Antipsychotics, Psychotic Illnesses Antipsychotics, Psychotic Illnesses and Cardiovascular Diseaseand Cardiovascular Disease

Stephen R. Marder, MDSemel Institute of Neuroscience at UCLA

VA Desert Pacific Mental Illness Research, Education, and Clinical Center

MIAMI Conf 5/18/10

Disclosure Information for Disclosure Information for Stephen R. Marder, MDStephen R. Marder, MD

• Advisory board– Wyeth; Schering; Bristol-Myers Squibb Company; Otsuka

America Pharmaceutical, Inc.• Speaker

– Bristol-Myers Squibb Company; Otsuka America Pharmaceutical, Inc.

Antipsychotics, Psychotic Illnesses, Antipsychotics, Psychotic Illnesses, Cardiovascular DiseasesCardiovascular Diseases

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

SMR = standardized mortality ratio (observed/expected deaths).

1. Harris et al. Br J Psychiatry. 1998;173:11.2. Osby et al. Arch Gen Psychiatry. 2001;58:844-850.3. Osby et al. BMJ. 2000;321:483-484.

Increased Mortality Rates for Medical Increased Mortality Rates for Medical Disorders in Mental Illness 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

Year of life lostYear of life lost

Schizophrenia, antipsychotics, and Schizophrenia, antipsychotics, and mortalitymortalityJoukamaa et al Brit J Psychiatry 2006Joukamaa 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

Cardiovascular risk factors Cardiovascular risk factors –– overviewoverview

BMI = body mass index; TC = total cholesterol; DM = diabetes mellitus; HTN = hypertension.Wilson PWF et al. Circulation. 1998;97:1837–1847.

0

2

4

6

8

10

12

14

HTNDMSmokingBMI >27 TC >220

Single Risk Factors

Multiple Risk Factors

Od

ds

rati

os

Smoking+ BMI

2

Smoking+ BMI

+ TC >220

3

Smoking+ BMI

+ TC >220+ DM

4

Smoking+ BMI

+ TC >220+ DM + HTN

5The Framingham Study

““Body Mass Index” (BMI) is anBody Mass Index” (BMI) is an Indicator of Weight Status Indicator of Weight Status

• A ratio taking into account an individual’sweight (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

Obesity Has Become More CommonObesity Has Become More Commonin the United Statesin the United States

Risk of Death Increases with BMIRisk of Death Increases with BMI

Waist Circumference and BMI IncreaseWaist Circumference and BMI Increasethe Risk of Diabetes, Hypertension,the Risk of Diabetes, Hypertension,

and Cardiovascular Diseaseand Cardiovascular Disease

BMI Waistmen ≤ 40 inches

women ≤ 35 inches

Waist> 40 inches> 35 inches

Underweight < 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

1. NCEP ATP III. JAMA.. 2001;285:2486-2497.

The Metabolic SyndromeThe Metabolic Syndrome

Risk Factor Defining Factor

Abdominal obesity Waist circumference

Men >40 in (>102 cm)

Women >35 in (>88 cm)

Triglycerides 150 mg/dL

HDL-C

Men <40 mg/dL

Women <50 mg/dL

Blood Pressure 130/85 mm Hg

Fasting Glucose 110 mg/dL

CHD risk increases with increasing number of CHD risk increases with increasing number of metabolic syndrome risk factorsmetabolic syndrome risk factors

00.5

11.5

22.5

33.5

44.5

55.5

66.5

7

one two three four

Rel

ativ

e R

isk

Sattar et al, Circulation, 2003;108:414-419Whyte et al, American Diabetes Association, 2001Adapted from Ridker, Circulation 2003;107:393-397Adapted from Ridker, Circulation 2003;107:393-397

Adiposity and Medical DiseasesAdiposity and Medical Diseases

Calle EE, Thun MJ, Petrelli JM, et al. N Engl J Med. 1999(Oct 7);341(15):1097-1105Calle EE, Thun MJ, Petrelli JM, et al. N Engl J Med. 1999(Oct 7);341(15):1097-1105

Body Mass IndexWomen

Body Mass IndexWomen

Body Mass IndexMen

Body Mass IndexMen

Rel

ativ

e R

isk

Rel

ativ

e R

isk

6

5

4

3

2

1

021 22 23 24 25 26 27 28 29 30

6

5

4

3

2

1

021 22 23 24 25 26 27 28 29 30

Type 2 DMCholelithiasis

HypertensionCoronary heart disease

18

Body Mass Index (BMI) And Relative Body Mass Index (BMI) And Relative Risk Of Type 2 DiabetesRisk Of Type 2 Diabetes

In women age 35-55 years in 1976; data adjusted for age.Adapted from Colditz et al. Am J Epidemiol. 1990;132:501-513.

