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Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
Metabolism and Mental Illness
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Metabolism and Mental Illness

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The slides that accompanied a lecture on the metabolic problems associated with major mental illnesses and their treatment.

The slides that accompanied a lecture on the metabolic problems associated with major mental illnesses and their treatment.

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  • 1. The Changing Landscape of Metabolic and Hormonal Disturbances in Major Mental Illness Richard G Petty MD, MSc, MRCP(UK), MRCPsych, Promedica Research Center, Georgia State University College of Health Sciences, Loganville, Georgia, USA Sunday, July 26, 2009
  • 2. Disclosure Richard G. Petty, MD, MSc, MRCP(UK), MRCPsych  Consultant • AstraZeneca; Eli Lilly and Company; Janssen Pharmaceuticals  Speaker’s Bureau • Abbott; AstraZeneca; Avanir; Janssen Pharmaceuticals  Grant Support • British Diabetic Association; Bristol Myers Squibb; British Heart Foundation; Du Pont Merck, Inc.; Eli Lilly and Company; Janssen; Medical Research Council (UK); National Institute of Mental Health; Pfizer  Dr. Petty’s presentation will include the discussion of off-label, experimental, and/or investigational use of drugs or devices Sunday, July 26, 2009
  • 3. There Is a Serious Lack of Physical Well-being in Individuals With Major Mental Illness Sunday, July 26, 2009
  • 4. There Is a Serious Lack of Physical Well-being in Individuals With Major Mental Illness  Mortality rates: people die on average 10-20 years earlier than the general population1-3 Sunday, July 26, 2009
  • 5. There Is a Serious Lack of Physical Well-being in Individuals With Major Mental Illness  Mortality rates: people die on average 10-20 years earlier than the general population1-3  In part because of suicide, but also:  Cardiovascular diseases  Coronary artery disease 4  Arrhythmias  Diabetes mellitus - Type II5  Obesity6  Some forms of cancer  Respiratory illness  Substance abuse7 1. Harris, E.C. and Barraclough, B. Br J Psychiatry 1998; 173: 11-53 2. Newman and Bland Can J Psychiatry 1991; 36: 239-245 3. Tabbane, K., R. Joober, et al. 1993; Encephale 19: 23-8 4. Allebeck, Schizophr Bull 1989; 15: 81-89 5. Dixon et al, J Nerv Ment Dis 1999; 187: 495-502 6. Allison, D., et al. J Clin Psychiatry 1999; 60: 215-220 7. Herran et al, Schizophr Res 2000; 41: 373-381 Sunday, July 26, 2009
  • 6. Metabolic Disturbances in Major Mental Illness  This is not one issue but several:  Obesity  Insulin Resistance  Insulin Resistance Syndrome  Diabetes Mellitus  Diabetic Ketoacidosis  Hyperlipidemia  Levels of evidence  Data interpretation  Monitoring protocol  Risk/benefit analysis of antipsychotics Sunday, July 26, 2009
  • 7. Is Schizophrenia a Systemic Illness?  Abnormalities throughout the body:  Neuromuscular:  Histological1,3,4  Electrophysiological2-4  Changes in cell membrane fatty acid composition5 Sunday, July 26, 2009
  • 8. Is Schizophrenia a Systemic Illness?  Abnormalities throughout the body:  Neuromuscular:  Histological1,3,4  Electrophysiological2-4  Changes in cell membrane fatty acid composition5 1. Meltzer, HY., Crayton, JW. Biol Psychiatry 1974; 8: 191-208 2. Crayton, J., et al. J Neurol Neurosurg Psychiatry 1977; 40: 455-463 3. Borg, J. et al. J Neurol Neurosurg Psychiatry 1987; 50: 1655-1664 4. Flyckt, L., et al. Biol Psychiatry 2000; 47: 991-999. 5. Horrobin, DF., et al. Schizophr Res 1994; 13: 495-501 Sunday, July 26, 2009
  • 9. Is Schizophrenia a Systemic Illness?  Enhanced activity of phospholipase A21,2 leading to:  Disturbed membrane phospholipid metabolism in:  Brain3,4  Periphery5 Sunday, July 26, 2009
  • 10. Is Schizophrenia a Systemic Illness?  Enhanced activity of phospholipase A21,2 leading to:  Disturbed membrane phospholipid metabolism in:  Brain3,4  Periphery5 1. Gattaz, WF., et al., Biol Psychiatry 1990; 28: 495-501 2. Ross, BM., et al., Arch Gen Psychiatry 1997; 54: 487-494 3. Pettegrew, JW., et al., Arch Gen Psychiatry 1991; 48: 563-568 4. Stanley, JA., et al, Arch Gen Psychiatry 1995; 52: 399-406 5. Horrobin, DF. Prostaglandins Leukot Essent Fatty Acids 1996; 55: 3-7 Sunday, July 26, 2009
  • 11. Is Schizophrenia a Systemic Illness?  Decreased levels of membrane phospholipids:  Erythrocytes1-3  Platelets4,5  Fibroblasts6  Phosphorus 31-magnetic resonance spectroscopy (MRS):  Increased levels of phosphodiesters in frontal and temporal cortices (implying increased phospholipid breakdown) in:  Drug naïve7,8  Medicated individuals with schizophrenia9 Sunday, July 26, 2009
  • 12. Is Schizophrenia a Systemic Illness?  Decreased levels of membrane phospholipids:  Erythrocytes1-3  Platelets4,5  Fibroblasts6  Phosphorus 31-magnetic resonance spectroscopy (MRS):  Increased levels of phosphodiesters in frontal and temporal cortices (implying increased phospholipid breakdown) in:  Drug naïve7,8  Medicated individuals with schizophrenia9 1. Hitzemann, R., et al., J Psychiatr Res 1984; 18: 319-326 2. Keshavan, MS., et al., Psychiatry Res 1993; 49: 89-95 3. Yao, JK., et al., Schizophr Res 1994; 13: 217-226 4. Pangerl, AM., et al., Biol Psychiatry 1991; 30: 837-840 5. Yao, JK., et al., Schizophr Res 1996; 60: 11-21 6. Mahadik, SP., et al., Schizophr Res 1994; 13: 239-247 7. Pettegrew, JW., et al., Arch Gen Psychiatry 1991; 48: 563-568 8. Keshavan, MS., et al., Schizophr Res 1993; 10: 241-246 9. Fukuzako, H., et al., Prog Neuropsychopharmacol Biol Psychiatry 1996; 20: 629-640 Sunday, July 26, 2009
  • 13. Is Schizophrenia a Systemic Illness?  Reduced vasodilator responses1  Niacin  Histamine  Altered immunological functions2  Aberrant tyrosine transport across the cell membrane3-5, and blood brain barrier6-7 in patients with schizophrenia Sunday, July 26, 2009
  • 14. Is Schizophrenia a Systemic Illness?  Reduced vasodilator responses1  Niacin  Histamine  Altered immunological functions2  Aberrant tyrosine transport across the cell membrane3-5, and blood brain barrier6-7 in patients with schizophrenia 1. Horrobin, DF. Prostaglandins Leukot Essent Fatty Acids 1996; 55: 3-7 2. Muller, N., et al., Eur Arch Psychiatry Clin Neurosci 1999; 249: 62-68 3. Hagenfeldt, L., et al., Life Sci 1987; 41: 2749-2757 4. Ramchand, CN., et al., Prostaglandins Leukot Essent Fatty Acids 1996; 55: 27-31 5. Flyckt, L., et al., Arch Gen Psychiatry 2001; 58: 953-958 6. Wiesel, FA., et al., J Nucl Med 1991; 32: 2043-2049 7. Wiesel, FA., et al., Schizophr Res 1999; 40: 37-42 Sunday, July 26, 2009
