THE METABOLIC SYNDROME IN PATIENTS TREATED BY ATYPICAL NEUROLEPTICS

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The Metabolic Syndrome in Patients Treated with Atypical Neuroleptcs:

The Metabolic Syndrome in Patients Treated with Atypical Neuroleptcs WALID SARHAN F.R.C.Psych Consultant Psychiatrist Amman-Jordan The First International Congress of the Jordanian Association of Psychiatrists 9 th .April 2010 3/20/2011 1

Synonyms of Metabolic Syndrome:

Synonyms of Metabolic Syndrome Metabolic Syndrome (MS) Insulin Resistance Syndrome (IRS) Syndrome X (Metabolic), Deadly Quartet Dysmetabolic Syndrome, Beer belly syndrome Cardiometabolic Syndrome Pleuri Metabolic Syndrome ICD Code # 277.7 Clustering of CV Risk Factors 3/20/2011 2

Chronology of Events:

Chronology of Events 3/20/2011 3 Eskil Kylin 1923 – HT,  Glucose,  UA Reaven 1988 – named Syndrome X (IR) WHO definition-1998 – Metabolic syndrome NCEP-ATP III – 2001 – MS – strong CV Risk First World Congress on IRS – Nov 2003 Second World Congress on IRS – 2004 2005 Quarrel about the word “syndrome” New IDF definition 2006 - consensus www.insulinresistance.us, www.drsarma.in

THE “ORIGINAL” SYNDROME X:

THE “ORIGINAL” SYNDROME X Resistance to insulin-stimulated glucose uptake Glucose intolerance Hyperinsulinaemia Increased VLDL-triglyceride Decreased HDL-cholesterol Hypertension Reaven , 1988 3/20/2011 4

METABOLIC SYNDROME – WHO 1999:

METABOLIC SYNDROME – WHO 1999 3/20/2011 5 At least 1 of Type 2 diabetes IGT Insulin resistance Hypertension Obesity Raised TG or low HDL Microalbuminuria at least 2 of + Metabolic syndrome Hyperuricaemia Hypercoagulability Hyperleptinaemia Not required for definition, but may be part of the syndrome

IDF CONSENSUS:

IDF CONSENSUS Plus any two of: Raised TRIGLYCERIDES Low HDL-CHOLESTEROL Raised BLOOD PRESSURE Raised FASTING PLASMA GLUCOSE (or PRE-EXISTING DM ) 3/20/2011 6 CENTRAL OBESITY Definition

IDF CONSENSUS:

IDF CONSENSUS Cutpoints TRIGLYCERIDES: ≥ 1.7 mM (150 mg/dl) HDL-CHOLESTEROL: < 1.04 mM (40 mg/dl) M < 1.29 mM (50 mg/dl) F BLOOD PRESSURE: ≥ 130 mm Hg Systolic or ≥ 85 mm Hg Diastolic or treatment F. PLASMA GLUCOSE: ≥ 5.6 mM (100 mg/dl ) 3/20/2011 7

IDF CONSENSUS:

IDF CONSENSUS Central Obesity M F (cm) Europids 94 80 South Asians 90 80 Chinese 90 80 Japanese 85 90 Sub-Saharan Africans, Middle East – use Europid figures South/Central Americans – use South Asian figures 3/20/2011 8

Diagnostic Criteria for Metabolic Syndrome USA:

Diagnostic Criteria for Metabolic Syndrome USA 3/20/2011 9 Waist circumference (visceral adiposity) Men Women >40 in (102 cm) >35 in (88 cm) Blood pressure ≥130 mmHG ≥85 mmHG Triglycerides ≥150 mg/dL High-density lipoprotein (HDL) cholesterol Men Women <40 mg/dL <50 mg/dL Fasting glucose ≥100 mg/dL Three or more risk factors must be present for diagnosis Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001.

Slide 10:

Ethnic specific values for waist circumference 3/20/2011 10 Waist circumference Country / Ethnic group 94 cm 80 cm Male Female Europids* In the USA , the ATP III values ( 102 cm male; 88 cm female) are likely to continue to be used for clinical purposes 90 cm 80 cm Male Female South Asians Based on a Chinese , Malay and Asian-Indian population 90 cm 80 cm Male Female Chinese 90 cm 80 cm Male Female Japanese** Use South Asian recommendations until more specific data are available Ethnic South and Central Americans Use European data until more specific data are available Sub-Saharan Africans Use South Asian recommendations until more specific data are available Arab populations

THE SIMPLE CONCEPT OF THE METABOLIC SYNDROME ( MTS ):

THE SIMPLE CONCEPT OF THE METABOLIC SYNDROME ( MTS ) The Metabolic Syndrome is a cluster of the most dangerous risk factors for heart attack : - Diabetes / raised fasting plasma glucose, + - Abdominal obesity , - High blood pressure - Defective Cholesterol Metabolism. 3/20/2011 11

Insulin Resistance Syndrome:

Insulin Resistance Syndrome 3/20/2011 12 ACE Position Statement on IRS Endocr Pract . 2003;9(3) CAD

IR and the Double Jeopardy !!:

