metabolic syndrome and psychiatry

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Metabolic Syndrome : What we can do?:

Metabolic Syndrome : What we can do? Prof. Ronnachai Kongsakon Ramathibodi Hos.

Global cardiometabolic risk*:

Global cardiometabolic risk* Gelfand EV et al , 2006; Vasudevan AR et al , 2005 * working definition

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2531 Syndrome X ( Reaven ) 2532 Deadly quartet ( Kaplan ) 2535 Insulin resistance syndrome ( Defronzo ) 2537 Metabolic syndrome ( Alberti ) 2541 Metabolic syndrome ( WHO ) 2544 Metabolic syndrome ( NCEP III ) 2548 Metabolic syndrome ( IDF/AHA ) 2549 Metabolic syndrome (IDF) Metabolic Syndrome: โรค อ้วนลงพุง

Metabolic syndrome (MetS):

Metabolic syndrome ( MetS ) Meyer JM, Stahl SM. Acta Psychiatr Scand 2009: 119: 4–14

NCEP ATP III Clinical Identification of the Metabolic Syndrome:

NCEP ATP III Clinical Identification of the Metabolic Syndrome Waist circumference: Men > 102 cm (> 40 in) Women > 88 cm (>35 in) Triglycerides >150 mg/ dL HDL cholesterol: Men<40 mg/ dL Women<50 mg/ dL Blood pressure > 130/ 85 mm Hg Fasting glucose >110 mg/ dL * * New ADA guidelines suggest >100mg/dl increases risk for Metabolic Syndrome NCEP: National Cholesterol Education Program Adult Treatment Panel III

International Diabetes Federation (IDF):

International Diabetes Federation (IDF ) Modified ATPIII definition Fasting Glucose > 100 mg/dl Adjusted waist circumference based on ethnicity (i.e. asians with lower waist circumference threshold than pacific islanders)

Metabolic syndrome (MetS):

Metabolic syndrome ( MetS ) Meyer JM, Stahl SM. Acta Psychiatr Scand 2009: 119: 4–14

Ethnic specific values for waist circumference (IDF) :

Ethnic specific values for waist circumference (IDF) Americans Male ≥ 102cm Female ≥ 88 cm Europids Male ≥ 94 cm Female ≥ 80 cm South Asians Male ≥ 90 cm Female ≥ 80 cm Chinese Male ≥ 90 cm Female ≥ 80 cm Japanese Male ≥ 90 cm Female ≥ 85 cm

Ethnic specific values for waist circumference (IDF) :

Ethnic specific values for waist circumference (IDF) Americans Male ≥ 102cm Female ≥ 88 cm Europids Male ≥ 94 cm Female ≥ 80 cm South Asians Male ≥ 90 cm Female ≥ 80 cm Chinese Male ≥ 90 cm Female ≥ 80 cm Japanese Male ≥ 90 cm Female ≥ 85 cm

Look at your patient’s shape:

Look at your patient’s shape

Pts with psychiatric disorder tend to have high prevalence of metabolic syndrome:

Pts with psychiatric disorder tend to have high prevalence of metabolic syndrome De Hert et al. Clinical Practice and Epidemiology in Mental Health 2006 2; 14

MetS prevalence in SCZ patients:

MetS prevalence in SCZ patients

MetS prevalence in SCZ patients:

MetS prevalence in SCZ patients

Mets in Thailand:

Mets in Thailand 20% of Thai schizophrenic pts receiving long-term antipsychotic Rx developed MetS within a year of F/U Srisurapanont M et al. BMC Psychiatry 2007;7: 14

Antipsychotic Medications: Metabolic Syndrome what can we do?:

Antipsychotic Medications: Metabolic Syndrome what can we do? Prof. Ronnachai Kongsakon Ramathibodi Hos.

Why Are Patients Gaining Weight?:

Why Are Patients Gaining Weight? Antagonism of H 1 and 5-HT 2c receptors Actions on the lateral and ventromedial hypothalamus Potential Mechanisms of Weight Gain Reduction in basal metabolic rate Macronutrient partitioning shift Reduction in akathisia Release of TNF-  and other cytokines Changes in sensitivity to the hormone leptin Baptista T. Acta Psychiatr Scand. 1999;100(1):3-16. Mercer LP, et al. J Nutr . 1994;124(7):1029-1036. Stanton JM. Schizophr Bull. 1995;21(3):463-472. Simansky KJ. Behav Brain Res. 1996;73(1-2):37-42. Tecott LH, et al. Nature. 1995;374(6522):542-546. Reynolds GP, et al. Lancet. 2002;359(9323):2086-2087 .

