Metabolism and Mental Illness
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Transcript of Metabolism and Mental Illness
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
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
There Is a Serious Lack of Physical Well-being in Individuals With Major Mental Illness
Sunday, July 26, 2009
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
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: 11-532. Newman and Bland Can J Psychiatry 1991; 36: 239-2453. Tabbane, K., R. Joober, et al. 1993; Encephale 19: 23-84. Allebeck, Schizophr Bull 1989; 15: 81-895. Dixon et al, J Nerv Ment Dis 1999; 187: 495-5026. Allison, D., et al. J Clin Psychiatry 1999; 60: 215-2207. Herran et al, Schizophr Res 2000; 41: 373-381
Sunday, July 26, 2009
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
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
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: 191-2082. Crayton, J., et al. J Neurol Neurosurg Psychiatry 1977; 40: 455-4633. Borg, J. et al. J Neurol Neurosurg Psychiatry 1987; 50: 1655-16644. 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
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
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: 495-5012. Ross, BM., et al., Arch Gen Psychiatry 1997; 54: 487-4943. Pettegrew, JW., et al., Arch Gen Psychiatry 1991; 48: 563-5684. Stanley, JA., et al, Arch Gen Psychiatry 1995; 52: 399-4065. Horrobin, DF. Prostaglandins Leukot Essent Fatty Acids 1996; 55: 3-7
Sunday, July 26, 2009
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
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: 319-3262. Keshavan, MS., et al., Psychiatry Res 1993; 49: 89-953. Yao, JK., et al., Schizophr Res 1994; 13: 217-2264. Pangerl, AM., et al., Biol Psychiatry 1991; 30: 837-8405. Yao, JK., et al., Schizophr Res 1996; 60: 11-216. Mahadik, SP., et al., Schizophr Res 1994; 13: 239-2477. Pettegrew, JW., et al., Arch Gen Psychiatry 1991; 48: 563-5688. Keshavan, MS., et al., Schizophr Res 1993; 10: 241-2469. Fukuzako, H., et al., Prog Neuropsychopharmacol Biol Psychiatry 1996; 20: 629-640
Sunday, July 26, 2009
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
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: 3-72. Muller, N., et al., Eur Arch Psychiatry Clin Neurosci 1999; 249: 62-683. Hagenfeldt, L., et al., Life Sci 1987; 41: 2749-27574. Ramchand, CN., et al., Prostaglandins Leukot Essent Fatty Acids 1996; 55: 27-315. Flyckt, L., et al., Arch Gen Psychiatry 2001; 58: 953-9586. Wiesel, FA., et al., J Nucl Med 1991; 32: 2043-20497. Wiesel, FA., et al., Schizophr Res 1999; 40: 37-42
Sunday, July 26, 2009
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
The Pandemic of Overweight and Obesity
Sunday, July 26, 2009
Obesity Trends* Among U.S. AdultsBRFSS, 1985
(*BMI ≥ 30, or ~ 30 lbs overweight for 5’4” woman)
Mokdad A H, et al. J Am Med Assoc 2001;286:10
No Data <10% 10%-14% 15-19% 20%
Sunday, July 26, 2009
Mokdad A H, et al. J Am Med Assoc 2001;286:10
No Data <10% 10%-14% 15-19% 20%
Obesity Trends* Among U.S. AdultsBRFSS, 2000
(*BMI ≥ 30, or ~ 30 lbs overweight for 5’4” woman)
Sunday, July 26, 2009
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
Body Mass Index Status and Diabetes Risk
0
20
40
60
80
100
22-22.9
23-23.9
24-24.9
25-26.9
27-28.9
29-30.9
31-32.9
33-34.9
>35
Body Mass Index
Rel
ativ
e R
isk
Colditz et al. Ann Intern Med. 1995;122:481Sunday, July 26, 2009
Body Mass Index Status and Diabetes Risk
0
20
40
60
80
100
22-22.9
23-23.9
24-24.9
25-26.9
27-28.9
29-30.9
31-32.9
33-34.9
>35
Body Mass Index
Rel
ativ
e R
isk
Colditz et al. Ann Intern Med. 1995;122:481Sunday, July 26, 2009
Potential Causes of Impaired Fasting Glucose
Sunday, July 26, 2009
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
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
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
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
