyte antipsychotic meds on serum lipids. 0 20 25 Low Moderate 30 35 High Very high 40 45 Adapted from Gray 1989 Diabetes and glucose tolerance Minimal effects of aripiprazole and ziprasidone on serum p lipids Mechanisms contributing to hyperlipidemia have focussed on weight gain, dietary changes and development of insulin resistance Moderate Very low BMI Effects on lipid profile Men Women 0.5 2.1 MI = myocardial infarction. Haffner et al. N Engl J Med. 1998;339:229. Cardiovascular and gall bladder disease diabetes mellitus 15 1.5 30 0 Digestive and pulmonary disease Mechanisms Patients taking olanzapine have a 44-fold greater risk of developing T2DM than do those taking typical antipsychotics. Similar risk with clozapine. l i The incidence of clinically significant weight gain with aripiprazole and ziprasidone is considerably less than that with olanzapine, hence the risk of developing metabolic syndrome with these 2 agents is comparable to placebo. 4 3/9/2010 Mean change in weight gain in patients receiving antipsychotic meds Mean change in weight with antipsychotics Metabolic disturbances associated with antipsychotic agents Dyslipidemia Clozapine Weight gain Diabetes Risk +++ + Olanzapine +++ + + D D Risperidone ++ Quetiapine * 13.2 11.0 8.8 6.6 4.4 2.2 0 -2.2 -4.4 -6.6 Allison et al. Am J Psychiatry. 1999;156:1686. J Clin Psychiatry and Schizophr Res Drug 6 5 4 3 2 1 0 -1 -2 -3 Weight change (lb) Weight chan nge (kg) Estimated Weight Change at 10 Weeks on “Standard” Dose Tachycardia + ++ D D Aripiprazole +/- _ _ Ziprasidone +/- _ _ Mostly secondary to anticholinergic effects of antipsychotics. Exacerbated by α1α1- adrenergic receptor antagonism seen commonly among lower potency antipsychotics and clozapine. Prolonged tachycardia can increase myocardial oxygen demand and could contribute to cardiac ischemia and subsequently cardiomyopathy. American Diabetes Association. Consensus Development Conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 2004. 5 3/9/2010 Myocarditis and Cardiomyopathy Orthostatic hypotension Most common CV side effect Can occur with any antipsychotic Mediated by α1α1-adrenergic antagonism Could be of particular concern in the elderly wherein orthostasis could result in neurologic symptoms like lightheadedness in a mild form and presyncope or syncope in the severe form. Clozapine has the strongest association, whereas olanzapine and ziprasidone have the lowest incidence. An uncommon, but potentially fatal effect from clozapine use. 15 cases of myocarditis and 8 cases of cardiomyopathy reported between 1993 and 1999 in i Australia li from f approximately i l 8000 patients starting clozapine during that period. All 15 cases of myocarditis occurred within 3 weeks of starting treatment and included 5 patient deaths. Review of electrocardiogram (ECG) and intervals 0.2 s QRS 1 mv QT interval PR interval P Normal QT interval T U PR ST segment segment Guyton and Hall 2000 Corrected QT interval (QTc) values adjust QT interval measurements for heart rate. A normal Q QTc interval is defined as <450 ms for women and <430 ms for men. The duration of the QT interval varies inversely with heart rate. Moss 1993 6 3/9/2010 QT prolongation Can predispose patients to syncope, ventricular arrhythmias, and sudden death. May increase i the h risk i k off torsade d de d pointes, a potentially fatal ventricular arrhythmia. Potential Consequences of QTc Interval Prolongation QTc prolongation Rarely Torsade de pointes arrhythmia (syncope) Rarely Ventricular fibrillation Clinically significant prolonged QTc values are defined as >500 ms. Welch and Chue 2000; Moss 1986; Glassman and Bigger 2001; Litherland 1997 Effects of Orally Orally--Administered Antipsychotics on the QT Interval Sudden death Glassman and Bigger. Am J Psychiatry. 2001;158:1774. Ray et al. Arch Gen Psychiatry. 2001;58:1161. Effect of antipsychotic drugs on QTc prolongation Mean QTc change from baseline* (ms) 40 35 30 25 20 15 10 5 0 -5 OlanzapineRisperidoneQuetiapineHaloperidol ZiprasidoneThioridazine 20 mg 160 mg 300 mg 16 mg 750 mg 15 mg (n=24) (n=31) (n=27) (n=25) (n=27) (n=30) FDA Psychopharmacological Drug Advisory Committee, July 2000 7 3/9/2010 Atypicals and the risk of sudden cardiac death Methods Cohort was restricted to persons 30 to 74 years of age. Typical antipsychotics analyzed were haloperidol and thioridazine. thioridazine Atypicals included were quetiapine, olanzapine, risperidone and clozapine. Do atypical antipsychotic meds carry the same or a reduced risk of serious ventricular arrythmias and sudden cardiac death than typical antipsychotics? Ray et al conducted a retrospective cohort study of Medicaid enrollees in Tennessee. Study groups included users of single typical, atypical and matched non users of antipsychotics. Results Current users of typical antipsychotics had an incidence rate ratio of 1.99 compared to non users. Atypical antipsychotics had an incidence ratio of 2 26 2.26. Among users of atypicals, the incidence rate ratios increased from 1.59 for those on low doses to 2.42 for those taking higher doses. 