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,

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

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

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

Is Schizophrenia a Systemic Illness?

Abnormalities throughout the body: Neuromuscular:

Histological1,3,4

Electrophysiological2-4

Changes in cell membrane fatty acid composition5

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

Enhanced activity of phospholipase A21,2

leading to: Disturbed membrane phospholipid metabolism

in: Brain3,4

Periphery5

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

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

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

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

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

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.

The Pandemic of Overweight and Obesity

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%

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)

Five “Other” Potential Contributors to Weight Gain

Stress1

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.

Body Mass Index Status and Diabetes Risk

22-22.9

23-23.9

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

Body Mass Index

Colditz et al. Ann Intern Med. 1995;122:481Sunday, July 26, 2009

Body Mass Index Status and Diabetes Risk

22-22.9

23-23.9

24-24.9

25-26.9

27-28.9

29-30.9

31-32.9

33-34.9

Body Mass Index

Colditz et al. Ann Intern Med. 1995;122:481Sunday, 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

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

All Fat is Not Equal

Lower body fat Upper body fat “Gynecoid” “Android”

Type 2 Diabetes Mellitus

“A Horizontally ChallengingCondition”

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

Overweight and Obesity in the Mentally Ill

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

BMI Distributions1989 National Health Interview Survey

<18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34

Without schizophrenia

With schizophrenia

Body mass index

Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220.

BMI Distributions1989 National Health Interview Survey

<18.5 18.5–20 20–22 22–24 24–26 26–28 28–30 30–32 32–34 >34

Without schizophrenia

With schizophrenia

Under-weight

Acceptable Overweight Obese

Body mass index

Allison, D.B. et al., J Clin Psychiatry 1999;60:215–220.

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

Polypharm

Risperi

Chlorpro

mazine

Olanza

Clozapine

Quetiap

Thioridaz

Mesorid

Placeb

Molindone

Fluphenaz

Ziprasidone

Aripipraz

Why Do Patients Gain Weight with Some Antipsychotics?

Potential Mechanisms of

Weight Gain

Reduction in Basal Metabolic Rate

Actions on the lateral and ventromedial

hypothalamus

Weight Gain

hypothalamus

Weight Gain

Insulin Resistance

hypothalamus

Weight Gain

Insulin Resistance

Release of TNF-αand other cytokines

hypothalamus

Weight Gain

Insulin Resistance

Reduction in akathisia

hypothalamus

Weight Gain

Insulin Resistance

Changes in sensitivity to the hormone leptin

Antagonism of H1 and 5HT2c receptors

hypothalamus

Weight Gain

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

Changes in sensitivity to the hormone leptin

Insulin Resistance and the

Insulin Resistance Syndrome

What is Insulin Resistance?

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

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

Synonyms Metabolic syndrome (Metabolic) Syndrome X Dysmetabolic syndrome Reaven’s syndrome Multiple metabolic syndrome

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.

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

XObesity

High total and LDL-

cholesterol

HypertensionHighTriglycerides

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

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

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

X5’10 217 poundsBMI = 31LDL cholesterol = 124

B/P = 150/90Triglycerides = 301

Insulin Resistance?

5’10 217 poundsBMI = 31

LDL cholesterol = 124

B/P = 150/90

Triglycerides = 301

XInsulin Resistance

Insulin resistance formula: Insulin (µU/ml) x glucose (mmol)

5’10 217 poundsBMI = 31

B/P = 150/90

Triglycerides = 301

XInsulin Resistance

Glucose in mg/ml Glucose in mmol

Insulin resistance formula: Insulin (µU/ml) x glucose (mmol)

5’10 217 poundsBMI = 31

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 =

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

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

tivity

0-4 • m

• ml-1

Clozapine Olanzapine Risperidone

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

tivity

0-4 • m

• ml-1

Clozapine Olanzapine Risperidone

Time to Diagnosis of Metabolic Syndrome in Patients With Acute Schizophrenia

L’Italien G. Preventive Med Manage Care. 2003;suppl 2:S38-S42.

0 120 14020 40 100 160 200180Days

AripiprazoleOlanzapinePlacebo

P=0.006

Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR)

HOMA-IR

BaselineEndpoint

Mean Changes in Homeostasis Model Assessment Insulin Resistance (HOMA-IR)

HOMA-IR

BaselineEndpoint

p = .04

Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City,May 2004

Mean Change in Weight

BMI200

Weight (lbs.)

BaselineEndpoint

Mean Change in Weight

BMI200

Weight (lbs.)