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: 29-482. Barrett-Connor, E. Epidemiol Rev 1989; 11: 172-813. 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
All Fat is Not Equal
Lower body fat Upper body fat “Gynecoid” “Android”
vs
Sunday, July 26, 2009
Type 2 Diabetes Mellitus
“A Horizontally ChallengingCondition”
Sunday, July 26, 2009
Type 2 Diabetes Mellitus
“A Horizontally ChallengingCondition”
Sunday, July 26, 2009
Type 2 Diabetes Mellitus
“A Horizontally ChallengingCondition”
Sunday, July 26, 2009
Role of Obesity in Insulin Resistance, Insulin Resistance Syndrome and Type 2 Diabetes Mellitus
Sunday, July 26, 2009
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): 876-83Campfield, L. A., F. J. Smith, et al. Science 1998; 280(5368): 1383-7Comuzzie, A. G. and D. B. Allison. Science 1998; 280(5368): 1374-7Hill, J. O. and J. C. Peters. Science 1998; 280(5368): 1371-4
Sunday, July 26, 2009
Overweight and Obesity in the Mentally Ill
Sunday, July 26, 2009
Weight Change in the Pre-Antipsychotic Era
Sunday, July 26, 2009
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
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
BMI Distributions1989 National Health Interview Survey
0
10
20
30
<18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34
Without schizophrenia
With schizophrenia
% S
ubje
cts
Body mass index
Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220.
Sunday, July 26, 2009
BMI Distributions1989 National Health Interview Survey
0
10
20
30
<18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34
Without schizophrenia
With schizophrenia
% S
ubje
cts
Under-weight
Acceptable Overweight Obese
Body mass index
Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220.
Sunday, July 26, 2009
Mean Change in Weight With Antipsychotics
*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.
Estimated Weight Change at 10 Weeks on “Standard” Dose
Haloperi
dol
Polypharm
acy
Risperi
done
Chlorpro
mazine
Olanza
pine
Clozapine
Quetiap
ine
Thioridaz
ine/
Mesorid
azine
6
Wei
ght c
hang
e (k
g)
5
4
3
2
1
0
-1
-2
-3
Placeb
o
Molindone
Fluphenaz
ine
Ziprasidone
13.2
Wei
ght c
hang
e (lb
)11.0
8.8
6.6
4.4
2.2
0
-2.2
-4.4
-6.6
†
Aripipraz
ole
*
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Potential Mechanisms of
Weight Gain
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Insulin Resistance
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Insulin Resistance
Release of TNF-αand other cytokines
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Insulin Resistance
Reduction in akathisia
Release of TNF-αand other cytokines
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Insulin Resistance
Reduction in akathisia
Release of TNF-αand other cytokines
Changes in sensitivity to the hormone leptin
Sunday, July 26, 2009
Why Do Patients Gain Weight with Some Antipsychotics?
Antagonism of H1 and 5HT2c receptors
Actions on the lateral and ventromedial
hypothalamus
Potential Mechanisms of
Weight Gain
Reduction in Basal Metabolic Rate
Insulin Resistance
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
Reduction in akathisia
Release of TNF-αand other cytokines
Changes in sensitivity to the hormone leptin
Sunday, July 26, 2009
Insulin Resistance and the
Insulin Resistance Syndrome
Sunday, July 26, 2009
What is Insulin Resistance?
Sunday, July 26, 2009
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;94:1714–17213. Bloomgarden ZT. Clin Ther 1998;20(2):216–2314. Comuzzie, A. G. and D. B. Allison Science 1998; 280(5368): 1374-7
Sunday, July 26, 2009
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;94:1714–17213. Bloomgarden ZT. Clin Ther 1998;20(2):216–2314. Comuzzie, A. G. and D. B. Allison Science 1998; 280(5368): 1374-7
Present in ~30-33% of the general population of the USA, but with marked ethnic differences
Sunday, July 26, 2009
Insulin Resistance Syndrome
Synonyms Metabolic syndrome (Metabolic) Syndrome X Dysmetabolic syndrome Reaven’s syndrome Multiple metabolic syndrome
Sunday, July 26, 2009
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
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.