BMI (kg/m2)

0

10

20

30

40

50

60

<22 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

70

Ad

just

ed R

elat

ive

Ris

k

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Insulin resistance

Hepatic glucose production

Endogenous insulin

Postprandial blood glucose

Fasting blood glucose

Typical Diagnosis of Diabetes

Microvascular ComplicationsMicrovascular Complications

Macrovascular ComplicationsMacrovascular Complications

Severity of Diabetes

Impaired Glucose Tolerance Frank Diabetes

Years to DecadesTime

Ramlo-Halsted BA, Edelman SV. Primary Care. 1999; 26: 771–789.

AsymptomaticStage

Obesity and Insulin ResistanceObesity and Insulin Resistance

Lipolytically Active Abdominal Adipose Tissue

GlucoseUtilization

Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.Caballero AE. Obesity Res. 2003;11:1278-1289.Reaven GM. Diabetes. 1988;37:1595-1607.

Hyperglycemia and Dyslipidemia

Adipose Tissue

Inhibition of

Lipolysis

Glucose Output

Adipose Tissue

Skeletal Muscle

Liver

Insulin ResistanceInsulin Resistance

““Inadequate” Inadequate” Insulin ResponseInsulin Response

CompensatoryCompensatoryHyperinsulinemiaHyperinsulinemia

Type 2 DiabetesType 2 Diabetes Insulin Resistance Insulin Resistance SyndromeSyndrome

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

HypertensionHypertensionPolycystic OvarianPolycystic Ovarian

SyndromeSyndrome

Non-Alcoholic FattyNon-Alcoholic FattyLiver DiseaseLiver Disease

CancerCancer

Sleep Breathing DisorderSleep Breathing Disorder

Cardio-vascularDisease(CVD)

Steinberg HO, Baron AD. Diabetologia. 2002;45:623-634.Caballero AE. Obesity Res. 2003;11:1278-1289.

Reaven GM. Diabetes. 1988;37:1595-1607.

Cognitive DysfunctionCognitive Dysfunction

Effects of 8 days of olanzapine Effects of 8 days of olanzapine treatment (Vidarsdotter et al 2010)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

Is This Just an Issue With Second Is This Just an Issue With Second Generation Antipsychotics (SGA’s)?Generation Antipsychotics (SGA’s)?

• Probably not• Early report from 1956 describes

hyperglycemia in 5 patients treated with chlorpromazine.

• Reports from the 1960’s describe increased prevalence of diabetes following introduction of chlorpromazine.

Glucose Tolerance in 1st Episode, Glucose Tolerance in 1st Episode, Drug Naive PatientsDrug Naive Patients

• Measured fasting glucose, insulin, lipids, in schizophrenia pts (n=26) and controls (n=26). Pts had normal BMI’s

• Schizophrenia pts had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl vs 95.8), insulin (mean=7.7vs 9.8 micro u/ml, SD=3.9).

• Pts were more insulin resistant, as measured with homeostasis model assessment

Ryan et al, Am J Psychiatry, 2003

ADA Consensus on Antipsychotic Drugs: Metabolic ADA Consensus on Antipsychotic Drugs: Metabolic Abnormalities of Second-Generation AntipsychoticsAbnormalities of Second-Generation Antipsychotics

DrugWeight

GainRisk 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. 2004;27:596.

Psychotropic-Associated Weight GainPsychotropic-Associated Weight Gain

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. 1980;2:303-310. 2. Bowden CL, et al. Arch Gen Psychiatry. 2000;57:481-489. 3. Adapted from: Prescribing Information. Physicians’ Desk Reference. 59th ed. Montvale, NJ: Medical Economics Co; 2005.

• 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 SGA’s

• Clozapine associated with the lowest mortality; Quetiapine with the highest

• A longer duration of antipsychotic use associated with lower mortality

Risk of Death for Any CauseRisk of Death for Any CauseTiihonen et al, 2009Tiihonen et al, 2009

Hennekens CH. Circulation. 1998;97:1095-1102.

Goals: Lower Risk for CVDGoals: Lower Risk for CVD

• Blood cholesterol – 10% = 30% in CHD (200-180)

• High blood pressure (> 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

Physical Health Monitoring for the Physical Health Monitoring for the Severely Mentally IllSeverely Mentally Ill

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

Guidelines for MonitoringGuidelines 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 >130mg/dL

Adapted from: Diabetes Care, Vol 27, No 1, February 2004. Am J Psychiatry. 161:2, February 2004 Supplement. Marder SR, et al. Am J Psychiatry. 2004; 161:1334-1349.Adapted from: Diabetes Care, Vol 27, No 1, February 2004. Am J Psychiatry. 161:2, February 2004 Supplement. Marder SR, et al. Am J Psychiatry. 2004; 161:1334-1349.

SummarySummary

• 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.

Summary (cont)Summary (cont)

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