Cipralex
Late life depression
The good life has no age

1
A broad selection of slides
• The set contains slides that will be of interest to different
audiences: nurses, pharmacists...
Content
•
•
•
•
•
•
•
•
•
•

Introduction
Epidemiology
What is different about late life depression
Population ageing
Scre...
Introduction

4
Introduction
Depression in older people is
• often missed
• under recognised

• untreated

5
Introduction
• Although many see the development depressive
symptoms as being inevitable … depression is
actually not a no...
“It is not enough to
add years to one’s
life…one must also
add life to those
years”

7
Epidemiology

8
Prevalence of depression in late life
40
Major depression

Minor depression

35
Percentage prevalence

25–40%

30
25
15–30...
Under treatment of late life depression
Only a minor fraction of the prevalence are identified
and treated
• WHO estimate ...
Broader goals of depression
treatment should not be forgotten

Raise disease
awareness

Reduce
stigma

Encourage
help-seek...
What is different
about late life
depression?

12
Myths about depression:
more common in elderly individuals?

•

Not a real medical illness

•

Cannot be treated

•

A sig...
The extensive impact of depression

• Is a major risk factor for suicide
• Amplifies physical symptoms, increases mortalit...
Factors affecting prognosis and
pharmacotherapy

•
•
•
•
•
•

Altered pharmacokinetics and pharmacodynamics
End-organ phys...
Specific risk factors for depression in late life
•
•
•
•
•

Bereavement
Sleep disturbances
Disability
Prior depression
Fe...
What is the added effect of depression on the

well-being of a patient who also suffers from a
chronic medical condition?
...
Poorer mean health scores with comorbidity

Moussavi S et al. 2007. The Lancet; 370: 851-858.

18
Quality of life in older adults with and without
depressive symptoms and chronic diseases
HRQOL scales and summary scores,...
Depression is often associated
with anxiety in the elderly
One or more anxiety
disorders during lifetime

50

Two or more ...
Fatality from suicide increases with age
60
Male

Rate (per 100000)

50

40

30
Female

20

10

0
5–14

15–24

25–34

35–4...
Suicide and suicidal ideation in late-life
depression
• Depression in later life is the major risk factor for suicide1
• T...
Population ageing

23
The demographic transition
The increasing proportion of elderly will impact upon the burden of diseases
Population pyramid...
Populations are ageing across the world
Percent of the population aged ≥80 years
2002

2025

5.0
4.5

Percentage

4.0
3.5
...
The average age is increasing

Millions

Evolution of the population of Europe by broad age groups
475
450
425
400
375
350...
Life expectancy is increasing
Past and projected female and male life expectancy at birth (US, 1900–2050)
Female

100

Mal...
Life expectancy – 65 does not necessarily
mean that life is coming to an end …
Number of years more to live when you have ...
Screening and
diagnostic tools

29
Many clinical tools are used in
late life depression

•

Geriatric Depression Scale (GDS)

•

Cornell Scale for Depression...
Screening is simple with short scales
•

•

Recognition of depression in the late life population can be facilitated
by si...
Geriatric Depression Scale 15 items
Choose the best answer for how you have felt over the past week
1. Are you basically s...
Treatment

33
Treatment phases
Phase 1: Getting started
At the start of treatment not all
patients feel a change and side
effects are mo...
What key factors influence our
selection of antidepressants
for the late life population ?

35
Key factors influencing selection

• Overall efficacy
• Safety and tolerability

• Potential to interact
• Control of co-m...
Antidepressant DDD/1000 population/day

Antidepressant usage increases with age

120
2003
2004

100

2005
2006

80
60
40

...
An inappropriate imbalance?

