Alex J Mitchell University of Leicester (UK) Acknowledgements Davy Vancampfort, Belgium Marc De Hert, Belgium Weight Gain, Diabetes.

Alex J Mitchell www.psycho-oncology.info

University of Leicester (UK)

AcknowledgementsDavy Vancampfort, BelgiumMarc De Hert, Belgium

Weight Gain, Diabetes and Metabolic Problems

in Patients prescribed Atypical Antipsychotics

Online Information Oct 2011. Only use these slides for personal use and/or with credit to the author

I. Background

What are Severe Mental Health problems?

These usually include

Schizophrenia and related disorders

Bipolar Affective Disorder (prev known as manic-depression)

Severe depression

These conditions are sometimes collectively called “SMI” and tend to be the ones where are antipsychotic is prescribed

Is there Accelerated mortality in SMI?

Yes, there is premature mortality by 20 years on average

This “mortality gap” has been increasing, as shown over….

Schizophrenia –Standardized Mortality Ratio

Pooled estimate=2.50 (95% CI=2.18-2.83)

>

>>>

Saha Arch Gen Psychiatry. 2007 Oct;64(10):1123-31.

*Controlling for age at first diagnosis and years of follow-up**Standardised by the sex and age distribution of the patients Data from Osby et al 2000

Mortality trends in Stockholm County 1976–79 to 1990–95, cardiovascular causes of death

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1976–79 1980–85 1986–89 1990–95

Dea

ths/

100,

000

197

6–79

per

iod

of

refe

ren

ce Patients with schizophrenia*

General population**

Cardiovascular disease is primary cause of death in persons with mental illness*

*Average data from 1996–2000

Per

cen

tag

e o

f d

eath

s

50

40

20

10

0

30

Heart disease Cancer Cerebrovascular Chronic respiratory

Diabetes Influenza/pneumoniaAccidents Suicide

MO OK RI TX UT VA

Data From Colton & Manderscheid 2006

What is the Concern Re Obesity in the Popn?

In 195025% US adults were overweight (BMI > 25)

In 200525% were obese (BMI > 30)

In 199825% of children were overweight

By 2012Only 25% of the US population will not be overweight

BMI = weight / height squared

Obesity increases the risk of disease

Willet et al. Guidelines for Healthy Weight (1999) NEJM 341, 427 - 433

Which Risk Factors Are Important?

For cardiovascular disease and general mortality…

Blood pressure (BP)

Smoking

Inactivity (fitness)

Weight / obesity

Cholesterol / lipids

Ranking of selected risk factors: 6 leading causes of death by income group, estimates for 2004

Percentage of total (total: 1.53 billion)

World Health Organization. http://www.who.int/healthinfo/global_burden_disease/global_health_risks/en/index.htm

The following are important for diabetes

IFG BP

WaistHDL TG

≥ 102 cm or 40 inches (m)

≥ 88 cm or 36 inches(f)≥150 mg/dl

< 40 mg/dL (m)

< 50 mg/dL (f)

≥ 130/85 mmHg≥ 6.1 mmol/L (110 mg/dl).

TG = triglycerides; IFG = impaired fasting glucose; HDL = high density lipids

Collectively known as “metabolic syndrome” (when 3x are present)

How Many Antipsychotics are prescribed?About 6million prescriptions in the UK per year

Perhaps to 0.5 million people in the UK annually (estimated)

Globally they generate about 20billion per year for the pharmaceutical industry

They are prescribed for several mental health conditions

About 15% are given to the under 18’s

$0

$2

$4

$6

$8

$10

$12

$14

$16

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2006(est.)

$ B

illio

ns

Source: IMS; Robert Rosenheck MD

Global Antipsychotic Market Sales(MAT Q1 by Yr)

Most common uses of atypical antipsychoticsOff label use accounts for ~ 1/3 of prescriptions

II. Weight, diabetes complications of Atypicals

The following are of high concern in SMI (next slide)

IFG

BP

Waist

HDL

TG

≥ 102 cm or 40 inches (m)

≥ 88 cm or 36 inches(f)≥150 mg/dl

< 40 mg/dL (m)

< 50 mg/dL (f)

–≥ 130/85 mmHg

≥ 6.1 mmol/L (110 mg/dl).