  • 15. Niacin Flush Test in Schizophrenia 1. Nilsson BM, Hultman CM, Wiesel FA. Leukot Essent Fatty Acids 2006;74(5):339-46. 2. Messamore E, Hoffman WF, Janowsky A. Schizophr Res 2003;62(3):251-8. Sunday, July 26, 2009
  • 16. The Pandemic of Overweight and Obesity Sunday, July 26, 2009
  • 17. Obesity Trends* Among U.S. Adults BRFSS, 1985 (*BMI ≥ 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Mokdad A H, et al. J Am Med Assoc 2001;286:10 Sunday, July 26, 2009
  • 18. Obesity Trends* Among U.S. Adults BRFSS, 2000 (*BMI ≥ 30, or ~ 30 lbs overweight for 5’4” woman) No Data <10% 10%-14% 15-19% 20% Mokdad A H, et al. J Am Med Assoc 2001;286:10 Sunday, July 26, 2009
  • 19. Five “Other” Potential Contributors to Weight Gain  Stress1  Salt2  Viruses3  Organic pollutants4  Intestinal flora5 1. Bjorntorp P. Obes Rev 2001;2(2):73-86. 2. Rocchini AP. Nutr Metab Cardiovasc Dis 2000;10(5):287-94. 3. Pasarica M, and Dhurandhar NV. Adv Food Nutr Res 2007;52:61-102. 4. Lee DH, et al. Diabetes Care 2007;30(3):622-8. 5. Turnbaugh PJ, et al. Nature 2006;444(7122):1027-31. Sunday, July 26, 2009
  • 20. Body Mass Index Status and Diabetes Risk 100 Relative Risk 80 60 40 20 0 22- 23- 24- 25- 27- 29- 31- 33- >35 22.9 23.9 24.9 26.9 28.9 30.9 32.9 34.9 Body Mass Index Colditz et al. Ann Intern Med. 1995;122:481 Sunday, July 26, 2009
  • 21. Body Mass Index Status and Diabetes Risk 100 Relative Risk 80 60 40 20 0 22- 23- 24- 25- 27- 29- 31- 33- >35 22.9 23.9 24.9 26.9 28.9 30.9 32.9 34.9 Body Mass Index Colditz et al. Ann Intern Med. 1995;122:481 Sunday, July 26, 2009
  • 22. Potential Causes of Impaired Fasting Glucose Sunday, July 26, 2009
  • 23. Potential Causes of Impaired Fasting Glucose The role of obesity in the pathogenesis of impaired fasting glucose (pre-diabetes) and type 2 diabetes mellitus is, of course, well established1,2 Sunday, July 26, 2009
  • 24. Potential Causes of Impaired Fasting Glucose The role of obesity in the pathogenesis of impaired fasting glucose (pre-diabetes) and type 2 diabetes mellitus is, of course, well established1,2 Sunday, July 26, 2009
  • 25. Potential Causes of Impaired Fasting Glucose The role of obesity in the pathogenesis of impaired fasting glucose (pre-diabetes) and type 2 diabetes mellitus is, of course, well established1,2 But Sunday, July 26, 2009
  • 26. Potential Causes of Impaired Fasting Glucose The role of obesity in the pathogenesis of impaired fasting glucose (pre-diabetes) and type 2 diabetes mellitus is, of course, well established1,2 But 1. Several other important genetic and environmental factors usually need to be present3 Sunday, July 26, 2009
  • 27. Potential Causes of Impaired Fasting Glucose The role of obesity in the pathogenesis of impaired fasting glucose (pre-diabetes) and type 2 diabetes mellitus is, of course, well established1,2 But 1. Several other important genetic and environmental factors usually need to be present3 And 2. It is probably not all forms of obesity4 1. West, K. M. Adv Metab Disord 1978; 9: 29-48 2. Barrett-Connor, E. Epidemiol Rev 1989; 11: 172-81 3. Gerich, J. E. Mayo Clin Proc 2003; 78(4): 447-56. 4. Despres, J-P., Marette, A. Obesity and Insulin Resistance. In: Contemporary Endocrinology: Insulin Resistance. Editors: Reaven, G., & Laws, A. Humana Press, 1999 Sunday, July 26, 2009
  • 28. All Fat is Not Equal Lower body fat Upper body fat “Gynecoid” “Android” vs Sunday, July 26, 2009
  • 29. Type 2 Diabetes Mellitus “A Horizontally Challenging Condition” Sunday, July 26, 2009
  • 30. Type 2 Diabetes Mellitus “A Horizontally Challenging Condition” Sunday, July 26, 2009
  • 31. Type 2 Diabetes Mellitus “A Horizontally Challenging Condition” Sunday, July 26, 2009
  • 32. Role of Obesity in Insulin Resistance, Insulin Resistance Syndrome and Type 2 Diabetes Mellitus Sunday, July 26, 2009
  • 33. Role of Obesity in Insulin Resistance, Insulin Resistance Syndrome and Type 2 Diabetes Mellitus • Prevalence of insulin resistance, insulin resistance syndrome and type 2 diabetes increases with obesity However: • Central obesity is a major determinant of insulin sensitivity:  Abdominal fat ( vs. gluteal and femoral): • Composed of larger adipose cells • Rapidly and more efficiently undergoes lipolysis • Quickly elevates serum triglycerides • Releases fatty acids that suppress the normal breakdown of insulin • Densely populated by cortisol receptors that can promote fat absorption Gasteyger, C. and A. Tremblay. J Endocrinol Invest 2002; 25(10): 876-83 Campfield, L. A., F. J. Smith, et al. Science 1998; 280(5368): 1383-7 Comuzzie, A. G. and D. B. Allison. Science 1998; 280(5368): 1374-7 Hill, J. O. and J. C. Peters. Science 1998; 280(5368): 1371-4 Sunday, July 26, 2009
  • 34. Overweight and Obesity in the Mentally Ill Sunday, July 26, 2009
  • 35. Weight Change in the Pre-Antipsychotic Era Sunday, July 26, 2009
  • 36. Weight Change in the Pre-Antipsychotic Era “The taking of food fluctuates from complete refusal to the greatest voracity. The body weight usually falls at first, often to a considerable degree, even to extreme emaciation, in spite of the most abundant nourishment. Later, on the contrary, we see the weight not infrequently rise quickly in the most extraordinary way, so that patients in short time acquire an uncommonly well-nourished turgid appearance” Sunday, July 26, 2009
  • 37. Weight Change in the Pre-Antipsychotic Era “The taking of food fluctuates from complete refusal to the greatest voracity. The body weight usually falls at first, often to a considerable degree, even to extreme emaciation, in spite of the most abundant nourishment. Later, on the contrary, we see the weight not infrequently rise quickly in the most extraordinary way, so that patients in short time acquire an uncommonly well-nourished turgid appearance” Kraepelin,E. Dementia Praecox and Paraphrenia, Munich 1919 Sunday, July 26, 2009