100

SSRIs

TCAs

80

SNRIs

70
Percentage

90

Other

60
50

40
30
20
10
0

≥65

35–44
Age g...
Cipralex
in late life depression

39
Escitalopram prevents relapse in
older patients with major
depressive disorder
Gorwood et al.
Am J Geriatr Psychiatry 2007...
Objectives and key findings

Objectives
•

To assess the efficacy and tolerability of escitalopram in the
prevention of re...
Study design
Period I
Acute treatment
(12-week, open label)

Period II
Continuation treatment
(24 weeks, double-blind)

n=...
Study overview
Patients
• Outpatients, ≥65 years, with moderate or severe MDD
(MADRS total score ≥22; MMSE total score ≥24...
Kaplan-Meier analysis of relapse over
24 weeks
Escitalopram

Kaplan-Meier estimate

1.0

Placebo

0.9
p<0.001 vs placebo (...
Secondary outcome measures
Response rates (≥50% reduction in MADRS score; CGI-I ≤2)
100
***

***

***

Response rate (%)

...
Tolerability

Open-label period
•
•
•

72 patients withdrew from study (18%)
46 patients withdrew as a result of AEs – inc...
Tolerability improves over time

Open-label escitalopram (n=405)

60

Taper escitalopram (n=152)

Percentage of patients

...
Conclusion
•

Escitalopram was four times as effective as placebo in preventing
relapse over 6 months in older patients wi...
Escitalopram in the long-term
treatment of Major Depressive
Disorder in elderly patients
Kasper et al.
Neuropsychobiology ...
Objectives and key findings

Objectives
•
•

Assess the safety and tolerability of escitalopram (10 or 20 mg/day)
in the l...
Study overview
Design
• Outpatients with MDD, ≥65 years (MADRS ≥22 and ≤40; MMSE ≥22)
• 52-week open-label extension study...
Tolerability – extension study

Completers, n (%)

171 (76.0)

Discontinuation, n (%)

54 (24.0)

Due to:

AEs

20 (8.9)

...
Tolerability – extension study
AEs reported in ≥5% of patients
Patients, n (%)
Patients with AEs

175 (77.8)

Accidental i...
Efficacy assessments during extension study –
MADRS and CGI-S scores

Mean MADRS total score

16

MADRS scores, mean (LOCF...
Response and remission – extension study
Response
• Start of extension study: 57% of patients were responders
• End of ext...
Patients in remission – extension study

Percentage of patients in remission

80
70
60
50
40
30
20
10
0
0

1

2

4

8

12
...
Conclusion
•

78% of patients reported AEs
•
•
•

•

The majority of AEs were considered unrelated to study drug
No new ty...
An open-label trial in 2,050 elderly
outpatients with depression treated
with escitalopram in a naturalistic
setting in Ge...
Objectives and key findings

Objectives
•

To investigate the efficacy and tolerability of escitalopram in the
treatment o...
Study overview
Design
•
8-week, naturalistic, open-label, multicentre, German trial of outpatients with depression receivi...
•

Decreasing svMADRS total
score [mean (SD)]:
•
•

•

•

Baseline: 31.9 (7.9)
Week 8: 14.2 (8.5)

Statistically significa...
Response and remission
Response
• 63.9% of patients were responders
•

•

Positive factors significantly affecting respons...
CGI-S
•
Decreasing CGI-S values [mean (SD)]:
•
•

•

Baseline: 3.75 (0.76)
Week 8: 2.27 (1.04)

Statistically significantl...
Tolerability
•
•

The majority (>90%) of patients and physicians rated tolerability as
good or very good
No statistical di...
Conclusions
•
•
•

•

Escitalopram treatment was shown to be efficacious and well
tolerated in this trial
Patients aged 66...
Escitalopram for comorbid depression
and anxiety in elderly patients:
a 12-week, open-label, flexible-dose,
pilot trial
Mo...
Objectives and key findings

Objectives
•

To assess the efficacy and tolerability of short-term (12 weeks)
administration...
Study overview
Design
• 12 week, open-label, flexible dose, pilot trial
• Outpatients, ≥65 years, with moderate to marked ...
Changes from baseline in MADRS and HAM-A
scores after 12 weeks of escitalopram
(10–20 mg/day) treatment
20