IR and the Double Jeopardy !! 3/20/2011 13 Insulin Resistance Obesity Diabetes Metabolic Syndrome Cardio Vascular Disease (CVD) 2 x 4 x Reilly MP et al – Circulation 2003; 108: 1546-1551

Visceral adiposity and the insulin-resistance syndrome:

Increased Visceral Adipose Tissue Increased Free Fatty Acids;TNF ; Leptin ; ? Increased VLDL Particles Decreased Hepatic Insulin Clearance Increased Free Fatty Acids Diabetic Dyslipidemia Increased PAI-1 Increased Peripheral Insulin Resistance Increased Hepatic Insulin Resistance Visceral adiposity and the insulin-resistance syndrome 3/20/2011 14 Increased Hepatic Triglycerides Endothelial Cells

Known adipocyte secretory proteins:

Known adipocyte secretory proteins Leptin Alternative complement pathway proteins ( adipsin , C3, B) Adiponectin (ACRP 30) Acylation -stimulating protein (ASP) Lipoprotein lipase Nonesterified fatty acids Cholesteryl ester transfer protein Apolipoprotein E Retinol-binding protein Vascular endothelial growth factor (VEGF) Monobutyrin Tumor necrosis factor-alpha (TNF ) Interleukin-6 Angiotensinogen Plasminogen activator inhibitor-1 Transforming growth factor  (TGF) Hepatocyte growth factor Insulin-like growth factor 1 (IGF-1) 3/20/2011 15 Bradley et al. Recent Prog Horm Res 2001; 56: 329–358

Slide 16:

Adverse cardiometabolic effects of products of adipocytes Adipose tissue ↑ IL-6 ↓ Adiponectin ↑ Leptin ↑ TNF α ↑ Adipsin (Complement D) ↑ Plasminogen activator inhibitor-1 (PAI-1) ↑ Resistin ↑ FFA ↑ Insulin ↑ Agiotensinogen ↑ Lipoprotein lipase ↑ Lactate Inflammation Type 2 diabetes Hypertension Atherogenic dyslipidaemia Thrombosis Atherosclerosis Lyon 2003; Trayhurn et al 2004; Eckel et al 2005 3/20/2011 16

Free fatty acids (FFA):

Free fatty acids (FFA) Increased plasma levels of FFA contributes to insulin resistance through inhibition of glucose transport activity in skeletal muscles Chronic elevation of FFA levels may also have a destructive effect on  -cell function – known as lipotoxicity . There is a growing evidence that this is a key contributor to type 2 diabetes problem 3/20/2011 17

Dyslipidemia of the Metabolic Syndrome:

Dyslipidemia of the Metabolic Syndrome Hypertriglyceridemia Postprandial lipemia Low HDL-C Predominantly small dense LDL particles Decreased activity of lipoprotein lipase Increase free fatty acid concentrations 3/20/2011 18 REAVEN G , 2001, ENDOCRINOLOGY, 4 TH ED 955-957, DEGROOT L.

Growing prevalence of abdominal obesity :

Growing prevalence of abdominal obesity 3/20/2011 19 + 18% 55.1% 46.7% Women + 28% 36.9% 29.5% Men Relative change NHANES (1999 – 2000) NHANES III (1988 – 1994) Ford et al 2003 US National Health and Nutrition Examination Survey (NHANES) Abdominal obesity defined as waist circumference: >102 cm (>40 in) in men or >88 cm (>35 in) in women

Slide 20:

“ Abdominal Obesity “ as measured by waist circumference is more indicative of the Metabolic Syndrome profile than increased BMI 3/20/2011 20

GLOBAL SIZE OF THE (MTS) PROBLEM:

GLOBAL SIZE OF THE (MTS) PROBLEM 20-25 % of the world adult population have the metabolic syndrome ( MTS) , and these are : - twice likely to die - 3 times likely to have a heart attack or stroke - 5 times at risk to develop diabetes type 2 3/20/2011 21

The MTS in Young People:

The MTS in Young People Research studies so far denote : 1. Prevalence ? probably 30 % in overweight adolescents (US sample) 2. A high BMI in childhood is predictive of MTS in adult life . 3. CV risk factors in ( LDH & BMI ) are present in childhood , and are predictive of CHD in adulthood 3/20/2011 22

MTS in the young ( cont.):

MTS in the young ( cont.) There are no established criteria for diagnosis in the young There is urgent need to decide : 1.The cut -off values in children. 2. if the 100 mg/dl fasting glucose is correct. 3.The proper method to assess central obesity by accurate measuring waist circumference. 3/20/2011 23

Slide 24:

The IDF definition of the at risk group and metabolic syndrome in children and adolescents Glucose (mg/ dl) or known T2DM Blood pressure HDL-C Triglycerides Obesity * ( WC ) Age group (years) Metabolic syndrome cannot be diagnosed , but further measurements should be made if there is a family history of metabolic syndrome, T2 DM , dyslipidemia, cardiovascular disease , hypertension and/or obesity  90 6 - <10 (100 mg/dL) [ or known T2DM ] Syst. 130 diast85mmHg ( < 40mg/dL) (  150 mg/dL)  90 or adult cut-off if lower 10 - < 16 Use existing IDF criteria for adults 16 + 3/20/2011 24

Slide 25:

> 1000 600- 1000 200-600 > 200 Bahrain 1047 Lebanon 1050 Qatar 1198 Oman 614 Tunisia 637 Jordan 711 Iran 744 Kuwait 806 Saudi Arabia 891 Emirates 929 Alger 273 Morocco 285 Egypt 286 Libya 384 Afghanistan 56 Iraq 72 Pakistan 99 Sudan 103 Yemen 110 Syria 185 3/20/2011 25 EMME Countries according to The Mean Health Expenditure per person with diabetes in ID (international Dollar) : Diabetes Atlas, 3rd Ed .