Present in ~22% of the general population of the USA, but with marked ethnic variations
Sunday, July 26, 2009
Sunday, July 26, 2009
XObesity
High total and LDL-
cholesterol
HypertensionHighTriglycerides
Sunday, July 26, 2009
XInsulin Resistance
ObesityHigh total and LDL-
cholesterol
HypertensionHighTriglycerides
Ford, E. S., W. H. Giles, et al. JAMA 2002; 287(3): 356-9Sunday, July 26, 2009
Homeostatis Model Assessment (HOMA)
Hafner et al. Diabetes Care 1996; 1138-1141Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419
Sunday, July 26, 2009
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; 1138-1141Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
X5’10 217 poundsBMI = 31LDL cholesterol = 124
B/P = 150/90Triglycerides = 301
Glucose 103 mg/ml; Insulin Level: 47µU/ml
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
X5’10 217 poundsBMI = 31LDL cholesterol = 124
B/P = 150/90Triglycerides = 301
Insulin Resistance?
Glucose 103 mg/ml; Insulin Level: 47µU/ml
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
5’10 217 poundsBMI = 31
LDL cholesterol = 124
B/P = 150/90
Triglycerides = 301
XInsulin Resistance
Glucose 103 mg/ml; Insulin Level: 47µU/ml
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
Insulin resistance formula: Insulin (µU/ml) x glucose (mmol)
22.5
5’10 217 poundsBMI = 31
LDL cholesterol = 124
B/P = 150/90
Triglycerides = 301
XInsulin Resistance
Glucose in mg/ml Glucose in mmol
Glucose 103 mg/ml; Insulin Level: 47µU/ml
Sunday, July 26, 2009
Evaluating “Ed” for Syndrome X
Insulin resistance formula: Insulin (µU/ml) x glucose (mmol)
22.5
5’10 217 poundsBMI = 31
LDL cholesterol = 124
B/P = 150/90
Triglycerides = 301
XInsulin Resistance
Insulin resistance
Insulin Glucose
Glucose in mg/ml Glucose in mmol
__11.95__
( __47____ x __5.72__ ÷ 22.5 =
Glucose 103 mg/ml; Insulin Level: 47µU/ml
Sunday, July 26, 2009
Insulin Resistance and Insulin Resistance Syndrome Amongst Patients with Schizophrenia:
Results
Insulin Resistance
Insulin ResistanceSyndrome
Outpatients (n=98 )
70.3% 51.0%
General Population*
30-33% 25%
*American College of EndocrinologyLittrell, KH., Petty, RG., et al., NR 550; American Psychiatric Association Annual Meeting, San Francisco, May 21st, 2003
Sunday, July 26, 2009
Antipsychotic-Associated Differences in Insulin Sensitivity
Insulin Sensitivity by Medication: IVGTT with Minimal Model Analysis
Significant difference among treatment groups, P=0.0057
Henderson D. et al. Arch Gen Psychiatry 2005 ; 62:19-28
Insu
lin s
ensi
tivity
(X 1
0-4 • m
in-1
• ml-1
)
0
5
10
15
Clozapine Olanzapine Risperidone
Sunday, July 26, 2009
Antipsychotic-Associated Differences in Insulin Sensitivity
Insulin Sensitivity by Medication: IVGTT with Minimal Model Analysis
Significant difference among treatment groups, P=0.0057
Henderson D. et al. Arch Gen Psychiatry 2005 ; 62:19-28
Insu
lin s
ensi
tivity
(X 1
0-4 • m
in-1
• ml-1
)
0
5
10
15
Clozapine Olanzapine Risperidone
Sunday, July 26, 2009
Time to Diagnosis of Metabolic Syndrome in Patients With Acute Schizophrenia
L’Italien G. Preventive Med Manage Care. 2003;suppl 2:S38-S42.
