Antipsychotics, Psychotic Illnesses and Cardiovascular Disease

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Antipsychotics, Psychotic Illnesses and
Cardiovascular Disease

• Stephen R. Marder, MD
• Semel Institute of Neuroscience at UCLA
• VA Desert Pacific Mental Illness Research,
  Education, and Clinical Center
• MIAMI Conf 5/18/10

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Disclosure Information for Stephen R. Marder, MD

• Advisory board
• Wyeth Schering Bristol-Myers Squibb Company
  Otsuka America Pharmaceutical, Inc.
• Speaker
• Bristol-Myers Squibb Company Otsuka America
  Pharmaceutical, Inc.

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Antipsychotics, Psychotic Illnesses,
Cardiovascular Diseases

• Risk of Premature Death
• Risk of heart disease in SMI patients
• Modifiable risk factors for heart disease

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Increased Mortality Rates for Medical Disorders
in Mental Illness

• 50 increased risk of death from medical causes
  in schizophrenia, and 20 shorter lifespan1
• Bipolar and unipolar affective disorders also
  associated with higher SMRs from medical causes2
• 1.9 males/2.1 females in bipolar disorder
• 1.5 males/1.6 females in unipolar disorder
• Cardiovascular mortality in schizophrenia
  increased from 1976-1995, with greatest increase
  in SMRs (8.3 males/5.0 females) from 1991-19953

• SMR standardized mortality ratio
  (observed/expected deaths).
• Harris et al. Br J Psychiatry. 199817311.
• 2. Osby et al. Arch Gen Psychiatry.
  200158844-850.
• 3. Osby et al. BMJ. 2000321483-484.

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Year of life lost
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Schizophrenia, antipsychotics, and
mortalityJoukamaa et al Brit J Psychiatry 2006

• 17 year follow-up of 7217 Finns
• Relative Mortality Risk (RR) for Schizophrenia
  was 2.84
• Controlling for factors such as HBP, BMI, ETOH,
  smoking, RR was 2.25
• Risk increased when antipsychotics combined

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Cardiovascular risk factors overview
The Framingham Study
BMI body mass index TC total cholesterol DM
diabetes mellitus HTN hypertension. Wilson
PWF et al. Circulation. 19989718371847.
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Body Mass Index (BMI) is an Indicator of
Weight Status

• A ratio taking into account an individualsweight
  (kilograms), and height (meters squared)
• kg / m2

With a BMI of You are
below 19 Underweight
19 - 24 Healthy Weight
25 - 29 Overweight
30 or higher Obese
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Obesity Has Become More Commonin the United
States
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Risk of Death Increases with BMI
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Waist Circumference and BMI Increasethe Risk of
Diabetes, Hypertension,and Cardiovascular Disease
BMI Waist men 40 inches women 35 inches Waist gt 40 inches gt 35 inches
Underweight lt 18.5 - -
Normal 18.5 24.9 - -
Overweight 25.0 29.9 Increased High
Obese 30.0 34.9 35.0 39.9 High Very High Very High Very High
Extremely Obese 40 Extremely High Extremely High
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The Metabolic Syndrome
Risk Factor Defining Factor
Abdominal obesity Waist circumference
Men gt40 in (gt102 cm)
Women gt35 in (gt88 cm)
Triglycerides ³150 mg/dL
HDL-C
Men lt40 mg/dL
Women lt50 mg/dL
Blood Pressure ³130/85 mm Hg
Fasting Glucose ³110 mg/dL
1. NCEP ATP III. JAMA.. 20012852486-2497.
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CHD risk increases with increasing number of
metabolic syndrome risk factors
Sattar et al, Circulation, 2003108414-419 Whyte
et al, American Diabetes Association,
2001 Adapted from Ridker, Circulation
2003107393-397
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Adiposity and Medical Diseases
Calle EE, Thun MJ, Petrelli JM, et al. N Engl J
Med. 1999(Oct 7)341(15)1097-1105
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Body Mass Index (BMI) And Relative Risk Of Type 2
Diabetes
70
60
50
40
Adjusted Relative Risk
30
20
10
0
lt22 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
BMI (kg/m2)
In women age 35-55 years in 1976 data adjusted
for age. Adapted from Colditz et al. Am J
Epidemiol. 1990132501-513.
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Natural History of Type 2 Diabetes
Severity of Diabetes
Impaired Glucose Tolerance
Frank Diabetes
Insulin resistance Hepatic glucose
production Endogenous insulin
Postprandial blood glucose Fasting blood glucose
Asymptomatic Stage
Microvascular Complications
Macrovascular Complications
Years to Decades
Typical Diagnosis of Diabetes
Time
Ramlo-Halsted BA, Edelman SV. Primary Care. 1999
26 771789.
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Obesity and Insulin Resistance
GlucoseUtilization
Lipolytically Active Abdominal Adipose Tissue
Skeletal Muscle
Inhibition of Lipolysis
Adipose Tissue
Adipose Tissue
Glucose Output
Liver
Hyperglycemia and Dyslipidemia
Steinberg HO, Baron AD. Diabetologia.
200245623-634. Caballero AE. Obesity Res.
2003111278-1289. Reaven GM. Diabetes.
1988371595-1607.
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Insulin Resistance
Inadequate Insulin Response
Compensatory Hyperinsulinemia
Type 2 Diabetes
Insulin Resistance Syndrome
Cardio- vascular Disease (CVD)
Hypertension Polycystic Ovarian Syndrome Non-Alco
holic Fatty Liver Disease Cancer Sleep Breathing
Disorder
Retinopathy Nephropathy Neuropathy
Cognitive Dysfunction
Steinberg HO, Baron AD. Diabetologia.
200245623-634. Caballero AE. Obesity Res.
2003111278-1289. Reaven GM. Diabetes.
1988371595-1607.
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Effects of 8 days of olanzapine treatment
(Vidarsdotter et al 2010)