Diabetes Incidence by Number of Metabolic Syndrome Components:

Diabetes Incidence by Number of Metabolic Syndrome Components 3/20/2011 26 Diabetes risk increases synergistically when at least four risk factors are present; risk factors evaluated comprise metabolic syndrome symptom clusters; those factors are increased waist circumference, blood pressure, triglyceride, and fasting glucose levels as well as decreased high-density lipoprotein levels Sattar N et al. Circulation 2003. In: Sacks FM. J Clin Psychiatry 2004.

Type 2 Diabetes and Myocardial Infarction (MI) :

Non-Diabetic n=1,373 Diabetic n=1,059 Type 2 Diabetes and Myocardial Infarction (MI) 3/20/2011 27 Haffner SM et al. N Engl J Med 1998. p<0.001 for prior MI vs. no prior MI p=0.1 for diabetes vs. no diabetes

NHANES III: Age-Specific Prevalence of the Metabolic Syndrome (ATP III):

NHANES III: Age-Specific Prevalence of the Metabolic Syndrome (ATP III) 3/20/2011 28 Data are presented as percentage (SE). 20-29 30-39 40-49 50-59 60-69  70 Age, y 50 45 40 35 30 25 20 15 10 5 0 Prevalence, % Men Women Ford ES, et al. JAMA . 2002;287:356-359.

Prevalence of Metabolic Syndrome: Implications for Intervention in Young Adults:

Prevalence of Metabolic Syndrome: Implications for Intervention in Young Adults Relatively high prevalence in young adults Marked increase in prevalence in type 2 diabetes in young adults 76% increase in prevalence among adults, age 30-39 years (1990-1999) Indicates need to focus attention on public health strategies that target adolescents and young adults 3/20/2011 29

Prevalence of Metabolic Syndrome: Implications for Intervention in Older Adults:

Prevalence of Metabolic Syndrome: Implications for Intervention in Older Adults Very high prevalence of metabolic syndrome in middle-aged and older people (35-45 %) Indicates need for public health strategies to reduce burden of syndrome in the future Requires attention on clinical strategies to deal with the high prevalence in already affected individuals 3/20/2011 30

The Metabolic Syndrome Prevalence of Components*:

The Metabolic Syndrome Prevalence of Components * Abdominal obesity 39% Hypertriglyceridemia 30% Low HDL cholesterol 37% High blood pressure or medication use 34% High fasting glucose or medication use 13%  1 Metabolic Abnormalities: 71%  2 Metabolic Abnormalities: 44%  3 Metabolic Abnormalities: 24% 47 MM US Residents 3/20/2011 31 Ford ES, et al. JAMA . 2002:287:356-359. *US adults age 20 and over (1988-1994)

Psychiatric Patients and Medical Co-Morbidity:

Psychiatric Patients and Medical Co-Morbidity Risk factors for cardiovascular disorders and rates of physical disorders are increased in the psychiatric population, partly due to low levels of help-seeking and lifestyle factors, poor diet, reduced of physical activity , smoking and medications Phelan, Stradins & Morrison(2001) Physical health of people with severe mental illness. BMJ 322:443-4 3/20/2011 32

Schizophrenia and the Metabolic Highway:

Schizophrenia and the Metabolic Highway Smoking 5x more likely Physical Inactivity ½ as likely to do light exercise ¼ as likely to do vigorous exercise Overweight/Obese 8x more likely Alcohol Consumption 2x as likely to abstain 4x more likely to drink harmful amounts Diabetes 1.5 – 2x greater prevalence Family History of Diabetes 6x more likely 3/20/2011 33 American Diabetes Association et al. Consensus statement. Diabetes Care 2004.; Kabinoff GS et al. J Clin Psychiatry 2003.; Cavazzoni P et al. Br J Psychiatry 2004.; Kirn TF. Critical Psychiatry News 2004. Davidson S. Anz J Psych 2001. Regardless of antipsychotic use, schizophrenia patients are at greater risk of developing diabetes and cardiovascular disease than the general population

Increased Visceral Fat in Medication-Free Schizophrenics: Computed Tomography Imaging (CT) Findings:

Increased Visceral Fat in Medication-Free Schizophrenics: Computed Tomography Imaging (CT) Findings 3/20/2011 34 0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 Total Body Fat Subcutaneous Fat Intra-Abdominal Fat Controls n=15 Schizophrenics n=15 *p<0.005 Fat (mm 2 ) Thakore JH et al. Int J Obes Relat Metab Disord 2002. p<0.68 p<0.12 *

Prim Care Companion J Clin Psychiatry. 2004; 6(4): 152–158 Patrick Toalson, R.Ph. Et al :

Prim Care Companion J Clin Psychiatry. 2004; 6(4): 152–158 Patrick Toalson , R.Ph . Et al 3/20/2011 35 Since the introduction of the first atypical antipsychotics in the early 1990s, this class of medication has been increasingly relied upon for the treatment of a variety of patients with psychotic and mood disorders .

Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry. 2001;62:

Allison DB, Casey DE. Antipsychotic-induced weight gain: a review of the literature. J Clin Psychiatry. 2001;62 3/20/2011 36 The relationship of obesity and bipolar disorder has been the focus of several more recent studies, which have found that patients with bipolar disorder are on average more obese than the general population; however, there is no evidence that patients with obesity have a higher risk for developing bipolar disorder

Cont.:

Cont. 3/20/2011 37 . A confounding factor in all these studies is that many medications used as treatments in bipolar disorder, such as lithium,valproic acid, and several atypical antipsychotic agents such as olanzapine, are associated with weight gain

Thakore, J. H., Vlahoos, J., Martin, A., et al (2002) Increased visceral fat distribution in drug-naïve and drug-free patients with schizophrenia. International Journal of Obesity Related Metabolic Disorders, :

Thakore , J. H., Vlahoos , J., Martin, A., et al (2002) Increased visceral fat distribution in drug-naïve and drug-free patients with schizophrenia. International Journal of Obesity Related Metabolic Disorders, One group of investigators found that people with schizophrenia (both those with first episodes and those chronically exposed to conventional and non-conventional medications) have more than three times as much intra-abdominal fat as controls matched for age, gender and lifestyle 3/20/2011 38

Cont.:

Cont . and that 6 months of treatment with either olanzapine or Risperidone, although increasing body mass index, does not significantly increase visceral fat stores 3/20/2011 39

Metabolic Syndrome and the Neuroleptics:

Metabolic Syndrome and the Neuroleptics This life threatening syndrome includes obesity, type 2 diabetes mellitus, hyperlipidaemia (high cholesterol) and diabetic ketoacidosis , abdominal obesity, insulin resistance and hypertension. A study shows that metabolic syndrome with atypical and typical neuroleptics was  2-4 times higher than people who are not prescribed neuroleptics Heiskanen T, Niskanen L, Lyytikainen R, Saarinen PI, Hintikka J: Metabolic syndrome in patients with schizophrenia. J Clin Psychiatry 2003; 64:575–579 oleptics 3/20/2011 40

Redefining the Standard of Care: What Is the Most Important Thing a Psychiatrist Can Do?:

Redefining the Standard of Care: What Is the Most Important Thing a Psychiatrist Can Do ? 3/20/2011 41 Copyright © 2006 Neuroscience Education Institute. All rights reserved. Figure reproduced, with permission from SM Stahl and N Muntner. Stahl SM. Essential Psychopharmacology. 3rd ed. In preparation. Do No Harm Genes/ Aging Lifestyle/ Diet Choice of Antipsychotic No options Most manageable options Modest chance of success Psychopharmacologist Insulin resistance

Effectiveness of Medical Nutrition Therapy in Type 2 Diabetes Management :

Effectiveness of Medical Nutrition Therapy in Type 2 Diabetes Management 3/20/2011 42 Franz MJ et al. J Am Diet Assoc 1995. * p<0.05 for 1-visit and 3-visit groups vs. control † No significant difference between 3-visit and 1-visit groups: p<0.001 significantly less than at entry 8.4 * † † 6.6 6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 Initial 6 Week 3 Month 6 Month HbA 1c (%) Control (n=62) One Visit with Dietician (n=85) Three Visits with Dietician (n=94) Participants included men and women aged 38 – 76 years.

Benefit of Lifestyle-Modification:

Benefit of Lifestyle-Modification 3/20/2011 43 Diabetes Prevention Program Research Group. New Engl J Med 2002. 0 5 10 15 20 25 30 35 40 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Placebo n=1082 Metformin (850 mg, bid) n=1073 Lifestyle-Modification* n=1079 Year Total Incidence of Diabetes (%) 3,234 non-diabetic individuals with elevated fasting glucose and glucose tolerance levels *Lifestyle-modification group was challenged to lose ≥7% of body weight and exercise 150 minutes/week.

Benefits of Exercise:

Benefits of Exercise Moderate to high cardio-respiratory exercise may lower CV and overall mortality by 45% – 70% over 12 – 14 years in type 2 diabetic patients Seven hours of brisk walking/week can lower 7-year mortality rate by 50% May facilitate weight loss and decrease BP 3/20/2011 44 Canadian Diabetes Association. Canadian Journal of Diabetes 2003.; Diabetes Prevention Program Research Group. N Engl J Med 2002.; Elmer et al. Prev Med 1995.