  • 38. BMI Distributions 1989 National Health Interview Survey 30 Without With schizophrenia schizophrenia % Subjects 20 10 0 <18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34 Body mass index Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220. Sunday, July 26, 2009
  • 39. BMI Distributions 1989 National Health Interview Survey 30 Without With schizophrenia Under- schizophrenia weight Acceptable Overweight Obese % Subjects 20 10 0 <18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34 Body mass index Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220. Sunday, July 26, 2009
  • 40. Mean Change in Weight With Antipsychotics Estimated Weight Change at 10 Weeks on “Standard” Dose 6 13.2 5 † 11.0 Weight change (kg) Weight change (lb) 4 8.8 3 6.6 2 4.4 1 * 2.2 0 0 -1 -2.2 -2 -4.4 -3 -6.6 pi e ne tia in ne e lo e ne le o M rida ne y Q id / ol e nz e on in or ine pi ue az eb ac on n zo zi do id io azi ap za rid ac na m ra es z er id in om ar ip Pl as op pe he ol C la ph rip pr M is pr up al O ly R H Zi A or Th Fl Po hl C *4-6 week pooled data. Marder SR, et al. Schizophr Res. 2003;61:123-36. †Extrapolated from 6-week data. Adapted from: Allison DB, et al. Am J Psychiatry. 1999;156:1686. Sunday, July 26, 2009
  • 41. Why Do Patients Gain Weight with Some Antipsychotics? Sunday, July 26, 2009
  • 42. Why Do Patients Gain Weight with Some Antipsychotics? Potential Mechanisms of Weight Gain Sunday, July 26, 2009
  • 43. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Metabolic Rate Potential Mechanisms of Weight Gain Sunday, July 26, 2009
  • 44. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Metabolic Rate Actions on the lateral and ventromedial hypothalamus Potential Mechanisms of Weight Gain Sunday, July 26, 2009
  • 45. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Metabolic Rate Actions on the lateral and ventromedial hypothalamus Potential Mechanisms of Weight Gain Insulin Resistance Sunday, July 26, 2009
  • 46. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Release of TNF-α Metabolic Rate Actions on the lateral and other cytokines and ventromedial hypothalamus Potential Mechanisms of Weight Gain Insulin Resistance Sunday, July 26, 2009
  • 47. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Release of TNF-α Metabolic Rate Actions on the lateral and other cytokines and ventromedial hypothalamus Reduction in Potential akathisia Mechanisms of Weight Gain Insulin Resistance Sunday, July 26, 2009
  • 48. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Release of TNF-α Metabolic Rate Actions on the lateral and other cytokines and ventromedial hypothalamus Reduction in Potential akathisia Mechanisms of Weight Gain Insulin Resistance Changes in sensitivity to the hormone leptin Sunday, July 26, 2009
  • 49. Why Do Patients Gain Weight with Some Antipsychotics? Reduction in Basal Release of TNF-α Metabolic Rate Actions on the lateral and other cytokines and ventromedial hypothalamus Reduction in Potential Antagonism of H1 and akathisia Mechanisms of 5HT2c receptors Weight Gain Insulin Resistance Changes in sensitivity to the hormone leptin Baptista,T., Acta Psychiatrica Scand 1999; 100: 3-16; Cohen, S., R. Glazewski, et al. J Clin Psychiatry 2001; 62(2): 114-6; Heiman, ML., Leander, JD. Breier, AF. American Psychiatric Association Annual Meeting, New Orleans, 2001, NR293; Mercer LP, et al. J Nutrition 1994; 124:1029-1036; Reynolds, G., et al., Lancet 2002; 359: 2086-7; Simansky KJ:. Behavioural Brain Research 1996; 73:37-42; Stanton J: Schizophr Bull 1995; 21:463-472; Tecott LH, et al. : Nature 1995; 374:542-546; Virkkunen, M., K. Wahlbeck, et al. Pharmacopsychiatry 2002; 35(3): 124-6 Sunday, July 26, 2009
  • 50. Insulin Resistance and the Insulin Resistance Syndrome Sunday, July 26, 2009
  • 51. What is Insulin Resistance? Sunday, July 26, 2009
  • 52. What is Insulin Resistance?  Insulin resistance is defined as an impaired biological response to insulin1  Insulin resistance is a primary defect in the majority of patients with Type 2 diabetes2  In non-diabetic individuals, insulin resistance, in combination with hyperinsulinemia, has a strong predictive value for the future development of Type 2 diabetes3  Hyperinsulinemia, may cause hyperplasia and hypertrophy of adipocytes4 1. American Diabetes Association. Diabetes Care 1998;21(2):310–314 2. Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 3. Bloomgarden ZT. Clin Ther 1998;20(2):216–231 4. Comuzzie, A. G. and D. B. Allison Science 1998; 280(5368): 1374-7 Sunday, July 26, 2009
  • 53. What is Insulin Resistance?  Insulin resistance is defined as an impaired biological response to insulin1  Insulin resistance is a primary defect in the majority of patients with Type 2 diabetes2  In non-diabetic individuals, insulin resistance, in combination with hyperinsulinemia, has a strong predictive value for the future development of Type 2 diabetes3  Hyperinsulinemia, may cause hyperplasia and hypertrophy of adipocytes4 Present in ~30-33% of the general population of the USA, but with marked ethnic differences 1. American Diabetes Association. Diabetes Care 1998;21(2):310–314 2. Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 3. Bloomgarden ZT. Clin Ther 1998;20(2):216–231 4. Comuzzie, A. G. and D. B. Allison Science 1998; 280(5368): 1374-7 Sunday, July 26, 2009
  • 54. Insulin Resistance Syndrome Synonyms  Metabolic syndrome  (Metabolic) Syndrome X  Dysmetabolic syndrome  Reaven’s syndrome  Multiple metabolic syndrome Sunday, July 26, 2009
  • 55. The Metabolic Syndrome and the Insulin Resistance Syndromes  Several sets of criteria  Most usually defined in the USA as the presence of 3 or more of the following:  Abdominal obesity  (Waist circumference >40 inches in men; >35 inches in women  Glucose intolerance (fasting glucose ≥110 mg/dL)  Blood pressure ≥130/85 mmHg  Triglycerides >150 mg/dL  Low HDL(Men: <40 mg/dL; women: <50 mg/dL) NCEP ATP III. Circulation. 2002;106;3143. Sunday, July 26, 2009
  • 56. The Metabolic Syndrome and the Insulin Resistance Syndromes  Several sets of criteria  Most usually defined in the USA as the presence of 3 or more of the following:  Abdominal obesity  (Waist circumference >40 inches in men; >35 inches in women  Glucose intolerance (fasting glucose ≥110 mg/dL)  Blood pressure ≥130/85 mmHg  Triglycerides >150 mg/dL  Low HDL(Men: <40 mg/dL; women: <50 mg/dL) Present in ~22% of the general population of the USA, but with marked ethnic variations NCEP ATP III. Circulation. 2002;106;3143. Sunday, July 26, 2009