BaselineEndpoint

p = .02

Littrell, KH., Petty, RG., et al. NR 602. American Psychiatric Association Annual Meeting, New York City,May 2004

And Finally, Diabetes Mellitus Itself

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

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

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

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

Insulin Resistance

CompensatoryHyperinsulinemia

HypertensionStrokePCOSNAFLD

Insulin Resistance

Inadequate Insulin Response + β-cell failure

Type 2 Diabetes Mellitus CVD

RetinopathyNephropathyNeuropathy

Impaired Glucose Tolerance

Insulin Resistance

Inadequate Insulin Response + β-cell failure

Type 2 Diabetes Mellitus CVD

RetinopathyNephropathyNeuropathy

Impaired Glucose Tolerance

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…….

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

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

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”

Themselves

“ Diabetes is a disease which often shows itself in families in which insanity prevails”

Sir Henry Maudsley, The Pathology of Mind, London, 1897.

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

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

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

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

CT Scan of Intra-Abdominal Fat

Thakore, J. H, Mann, J.N., et al., International Journal of Obesity & Metabolism 2002; 26(1): 137-41

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

Intrapsychic or Environmental Stress Can Lead to Increased Insulin Resistance

BasalCorticosteroid

Release

Intra-Abdominal

FatInsulin Levels

PeripheralInsulin

Resistance

Stress

BasalCorticosteroid

Release

Intra-Abdominal

FatInsulin Levels

PeripheralInsulin

Resistance

Stress

BasalCorticosteroid

Release

Intra-Abdominal

FatInsulin Levels

PeripheralInsulin

Resistance

Stress

BasalCorticosteroid

Release

Intra-Abdominal

Release of FFA and TG

Stimulation of Pancreatic

Insulin Release

Reduced Insulin

Breakdown

Insulin Levels

PeripheralInsulin

Resistance

Stress

BasalCorticosteroid

Release

Intra-Abdominal

Insulin Release

Reduced Insulin

Breakdown

Insulin Levels

PeripheralInsulin

Resistance

Stress

BasalCorticosteroid

Release

Intra-Abdominal

Insulin Release

Reduced Insulin

Breakdown

Insulin Levels

PeripheralInsulin

Resistance

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

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.

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

Fluperlapine2,3

Clozapine4-8

Olanzapine7-10

Quetiapine10,11

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

Fluperlapine2,3

Clozapine4-8

Olanzapine7-10

Quetiapine10,11

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….

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

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.

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

Decreasing Insulin Sensitivity (i.e. Increasing Hepatic Insulin Resistance) in Dogs Exposed to Some Antipsychotic Agents

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.

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.

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.

FDA Warning: Hyperglycemia and Diabetes Mellitus

FDA. September 15, 2003.

“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 …”

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

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

Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes

Drug Weight Gain Risk for Diabetes

Worsening Lipid Profile

Clozapine +++ + +

Olanzapine +++ + +

Risperidone ++ D D

Quetiapine ++ D D

Aripiprazole +/- - -

Ziprasidone +/- - -(D= “Discrepant data”)

Managing Metabolic Effects of Antipsychotic Agents

Tuomilehto J et al. N Engl J Med 2001;344:1343–9

0 1 2 3 4 5 6Year

Intervention

Control

Finnish DPS: Intensive Lifestyle Intervention Reduces Diabetes Risk by 58%

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

Weight (BMI) X X X X X

Waist circumference

Blood pressure X X X

Fasting plasma glucose

Fasting lipid profile

Monitoring Protocol for Patients on Second Generation Antipsychotics

Waist?

XXXFasting lipid profile

XXXFasting plasma glucose

XXXBlood pressure

XXWaist circumference

XXXXXWeight (BMI)

XXPersonal/ Family History

5 yrsAnnualQtr12 wks8 wks4 wksBaseLine

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

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.

Clinical Features of Ketoacidosis

Signs Drowsiness and confusion Dehydration Hyperventilation Acetones on the breath Hypothermia Hypotension, tachycardia Shock Loss of consciousness

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

Insulin Resistance

Intra-Abdominal Obesity

Glucose Intolerance

CigaretteSmoking

Genetics

Medications

Fetal Malnutrition

Inactivity

Insulin Resistance

Type 2 Diabetes

Glucose Intolerance

CigaretteSmoking

Genetics

Medications

Fetal Malnutrition

Inactivity

Insulin Resistance

Type 2 Diabetes

Glucose Intolerance

CigaretteSmoking

Genetics

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

The Fundamental Issues in Managing Metabolic Problems in the Mentally Ill

1. Carbohydrate Craving

1. Carbohydrate Craving2. Insulin Resistance

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?

The Three Steps

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)

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

Useful Addresses

www.RichardGPettyMD.com

www.RichardGPettyMD.blogs.com

rpettyus@aol.com

www.Healia.com

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