0
5
10
15
20
25
0 120 14020 40 100 160 200180Days
AripiprazoleOlanzapinePlacebo
60 80
Cum
ulat
ive
Inci
denc
e (%
)
P=0.006
Sunday, July 26, 2009
Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR)
0
0.5
1
1.5
2
2.5
3
3.5
4
HOMA-IR
BaselineEndpoint
Sunday, July 26, 2009
Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR)
0
0.5
1
1.5
2
2.5
3
3.5
4
HOMA-IR
BaselineEndpoint
p = .04
Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City,May 2004
Sunday, July 26, 2009
Mean Change in Weight
25
27
29
31
BMI200
202
204
206
208
210
Weight (lbs.)
BaselineEndpoint
Sunday, July 26, 2009
Mean Change in Weight
25
27
29
31
BMI200
202
204
206
208
210
Weight (lbs.)
BaselineEndpoint
p = .02
p = .02
Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City,May 2004
Sunday, July 26, 2009
And Finally, Diabetes Mellitus Itself
Sunday, July 26, 2009
Types of Diabetes: Type 2
>90% of people with diabetes have type 2Usually insulin resistant with inadequate insulin
production to maintain normal glucose levelsOnset (usually gradual) at any age, usually >20 yearsUsually 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
Types of Diabetes: Type 2
Worldwide very high prevalence in rural to urban migrant communitiesAge at diagnosis falling rapidlyOften found in 3rd and 4th decade in Northern European
Whites, and even earlier in “High Risk” ethnic groupsSlight male preponderanceTo manage hyperglycaemia, oral medication may be
requiredFor metabolic control, insulin may be required
Sunday, July 26, 2009
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
Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes
Sunday, July 26, 2009
Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes
Insulin Resistance
CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver diseaseAdapted 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
Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes
Insulin Resistance
CompensatoryHyperinsulinemia
CVD
Insulin Resistance Syndrome
HypertensionStrokePCOSNAFLD
CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver diseaseAdapted 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
Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes
Insulin Resistance
CompensatoryHyperinsulinemia
Inadequate Insulin Response + β-cell failure
Type 2 Diabetes Mellitus CVD
Insulin Resistance Syndrome
RetinopathyNephropathyNeuropathy
HypertensionStrokePCOSNAFLD
Impaired Glucose Tolerance
CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver diseaseAdapted 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
Differentiation Between Insulin Resistance Syndrome and Type 2 Diabetes
Insulin Resistance
CompensatoryHyperinsulinemia
Inadequate Insulin Response + β-cell failure
Type 2 Diabetes Mellitus CVD
Insulin Resistance Syndrome
RetinopathyNephropathyNeuropathy
HypertensionStrokePCOSNAFLD
Impaired Glucose Tolerance
CVD= Coronary vascular disease; PCOS = Polycystic ovarian syndrome; NAFLD = Non-alcoholic fatty liver diseaseAdapted 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
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
Hyperglycemia And Psychiatric Disorders
Sunday, July 26, 2009
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, 1897Kraepelin, E. Dementia Praecox, Munich, 1919Lorenz, WF. Arch Neurol Psychiatry, 1922;8:184-196Diethelm, 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
Diabetes Mellitus and Serious Mental Illness
Sunday, July 26, 2009
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: 341-3442. McKee, et al, J Clin Hosp Pharmacology 1986; 11: 297-2993. Mukherjee, S., et al, Comp Psychiatry 1996; 37: 68-734. Hagg, et al, J Clin Psychiatry 1998; 59: 294-2995. Dixon, L., et al, Schizophrenia Bull 2000; 26: 903-9126. 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
Sunday, July 26, 2009
The Increased Prevalence of Type 2 Diabetes Associated with Mental
Illness is Not Confined to the Sufferers
Themselves
Sunday, July 26, 2009
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
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
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
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): 4953. Cheta, D., C. Dumitrescu, et al. 1990; Diabete Metab 16(1): 11-54. Erasmus, R. T., E. Blanco Blanco, et al. 2001; S Afr Med J 91(2): 157-605. Erasmus, R. T., E. Blanco Blanco, et al. 2001; Postgrad Med J 77(907): 323-56. Hagura, R., A. Matsuda, et al. 1994; Diabetes Res Clin Pract 24 Suppl: S69-73
Sunday, July 26, 2009
Visceral (Intra-abdominal) Fat Plays a Critical Role in the Development of Type 2
Diabetes Mellitus
Sunday, July 26, 2009
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
Visceral (Intra-abdominal) Fat Plays a Critical Role in the Development of Type 2
Diabetes Mellitus
Is there any evidence to suggest that patients with schizophrenia have increased visceral fat
distribution?