  • 57. Sunday, July 26, 2009
  • 58. X High total and LDL- Obesity cholesterol High Hypertension Triglycerides Sunday, July 26, 2009
  • 59. X High total and LDL- Obesity cholesterol Insulin Resistance High Hypertension Triglycerides Ford, E. S., W. H. Giles, et al. JAMA 2002; 287(3): 356-9 Sunday, July 26, 2009
  • 60. Homeostatis Model Assessment (HOMA) Hafner et al. Diabetes Care 1996; 1138-1141 Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419 Sunday, July 26, 2009
  • 61. Homeostatis Model Assessment (HOMA) Normal: Insulin resistance (R) =1 Insulin resistance: Insulin (µU/ml) x glucose (mmol) 22.5 Hafner et al. Diabetes Care 1996; 1138-1141 Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419 Sunday, July 26, 2009
  • 62. Evaluating “Ed” for Syndrome X Sunday, July 26, 2009
  • 63. Evaluating “Ed” for Syndrome X X 5’10 217 pounds LDL cholesterol = 124 BMI = 31 Triglycerides = 301 B/P = 150/90 Glucose 103 mg/ml; Insulin Level: 47µU/ml Sunday, July 26, 2009
  • 64. Evaluating “Ed” for Syndrome X X 5’10 217 pounds LDL cholesterol = 124 BMI = 31 Insulin Resistance? Triglycerides = 301 B/P = 150/90 Glucose 103 mg/ml; Insulin Level: 47µU/ml Sunday, July 26, 2009
  • 65. Evaluating “Ed” for Syndrome X 5’10 217 LDL cholesterol = pounds X 124 BMI = 31 Insulin Resistance Triglycerides = B/P = 301 150/90 Glucose 103 mg/ml; Insulin Level: 47µU/ml Sunday, July 26, 2009
  • 66. Evaluating “Ed” for Syndrome X 5’10 217 Insulin resistance formula: LDL cholesterol = pounds Insulin (µU/ml) x glucose (mmol) X 124 BMI = 31 22.5 Insulin Resistance Glucose in mg/ml Glucose in mmol Triglycerides = B/P = 301 150/90 Glucose 103 mg/ml; Insulin Level: 47µU/ml Sunday, July 26, 2009
  • 67. Evaluating “Ed” for Syndrome X 5’10 217 Insulin resistance formula: LDL cholesterol = pounds Insulin (µU/ml) x glucose (mmol) X 124 BMI = 31 22.5 Insulin Resistance Glucose in mg/ml Glucose in mmol ( __47____ x __5.72__  ÷ 22.5 = Triglycerides = B/P = Insulin Glucose 301 150/90 __11.95__ Insulin resistance Glucose 103 mg/ml; Insulin Level: 47µU/ml Sunday, July 26, 2009
  • 68. Insulin Resistance and Insulin Resistance Syndrome Amongst Patients with Schizophrenia: Results Insulin Insulin Resistance Resistance Syndrome Outpatients 70.3% 51.0% (n=98 ) General 30-33% 25% Population* *American College of Endocrinology Littrell, KH., Petty, RG., et al., NR 550; American Psychiatric Association Annual Meeting, San Francisco, May 21st, 2003 Sunday, July 26, 2009
  • 69. Antipsychotic-Associated Differences in Insulin Sensitivity Insulin Sensitivity by Medication: IVGTT with Minimal Model Analysis 15 (X 10-4• min-1 • ml-1) Insulin sensitivity 10 5 0 Clozapine Olanzapine Risperidone Significant difference among treatment groups, P=0.0057 Henderson D. et al. Arch Gen Psychiatry 2005 ; 62:19-28 Sunday, July 26, 2009
  • 70. Antipsychotic-Associated Differences in Insulin Sensitivity Insulin Sensitivity by Medication: IVGTT with Minimal Model Analysis 15 (X 10-4• min-1 • ml-1) Insulin sensitivity 10 5 0 Clozapine Olanzapine Risperidone Significant difference among treatment groups, P=0.0057 Henderson D. et al. Arch Gen Psychiatry 2005 ; 62:19-28 Sunday, July 26, 2009
  • 71. Time to Diagnosis of Metabolic Syndrome in Patients With Acute Schizophrenia 25 Placebo Cumulative Incidence (%) Olanzapine 20 Aripiprazole 15 P=0.006 10 5 0 0 20 40 60 80 100 120 140 160 180 200 Days L’Italien G. Preventive Med Manage Care. 2003;suppl 2:S38-S42. Sunday, July 26, 2009
  • 72. Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR) 4 3.5 3 2.5 Baseline 2 Endpoint 1.5 1 0.5 0 HOMA-IR Sunday, July 26, 2009
  • 73. Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR) 4 3.5 p = .04 3 2.5 Baseline 2 Endpoint 1.5 1 0.5 0 HOMA-IR Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City, May 2004 Sunday, July 26, 2009
  • 74. Mean Change in Weight 31 210 208 29 206 Baseline Endpoint 204 27 202 25 200 BMI Weight (lbs.) Sunday, July 26, 2009
  • 75. Mean Change in Weight 31 210 208 p = .02 29 206 Baseline Endpoint 204 27 p = .02 202 25 200 BMI Weight (lbs.) Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City, May 2004 Sunday, July 26, 2009
  • 76. And Finally, Diabetes Mellitus Itself Sunday, July 26, 2009
  • 77. Types of Diabetes: Type 2 >90% of people with diabetes have type 2 Usually insulin resistant with inadequate insulin production to maintain normal glucose levels Onset (usually gradual) at any age, usually >20 years Usually overweight or obese Less often ketotic than Type 1 diabetes, and often no symptoms at presentation Occurs mainly in adults but is becoming much more common in young people Sunday, July 26, 2009
  • 78. Types of Diabetes: Type 2 Worldwide very high prevalence in rural to urban migrant communities Age at diagnosis falling rapidly Often found in 3rd and 4th decade in Northern European Whites, and even earlier in “High Risk” ethnic groups Slight male preponderance To manage hyperglycaemia, oral medication may be required For metabolic control, insulin may be required Sunday, July 26, 2009
  • 79. Causes of Type 2 Diabetes Underlying insulin resistance • Genetic (90% identical twin concordance) • Ethnicity (thrifty genotype hypothesis) • Central obesity • Inactivity / low physical fitness • Intrauterine malnutrition (Barker hypothesis) • Smoking & drugs Impaired insulin secretion • Genetic • Environmental Insulin secretion worsens with time Sunday, July 26, 2009
  • 80. Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes Sunday, July 26, 2009
  • 81. Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes Insulin Resistance CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver disease Adapted from: ACE Position Statement on the Insulin Resistance Syndrome, Endocr Pract. 2003; 9(No. 3) 240-252; Reaven GM. Diabetes 1988;37:1595–1607; Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 Sunday, July 26, 2009
