alex j mitchell university of leicester (uk) acknowledgements davy vancampfort, belgium marc de...
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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