1. Antipsychotics, Psychotic Illnesses and Cardiovascular Disease Stephen R. Marder, MD Semel Institute of Neuroscience at UCLA VA Desert Pacific Mental Illness Research, Education, and Clinical Center MIAMI Conf 5/18/10

2. Disclosure Information for Stephen R. Marder, MD Advisory board – Wyeth; Schering; Bristol-Myers Squibb Company; Otsuka America Pharmaceutical, Inc. Speaker – Bristol-Myers Squibb Company; Otsuka America Pharmaceutical, Inc.

3. Antipsychotics, Psychotic Illnesses, Cardiovascular Diseases Risk of Premature Death Risk of heart disease in SMI patients Modifiable risk factors for heart disease

4. SMR = standardized mortality ratio (observed/expected deaths). 1.Harris et al. Br J Psychiatry. 1998;173:11. 2.Osby et al. Arch Gen Psychiatry. 2001;58:844-850. 3.Osby et al. BMJ. 2000;321:483-484. Increased Mortality Rates for Medical Disorders in Mental Illness 50% increased risk of death from medical causes in schizophrenia, and 20% shorter lifespan 1 Bipolar and unipolar affective disorders also associated with higher SMRs from medical causes 2 – 1.9 males/2.1 females in bipolar disorder – 1.5 males/1.6 females in unipolar disorder Cardiovascular mortality in schizophrenia increased from 1976-1995, with greatest increase in SMRs (8.3 males/5.0 females) from 1991-1995 3

5. Year of life lost

9. Schizophrenia, antipsychotics, and mortality Joukamaa et al Brit J Psychiatry 2006 17 year follow-up of 7217 Finns Relative Mortality Risk (RR) for Schizophrenia was 2.84 Controlling for factors such as HBP, BMI, ETOH, smoking, RR was 2.25 Risk increased when antipsychotics combined

10. Cardiovascular risk factors – overview BMI = body mass index; TC = total cholesterol; DM = diabetes mellitus; HTN = hypertension. Wilson PWF et al. Circulation. 1998;97:1837–1847. 0 2 4 6 8 10 12 14 HTNDMSmokingBMI >27TC >220 Single Risk Factors Multiple Risk Factors Odds ratios Smoking + BMI 2 + TC >220 3 Smoking + BMI + TC >220 + DM 4 Smoking + BMI + TC >220 + DM + HTN 5 The Framingham Study

11. “Body Mass Index” (BMI) is an Indicator of Weight Status A ratio taking into account an individual’s weight (kilograms), and height (meters squared) – kg / m 2 With a BMI of:You are: below 19Underweight 19 - 24Healthy Weight 25 - 29Overweight 30 or higherObese

12. Obesity Has Become More Common in the United States

13. Risk of Death Increases with BMI

14. Waist Circumference and BMI Increase the Risk of Diabetes, Hypertension, and Cardiovascular Disease BMIWaist men ≤ 40 inches women ≤ 35 inches Waist > 40 inches > 35 inches Underweight< 18.5-- Normal18.5 – 24.9-- Overweight25.0 – 29.9IncreasedHigh Obese30.0 – 34.9 35.0 – 39.9 High Very High Extremely Obese≥ 40Extremely High

15. 1. NCEP ATP III. JAMA.. 2001;285:2486-2497. The Metabolic Syndrome Risk FactorDefining Factor Abdominal obesityWaist circumference Men >40 in (>102 cm) Women >35 in (>88 cm) Triglycerides  150 mg/dL HDL-C Men <40 mg/dL Women <50 mg/dL Blood Pressure  130/85 mm Hg Fasting Glucose  110 mg/dL

16. CHD risk increases with increasing number of metabolic syndrome risk factors Sattar et al, Circulation, 2003;108:414-419 Whyte et al, American Diabetes Association, 2001 Adapted from Ridker, Circulation 2003;107:393-397

17. Adiposity and Medical Diseases Calle EE, Thun MJ, Petrelli JM, et al. N Engl J Med. 1999(Oct 7);341(15):1097-1105 Body Mass Index Women Body Mass Index Men Relative Risk 6 5 4 3 2 1 0  21 222324252627282930 6 5 4 3 2 1 0  21 222324252627282930 Type 2 DM Cholelithiasis Hypertension Coronary heart disease

18. 18 Body Mass Index (BMI) And Relative Risk Of Type 2 Diabetes In women age 35-55 years in 1976; data adjusted for age. Adapted from Colditz et al. Am J Epidemiol. 1990;132:501-513. BMI (kg/m 2 ) 0 10 20 30 40 50 60 <2222–23–24–25–27–29–31–33– 35+22.923.924.926.928.930.932.934.9 70 Adjusted Relative Risk

19. Natural History of Type 2 Diabetes Insulin resistance Hepatic glucose production Endogenous insulin Postprandial blood glucose Fasting blood glucose Typical Diagnosis of Diabetes Microvascular Complications Macrovascular Complications Severity of Diabetes Impaired Glucose ToleranceFrank Diabetes Years to Decades Time Ramlo-Halsted BA, Edelman SV. Primary Care. 1999; 26: 771–789. Asymptomatic Stage