What can a clinician do ?:

What can a clinician do ? Meyer JM, Stahl SM. Acta Psychiatr Scand 2009: 119: 4–14

Considerations in prescribing atypical antipsychotics:

Considerations in prescribing atypical antipsychotics Efficacy in positive symptoms negative symptoms depressive symptoms cognitive symptoms Potential for side effects weight gain prolactin elevation sedation dyslipidemia metabolic effects (glucose dysregulation ) Reduced incidence of EPS compared with conventional agents Potentially reduced TD liability

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The use of SGA may also place pt at risk for a metabolic syndrome With the increase use of SGA over the last decade. There has been increasing concern that some medications are associated with metabolic disturbances.

Shift in Risk:

Shift in Risk Typical Atypical

Pharmacology of atypical antipsychotics:

Pharmacology of atypical antipsychotics Zorn SH et al. Interactive Monoaminergic Brain Disorders . 1999;377-393. Schmidt AW et al. Eur J Pharmacol . 2001;425:197-201. Quetiapine M 1 5-HT 2A D 2 5-HT 2C 5-HT 1A  1 H 1 Risperidone D 2  1 5-HT 2A 5-HT 2C H 1 Olanzapine M 1 H 1 5-HT 2C 5-HT 2A D 2  1 Ziprasidone D 2 5-HT 1D 5-HT 2C 5-HT 1A 5-HT 2A  1 H 1 Clozapine 5-HT 2C M 1 5-HT 2A H 1  1 D 2

Wt gain: Involving blockages of receptors:

Wt gain: Involving blockages of receptors X

H1 combined with 5-HT2c antagonism:

H1 combined with 5-HT 2c antagonism Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

Receptor X antagonism:

Receptor X antagonism Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

M3 cholinergic antagonism:

M3 cholinergic antagonism Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

Metabolic Highway:

Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179 Metabolic Highway

Receptor Binding Profile of Antipsychotics:

Arnt & Skarsfeld , 1998; Bymaster et al, 1996; Seeger et al, 1995 Receptor Binding Profile of Antipsychotics Receptors Aripiprazole (Abilify) Olanzapine (Zyprexa) Risperidone (Risperdal) Clozapine (Clozaril) Haloperidol (Haldol) D 1 265 31 430 85 210 D 2 0.45 11 4 126 0.7 D 3 0.8 49 10 473 2 D 4 44 27 9 35 3 5-HT 1A 4.4 >10,000 210 875 1,100 5-HT 2A 3.4 4 0.5 16 45 5-HT 2C 15 23 25 16 >10,000 a 1 57 19 0.7 7 6 H 1 61 7 20 6 440 M 1 >10,000 1.9 >10,000 Quetiapine (Seroquel) 455 160 2,800 295 7 11 120 Ziprasidone (Geodon) 525 5 7 32 3 0.4 1 10 47 >1,000 1.9 >1,500 340 1,600 1,500

Mean Change in Weight With Antipsychotics:

Mean Change in Weight With Antipsychotics * Extrapolated from 6-week data.Allison et al. Am J Psychiatry. 1999;156:1686. Estimated Weight Change at 10 Weeks on “Standard” Dose Placebo Molindone Fluphenazine Ziprasidone Haloperidol Polypharmacy Risperidone Chlorpromazine Olanzapine Clozapine Quetiapine Thioridazine/ mesoridazine 6 Weight change (kg) 5 4 3 2 1 0 -1 -2 -3 13.2 Weight change (lb) 11.0 8.8 6.6 4.4 2.2 0 -2.2 -4.4 -6.6 *

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Newcomer J. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs. 2005, 19 Suppl 1:1-9

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Incidence of ≥7% Increase in Body Weight in Short-Term Trials*

1-Year Weight Gain: Mean Change from Baseline Weight :