Mean (SD) chan...
Response rates in MADRS and HAM-A scores after
12 weeks of escitalopram (10–20 mg/day) treatment

Percentage of patients r...
Quality of life and social functioning before and after
12 weeks of escitalopram treatment

Physical
functioning

*

Menta...
Tolerability

Completers, n (%)

17 (85)

Discontinuation, n (%)

3 (15)

Discontinuation due to AEs, n (%)

2 (10)

Disco...
Conclusions
•

Elderly patients with comorbid moderate to marked depression and
anxiety treated with escitalopram (10 or 2...
Antidepressive therapy with
escitalopram improves mood, cognitive
symptoms, and identity memory for
angry faces in elderly...
Objectives and key findings

Objectives
•

To assess the effects of treatment with escitalopram on affective and
cognitive...
Study overview
Design
•
4-week, single centre, open-label trial
•
Elderly depressed in-patients (ICD-10; >65 years old) vs...
GDS and MMSE score from baseline to Week
4 of treatment

Baseline

Week 4

p-value

GDS,
Mean (SEM)

9.4 (0.4)

4.7 (0.6)
...
Identity recognition memory performance
Prior to escitalopram treatment

•

Depressive patients have lower
identity recogn...
Identity recognition memory performance

Depressed patients after escitalopram treatment
• No improvement in identity reco...
Conclusions
•
•
•

Antidepressant therapy with escitalopram improved mood and overall
cognitive performance
Elderly depres...
Drug interactions

82
Metabolism of antidepressants –
an important consideration in late life
Second generation
antidepressant

Enzymes involved...
Health economics

84
Depression alone is costly
Global drug costs by therapy area1

Depression treatment: cost distribution2
100%

Cholesterol ...
Escitalopram vs citalopram
– healthcare costs in the late life population
Comparison of 6-month healthcare costs per patie...
Conclusion

87
Conclusions
• Safety and tolerability, efficacy, potential to interact and
healthcare costs are key criteria for selecting...
Final thought

In 1890, Vincent van Gogh
painted this picture.
Seen by some as
symbolizing the despair
and hopelessness fe...
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דיכאון בגיל מבוגר