Consensus Development Conference on Antipsychotic Drugs, Obesity, and Diabetes:

American Diabetes Association et al. Consensus Statement. Diabetes Care 2004. Summary of Treatment Recommendations Consensus Development Conference on Antipsychotic Drugs, Obesity, and Diabetes 3/20/2011 45 Consideration of metabolic risks when starting second-generation antipsychotics Patient, family, and caregiver education Baseline screening Regular monitoring Referral to specialized services when appropriate

Atypical Antipsychotics and Risk Cardiometabolic :

46 Copyright © 2006 Neuroscience Education Institute. All rights reserved. Figure reproduced, with permission from SM Stahl and N Muntner.; Stahl SM. Essential Psychopharmacology . 3rd ed. In preparation.; Newcomer JW. CNS Drugs . 2005;19(suppl 1):1-93. Atypical Antipsychotics and Risk Cardiometabolic Diabetes Pre-diabetes Beta cell failure Hyperinsulinemia Hyperinsulinemia Insulin resistance Insulin resistance Increased appetite Weight gain 0 -10 to -20 +20 Antipsychotic action Diabetes Cardiovascular events Pre-diabetes Beta-cell failure Premature death and loss of 20-30 years of normal life span Weight gain Antipsychotic action Antipsychotic action Years 3/20/2011

CATIE study Phase I – All cause discontinuations:

CATIE study Phase I – All cause discontinuations 3/20/2011 47 Lieberman et al. N Eng J Med 2005; 353(12): 1209-23 (Double-blind study, 5 arms) Most common reason: patient’s choice/own decision : 23−34% Discontinuation for lack of efficacy : 14.5−25% Discontinuation for lack of tolerability : 10 − 19% N=1432 N=330 Patients (%) N=183 N=257 N=329 N=330 26 26 18 21 36 25 74 74 82 79 64 75 0 10 20 30 40 50 60 70 80 90 100 All drugs 18 months Oral Risperidone Quetiapine Ziprasidone Olanzapine Perphenazine Completed Discontinued

Reasons for discontinuation of antipsychotic medication:

Reasons for discontinuation of antipsychotic medication 3/20/2011 48 N=1582 *Percentages based on total number of subjects ever having received antipsychotic medication; more than one reason could be cited. Adapted from Tandon R et al. Schizophr Res . 2006;84:77-89 Patients with medication change (%)* Symptoms AEs

Cardiometabolic Risks in Patients with Schizophrenia and Bipolar Disorder:

Cardiometabolic Risks in Patients with Schizophrenia and Bipolar Disorder Increased mortality rates for mental disorders Loss of 20-30 years from life span Cause of death due to medical causes, as in normal population (i.e., not suicide) Schizophrenic patients: 40% increased risk of death from medical causes Bipolar patients are twice as likely to die from heart disease as the average person 3/20/2011 49 Newcomer JW. J Clin Psychiatry . 2006:25-30. 2. Osby U et al. Arch Gen Psychiatry . 2001:844-850.

Increased Mortality Rates for Medical Disorders in Mental Illness :

Increased Mortality Rates for Medical Disorders in Mental Illness Increased risk of death from medical causes in schizophrenia and 20% shorter life span Bipolar and unipolar affective disorders associated with higher mortality rates from medical causes 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 to 1995, with greatest increase in men from 1991 to 1995 3/20/2011 50 SMR = standardized mortality ratio (observed/expected deaths) Harris EC et al. Br J Psychiatry . 1998;173:11-53.; Newman SC, Bland RC. Can J Psychiatry . 1991;36:239-245. Ösby U et al. Arch Gen Psychiatry . 2001;58:844-850.; Ösby U et al. BMJ . 2000;321:483-484.

Cardiovascular Disease Risk Factors:

Cardiovascular Disease Risk Factors 3/20/2011 51 Modifiable Risk Factors Estimated Prevalence and Relative Risk (RR) Schizophrenia Bipolar Disorder Obesity 45%-55%, 1.5-2X RR 1 26% 5 Smoking 50%-80%, 2-3X RR 2 55% 6 Diabetes 10%-14%, 2X RR 3 10% 7 Hypertension ≥18% 4 15% 5 Dyslipidemia Up to 5X RR 8,9 1. Davidson S et al. Aust N Z J Psychiatry . 2001;35:196-202. 2. Allison DB et al. J Clin Psychiatry. 1999;60:215-220. 3. Dixon L et al. J Nerv Ment Dis. 1999;187:496-502 . 4. Herran A et al. Schizophr Res. 2000;41:373-381 . 5. McElroy SL et al. J Clin Psychiatry . 2002;63:207-213. 6. Ucok A et al. Psychiatry Clin Neurosci. 2004;58:434-437. 7. Cassidy F et al. Am J Psychiatry. 1999;156:1417-1420. 8. Allebeck P. Schizophr Bull. 1989;15:81-89. 9. Koro CE et al. Arch Gen Psychiatry. 2002;59:1021-1026.

Atypical Antipsychotics and Cardiometabolic Risk:

Atypical Antipsychotics and Cardiometabolic Risk The atypical antipsychotics vary in prevalence of associated weight gain, diabetes, and dyslipidemia ( ADA/APA) Consensus Statement) Proposed mechanisms of action of atypical antipsychotic-induced Cardiometabolic risk Increase appetite  weight gain Reduce insulin release by blocking M 3 receptors on beta cells Insulin resistance (unknown mechanism) 3/20/2011 52 ADA et al. Diabetes Care . 2004;27:596-601.