  • 82. Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes Insulin Resistance Compensatory Hyperinsulinemia Insulin Resistance Syndrome CVD Hypertension Stroke PCOS NAFLD CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver disease Adapted from: ACE Position Statement on the Insulin Resistance Syndrome, Endocr Pract. 2003; 9(No. 3) 240-252; Reaven GM. Diabetes 1988;37:1595–1607; Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 Sunday, July 26, 2009
  • 83. Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes Insulin Resistance Inadequate Insulin Response + Compensatory β-cell failure Hyperinsulinemia Impaired Glucose Tolerance Insulin Resistance Syndrome Type 2 Diabetes Mellitus CVD Hypertension Retinopathy Stroke Nephropathy PCOS Neuropathy NAFLD CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver disease Adapted from: ACE Position Statement on the Insulin Resistance Syndrome, Endocr Pract. 2003; 9(No. 3) 240-252; Reaven GM. Diabetes 1988;37:1595–1607; Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 Sunday, July 26, 2009
  • 84. Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes Insulin Resistance Inadequate Insulin Response + Compensatory β-cell failure Hyperinsulinemia Impaired Glucose Tolerance Insulin Resistance Syndrome Type 2 Diabetes Mellitus CVD Hypertension Retinopathy Stroke Nephropathy PCOS Neuropathy NAFLD CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver disease Adapted from: ACE Position Statement on the Insulin Resistance Syndrome, Endocr Pract. 2003; 9(No. 3) 240-252; Reaven GM. Diabetes 1988;37:1595–1607; Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721 Sunday, July 26, 2009
  • 85. Risk Factors for Type 2 Diabetes ♦Family history of diabetes ♦Obesity (BMI >30) ♦> 40 years of age ♦Previous impairment of fasting glucose ♦Hypertension (>140/90) ♦Low HDL cholesterol (<35mg/dl) ♦Triglycerides >250 mg/dl ♦History of gestational diabetes ♦Personal or family history of macrovascular disease ♦Delivery of infant >9 lbs ♦Member of high risk ethnic group ♦African American ♦Hispanic ♦Native American ♦Asian ♦Polycystic ovarian disease ♦Acanthosis nigricans ♦And……. Sunday, July 26, 2009
  • 86. Hyperglycemia And Psychiatric Disorders Sunday, July 26, 2009
  • 87. Hyperglycemia And Psychiatric Disorders  There were many reports of abnormalities of carbohydrate metabolism occurring with higher than expected frequency in patients with psychotic and mood disorders long before the advent of antipsychotic agents (primarily hyperglycemia and glycosuria)  These included:  Delayed responses to insulin and  Glucose tolerance tests indicative of diabetes mellitus  Which are both highly suggestive of insulin resistance Maudsley, H. The Pathology of Mind, London, 1897 Kraepelin, E. Dementia Praecox, Munich, 1919 Lorenz, WF. Arch Neurol Psychiatry, 1922;8:184-196 Diethelm, O. Arch Neurol Psychiatry, 1936;36:342-361 Braceland, F., et al. Am J Psychiatry, 1945;102:108-110 Aldrich, CK. Arch Neurol Psychiatry, 1948;60:498-503 Sunday, July 26, 2009
  • 88. Diabetes Mellitus and Serious Mental Illness Sunday, July 26, 2009
  • 89. Diabetes Mellitus and Serious Mental Illness  Type II Diabetes is common  In 9-14% of patients with schizophrenia and bipolar disorder1-6  c.f. 6.5% (already diagnosed) - 7.8% (estimated total) of the general population of the US7  Probably no excess of Type I Diabetes 1. Dynes, JB. Dis Nervous System 1969; 30: 341-344 2. McKee, et al, J Clin Hosp Pharmacology 1986; 11: 297-299 3. Mukherjee, S., et al, Comp Psychiatry 1996; 37: 68-73 4. Hagg, et al, J Clin Psychiatry 1998; 59: 294-299 5. Dixon, L., et al, Schizophrenia Bull 2000; 26: 903-912 6. Regenold, W. T., R. K. Thapar, et al. J Affect Disord 2002; 70(1): 19-26. 7. American Diabetes Association Report, 2000 Sunday, July 26, 2009
  • 90. Sunday, July 26, 2009
  • 91. The Increased Prevalence of Type 2 Diabetes Associated with Mental Illness is Not Confined to the Sufferers Themselves Sunday, July 26, 2009
  • 92. The Increased Prevalence of Type 2 Diabetes Associated with Mental Illness is Not Confined to the Sufferers Themselves “ Diabetes is a disease which often shows itself in families in which insanity prevails” Sunday, July 26, 2009
  • 93. The Increased Prevalence of Type 2 Diabetes Associated with Mental Illness is Not Confined to the Sufferers Themselves “ Diabetes is a disease which often shows itself in families in which insanity prevails” Sir Henry Maudsley, The Pathology of Mind, London, 1897. Sunday, July 26, 2009
  • 94. Schizophrenia & Diabetes Mellitus • Family history of Type 2 DM in 18-30% of patients with schizophrenia1,2 • Comparable to the rates - 27-49% - in first degree relatives of those with Type 2 DM3-5 • Considerably in excess of those seen within the general population, 1.2 - 6.3%6 Sunday, July 26, 2009
  • 95. Schizophrenia & Diabetes Mellitus • Family history of Type 2 DM in 18-30% of patients with schizophrenia1,2 • Comparable to the rates - 27-49% - in first degree relatives of those with Type 2 DM3-5 • Considerably in excess of those seen within the general population, 1.2 - 6.3%6 1. Dynes, JB. Dis Nervous System 1969; 30: 341-344 2. Mukherjee, S., D. B. Schnur, et al. 1989; Lancet 1(8636): 495 3. Cheta, D., C. Dumitrescu, et al. 1990; Diabete Metab 16(1): 11-5 4. Erasmus, R. T., E. Blanco Blanco, et al. 2001; S Afr Med J 91(2): 157-60 5. Erasmus, R. T., E. Blanco Blanco, et al. 2001; Postgrad Med J 77(907): 323-5 6. Hagura, R., A. Matsuda, et al. 1994; Diabetes Res Clin Pract 24 Suppl: S69-73 Sunday, July 26, 2009
  • 96. Visceral (Intra-abdominal) Fat Plays a Critical Role in the Development of Type 2 Diabetes Mellitus Sunday, July 26, 2009
  • 97. Visceral (Intra-abdominal) Fat Plays a Critical Role in the Development of Type 2 Diabetes Mellitus Since diabetes is considerably more common in patients with schizophrenia and in their relatives Sunday, July 26, 2009
  • 98. Visceral (Intra-abdominal) Fat Plays a Critical Role in the Development of Type 2 Diabetes Mellitus Since diabetes is considerably more common in patients with schizophrenia and in their relatives Is there any evidence to suggest that patients with schizophrenia have increased visceral fat distribution? Sunday, July 26, 2009
  • 99. CT Scan of Intra-Abdominal Fat Thakore, J. H, Mann, J.N., et al., International Journal of Obesity & Metabolism 2002; 26(1): 137-41 Sunday, July 26, 2009