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דיכאון בגיל מבוגר

  1. 1. Cipralex Late life depression The good life has no age 1
  2. 2. A broad selection of slides • The set contains slides that will be of interest to different audiences: nurses, pharmacists, general practitioners, geriatricians and psychiatrists • The current order of slides represents only one example of a presentation flow – there are many possibilities. The set is designed to allow the user to pick and choose depending on the audience, the theme of the presentation as well as the local market situation • Some slides are hidden as they may be of secondary importance 2
  3. 3. Content • • • • • • • • • • Introduction Epidemiology What is different about late life depression Population ageing Screening and diagnostic tools Treatment Cipralex in late life depression Drug interactions Health economics Conclusion 3
  4. 4. Introduction 4
  5. 5. Introduction Depression in older people is • often missed • under recognised • untreated 5
  6. 6. Introduction • Although many see the development depressive symptoms as being inevitable … depression is actually not a normal part of ageing • Depression is a serious medical condition • Untreated depression can delay recovery or worsen the outcome of other medical illnesses via increased morbidity or mortality 6
  7. 7. “It is not enough to add years to one’s life…one must also add life to those years” 7
  8. 8. Epidemiology 8
  9. 9. Prevalence of depression in late life 40 Major depression Minor depression 35 Percentage prevalence 25–40% 30 25 15–30% 20 20% 15 15% 10 5 10% 5% 0 Community elders1,2 Primary care3,4 Nursing homes2 1. Gallo & Lebowitz. Psychiatric Services 1999; 50: 1158–1166; 2. Djernes. Acta Psychiatr Scand 2006; 113: 372–387; 3. Friedman et al. Am J Geriatr Psychiatry 2007; 15: 28–41; 4. Zung et al. J Fam Pract 1993; 37 (4): 337–344 9
  10. 10. Under treatment of late life depression Only a minor fraction of the prevalence are identified and treated • WHO estimate that only app. 50 % of depressed patients is diagnosed with a psychological illness by their treating physician • Recognition of depression in the late life population may be even more difficult • Rates for under-treatment appears to be more significant in late life population Wittchen et al. Int Clin Psychopharmacol 2001 16:121-135 Crystal et al J Am Geriatr Soc 51:1718–1728, 2003. 10
  11. 11. Broader goals of depression treatment should not be forgotten Raise disease awareness Reduce stigma Encourage help-seeking behaviour 11
  12. 12. What is different about late life depression? 12
  13. 13. Myths about depression: more common in elderly individuals? • Not a real medical illness • Cannot be treated • A sign of weakness • Will go away by itself • A normal part of getting older • Only affects women 13
  14. 14. The extensive impact of depression • Is a major risk factor for suicide • Amplifies physical symptoms, increases mortality • Often coexists with and worsens the outcome other medical conditions • Decreases adherence to prescribed treatments • Impairs daily functioning • Often requires personalized long-term care • Is costly for the individual and society as a whole Moussavi S et al. 2007. Lancet; 370: 851-858. Prince M et al. 2007 Lancet; 370: 859-877. DiMatteo MR et al. Arch Intern Med. 2000; 160 (14):2101-2107. 14 Ciechanowski et al. 2000 Arch Intern Med 2000 160(21):3278-3285.
  15. 15. Factors affecting prognosis and pharmacotherapy • • • • • • Altered pharmacokinetics and pharmacodynamics End-organ physiological changes Coexisting medical conditions Cognitive decline Polypharmacy Social isolation 15
  16. 16. Specific risk factors for depression in late life • • • • • Bereavement Sleep disturbances Disability Prior depression Female gender • Management of the modifiable risks and application of relevant therapy may reduce depression symptoms • Individuals with these characteristics should be screened for depression Cole & Dendukuri (Am J Psychiatry 2003; 160:1147–1156) 2003 16
  17. 17. What is the added effect of depression on the well-being of a patient who also suffers from a chronic medical condition? 17
  18. 18. Poorer mean health scores with comorbidity Moussavi S et al. 2007. The Lancet; 370: 851-858. 18