• 12 healthy men received 1 of 2 oral formulations
  of olanzapine or placebo for 8 days.
• Olanzapine treatment led to increased insulin
  resistance and increased fasting and
  post-prandial triglycerides. These effects were
  independent on diet and physical activity

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Is This Just an Issue With Second Generation
Antipsychotics (SGAs)?

• Probably not
• Early report from 1956 describes hyperglycemia in
  5 patients treated with chlorpromazine.
• Reports from the 1960s describe increased
  prevalence of diabetes following introduction of
  chlorpromazine.

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Glucose Tolerance in 1st Episode, Drug Naive
Patients

• Measured fasting glucose, insulin, lipids, in
  schizophrenia pts (n26) and controls (n26).
  Pts had normal BMIs
• Schizophrenia pts had significantly higher
  fasting plasma levels of glucose (mean88.2 mg/dl
  vs 95.8), insulin (mean7.7vs 9.8 micro u/ml,
  SD3.9).
• Pts were more insulin resistant, as measured with
  homeostasis model assessment

Ryan et al, Am J Psychiatry, 2003
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ADA Consensus on Antipsychotic Drugs Metabolic
Abnormalities of Second-Generation Antipsychotics
Drug Weight Gain Risk for Diabetes Worsening Lipid Profile
Clozapine
Olanzapine
Risperidone D D
Quetiapine D D
Aripiprazole /
Ziprasidone /
increased effect no effect D
discrepant results. Newer drugs with limited
long-term data. American Diabetes Association et
al. Diabetes Care. 200427596.
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Psychotropic-Associated Weight Gain
Data from Pivotal Trials Data from Pivotal Trials Data from Pivotal Trials Data from Pivotal Trials
Agents 5 Weight Gain Length Mean Change
Lithium1 62 1 year 4.0 kg
Valproate2 21 1 year Not reported
Agents 7 Weight Gain Length Mean Change
Olanzapine3 29 6 weeks 2.8 kg
Quetiapine3 21 6 weeks 2.6 kg
Risperidone3 18 6 weeks 1.6 kg
FDA US Food and Drug Administration N/R not
reported. Weight gain was stratified according
to BMI. 1. Peselow ED, et al. J Affect Disord.
19802303-310. 2. Bowden CL, et al. Arch Gen
Psychiatry. 200057481-489. 3. Adapted from
Prescribing Information. Physicians Desk
Reference. 59th ed. Montvale, NJ Medical
Economics Co 2005.
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• Compared mortality among 66,881 patients and the
  population of Finland (5.2 million) between 1996
  and 2006
• Life expectancy for schizophrenia did not decline
  as more patients were treated with SGAs
• Clozapine associated with the lowest mortality
  Quetiapine with the highest
• A longer duration of antipsychotic use associated
  with lower mortality

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Risk of Death for Any CauseTiihonen et al, 2009
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Goals Lower Risk for CVD

• Blood cholesterol
• 10 ? 30 ? in CHD (200-180)
• High blood pressure (gt 140 SBP or 90 DBP)
• 4-6 mm Hg ? 16 ? in CHD 42 ? in stroke
• Cigarette smoking cessation
• 50-70 ? in CHD
• Maintenance of ideal body weight (BMI 25)
• 35-55 ? in CHD
• Maintenance of active lifestyle (20-min walk
  daily)
• 35-55 ? in CHD

Hennekens CH. Circulation. 1998971095-1102.
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Physical Health Monitoring for the Severely
Mentally Ill

• Where should it occur?
• Who should monitor?
• What should be monitored and how often?

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Guidelines for Monitoring
Monitoring APA ADA/APA Mt. Sinai
Body weight and height BMI every visit for 6 months quarterly thereafter BMI at baseline every 4 weeks for the 12 weeks quarterly thereafter BMI at baseline at every visit for next 6 mos quarterly when stable
Fasting plasma glucose Fasting blood glucose at baseline. Fasting plasma glucose or HbA1c at 4 months after initiating new treatment and annually thereafter Fasting plasma glucose at baseline, 12 weeks and annually thereafter Fasting plasma glucose or HbA1c before initiating an antipsychotic, annually thereafter
Lipid panel At least every 5 years Baseline at 12 weeks every 5 years Every 2 years or more often if levels are in the normal range and every 6 months if LDL levels are gt130mg/dL
Adapted from Diabetes Care, Vol 27, No 1,
February 2004. Am J Psychiatry. 1612, February
2004 Supplement. Marder SR, et al. Am J
Psychiatry. 2004 1611334-1349.
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Summary

• Antipsychotic are associated with increased
  mortality
• Patients with Serious Mental Illnesses are at a
  high risk for Metabolic Syndrome and
  cardiovascular disease
• Monitoring of modifiable risk factors should take
  place in either a primary care or mental health
  setting.

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Summary (cont)

• This often means it will be the psychiatric
  setting by default

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