  • 100. Increased Visceral Fat Distribution in Drug-naïve and Drug-free Patients With Schizophrenia Patients had 3.4 x intra-abdominal fat (IAF) as compared to controls No difference in IAF between first episode and drug free patients Patients had hypercortisolaemia Thakore, J. H, Mann, J.N., et al., International Journal of Obesity & Metabolism 2002; 26(1): 137-41 Sunday, July 26, 2009
  • 101. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 102. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Stress Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 103. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Stress Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 104. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Stimulation Release of Pancreatic of FFA Insulin and TG Release + Stress Reduced Insulin Breakdown Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 105. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Stimulation Release of Pancreatic of FFA Insulin and TG Release + Stress Reduced Insulin Breakdown Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 106. Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance Stimulation Release of Pancreatic of FFA Insulin and TG Release + Stress Reduced Insulin Breakdown Basal Intra- Peripheral Corticosteroid Abdominal Insulin Insulin Release Fat Levels Resistance Sunday, July 26, 2009
  • 107. Conditions Associated With Hypercortisolaemia and Increased Visceral Fat Distribution Melancholic depression1-4 Cushing’s syndrome5,6 Schizophrenia7 Alcoholic “Pseudo-Cushing’s syndrome” 8,9 Anorexia Nervosa 1. Wajchenberg, B.L., et al., J Clin Endocrinol Metab, 1995; 80:2791-4 2. Thakore J.H., et al., Biol Psychiatry 1997; 41: 1140-1143 3. Weber, B., S. Lewicka, et al. 2000; J Clin Endocrinol Metab 85(3): 1133-6 4. Weber, B., U. Schweiger, et al. 2000; Exp Clin Endocrinol Diabetes 108(3): 187-90 5. Schafroth, U., K. Godang, et al. 2000; J Endocrinol Invest 23(6): 349-55 6. Masuzaki, H., J. Paterson, et al. 2001; Science 294(5549): 2166-70 7. Thakore, J. H, Mann, J.N., et al., International Journal of Obesity & Metabolism 2002; 26(1): 137-41 8. Bjorntorp, P. 1996; Int J Obes Relat Metab Disord 20(4): 291-302 9. Groote Veldman, R. and A. E. Meinders 1996; Endocr Rev 17(3): 262-8 Sunday, July 26, 2009
  • 108. Hyperglycemia and Older Antipsychotic Agents Sunday, July 26, 2009
  • 109. Hyperglycemia and Older Antipsychotic Agents  Chlorpromazine was linked to hyperglycemia and glycosuria within one year of its introduction in France  This was confirmed in subsequent studies, not only with chlorpromazine, but also with other phenothiazines  The link to butyrophenones has never been quite so clear Courvoisier, S., et al. Arch Int Pharmacodyn, 1953;92:305-361. Dobkin, A.B., et al. Canad Med Assoc J,1954;70:636-638. Giacobini, A.E., Lassenius, B. Nord Med, 1954;52:1693-1699. Moyer, J.H., et al. Arch Int Med, 1955;95:202-218. Sunday, July 26, 2009
  • 110. Dibenzodiazepines, Hyperglycemia and Hypertriglyceridemia  Apart from the phenothiazines, case reports and case series have more frequently reported hyperglycemia, hypertriglyceridemia and ketoacidosis with dibenzodiazepines than with other antipsychotics, even in the absence of weight gain, including:  Loxapine1  Fluperlapine2,3  Clozapine4-8  Olanzapine7-10  Quetiapine10,11  This could represent reporter bias Sunday, July 26, 2009
  • 111. Dibenzodiazepines, Hyperglycemia and Hypertriglyceridemia  Apart from the phenothiazines, case reports and case series have more frequently reported hyperglycemia, hypertriglyceridemia and ketoacidosis with dibenzodiazepines than with other antipsychotics, even in the absence of weight gain, including:  Loxapine1  Fluperlapine2,3  Clozapine4-8  Olanzapine7-10  Quetiapine10,11  This could represent reporter bias 1. Tollefson, G. and T. Lesar J Clin Psychiatry 1983; 44(9): 347-8. 2. Muller-Oerlinghausen, B. Arzneimittelforschung 1984; 34(1A): 131-4. 3. Fleischhacker, W. W., C. Stuppack, et al. Pharmacopsychiatry 1986; 19(3): 111-4. 4. Ghaeli, P. and R. L. Dufresne. Am J Health Syst Pharm 1996; 53(17): 2079-81. 5. Baymiller, S. P., P. Ball, et al. Schizophr Res 2003; 59(1): 49-57. 6. Henderson, D. C., E. Cagliero, et al. Am J Psychiatry 2000; 157(6): 975-81. 7. Meyer, J. M. J Clin Psychopharmacol 2001; 21(4): 369-74. 8. Wirshing, D. A., J. A. Boyd, et al. J Clin Psychiatry 2002; 63(10): 856-65. 9. Melkersson, K. I. and M. L. Dahl. Psychopharmacology (Berl) 2003; 170(2): 157-66. 10. Atmaca, M., M. Kuloglu, et al. J Clin Psychiatry 2003; 64(5): 598-604 11. McIntyre, R. S., S. M. McCann, et al. Can J Psychiatry 2001; 46(3): 273-81 Sunday, July 26, 2009
  • 112. Dibenzodiazepines, Hyperglycemia and Hypertriglyceridemia  Apart from the phenothiazines, case reports and case series have more frequently reported hyperglycemia, hypertriglyceridemia and ketoacidosis with dibenzodiazepines than with other antipsychotics, even in the absence of weight gain, including:  Loxapine1  Fluperlapine2,3  Clozapine4-8  Olanzapine7-10  Quetiapine10,11  This could represent reporter bias However…. 1. Tollefson, G. and T. Lesar J Clin Psychiatry 1983; 44(9): 347-8. 2. Muller-Oerlinghausen, B. Arzneimittelforschung 1984; 34(1A): 131-4. 3. Fleischhacker, W. W., C. Stuppack, et al. Pharmacopsychiatry 1986; 19(3): 111-4. 4. Ghaeli, P. and R. L. Dufresne. Am J Health Syst Pharm 1996; 53(17): 2079-81. 5. Baymiller, S. P., P. Ball, et al. Schizophr Res 2003; 59(1): 49-57. 6. Henderson, D. C., E. Cagliero, et al. Am J Psychiatry 2000; 157(6): 975-81. 7. Meyer, J. M. J Clin Psychopharmacol 2001; 21(4): 369-74. 8. Wirshing, D. A., J. A. Boyd, et al. J Clin Psychiatry 2002; 63(10): 856-65. 9. Melkersson, K. I. and M. L. Dahl. Psychopharmacology (Berl) 2003; 170(2): 157-66. 10. Atmaca, M., M. Kuloglu, et al. J Clin Psychiatry 2003; 64(5): 598-604 11. McIntyre, R. S., S. M. McCann, et al. Can J Psychiatry 2001; 46(3): 273-81 Sunday, July 26, 2009
  • 113. Dibenzodiazepines, Hyperglycemia and Hypertriglyceridemia  Dwyer et al found a strong correlation between the ability of phenothiazines and dibenzodiazepines to inhibit glucose transport in vitro and their ability to induce hyperglycemia in mice in vivo  Neither was found with other antipsychotics1 Sunday, July 26, 2009