  19. 19. Quality of life in older adults with and without depressive symptoms and chronic diseases HRQOL scales and summary scores, SF-36 100 GDS-15 ≤5 (n=795) 90 GDS-15 >6 (n=290) 80 Mean scores 70 60 50 40 30 20 10 0 Physical Physical functioning role Bodily pain General health Vitality Social Emotional Mental Physical Mental functioning role health component component summary summary Without depressive symptoms and without chronic diseases With depressive symptoms and without chronic diseases Without depressive symptoms and with ≥2 chronic diseases With depressive symptoms and with ≥2 chronic diseases HRQOL: Health related quality of life GDS: Geriatric Depression Scale 19 Gallegos-Carrillo et al. J Psychosom Res 2009; 66: 127–135
  20. 20. Depression is often associated with anxiety in the elderly One or more anxiety disorders during lifetime 50 Two or more anxiety disorders during lifetime 45 40 Percentage 35 30 25 20 15 10 5 0 Primary care patients with MDD (n=36) Psychiatric setting outpatients with MDD (n=40) Psychiatric setting inpatients with MDD (n=40) Lenze et al. Am J Psychiatry 2000; 157: 722–72820
  21. 21. Fatality from suicide increases with age 60 Male Rate (per 100000) 50 40 30 Female 20 10 0 5–14 15–24 25–34 35–44 45–54 Age group (years) 55–64 65–74 75+ WHO, 200021
  22. 22. Suicide and suicidal ideation in late-life depression • Depression in later life is the major risk factor for suicide1 • Treatment-resistant late life depression increases the risk for early mortality, including suicide2 • Suicidal ideation is common in elderly depressed patients being treated in primary care3 • Care providers should monitor suicidal ideation through the course of depression treatment3 1 Hawton et al. Int J Geriatric Psychiatry 2006; 21(6): 572–581 2 Lenze et al. Dialogues Clin Neurosci 2008; 10(4): 419–430 3 Vannoy et al. Am J Geriatr Psychiatry 2007; 15(12): 1024–1033 22
  23. 23. Population ageing 23
  24. 24. The demographic transition The increasing proportion of elderly will impact upon the burden of diseases Population pyramids 60+ 0–59 1950 Age 80 Male 2000 2050 Female 60 40 20 10 5 0 5 Percentage 10 10 5 0 5 Percentage 10 10 5 0 5 Percentage 10 The UN estimates that the number of 80–89-year olds will increase 5-fold from 2000–2050 24
  25. 25. Populations are ageing across the world Percent of the population aged ≥80 years 2002 2025 5.0 4.5 Percentage 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 World total Africa Asia Europe Latin Northern America America & Caribbean Oceania Adapted from US Census Bureau: http://www.census.gov/ipc/prod/wp02/tabA-07a.xls; http://www.census.gov/ipc/prod/wp02/tabA-07b.xls 25
  26. 26. The average age is increasing Millions Evolution of the population of Europe by broad age groups 475 450 425 400 375 350 325 300 275 250 225 200 175 150 125 100 75 50 25 0 0–14 15–59 60+ 26 World Population Prospects: The 2006 Revision United Nations Population Division
  27. 27. Life expectancy is increasing Past and projected female and male life expectancy at birth (US, 1900–2050) Female 100 Male Projection Years of life 90 84.3 80 79.7 70 60 50 40 1900* 1910* 1920* 1930* 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050 *Death registration area only. The death registration area increased from 10 states and the District of Columbia in 1900 to the entire US in 1933 27 US Department of Commerce, Bureau of the Census
  28. 28. Life expectancy – 65 does not necessarily mean that life is coming to an end … Number of years more to live when you have reached a given age e.g., if you are a 65 year-old female, you can expect to live for an additional 20 years Current age Males Females At birth 75.2 80.4 55 years 24.7 28.3 65 years 17.1 20.0 75 years 10.7 12.8 85 years 6.1 7.2 28 National Vital Statistics Reports, 2007 (Volume 56; Number 9)
  29. 29. Screening and diagnostic tools 29
  30. 30. Many clinical tools are used in late life depression • Geriatric Depression Scale (GDS) • Cornell Scale for Depression in Dementia • Center for Epidemiologic Studies of Depression Scale (CES-D) • Patient Health Questionnaire 9 • Geriatric Mental State Schedule (research) • Hamilton Depression Rating Scale (severity) • Montgomery-Asberg Depression Rating Scale (severity) 30