1-Year Weight Gain: M ean Change from Baseline Weight 0 2 4 6 8 10 12 14 Weeks Change from Baseline Weight (kg) 52 48 44 40 36 32 28 24 20 16 12 8 4 0 52 48 44 40 36 32 28 24 20 16 12 8 4 0 Nemeroff CB. J Clin Psychiatry. 1997;58( suppl 10):45-49; Kinon BJ. J Clin Psychiatry. 1998;59( suppl 19):18-22; Jones AM et al. 2000; USPI Change from Baseline Weight (lb) Olanzapine (12.5-17.5 mg) Olanzapine (all doses) Quetiapine Risperidone Ziprasidone Aripiprazole 0 4 8 12 16 20 22 24

Atypical Antipsychotic and Wt gain risk:

Atypical Antipsychotic and Wt gain risk Highest risk Moderate risk Minimal risk Clozapine Olanzapine Risperidone Quetiapine Ziprasidone Aripiprazole Adapted from Newcomer JW CNS Drugs.2005 ;19( suppl 1): 1-93

Diabetes:

Diabetes

General information on diabetes:

General information on diabetes In the general population, the NHIS 1994 diabetes rate was 1.2% for persons aged 18-44 and 6.3% for persons aged 45-64 In patients with schizophrenia , 9-14% have current treated diabetes Adams and Morano 1995; Dixon et al 2000

Diabetes:

Diabetes Recent US study concluded that the risk of developing type II diabetes was approximately 1.5 times greater in patients taking olanzapine , risperidone , or quetiapine than in those taking conventional antipsychotics . Previous studies had shown an increased risk with clozapine use.

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The mechanism responsible for the development of the iatrogenic diabetes seen with SGAs remain unclear Proposed mechanism : 1. Wt.gain seen with certain antipsychotics may produce a state of overweight or obesity, that is a risk factor for the development of insulin resistant , leading to type 2 DM

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Antipsychotic Inhibit glucose transporter Hyperglycemia Insulin release Insulin resistance DM type 2 Prolonged hyperinsulinemia 2. A direct metabolic effect

Time to diabetes onset differs among atypicals:

Month Time to diabetes onset differs among atypicals Diabetes incidence Rosenheck RA, et al. Am J Psychiatry 2004;161:1709-1711

Incidence of Type II Diabetes Associated With Antipsychotic Use in Patients With Schizophrenia:

15.5% 11.0% 6.6% 7.3% 6.0% 6.0% 5 7 9 11 13 15 17 Clozapine Olanzapine Haloperidol Other Antipsychotics Risperidone General Population 1 Incidence of Type II Diabetes Associated With Antipsychotic Use in Patients With Schizophrenia 1. CPA. Can J Psychiatry. 1998;43( suppl 2):25S-40S. Pittsburgh Schizophrenia Treatment and Research Center: Zoler , Ganguli , 1999. % Incidence

Weight Change in Long-Term Trials With Aripiprazole: Mean Change From Baseline :

Weight Change in Long-Term Trials With Aripiprazole : Mean Change From Baseline Baseline wt (kg) 75.2 74.6 74.1 72.8 26 Weeks 52 Weeks n=151 n=425 n=842 n=151 Mean change in weight (kg) Mean change in weight (kg) Carson et al. Int J Neuropsychopharmacol . 2002;5( suppl 1):S187. Jody et al. Int J Neuropsychopharmacol . 2002;5( suppl 1):S186.

Mean Change in Weight at 52 Weeks Stratified by Baseline BMI :

Mean Change in Weight at 52 Weeks Stratified by Baseline BMI * * P <0.05. BMI = body mass index. LOCF analysis. Jody et al. Int J Neuropsychopharmacol . 2002;5( suppl 1):S186. n= 314 167 265 139 260 119

Aripiprazole 26-Week Trial: Change From Baseline in Fasting Glucose Levels :

Aripiprazole 26-Week Trial: Change From Baseline in Fasting Glucose Levels n= 92 93 Change from baseline in glucose concentration

Aripiprazole 26-Week Trial: Effects on Serum Lipids:

Aripiprazole 26-Week Trial: Effects on Serum Lipids HDL = high-density lipoprotein. Fasted plasma samples. LOCF analysis. . n= 83 80 82 74 83 80 91 93 Median change from baseline (mg/dL)

