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


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


 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


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: 191-208
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



 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: 495-501
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


 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


 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



 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: 3-7
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


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. 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

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

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.


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

Potential Causes of Impaired Fasting
Glucose


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


Glucose

But


Glucose

But
1. Several other important genetic and environmental
factors usually need to be present3


Glucose

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


All Fat is Not Equal

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

vs


Type 2 Diabetes Mellitus

“A Horizontally
Challenging
Condition”


Role of Obesity in Insulin Resistance, Insulin
Resistance Syndrome and Type 2 Diabetes Mellitus


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

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”



“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 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.

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.

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

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*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.

Why Do Patients Gain Weight with Some Antipsychotics?



Potential
Mechanisms of
Weight Gain



Reduction in Basal
Metabolic Rate

Potential
Mechanisms of
Weight Gain



Reduction in Basal
Metabolic Rate Actions on the lateral
and ventromedial
hypothalamus

Potential
Mechanisms of
Weight Gain



Reduction in Basal
Metabolic Rate Actions on the lateral
and ventromedial
hypothalamus

Potential
Mechanisms of
Weight Gain

Insulin Resistance



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



Reduction in Basal
hypothalamus

Reduction in Potential
akathisia
Mechanisms of
Weight Gain

Insulin Resistance



Reduction in Basal
hypothalamus

Reduction in Potential
akathisia
Mechanisms of
Weight Gain

Insulin Resistance Changes in sensitivity
to the hormone leptin



Reduction in Basal
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


Insulin Resistance
and the
Insulin Resistance Syndrome


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

 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

Insulin Resistance Syndrome
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)

Present in ~22% of the general population of the USA, but with marked
ethnic variations

NCEP ATP III. Circulation. 2002;106;3143.


X
High total
and LDL- Obesity
cholesterol

High
Hypertension
Triglycerides


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

Homeostatis Model Assessment (HOMA)

Hafner et al. Diabetes Care 1996; 1138-1141
Mathews 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; 1138-1141
Mathews DR, Hoskeer JP, et al. Diabetologia, 1985; 28:412-419

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


X
5’10 217 pounds
LDL cholesterol = 124 BMI = 31

Insulin Resistance?

Triglycerides = 301 B/P = 150/90


5’10 217
LDL cholesterol = pounds

X
124 BMI = 31

Insulin Resistance

Triglycerides = B/P =
301 150/90




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




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



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

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


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.


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


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

Mean Change in Weight

31 210

208
29
206
Baseline
Endpoint
204
27
202

25 200
BMI Weight (lbs.)


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

And Finally, Diabetes Mellitus
Itself


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


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


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


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

Type 2 Diabetes
Insulin Resistance

Compensatory
Hyperinsulinemia

Insulin Resistance
Syndrome

CVD

Hypertension
Stroke
PCOS
NAFLD


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


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


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


Diabetes Mellitus and Serious Mental
Illness


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


The Increased Prevalence of Type 2
Diabetes Associated with Mental
Illness is
Not Confined to the Sufferers
Themselves


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


Illness is
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): 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


Visceral (Intra-abdominal) Fat Plays a
Critical Role in the Development of Type 2
Diabetes Mellitus


Diabetes Mellitus
Since diabetes is considerably
more common in patients
with schizophrenia and in their relatives


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?


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

Basal Intra- Peripheral
Corticosteroid Abdominal Insulin
Insulin
Release Fat Levels
Resistance



Stress

Insulin
Release Fat Levels
Resistance



Stimulation
Release of Pancreatic
of FFA Insulin
and TG Release
+
Stress Reduced
Insulin
Breakdown

Insulin
Release Fat Levels
Resistance


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


Hyperglycemia and Older Antipsychotic Agents


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


 Loxapine1
 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


 Loxapine1
 Fluperlapine2,3
 Clozapine4-8
 Olanzapine7-10
 Quetiapine10,11
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



 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 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.


FDA Warning:
Hyperglycemia and Diabetes Mellitus

FDA. September 15, 2003.

FDA Warning:
 “Hyperglycemia, in some cases extreme and associated with
ketoacidosis or hyperosmolar coma or death, has been reported in
patients treated with atypical antipsychotics …


FDA Warning:
 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 Warning:
 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 Warning:
 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 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


Managing Metabolic Effects of
Antipsychotic Agents


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

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

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


Waist?


Waist
Waist?


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


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


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 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


Insulin
Resistance


Intra-Abdominal Inactivity Glucose
Genetics Medications
Obesity Intolerance

Cigarette
Smoking
Aging

Fetal
Malnutrition

Insulin
Resistance


Obesity Intolerance

Cigarette
Smoking
Aging

Fetal
Malnutrition

Insulin
Resistance

Type 2
Diabetes


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


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?



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


The Three Steps
 Other programs
 2. A specific dietary strategy
 Insulin resistance diets initially, followed by more carefully balanced diets


The Three Steps
 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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