20. Obesity and Insulin Resistance Lipolytically Active Abdominal Adipose Tissue Glucose Utilization Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634. Caballero AE. Obesity Res. 2003;11:1278-1289. Reaven GM. Diabetes. 1988;37:1595-1607. Hyperglycemia and Dyslipidemia Adipose Tissue Inhibition of Lipolysis Glucose Output Adipose Tissue Skeletal Muscle Liver

21. Insulin Resistance “Inadequate” Insulin Response CompensatoryHyperinsulinemia Type 2 Diabetes Insulin Resistance Syndrome RetinopathyNephropathyNeuropathy Hypertension Polycystic Ovarian Syndrome Non-Alcoholic Fatty Liver Disease Cancer Sleep Breathing Disorder Cardio- vascular Disease (CVD) Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634. Caballero AE. Obesity Res. 2003;11:1278-1289. Reaven GM. Diabetes. 1988;37:1595-1607. Cognitive Dysfunction

22. Effects of 8 days of olanzapine treatment (Vidarsdotter et al 2010) 12 healthy men received 1 of 2 oral formulations of olanzapine or placebo for 8 days. Olanzapine treatment led to increased insulin resistance and increased fasting and post- prandial triglycerides. These effects were independent on diet and physical activity

23. Is This Just an Issue With Second Generation Antipsychotics (SGA’s)? Probably not Early report from 1956 describes hyperglycemia in 5 patients treated with chlorpromazine. Reports from the 1960’s describe increased prevalence of diabetes following introduction of chlorpromazine.

24. Glucose Tolerance in 1st Episode, Drug Naive Patients Measured fasting glucose, insulin, lipids, in schizophrenia pts (n=26) and controls (n=26). Pts had normal BMI’s Schizophrenia pts had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl vs 95.8), insulin (mean=7.7vs 9.8 micro u/ml, SD=3.9). Pts were more insulin resistant, as measured with homeostasis model assessment Ryan et al, Am J Psychiatry, 2003

25. ADA Consensus on Antipsychotic Drugs: Metabolic Abnormalities of Second-Generation Antipsychotics Drug Weight Gain Risk for Diabetes Worsening Lipid Profile Clozapine+++++ Olanzapine+++++ Risperidone++DD Quetiapine++DD Aripiprazole*+/––– Ziprasidone*+/––– + = increased effect; – = no effect; D = discrepant results. *Newer drugs with limited long-term data. American Diabetes Association et al. Diabetes Care. 2004;27:596.

26. Psychotropic-Associated Weight Gain Data from Pivotal Trials Agents5% Weight GainLengthMean Change Lithium 1 62%1 year4.0 kg Valproate 2 21%1 yearNot reported Agents7% Weight GainLengthMean Change Olanzapine 3 29%6 weeks+2.8 kg Quetiapine 3 21%6 weeks+2.6 kg Risperidone 3 18%6 weeks+1.6 kg FDA = US Food and Drug Administration; N/R = not reported. *Weight gain was stratified according to BMI. 1. Peselow ED, et al. J Affect Disord. 1980;2:303-310. 2. Bowden CL, et al. Arch Gen Psychiatry. 2000;57:481-489. 3. Adapted from: Prescribing Information. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Medical Economics Co; 2005.

27. Compared mortality among 66,881 patients and the population of Finland (5.2 million) between 1996 and 2006 Life expectancy for schizophrenia did not decline as more patients were treated with SGA’s Clozapine associated with the lowest mortality; Quetiapine with the highest A longer duration of antipsychotic use associated with lower mortality

28. Risk of Death for Any Cause Tiihonen et al, 2009

29. Hennekens CH. Circulation. 1998;97:1095-1102. Goals: Lower Risk for CVD Blood cholesterol – 10%  = 30%  in CHD (200-180) High blood pressure (> 140 SBP or 90 DBP) – 4-6 mm Hg  = 16%  in CHD; 42%  in stroke Cigarette smoking cessation – 50%-70%  in CHD Maintenance of ideal body weight (BMI = 25) – 35%-55%  in CHD Maintenance of active lifestyle (20-min walk daily) – 35%-55%  in CHD

30. Physical Health Monitoring for the Severely Mentally Ill Where should it occur? Who should monitor? What should be monitored and how often?

31. Guidelines for Monitoring MonitoringAPAADA/APAMt. Sinai Body weight and height BMI every visit for 6 months; quarterly thereafter BMI at baseline; every 4 weeks for the 12 weeks; quarterly thereafter BMI at baseline; at every visit for next 6 mos; quarterly when stable Fasting plasma glucose Fasting blood glucose at baseline. Fasting plasma glucose or HbA1c at 4 months after initiating new treatment and annually thereafter Fasting plasma glucose at baseline, 12 weeks and annually thereafter Fasting plasma glucose or HbA1c before initiating an antipsychotic, annually thereafter Lipid panel At least every 5 yearsBaseline; at 12 weeks; every 5 years Every 2 years or more often if levels are in the normal range and every 6 months if LDL levels are >130mg/dL Adapted from: Diabetes Care, Vol 27, No 1, February 2004. Am J Psychiatry. 161:2, February 2004 Supplement. Marder SR, et al. Am J Psychiatry. 2004; 161:1334-1349.

32. Summary Antipsychotic are associated with increased mortality Patients with Serious Mental Illnesses are at a high risk for Metabolic Syndrome and cardiovascular disease Monitoring of modifiable risk factors should take place in either a primary care or mental health setting.

33. Summary (cont) This often means it will be the psychiatric setting by default