Since diabetes is considerably more common in patients
with schizophrenia and in their relatives
Sunday, July 26, 2009
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
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
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
BasalCorticosteroid
Release
Intra-Abdominal
FatInsulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
Stress
BasalCorticosteroid
Release
Intra-Abdominal
FatInsulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
Stress
BasalCorticosteroid
Release
Intra-Abdominal
FatInsulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
Stress
BasalCorticosteroid
Release
Intra-Abdominal
Fat
Release of FFA and TG
Stimulation of Pancreatic
Insulin Release
+
Reduced Insulin
Breakdown
Insulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
Stress
BasalCorticosteroid
Release
Intra-Abdominal
Fat
Release of FFA and TG
Stimulation of Pancreatic
Insulin Release
+
Reduced Insulin
Breakdown
Insulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance
Stress
BasalCorticosteroid
Release
Intra-Abdominal
Fat
Release of FFA and TG
Stimulation of Pancreatic
Insulin Release
+
Reduced Insulin
Breakdown
Insulin Levels
PeripheralInsulin
Resistance
Sunday, July 26, 2009
Conditions Associated With Hypercortisolaemia and Increased Visceral
Fat Distribution
1. Wajchenberg, B.L., et al., J Clin Endocrinol Metab, 1995; 80:2791-42. Thakore J.H., et al., Biol Psychiatry 1997; 41: 1140-11433. Weber, B., S. Lewicka, et al. 2000; J Clin Endocrinol Metab 85(3): 1133-64. Weber, B., U. Schweiger, et al. 2000; Exp Clin Endocrinol Diabetes 108(3): 187-905. Schafroth, U., K. Godang, et al. 2000; J Endocrinol Invest 23(6): 349-556. Masuzaki, H., J. Paterson, et al. 2001; Science 294(5549): 2166-707. Thakore, J. H, Mann, J.N., et al., International Journal of Obesity & Metabolism 2002; 26(1): 137-418. Bjorntorp, P. 1996; Int J Obes Relat Metab Disord 20(4): 291-3029. Groote Veldman, R. and A. E. Meinders 1996; Endocr Rev 17(3): 262-8
Melancholic depression1-4
Cushing’s syndrome5,6
Schizophrenia7
Alcoholic “Pseudo-Cushing’s syndrome” 8,9
Anorexia Nervosa
Sunday, July 26, 2009
Hyperglycemia and Older Antipsychotic Agents
Sunday, July 26, 2009
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
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
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
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
However….
Sunday, July 26, 2009
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
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
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
Ader, M., et al, Diabetes 2005; 54(3): 862-71
Sunday, July 26, 2009
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
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
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
Reports of Diabetes-Related EventsAmong “Atypical” Antipsychotic Agents
Clozapine1 Olanzapine2 Risperidone3 Quetiapine4
Surveillance period
New-onset diabetes
Exacerbation of diabetes
“Unclassified”
With “ketoacidosis”
1990-2001 1994-2001 1993-2001 1997-2002
323 188 78 46
54 44 46 34
7 5 7 8
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
FDA Warning: Hyperglycemia and Diabetes Mellitus
FDA. September 15, 2003.
Sunday, July 26, 2009
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
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
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
FDA Warning: Hyperglycemia and Diabetes Mellitus
FDA. September 15, 2003.