8 3/9/2010 The CATIE Schizophrenia Study Limitations of this study Though several provisions were made to avoid confounding factors, there exists a serious potential for the same. This study did not assess the mechanisms by which antipsychotics increased the risk of sudden cardiac death. What about ziprasidone?? What Should We Monitor? CATIE Study (Contd.) Olanzapine and quetiapine were associated with increased risk; whereas risk decreased in patients treated with perphenazine, risperidone, and ziprasidone ziprasidone. Overall differences in CAD risk appeared secondary to lowering of total cholesterol in patients treated with risperidone and ziprasidone, and increase in HDL with perphenazine and ziprasidone. The study objective was to examine effects of different antipsychotic treatments on estimates of 10 year CAD risk calculated by the Framingham Heart Study Formula. Change h in i 10 year risk i k for f CHD was comparedd between treatment groups in 1125 patients followed for 18 months. Antipsychotic meds involved were olanzapine, perphenazine, quetiapine, risperidone and ziprasidone. Physical Exam Check weight - each visit Check blood pressure - each visit Lab Tests Hemoglobin A1c - every 3 3––6 months Fasting blood glucose - every 3 months Triglycerides - every 3 months Cholesterol - every 3 months 9 3/9/2010 ADA Screening Guidelines for Patients on Second Second--Generation Antipsychotics1 Baseline 4 Weeks 8 Weeks 12 Weeks X X X Clinical insights for optimal cardiac safety with antipsychotics Annually Personal family history X Weight (BMI) Overweight (25.0-29.9) Obese (30.0) X Waist circumference (<40″ in males, <35″ in females)2 X Blood pressure X X X Fasting plasma glucose IFG (100-125 mg/dL)3 Diabetes (126 mg/dL)3 X X X Fasting lipid profile Total cholesterol (<200 mg/dL)2 HDL (>40)2 LDL (<100)2 TG (<150)2 X X X X Normal values (in parentheses) based on 2007 ADA Guidelines and National Cholesterol Education Program (NCEP) Guidelines. 1. ADA. Diabetes Care. 2004;27(2):596-601. 2. Adult Treatment Panel. JAMA. 2001;285(19):2486-2497 3. ADA. Diabetes Care. 2007;30(suppl 1):S4-S41. Probe for patient and/or family history of dizziness, syncope, palpitations, arrhythmias, or sudden death Evaluate overdose risk Consider patient’s use of coronary vasospastic substances, bt suchh as nicotine i ti or cocaine i Maintain normal electrolyte levels, especially potassium and magnesium Monitor for alcohol use, dehydration, and diuretics which may cause abnormal electrolyte levels Monitor for drug interactions with metabolic inhibitors and drugs that prolong the QT interval. Concerns regarding prolonged QTc Prolonged QTc is an unreliable and a crude predictor of TdP. There have been rare postpost-marketing reports of TdP (in the presence of multiple confounding factors) with quetiapine, quetiapine risperidone and ziprasidone in which no causal relationship was established. For pts. taking antipsychotics who experience symptoms that could indicate the occurrence of TdP (dizziness, palpitations, or syncope), further evaluation like Holter monitoring may be useful. EKG monitoring guidelines No need to routinely perform an EKG before initiating antipsychotic therapy in pts. without any risk factors for QTc prolongation. prolongation Obtain a baseline EKG in pts with risk factors for QTc prolongation or cardiac problems, including a hx of cardiac disease, HR < 50, hypokalemia, hypomagnesemia, or chronic alcohol abuse. 10 3/9/2010 In a nutshell EKG monitoring guidelines (contd.) No need to perform an EKG when the doses of antipsychotic meds are increased, since changes in QTc do not appear to be dose dose-related in a clinically significant way at clinically relevant doses. Baseline EKG before initiating antipsychotics if: personal hx of heart disease or syncope; family hx of sudden death, or congenital long QT syndrome. Patients with severe mental illness have higher standardized mortality rates from cardiovascular disease than the general population. Certain cardiovascular adverse effects like orthostasis, tachycardia and lethal tachyarrhythmias from QTc prolongation are of less concern with atypical antipsychotics. Traditional risk factors for cardiovascular morbidity and mortality are of significant concern during atypical antipsychotic treatment particularly for olanzapine and clozapine. Weiden et al, 2002 Summary (contd.) Clozapine and olanzapine are associated with greatest risk of insulin resistance, or T2DM, but there are cases linked to exposure with other atypicals. Adiposity--independent mechanisms have also been shown Adiposity increase the propensity of certain antipsychotics to cause insulin resistance. Myocarditis and QTc prolongation may result in fatal dysrhythmias, yet these events are exceedingly rare and contribute nominally to excessive CV mortality seen among patients with schizophrenia Current practice guidelines suggest trials of metabolically more neutral agent like aripiprazole and ziprasidone when appropriate, and routine monitoring of weight, lipids and glucose for all patients receiving antipsychotic treatment. 11 3/9/2010 12