Adjusted* Odds Ratio for Clinically Significant Dyslipidemia*** on Antipsychotic Medication in the California Medicaid Population (2002-2004)** :

Adjusted* Odds Ratio for Clinically Significant Dyslipidemia *** on Antipsychotic Medication in the California Medicaid Population (2002-2004)** ** Olfson et al, accepted, APA ’05 *** dyslipidemia diagnosis or treatmentI * Controlled for age, gender, race, primary diagnosis,duration of exposure, number of prior antipsychotic meds– referent: conventionals conv

Atypical antipsychotics induced weight gain:

Atypical antipsychotics induced weight gain Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

Atypical antipsychotics induced weight gain:

Atypical antipsychotics induced weight gain Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

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Risperidone and Quetiapine appear to have some impact on dyslipidemia , less than Clozapine and Olanzapine Aripiprazole and Ziprasidone were associated with little or no dyslipidemia

ADA Consensus on Antipsychotic Drugs and Obesity and Diabetes:

ADA Consensus on Antipsychotic Drugs and Obesity and Diabetes + = increased effect; - = no effect; 0 = discrepant results. *Newer drugs with limited long-term data. Drug Weight Gain Diabetes Risk Dyslipidemia clozapine +++ + + olanzapine +++ + + risperidone ++ 0 0 quetiapine ++ 0 0 aripiprazole * +/- - - ziprasidone * +/- - - Diabetes Care 27:596-601, 2004

Antipsychotic polypharmacy increase risk for Mets:

Antipsychotic polypharmacy increase risk for Mets

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Compared with pts receiving antipsychotic monotherapy , pts on antipsychotic polytherapy have higher rates of metabolic syndrome Polypharmacy VS Monotherapy

Metabolic Impact :

Metabolic Impact CATIE confirmed findings Metabolic syndrome at baseline 42.7% (twice general population. Olanzapine treatment: 30% gained > 7% weight compared to 7% ( ziprasidone ), 13% ( risperidone , quetiapine ) Consistent increase in blood glucose (13.8 mg/ dL ), Hg A1c (0.97%), cholesterol (17.5 mg/ dL ), triglyceride (94.1mg/ dL )

Metabolic adverse events:

55 Metabolic adverse events CVD risk factors such as weight gain/obesity and diabetes are more common in people with schizophrenia than in the general population Risk of metabolic disturbances related to CVD is compounded by some SGAs weight gain hyperglycemia dyslipidemia Patients should be monitored at baseline and regularly thereafter for possible metabolic side effects of SGAs weight fasting plasma glucose fasting lipids blood pressure Consider switching the SGA if it is causing excessive weight gain, diabetes, or other metabolic side effects Risk factors and monitoring recommendations Chue P. Can J Psychiatry . 2004;49:200-207. Bridler R, et al. Swiss Med Wkly . 2003;133:63-76. National Institute for Clinical Excellence. Clinical Guideline 1. 2002:1-62. American Diabetes Association. Diabetes Care. 2004;27:596-601.

Monitoring and Managements:

Monitoring and Managements Stahl SM, Mignon L, Meyer JM. Acta Psychiatr Scand 2009: 119: 171–179

Monitoring:

Monitoring At baseline, 1 month, 3 months weight, BP, fasting glucose, fasting lipid panel Yearly weight, BP, fasting glucose Every three years fasting lipid panel Looking for: > 5-7% increase from initial weight or BMI > 25 Fasting glucose > 126 BP > 140/90 Cholesterol thresholds depends on risk factors

Monitoring of metabolic SE in pts receiving antipsychotics:

Monitoring of metabolic SE in pts receiving antipsychotics ADA/ APA,Diabetes Care,Feb 2004

Summary:

Summary Consideration of metabolic risks when starting SGAs. Choice of antipsychotics may keep in mind. Patient, family, and caregiver education . Baseline screening. Regular monitoring. Risk  switching of antipsychotic with low risk of MetS .

Considerations in Prescribing Atypical Antipsychotics:

Considerations in Prescribing Atypical Antipsychotics Efficacy Tolerability Objective Success of your practice

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Thank You For Your Attention

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