Diab

Smoking

Prevalence of diabetes in schizophrenia compared to general population

8.6% diabetes; n=415 Slide thanks to De Hert et al 2006

15

Age group (years)

General population Patients

15–25 25–35 35–45 45–55 55–650

5

10

20

25

30

0.42.0 0.9 1.1

6.1

25.0

5.8

Pre

vale

nce

of

dia

bet

es (

%)

3.2 2.4

12.7

Bipolar comparison study – prevalence of metabolic disturbances

72.359.8

71.6

17.029.3

22.1

10.7 10.9 6.4

0

10

20

30

40

50

60

70

80

90

100

Bipolar(n=112)

Schizoaffective(n=92)

Schizophrenia(n=503)

Pre

vale

nce

of

met

abo

licd

istu

rban

ces

(%)

Normal glucose values (n=496) Pre-diabetes (n=157) Diabetes (n=54)

van Winkel et al 2008

BMI change after 52 weeks of olanzapine in bipolar patients

Image Credit: Hennen (2004)

Antipsychotic-induced diabetes mellitus..warning in 2003

October 20, 2003FDA warns diabetes and antipsychotic medicationsFDA to require diabetes warning on antipsychotics

In a series of letters delivered in mid-September, the US FDA disclosed to makers of atypical antipsychotic medications that it will require each drug maker to re-label its product to include warnings regarding risk of hyperglycaemia and diabetes mellitus

About the CATIE Study of Atypicals…..

• Non-industry sponsored. • 1493 patients.• 18 month double blind.• Olanzapine, quetiapine, risperidone, ziprasidone &

perphenazine74% discontinued before 18 months, median 4.6

months. Olanzapine 9.2 months

Metabolic problems much greater versus general population

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223

26

Comparison of Metabolic Syndrome and Individual Criterion Prevalence: Fasting CATIE vs Matched NHANES III Subjects

Men Women

CATIE (%)

(N=509)

NHANES (%)(N=509)

PCATIE (%)

(N=180)

NHANES III (%)

(N=180)P

Metabolic syndrome prevalence

36.0 19.7 .0001 51.6 25.1 .0001

Waist circumference criterion

35.5 24.8 .0001 76.3 57.0 .0001

Triglyceride criterion 50.7 32.1 .0001 42.2 19.6 .0001

HDL criterion 48.9 31.9 .0001 63.3 36.3 .0001

BP criterion 47.2 31.1 .0001 46.9 26.8 .0001

Glucose criterion 14.1 14.2 .9635 21.7 11.2 .0075

CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey.McEvoy JP et al. Schizophr Res. 2005;80:19-32.

CATIE: rates of pharmacological interventions for abnormal blood pressure, lipids and glucose

Nasrallah et al 2006

n=1488 n=685 n=690

Pat

ien

ts (

%)

n=481 n=300 n=75 n=34 n=471 n=421

33.2

10.9

68.362.4

45.3

89.4

0

20

40

60

80

100

Hypertension Diabetes Dyslipidaemia

Prevalence Lack of medical intervention

But not everyone gains weight….

20% do not gain weight over 2yrs of Olanzapine Treatment

Data from Basson, Kinon JCP

Weight gain begins early, typically plateaus

Weight Gain 3yrs of Olanzapine (n=573) vs Haloperidol (n=103) Treatment

Data from Kinon (2001) J Clin Psychiatry 62:92-100; Image Credit: JCP / Physicians Press

7kg

Weight Gain During 3yrs of Olanzapine (n=573) by baseline weight

9.5kg

7kg

3kg

Data from Kinon (2001) J Clin Psychiatry 62:92-100; Image Credit: JCP / Physicians Press

Weight gain seen in bipolar disorder too

Weight Gain During 32 weeks of Olanzapine (n=948) by baseline weight in bipolar disorder

8kg

Lipkovich Early Predictors of Substantial Weight Gain in Bipolar Patients Treated with Olanzapine. J Clin Psychopharm 2006;26:316-320

6kg

4.5kg

Weight gain highest in drug-naive patients

36

2-Year Weight Gain in First-Episode Schizophrenia: Effect of Type of Analysis

Zipursky RB et al. Br J Psychiatry. 2005;187:537-543. OLZ = olanzapine HAL = Haloperidol

18

16

14

12

10

8

6

4

2

00 10 20 30 40 50 60 70 80 90 100 110

OLZ( Yr 1): n=35OLZ (Yr 2): n=13

HAL (Yr 1): n=47HAL (Yr 2): n=28

15.4 kg

7.5 kg

Week of Therapy

Haloperidol Amisulpride Olanzapine

Quetiapine Ziprasidone

0

10

20

30

40

50

60

70

80

90

Wei

gh

t g

ain

>7%

fro

m

bas

elin

e (%

)

p=0.053*

5363

86%

65

37

0

2

4

6

8

10

12

14

16

7.3

9.7

13.9

4.8

10.5

p<0.0001*

Wei

gh

t ch

ang

e fr

om

b

asel

ine

(kg

)

EUFEST – randomised controlled 12-month trial (n=498)

Kahn RS et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. Lancet . 2008 Mar 29 ; 371(9618):1085-97

CAFE study – weight and related measures in first-episode schizophrenia

McEvoy et al 2007

5.7

Weight change

*

*

7.0

11.0

3.74.0

6.6

0

2

4

6

8

10

12

Week 12 Week 52

Lea

st s

qu

ares

mea

n c

han

ge

(kg

)