Sunday, July 26, 2009
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
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
Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes
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
Drug Weight Gain Risk for Diabetes
Worsening Lipid Profile
Clozapine +++ + +
Olanzapine +++ + +
Risperidone ++ D D
Quetiapine ++ D D
Aripiprazole +/- - -
Ziprasidone +/- - -(D= “Discrepant data”)
Sunday, July 26, 2009
Managing Metabolic Effects of Antipsychotic Agents
Sunday, July 26, 2009
Tuomilehto J et al. N Engl J Med 2001;344:1343–9
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6Year
Prob
abili
ty o
f not
hav
ing
diab
etes
Intervention
Control
Finnish DPS: Intensive Lifestyle Intervention Reduces Diabetes Risk by 58%
Sunday, July 26, 2009
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 Program Progression to Diabetes
Diabetes Prevention Research Group. N Engl J Med 2002; 346:393–403Sunday, July 26, 2009
BaseLine
4 wks 8 wks 12 wks Qtr Ann 5 yrs
Personal/ Family History
X X
Weight (BMI) X X X X X
Waist circumference
X X
Blood pressure X X X
Fasting plasma glucose
X X X
Fasting lipid profile
X X X
Monitoring Protocol for Patients on Second Generation Antipsychotics
Sunday, July 26, 2009
Sunday, July 26, 2009
Waist?
Sunday, July 26, 2009
Waist
Waist?
Sunday, July 26, 2009
XXXFasting lipid profile
XXXFasting plasma glucose
XXXBlood pressure
XXWaist circumference
XXXXXWeight (BMI)
XXPersonal/ Family History
5 yrsAnnualQtr12 wks8 wks4 wksBaseLine
Monitoring Protocol for Patients on Second Generation Antipsychotics
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
LDL > 100mg/dlHDL Men < 40mg/dLWomen < 50mg/dL
TG > 150mg/dL
Pre-diabetes: 100-125mg/dL
Diabetes: > 126mg/dL
>130/>85 mm Hg
Men > 40 inchesWomen > 35 inches
Overweight:25.0-29.9Obese > 30.0
Critical (“Action Needed”)
Values
XXXFasting lipid profile
XXXFasting plasma glucose
XXXBlood pressure
XXWaist circumference
XXXXXWeight (BMI)
XXPersonal/ Family History
5 yrsAnnualQtr12 wks8 wks4 wksBaseLine
Monitoring Protocol for Patients on Second Generation Antipsychotics
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
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
Clinical Features of Ketoacidosis
Sunday, July 26, 2009
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
Clinical Features of Ketoacidosis
Symptoms Thirst Polyuria Weight loss Nausea, vomiting,
diarrhoea, abdominal pain Precipitating event (e.g.
infection)
Signs Drowsiness and confusion Dehydration Hyperventilation Acetones on the breath Hypothermia Hypotension, tachycardia Shock Loss of consciousness
Sunday, July 26, 2009
Sunday, July 26, 2009
Insulin Resistance
Sunday, July 26, 2009
Insulin Resistance
Intra-Abdominal Obesity
Glucose Intolerance
CigaretteSmoking
Genetics
Aging
Medications
Fetal Malnutrition
Inactivity
Sunday, July 26, 2009
Insulin Resistance
Type 2 Diabetes
Intra-Abdominal Obesity
Glucose Intolerance
CigaretteSmoking
Genetics
Aging
Medications
Fetal Malnutrition
Inactivity
Sunday, July 26, 2009
Insulin Resistance
Type 2 Diabetes
Intra-Abdominal Obesity
Glucose Intolerance
CigaretteSmoking
Genetics
Aging
Medications
Fetal Malnutrition
Inactivity
Dyslipidemias
Polycystic Ovary
Syndrome
Endothelial Dysfunction
Hypertension
?CertainMalignancies
Microalbuminuria
Macrovascular Disease
Dysfibrinolysis
Other Metabolic Effects: e.g.
Hyperuricemia
QTcProlongation
Non Alcoholic Fatty Liver
Disease
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
1. Carbohydrate Craving
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
1. Carbohydrate Craving2. Insulin Resistance
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
1. Carbohydrate Craving2. Insulin Resistance3. Hypercortisolaemia
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
1. Carbohydrate Craving2. Insulin Resistance3. Hypercortisolaemia
How can we use this knowledge in practice?
Sunday, July 26, 2009
The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill
1. Carbohydrate Craving2. Insulin Resistance3. 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
The Three Steps
Sunday, July 26, 2009
The Three Steps 1. An appropriate psychoeducational program
Solutions for Wellness Other programs
Sunday, July 26, 2009
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
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
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
Useful Addresses
www.RichardGPettyMD.com
www.RichardGPettyMD.blogs.com
www.Healia.com
Sunday, July 26, 2009