Choosing an Antipsychotic:

Choosing an Antipsychotic Psychiatric considerations: Nature of psychiatric condition Target signs and symptoms Past history of drug response Patient preference, history of adherence Need for special monitoring Consider risk of obesity, diabetes, and dyslipidemia For patients with diabetes or high metabolic risks, consider more metabolically benign antipsychotic agents; however, psychiatric efficacy should drive selection None of the atypical antipsychotics are approved for use in children; use greater caution and more frequent monitoring guidelines 3/20/2011 53 American Diabetes Association et al. Diabetes Care 2004. Citrome L. Br Med J 2003 .

ATYPICAL NEUROLEPTICS:

ATYPICAL NEUROLEPTICS They are different in their contribution to the : METABOLIC SYNDROME 3/20/2011 54

ADA/APA Consensus Statement* on Atypical Therapy:

ADA/APA Consensus Statement* on Atypical Therapy Drug Weight Gain Risk for Diabetes Worsening Lipid Profile Olanzapine +++ + + Clozapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole +/- - - Ziprasidone +/- - - 3/20/2011 55 The Prevalence of Obesity, Diabetes, and Dyslipidemia Differs Among the Second-Generation Antipsychotics (SGAs) + Increased effect - No effect D Discrepant results ADA/APA recommends careful consideration of metabolic risk when starting a SGA. If a patient gains ≥5% of initial weight and/or develops worsening glycemia or dyslipidemia during therapy, an assessment of therapy should be considered *Adapted from Diabetes Care. 2004;27:596-601 and J Clin Psychiatry. 2004;65:267-272.

Ziprasidone: Weight-Neutral Profile in Short- and Long-Term Studies of Schizophrenia:

Ziprasidone: Weight-Neutral Profile in Short- and Long-Term Studies of Schizophrenia 3/20/2011 56 Patients Exposed for 1 Year Short-Term Studies * p <0.001, * p <0.0001 ( vs placebo for distribution of weight change from baseline). Short-term: up to 12 weeks; Long-term: 1-year exposure . Parsons B et al. Presented APA 2006. N=187 N=1,067 N=230 N=112 N=92 Mean Change (lb) -0.7 1.3 -0.02 4.2 11.2 N=301 N=322 N=18 N=85 N=15 Mean Change (lb) -9.4 -4.1 3.4 7.5 9.5

Weight Change with Switch to Ziprasidone:

Weight Change with Switch to Ziprasidone 3/20/2011 57 Weiden P et al. Poster presented at APA 2004. Week *p<0.05, †p<0.001, ‡p<0.0001 6 14 23 19 32 27 36 10 58 53 49 45 40 -20 -15 -10 -5 0 -30 -25 LS Mean Change (lbs) Conventionals n=71 Risperidone n=43 Olanzapine n=73 ‡ * † ‡ ‡ †

Triglyceride Change with Switch to Ziprasidone:

Triglyceride Change with Switch to Ziprasidone 3/20/2011 58 Weiden P et al. Poster: APA 2004. * p<0.05, †p<0.0001, ‡p<0.0005 45 * * † ‡ † Week 6 10 49 40 36 32 27 23 19 14 53 58 -60 -50 -40 -30 -20 -10 0 10 -70 -80 -90 LS Mean Change (mg/dL) Conventional antipsychotics n=71 Risperidone n=43 Olanzapine n=71

Ziprasidone Associated with Improvement in Metabolic Variables in CATIE:

59 Ziprasidone Associated with Improvement in Metabolic Variables in CATIE Mean Change in Weight (lb) from Baseline (LOCF) -1.6 0.8 1.1 9.4 -2.0 Weight Change Mean Change in Glycosylated Hemoglobin (%) from Baseline (LOCF) Mean Change in Cholesterol (mg/dL) from Baseline (LOCF) Cholesterol Levels -9.2 Mean Change in Triglycerides (mg/dL) from Baseline (LOCF) Lieberman JA et al. N Engl J Med. 2005;353:1209-1223. Hemoglobin A 1 C Levels Triglycerides 42.9 N=185 N=336 N=337 N=341 N=261 N=89 N=139 N=137 N=107 N=157 N=143 N=262 N=268 N=286 N=212 N=143 N=262 N=268 N=286 N=212 Ziprasidone Risperidone Quetiapine Olanzapine Perphenazine -2.1 5.3 9.7 0.5 8.3 19.2 -2.6 -18.1 0.41 0.10 0.05 0.08 -0.10 3/20/2011

Estimated Change in Triglycerides More Than 58 Weeks After Switch to Ziprasidone†:

Estimated Change in Triglycerides More Than 58 Weeks After Switch to Ziprasidone † 3/20/2011 60 LS=Least squares. * P <0.05; ** P <0.001; *** P <0.0001. † Repeated measures analysis (MMRM ). Weiden PJ et al. APA 2004. Ziprasidone in Schizophrenia: Observed Metabolic Advantage s 55 mg/ dL decrease after switching from olanzapine to ziprasidone 37 mg/ dL decrease after switching from risperidone to ziprasidone *** *** * ** * Switched from Weeks LS mean change in triglycerides (mg/dL)

Weight Gain with Atypical Antipsychotics:

61 Weight Gain with Atypical Antipsychotics Incidence of ≥7% Increase in Body Weight in Short-Term Trials*

Where on the Metabolic Highway Should Psychopharmacologists Monitor Antipsychotics?:

62 Where on the Metabolic Highway Should Psychopharmacologists Monitor Antipsychotics? raised triglycerides obesity and increased fat mass hyperinsulinemia pre-diabetes diabetes weight gain premature death and loss of 20-30 years of normal lifespan RIP increased appetite BEWARE: cardiometabolic risk ahead beta cell failure cardiovascular events monitor antipsychotic action beta cell failure increased appetite weight gain monitor antipsychotic action insulin resistance raised triglycerides insulin resistance monitor antipsychotic action 3/20/2011

Generic Monitoring Protocol for Patients on Atypical Antipsychotics:

Generic Monitoring Protocol for Patients on Atypical Antipsychotics Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years Personal/family history + + Weight (BMI) + + + + + Waist circumference + + Blood pressure + + + Fasting plasma glucose + + + Fasting lipid profile + + + 3/20/2011 63 American Diabetes Association et al. Consensus Statement. Diabetes Care 2004.

The change in psychiatric practice:

The change in psychiatric practice Back to physical examinations. Laboratory test are basic. The choice of medication is important. Collaborations with other specialists is the right approach. The ties between physical and metal health are getting stronger 3/20/2011 64

Potential Strategies for Anti-Obesity Drug Action:

Potential Strategies for Anti-Obesity Drug Action Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake Blocking nutrient absorption (especially fat or carbohydrates) in the intestine. Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat or increase energy expenditure through the enhancement of physical activity. Modulating fat metabolism/storage . Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy expenditure. Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat stores. 3/20/2011 65

Currently Available Agents Indicated for Treatment of Obesity:

Currently Available Agents Indicated for Treatment of Obesity 3/20/2011 66 Generic/Brand Name Usual Dose Mechanism of Action Side Effects Orlistat/Xenical Sibutramine/Meridia Phentermine/ Adipex, Fastin, Ionamin and others 120 mg with each meal 5-15 mg/d 15-37.5 mg per day as a single or split dose Peripheral: Blocks absorption of about 30% of consumed fat Central: Inhibits synaptic reuptake of norepinephrine and serotonin Central: Stimulates release of norepinephrine GI symptoms (oily spotting, flatus with discharge, fecal urgency, oily stools, incontinence) Dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia CNS stimulation, tachycardia, dry mouth, insomnia, palpitations

Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved:

Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved 3/20/2011 67 Generic/Brand Name Usual Dose Mechanism of Action Side Effects ephedrine+/-caffeine " Elsinore"pill Bupropion / Wellbutrin Topiramate/ Topamax Varies: usually 75-150 mg ephedrine and 100-150 mg caffeine 100-300 mg/d 96-192 mg/d Central: Stimulates adrenergic receptors Central: Inhibits reuptake of dopamine norepinephrine and serotonin Uncertain: Central ? CNS stimulation, tachycardia, dry mouth, insomnia, palpitations CNS stimulation, dry mouth, headache, GI effects CNS: paresthesia , fatigue, dizziness, memory difficulty, concentration difficulty, and depression

Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved:

Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved 3/20/2011 68 Generic/Brand Name Usual Dose Mechanism of Action Side Effects ephedrine+/-caffeine " Elsinore"pill Bupropion / Wellbutrin Topiramate/ Topamax Varies: usually 75-150 mg ephedrine and 100-150 mg caffeine 100-300 mg/d 96-192 mg/d Central: Stimulates adrenergic receptors Central: Inhibits reuptake of dopamine norepinephrine and serotonin Uncertain: Central ? CNS stimulation, tachycardia, dry mouth, insomnia, palpitations CNS stimulation, dry mouth, headache, GI effects CNS: paresthesia, fatigue, dizziness, memory difficulty, concentration difficulty, and depression

Narula PK, Rehan Hs, Unni Ke, Gupta N, India Schizophr Res. 2010 Mar 6:

Narula PK, Rehan Hs, Unni Ke , Gupta N, India Schizophr Res. 2010 Mar 6 Topiramate could prevent olanzapine induced weight gain and adverse metabolic effects. It also results in a greater clinical improvement when used with olanzapine in schizophrenia 3/20/2011 69

Hasnain, Mehrul; Vieweg, W. Victor R.; Fredrickson, Sonja K.CNS Drugs: 1 March 2010 -:

Hasnain, Mehrul ; Vieweg , W. Victor R.; Fredrickson, Sonja K.CNS Drugs: 1 March 2010 - This study suggests that metformin is beneficial if started early in antipsychotic drug treatment. Metformin has also been shown to prevent or delay the onset of type 2 diabetes mellitus in high-risk individuals from the general population. Based on these findings, we identify antipsychotic drug-treated patients who might benefit from metformin therapy and offer clinical guidelines for its use. Further long-term studies are needed to extend our observations and improve this strategy. 3/20/2011 70

David J. Klein, M.D., Ph.D., Elizabeth M. Cottingham, M.D., Michael Sorter, M.D., Bruce A. Barton, Ph.D., and John A. Morrison, Ph.D Am J Psychiatry 163:2072-2079, December 2006 doi: 10.1176/appi.ajp.163.12.2072 :