  31. 31. Screening is simple with short scales • • Recognition of depression in the late life population can be facilitated by simple and quick tools for identification and management of individual patients One single question may be enough for initial screening1 “Do you think you suffer from depression?” • • • Geriatric Depression Scale 15 items (GDS15) can detect and indicate illness severity2 GDS15 is acceptable in primary care due to its shortness and high probability of identifying depressed patients2 More thorough tools will be necessary to assess severity of specific symptoms and to follow-up over time3 1. Aylon et al. Int J Geriatr Psychiatry 2009 (e-pub ahead of print) 2. Mitchell et al. J Affect Disord 2009 (e-pub ahead of print) 31 3. Almeida et al. Int J Geriat Psychiatry 14, 858-865 (1999)
  32. 32. Geriatric Depression Scale 15 items Choose the best answer for how you have felt over the past week 1. Are you basically satisfied with your life? Yes No 2. Have you dropped many of your activities and interests? Yes No 4. Do you often get bored?  Yes  Yes  5. Are you in good spirits most of the time? Yes No 6. Are you afraid that something bad is going to happen to you? Yes 7. Do you feel happy most of the time? Yes 8. Do you often feel helpless? Yes 9. Do you prefer to stay at home, rather than going out and doing new things? Yes  3. Do you feel that your life is empty? No No   No No   No No 10. Do you feel you have more problems with memory than most?  Yes  11. Do you think it is wonderful to be alive now? Yes No 12. Do you feel pretty worthless the way you are now? Yes 13. Do you feel full of energy? Yes 14. Do you feel that your situation is hopeless? Yes 15. Do you think that most people are better off than you are? Total score • Although differing sensitivities and specificities have been obtained across studies, for clinical purposes a score >5 points is suggestive of depression and should warrant a follow-up interview • Scores >10 are almost always depression No  • Answers ticked indicate depression, and each score one point  No No  Yes  No No 15  Sheikh & Yesavage (p165–173) In: Clinical gerontology: a guide to assessment and intervention. (Ed. Brink TL). 1986 Haworth, New York Mitchell et al. J Affect Disord 2009 (e-pub ahead of print) 32
  33. 33. Treatment 33
  34. 34. Treatment phases Phase 1: Getting started At the start of treatment not all patients feel a change and side effects are more likely Phase 2: To the top Most patients begin feel more optimistic and have more energy. Functionality tends to improve Phase 3: Keep going Persistence with treatment is important to achieving remission. Premature discontinuation, despite feeling better can “undo” the progress already made Phase 4: Back to the good life Better disease awareness and optimized thought patterns can help to prevent reoccurrence 34
  35. 35. What key factors influence our selection of antidepressants for the late life population ? 35
  36. 36. Key factors influencing selection • Overall efficacy • Safety and tolerability • Potential to interact • Control of co-morbid anxiety • Healthcare costs 36
  37. 37. Antidepressant DDD/1000 population/day Antidepressant usage increases with age 120 2003 2004 100 2005 2006 80 60 40 20 0 0–4 5–14 15–24 25–34 35–44 45–54 55–64 65–74 75–84 ≥85 Age (years) Smith & Tett. Drugs Aging 2009; 26 (2): 113–12237
  38. 38. An inappropriate imbalance? 100 SSRIs TCAs 80 SNRIs 70 Percentage 90 Other 60 50 40 30 20 10 0 ≥65 35–44 Age groups (years) SSRIs = Fluvoxamine, fluoxetine, escitalopram, paroxetine, citalopram and sertraline TCAs = Dothiepin and amitriptyline; SNRIs = Venlafaxine; Other = Mirtazapine Smith & Tett. Drugs Aging 2009; 26 (2): 113–12238
  39. 39. Cipralex in late life depression 39
  40. 40. Escitalopram prevents relapse in older patients with major depressive disorder Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 40
  41. 41. Objectives and key findings Objectives • To assess the efficacy and tolerability of escitalopram in the prevention of relapse of major depressive disorder (MDD) in older patients who had responded to acute treatment with escitalopram Key findings • • Escitalopram was effective in preventing relapse of MDD – elderly patients who achieved remission after 12 weeks of open-label treatment with escitalopram were four times more likely to remain in remission over a 6-month period, if taking escitalopram than if taking placebo Escitalopram was well tolerated as continuation treatment Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 41
  42. 42. Study design Period I Acute treatment (12-week, open label) Period II Continuation treatment (24 weeks, double-blind) n=152 Escitalopram fixed dose (10 or 20 mg) Escitalopram 10 or 20 mg TAPER Relapse MADRS 22 or lack of efficacy Flexible dose for the first 6-week MADRS 22 n=405 TAPER Placebo n=153 Relapse MADRS 22 or lack of efficacy Run in W-1 W0 Remitters only MADRS 12 W12 W13 W36 W37 Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 42