  • 114. Dibenzodiazepines, Hyperglycemia and Hypertriglyceridemia  Dwyer et al found a strong correlation between the ability of phenothiazines and dibenzodiazepines to inhibit glucose transport in vitro and their ability to induce hyperglycemia in mice in vivo  Neither was found with other antipsychotics1 1. Dwyer, D. S. and D. Donohoe. Pharmacol Biochem Behav 2003; 75(2): 255-60. Sunday, July 26, 2009
  • 115. Marked Increase in Adiposity during Olanzapine vs. Risperidone Treatment: Results of a Placebo-Controlled Study in Normal Dogs  Psychotic illnesses may themselves be associated with an increased risk of obesity, insulin resistance, hyperglycemia and diabetes mellitus  Study designed to avoid these confounding effects in a conscious dog model  Dogs were fed ad libitum and given olanzapine (n=7; 2.5 mg/d p.o. for 3 d, 15 mg/d thereafter), risperidone (n=7; 1 mg/d p.o for 3 d, 5 mg/d thereafter), or gelatin capsules (n=5) for 4 wks. (I.e. Typical therapeutic doses)  Measured fat deposited in specific depots (visceral and subcutaneous) by abdominal MRI  Hyperinsulinemic Clamp Procedure as a measure of insulin sensitivity and  Hyperglycemic Clamp Procedure as a measure of insulin secretion Ader, M., et al, Diabetes 2005; 54(3): 862-71 Sunday, July 26, 2009
  • 116. Ader, M., et al, Diabetes 2005; 54(3): 862-71 Sunday, July 26, 2009
  • 117. Decreasing Insulin Sensitivity (i.e. Increasing Hepatic Insulin Resistance) in Dogs Exposed to Some Antipsychotic Agents Ader, M., et al, Diabetes 2005; 54(3): 862-71 Sunday, July 26, 2009
  • 118. Prospective Study of Olanzapine and Insulin Resistance  Eight week study of 10 olanzapine treated in- patients with schizophrenia and 10 healthy controls  Weight increased from 68.8 + 11.3kg to 72.1 + 10.5 (p=.001)  As did body fat (13.1 + 4.5kg to 15.3 + 4.2kg (p=.004)  And BMI (22.4 + 3.0 kg/m2 to 23.5 + 2.6 kg/ m2 ) Ebenbichler, C. F., M. Laimer, et al. J Clin Psychiatry 2003; 64(12): 1436-9. Sunday, July 26, 2009
  • 119. Prospective Study of Olanzapine and Insulin Resistance  Fasting serum glucose increased significantly (p=.008), as did serum insulin (p=.006)  HOMA-IR increased from 1.3mmol.mU-1.L-2 to 2.6mmol.mU-1.L-2 (p=.008) within eight weeks  In some, before any weight gain had occurred  HOMA ß cell function was unchanged Ebenbichler, C. F., M. Laimer, et al. J Clin Psychiatry 2003; 64(12): 1436-9. Sunday, July 26, 2009
  • 120. Reports of Diabetes-Related Events Among “Atypical” Antipsychotic Agents Clozapine1 Olanzapine2 Risperidone3 Quetiapine4 Surveillance period 1990-2001 1994-2001 1993-2001 1997-2002 New-onset diabetes 323 188 78 46 Exacerbation of diabetes 54 44 46 34 “Unclassified” 7 5 7 8 With “ketoacidosis” 80 80 26 21 FDA Medwatch Surveillance Program, +Medline search, and abstract search. 1. Koller E, et al. Am J Med. 2001;111(9):716-723. 2. Koller EA, Doraiswamy PM. Pharmacotherapy. 2002;22(7):841-852. 3. Koller EA, et al. Pharmacotherapy. 2003;23(6):735-744. 4. Koller EA, et al. Presented at: 156th APA Annual Meeting; May 17-22, 2003; San Francisco, Calif. Sunday, July 26, 2009
  • 121. FDA Warning: Hyperglycemia and Diabetes Mellitus FDA. September 15, 2003. Sunday, July 26, 2009
  • 122. FDA Warning: Hyperglycemia and Diabetes Mellitus  “Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics … FDA. September 15, 2003. Sunday, July 26, 2009
  • 123. FDA Warning: Hyperglycemia and Diabetes Mellitus  “Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics …  Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population FDA. September 15, 2003. Sunday, July 26, 2009
  • 124. FDA Warning: Hyperglycemia and Diabetes Mellitus  “Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics …  Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population  Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics studied …” FDA. September 15, 2003. Sunday, July 26, 2009
  • 125. FDA Warning: Hyperglycemia and Diabetes Mellitus FDA. September 15, 2003. Sunday, July 26, 2009
  • 126. FDA Warning: Hyperglycemia and Diabetes Mellitus  Patients with pre-existing diabetes who are started on an atypical should receive regular monitoring for a worsening of glucose control  Patients with known risk factors for diabetes should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment  Patients should be monitored for symptoms of hyperglycemia  Patients who develop symptoms of hyperglycemia should undergo fasting blood glucose testing FDA. September 15, 2003. Sunday, July 26, 2009
  • 127. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes  Joint statement released in February 2004 and developed by:  American Diabetes Association  American Psychiatric Association  American Association of Clinical Endocrinologists  North American Association for the Study of Obesity American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Diabetes Care 2004; 27(2): 596-601 Sunday, July 26, 2009
  • 128. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes Drug Weight Gain Risk for Worsening Diabetes Lipid Profile Clozapine +++ + + Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole +/- - - Ziprasidone +/- - - (D= “Discrepant data”) American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Diabetes Care 2004; 27(2): 596-601 Sunday, July 26, 2009
  • 129. Managing Metabolic Effects of Antipsychotic Agents Sunday, July 26, 2009
  • 130. Finnish DPS: Intensive Lifestyle Intervention Reduces Diabetes Risk by 58% 1.0 Probability of not having 0.9 Intervention diabetes 0.8 0.7 Control 0.6 0.5 0 1 2 3 4 5 6 Year Tuomilehto J et al. N Engl J Med 2001;344:1343–9 Sunday, July 26, 2009
  • 131. Diabetes Prevention Program Progression to Diabetes Lifestyle (n=1,079, p<0.001 vs metformin, p<0.001 vs placebo) Metformin (n=1,073, p<0.001 vs placebo) Placebo (n=1,082) Diabetes Prevention Research Group. N Engl J Med 2002; 346:393–403 Sunday, July 26, 2009
  • 132. Monitoring Protocol for Patients on Second Generation Antipsychotics Base 4 wks 8 wks 12 wks Qtr Ann 5 yrs Line Personal/ X X Family History Weight (BMI) X X X X X Waist X X circumference Blood pressure X X X Fasting plasma X X X glucose Fasting lipid X X X profile Sunday, July 26, 2009
  • 133. Sunday, July 26, 2009
  • 134. Waist? Sunday, July 26, 2009
  • 135. Waist Waist? Sunday, July 26, 2009