Risperidone (n=133)Quetiapine (n=134)Olanzapine (n=133)

0

20

40

60

80

100

Week 12 Week 52P

erce

nta

ge

of

pat

ien

ts

**

**80.0

50.058.060.0

29.0 32.0

Weight gain 7%#

Summary of Metabolic Complications

We have summarized all existing data of studies measuring metabolic problems in three groups:

Established schizophrenia

Vs early (first epsiode schizophrenia)

Vs unmedicated patients with schizophrenia

0.101

0.266

0.243

0.169

0.051

0.204

0.402

0.027

0.099

0.22

0.304

0.196

0.052

0.219

0.468

0.119

0.33

0.49

0.390.4

0.2

0.43

0.54

0.11

0

0.1

0.2

0.3

0.4

0.5

0.6

MetS Waist (m > 102 f >88)

BP Triglycerides >150 mg/dl

IFG HDL (M <40mg/dl,F <50 mg/dl)

Smoking Diabetes

Unmedicated

First Episode

Schizophrenia

….and against general population rates?

0.101

0.266

0.243

0.169

0.051

0.204

0.402

0.027

0.099

0.22

0.304

0.196

0.052

0.219

0.468

0.119

0.33

0.49

0.390.4

0.2

0.43

0.54

0.11

0.25 0.25

0.3 0.3

0.15

0.3

0.2

0.04

0

0.1

0.2

0.3

0.4

0.5

0.6

MetS (3 of 5) Waist (m >102f>88)

BP (>130/85) Triglycerides(>150 mg/dl)

IFG (6.1 mmol/L or110 mg/dl)

HDL (M<40mg/dl,F<50 mg/dl)

Smoking Diabetes

Unmedicated

First Episode

Schizophrenia

General Population

…are patients monitored for these problems?

Mitchell AJ, Delaffon V, Vancampfort D, Correll CU, De Hert M.

Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices.

Psychol Med. 2011 Aug 10:1-23. [Epub ahead of print]

Psychol Med. 2011 Aug 10:1-23. [Epub ahead of print]

Can metabolic complications be avoided?

Yes by….

• By switching to a weight sparing antipsychotic

• By giving lifestyle advice and assistance

• By adding in weight loss medication (early or late)

• By avoiding weight gaining antipsychotics (only a few exist)

Estimated Weight Change (lb) After Switch to Ziprasidone†

†Repeated measures analysis

Conventionals Olanzapine Risperidone

-25

-20

-15

-10

-5

0

5

LS

Mea

n C

han

ge,

lb

49 53 584540363227231914106

Weeks

*

***

***

**

**

***

*P<0.05 **P<0.001***P<0.0001

Switched from

Imp

rovem

ent

Presented at APA 2004, New York, NY

Alvarez-Jiménez– lifestyle in Unmedicated 1st Episode (10-14 sessions over 3mo)

Alvarez-Jiménez M J Clin Psychiatry. 2006 Aug;67(8):1253-60. Attenuation of antipsychotic-induced weight gain with early behavioral intervention in drug-naive first-episode psychosis patients: A randomized controlled trial.

Chen – Metformin after 3mo of Olanzapine Rx

50

29.2

50

33.3

25 25

41.7

29.2

45.9

29.2

16.7

20.8

41.7

29.2

41.7

29.2

16.7

12.5

25 25

29.2

20.8

12.6 12.5

0

10

20

30

40

50

60

Metabolic syndrome Abdominal obesity Fastinghypertriglyceridemia

Low fasting HDL High blood pressure High fasting glucose

Baseline

2 weeks

4 weeks

8 weeks

Chen et al (2008) Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine. Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 925–931

Metformin Coprescription at start of Olanzapine

Wu et al Metformin Addition Attenuates Olanzapine-Induced Weight Gain in Drug-Naive First-Episode Schizophrenia Patients: Am J Psychiatry 2008; 165:352–358

1.491.37

0.45 0.41

2.13

1.86

0.59 0.53

5.14

1.87 1.92

0.53

6.87

1.9

2.26

0.54

0

1

2

3

4

5

6

7

8

Kg_Olan+Plb Kg_Olan+Met BMI_Olan+Plb BMI_Olan+Met

Week 2

Week 4

Week 8

Week 12

Metformin in patients on antipsychotic drugs: a systematic review and meta-analysis

Bjorkhem-Bergman Journal of Psychopharmacology 2010; 25(3) 299–305

Alex J Mitchell www.psycho-oncology.infoUniversity of Leicester (UK)

AcknowledgementsDavy Vancampfort, BelgiumMarc De Hert, Belgium

Weight Gain, Diabetes and Metabolic Problems

in Patients prescribed Atypical Antipsychotics

Online Information Oct 2011