David J. Klein, M.D., Ph.D., Elizabeth M. Cottingham , M.D., Michael Sorter, M.D., Bruce A. Barton, Ph.D., and John A. Morrison, Ph.D Am J Psychiatry 163:2072-2079, December 2006 doi : 10.1176/appi.ajp.163.12.2072 3/20/2011 71 A Randomized, Double-Blind, Placebo-Controlled Trial of Metformin Treatment of Weight Gain Associated With Initiation of Atypical Antipsychotic Therapy in Children and Adolescents

Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-Generation Antipsychotic-Induced Weight Gain; Ipema HJ, Ellinger LK, Stachnik JM; Annals of Pharmacotherapy (Mar 2010) Tags: metformin topiramate:

Efficacy of Metformin and Topiramate in Prevention and Treatment of Second-Generation Antipsychotic-Induced Weight Gain; Ipema HJ, Ellinger LK, Stachnik JM; Annals of Pharmacotherapy (Mar 2010) Tags: metformin topiramate 3/20/2011 72 : Data for the use of metformin and Topiramate in the treatment and prevention of second-generation antipsychotic-induced weight gain are limited. Both may be effective in helping patients lose weight via mechanisms that have yet to be clearly defined. The use of metformin results in greater weight loss than Topiramate, and Topiramate is associated with more risks and may compromise the treatment of schizophrenia. Treatment of antipsychotic-induced weight gain with metformin may be an option after lifestyle and dietary changes have failed.

INDICATIONS FOR USE OF OBESITY DRUGS:

INDICATIONS FOR USE OF OBESITY DRUGS 3/20/2011 73 A combined intervention of behavior therapy, dietary changes and increased physical activity should be maintained for at least 6 months before considering pharmacotherapy. NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults

CONLUSION-1:

CONLUSION-1 Patients with a major mental disorder die up to 3 decades earlier, on average, than the general population Several modifiable cardiovascular risk factors are higher in these patients, leading to increased risk of cardiovascular disease Monitoring patients early on the metabolic highway and determining insulin resistance by measuring triglycerides are important Primary prevention of Cardiometabolic complications by initiating efficacious and metabolically-friendly antipsychotic treatment 74 Stahl SM. Essential 401-458. Harvey PD et al. Schizophr Res. 2004;66:101-113. Schmidt AW et al001;425:197-201. Keck PE et al. Am J Psychiatry. 2003;160:741-748. Data on file. Pfizer Inc. Addington DE. J Clin Psychiatry. 2004;65:1624-1633. Daniel DG et al. Neuropsychopharma. 99;20:491-505. Lieberman JA. N Engl J Med. 2005;353:1209-1223. Psychopharmac 2000: 99-133, 135-197, 365-399, 3/20/2011

CONCUSION-2:

CONCUSION-2 Ziprasidone Offers Proven Efficacy and a Favorable Metabolic Profile Unique receptor profile Broad efficacy Approved for schizophrenia Demonstrated efficacy in positive, negative, depressive, and cognitive symptoms of schizophrenia Acute agitation: intramuscular formulation Approved for acute manic or mixed episodes associated with bipolar disorder 3/20/2011 75 Stahl SM. Essential Psychopharmacology . 2000: 99-133, 135-197, 365-399, 401-458. Harvey PD et al. Schizophr Res. 2004;66:101-113. Schmidt AW et al. Eur J Pharmacol . 2001;425:197-201. Keck PE et al. Am J Psychiatry. 2003;160:741-748. Data on file. Pfizer Inc. Addington DE. J Clin Psychiatry. 2004;65:1624-1633. Daniel DG et al. Neuropsychopharmacology . 1999;20:491-505. Lieberman JA. N Engl J Med. 2005;353:1209-1223.

CONLUSION-3:

CONLUSION-3 Comparable efficacy demonstrated in head-to-head trials versus haloperidol, risperidone, olanzapine, and clozapine Significant improvement of by Day 2 in patients with acute manic/mixed episodes Well established tolerability and safety profile Favorable metabolic profile 3/20/2011 76

CONCLUSIONS-4:

CONCLUSIONS-4 Patients with severe mental illnesses, particularly schizophrenia and chronic mood disorders, have demonstrated a higher prevalence of metabolic syndrome or its components compared with the general population in several countries. Therefore, baseline and periodic medical evaluations should become a standard component in the ongoing assessment of these patients . 3/20/2011 77

CONCLUSIONS-5:

CONCLUSIONS-5 . Although individual risk factors associated with the metabolic syndrome are typically amenable to behavioral or pharmacologic treatment, management of these comorbidities in many patients with serious mental illness will require cooperation between psychiatrists and primary health care providers &other specialists . 3/20/2011 78

THANK YOU FOR ATTENTION:

THANK YOU FOR ATTENTION www.walidsarhan.net 3/20/2011 79

References:

References Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). (2)Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. International Diabetes Federation Insulin-sensitising drugs, The Cochrane Database of Systematic Reviews Date of last Substantial Update: December 31. 2002 Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia, NEJM. Nov 2005 3/20/2011 80

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