  • 136. Monitoring Protocol for Patients on Second Generation Antipsychotics Base 4 wks 8 wks 12 wks Qtr Annual 5 yrs Line Personal/ X X Family History Weight (BMI) X X X X X Waist X X circumference Blood pressure X X X Fasting plasma X X X glucose Fasting lipid X X X profile American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Diabetes Care 2004; 27(2): 596-601 Sunday, July 26, 2009
  • 137. Monitoring Protocol for Patients on Second Generation Antipsychotics Critical (“Action Base Needed”) 4 wks 8 wks 12 wks Qtr Annual 5 yrs Line Values Personal/ X X Family History Overweight:25.0-29.9 Weight (BMI) Obese > 30.0 X X X X X Waist Men > 40 inches X X circumference Women > 35 inches Blood pressure >130/>85 mm Hg X X X Pre-diabetes: 100-125mg/ Fasting plasma dL X X X glucose Diabetes: > 126mg/dL LDL > 100mg/dl Fasting lipid HDL Men < 40mg/dL X X X profile Women < 50mg/dL TG > 150mg/dL American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Diabetes Care 2004; 27(2): 596-601 Sunday, July 26, 2009
  • 138. Hemoglobin A1c (a.k.a.“Glycated” {“Glycosylated”}) Hemoglobin and Estimated Average Glucose {eAG}  A good indicator of blood glucose control, in people with established diabetes mellitus  Gives a percentage that indicates control over the preceding 2-3 months  A hemoglobin A1c of < 6% (eAG 126mg/dl) indicates good diabetic control and a level >8% (eAG 183mg/dl) indicates that action is needed  NOT a diagnostic test  In 2003 the American Diabetes Association stated that it had no real value in screening in most populations1  This position is currently being re-evaluated in research on specific patient groups2 1. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003;26(suppl 1):S5-S20 2. 2. Buell, C. et al. 2007; 30: 2233-22351. Sunday, July 26, 2009
  • 139. Clinical Features of Ketoacidosis Sunday, July 26, 2009
  • 140. Clinical Features of Ketoacidosis Signs  Drowsiness and confusion  Dehydration  Hyperventilation  Acetones on the breath  Hypothermia  Hypotension, tachycardia  Shock  Loss of consciousness Sunday, July 26, 2009
  • 141. Clinical Features of Ketoacidosis  Symptoms Signs  Thirst  Drowsiness and confusion  Polyuria  Dehydration  Weight loss  Hyperventilation  Nausea, vomiting,  Acetones on the breath diarrhoea, abdominal pain  Hypothermia  Precipitating event (e.g.  Hypotension, tachycardia infection)  Shock  Loss of consciousness Sunday, July 26, 2009
  • 142. Sunday, July 26, 2009
  • 143. Insulin Resistance Sunday, July 26, 2009
  • 144. Intra-Abdominal Inactivity Glucose Genetics Medications Obesity Intolerance Cigarette Smoking Aging Fetal Malnutrition Insulin Resistance Sunday, July 26, 2009
  • 145. Intra-Abdominal Inactivity Glucose Genetics Medications Obesity Intolerance Cigarette Smoking Aging Fetal Malnutrition Insulin Resistance Type 2 Diabetes Sunday, July 26, 2009
  • 146. Intra-Abdominal Inactivity Glucose Genetics Medications Obesity Intolerance Cigarette Smoking Aging Fetal Polycystic Malnutrition Ovary Syndrome Dyslipidemias Insulin Microalbuminuria Resistance Endothelial Dysfunction QTc Prolongation Dysfibrinolysis ?Certain Macrovascular Malignancies Disease Other Type 2 Non Alcoholic Hypertension Metabolic Effects: e.g. Hyperuricemia Diabetes Fatty Liver Disease Sunday, July 26, 2009
  • 147. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill Sunday, July 26, 2009
  • 148. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill 1. Carbohydrate Craving Sunday, July 26, 2009
  • 149. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill 1. Carbohydrate Craving 2. Insulin Resistance Sunday, July 26, 2009
  • 150. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill 1. Carbohydrate Craving 2. Insulin Resistance 3. Hypercortisolaemia Sunday, July 26, 2009
  • 151. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill 1. Carbohydrate Craving 2. Insulin Resistance 3. Hypercortisolaemia How can we use this knowledge in practice? Sunday, July 26, 2009
  • 152. The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill 1. Carbohydrate Craving 2. Insulin Resistance 3. Hypercortisolaemia How can we use this knowledge in practice? And What Specific Problems Will We Have to Contend With, When Treating Weight and Metabolic Problems in the Mentally Ill? Sunday, July 26, 2009
  • 153. The Three Steps Sunday, July 26, 2009
  • 154. The Three Steps  1. An appropriate psychoeducational program  Solutions for Wellness  Other programs Sunday, July 26, 2009
  • 155. The Three Steps  1. An appropriate psychoeducational program  Solutions for Wellness  Other programs  2. A specific dietary strategy  Insulin resistance diets initially, followed by more carefully balanced diets Sunday, July 26, 2009
  • 156. The Three Steps  1. An appropriate psychoeducational program  Solutions for Wellness  Other programs  2. A specific dietary strategy  Insulin resistance diets initially, followed by more carefully balanced diets  3. As a last resort, (and if BMI >30kg/m2, or >27kg/m2 with physical complications of obesity), consider medications. None has received FDA approval for the treatment of antipsychotic induced weight gain. Therefore we obtain consent and work through them systematically:  Add aripiprazole  Metformin  If physical safety criteria have been met  Topiramate  Cautions: Glaucoma; cognitive impairment; renal stones  Amantadine  May exacerbate psychosis or mood disturbance  + Six other potential approaches: e.g. Sibutramine; buproprion; trazodone; mazindol; (reboxetine); (fluoxetine); (nizatidine to prevent weight gain) Sunday, July 26, 2009
  • 157. Summary: Impact of Metabolic Adverse Effects on Overall Patient Health  Patients with schizophrenia are at increased risk for obesity, insulin resistance, diabetes mellitus, cardiovascular disease, and medical illness  Adverse metabolic effects of some psychotropics may impose an additional medical burden on this high-risk population  Important differences exist between the weight and metabolic effects profiles of “atypical” antipsychotic agents  We now have clear guidelines on how to monitor our patients and how to deal with some of the metabolic issues Sunday, July 26, 2009
  • 158. Useful Addresses  www.RichardGPettyMD.com  www.RichardGPettyMD.blogs.com  rpettyus@aol.com  www.Healia.com Sunday, July 26, 2009

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