  43. 43. Study overview Patients • Outpatients, ≥65 years, with moderate or severe MDD (MADRS total score ≥22; MMSE total score ≥24) Endpoints • Primary • The time to relapse (MADRS ≥22, or lack of efficacy as judged by investigator) from the start of the double-blind period Demographics Open-label Double-blind period Escitalopram Escitalopram Placebo Patients, n 405 152 153 Age, years, mean 73 73 72 313 (77) 119 (78) 121 (79) Gender, women, n (%) MADRS=Montgomery-Åsberg Depression Rating Scale; MMSE=Mini-Mental State Examination CGI-I=Clinical Global Impression – Improvement; CGI-S=Clinical Global Impression – Severity Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 43
  44. 44. Kaplan-Meier analysis of relapse over 24 weeks Escitalopram Kaplan-Meier estimate 1.0 Placebo 0.9 p<0.001 vs placebo (log-rank test) Hazard ratio for time to relapse: 4.44 Number needed to treat: 5 0.8 0.7 0.6 12 16 20 24 28 32 36 40 Treatm ent w eek • • Open-label period: 79.5% of patients achieved remission after 12 weeks of escitalopram treatment Double-blind period: 88.2% of escitalopram-treated patients remained in remission after 24 weeks, compared with 59.5% of placebo-treated patients Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 44
  45. 45. Secondary outcome measures Response rates (≥50% reduction in MADRS score; CGI-I ≤2) 100 *** *** *** Response rate (%) 90 *** *** MADRS escitalopram (n=152) 80 MADRS placebo (n=153) 70 CGI-I escitalopram (n=152) 60 CGI-I placebo (n=153) 50 12 • • • 13 14 16 20 24 Study week 28 32 36 Response rates were statistically significantly greater with escitalopram than placebo from Week 20 to study end MADRS total score was stable over long-term treatment; placebo group saw slight deterioration Statistically significant differences in all secondary measures in favour of escitalopram vs placebo Intent-to-treat population; Last observation carried forward; ***p<0.001 for both MADRS and CGI-I response definitions Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 45
  46. 46. Tolerability Open-label period • • • 72 patients withdrew from study (18%) 46 patients withdrew as a result of AEs – including nausea (n=14), anxiety (n=7), depression (n=5) Majority of AEs were mild to moderate Double-blind period • • • Excluding patients who withdrew due to relapse, the overall withdrawal rate for both treatment groups was comparable – escitalopram, n=10, 6.6%; placebo, n=13, 8.5% Incidence of AEs similar in both groups (40.1% escitalopram; 41.2% placebo); the majority of AEs were mild to moderate Withdrawal due to AEs – escitalopram 1.3%; placebo 3.9% Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 46
  47. 47. Tolerability improves over time Open-label escitalopram (n=405) 60 Taper escitalopram (n=152) Percentage of patients 50 Taper placebo (n=153) * 40 Week 2 to completion escitalopram (n=130) 30 Week 2 to completion placebo (n=91) 20 10 0 ≥ 1 AE Nausea Taper = 2-week dose adjustment period following randomisation to double-blind treatment *Patients tapering from escitalopram to placebo Headache Dizziness Diarrhoea Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 47
  48. 48. Conclusion • Escitalopram was four times as effective as placebo in preventing relapse over 6 months in older patients with MDD who had achieved remission during 12-weeks of open-label treatment with escitalopram • Good tolerability in a vulnerable population (the study did not exclude patients who were 75 years and over, had late-onset depression or recurrent depressive episodes) • The study is a good representation of treatment of patients in the „real-life‟ setting Escitalopram is significantly superior to placebo in preventing relapse of MDD in older patients, and is well tolerated in acute and continuation treatment Gorwood et al. Am J Geriatr Psychiatry 2007; 15: 581–593 48
  49. 49. Escitalopram in the long-term treatment of Major Depressive Disorder in elderly patients Kasper et al. Neuropsychobiology 2006; 54: 152–159 49
  50. 50. Objectives and key findings Objectives • • Assess the safety and tolerability of escitalopram (10 or 20 mg/day) in the long-term treatment of elderly outpatients from MDD Evaluation of the long-term response of elderly outpatients with MDD to open-label treatment with escitalopram Key findings • • Escitalopram has a favourable tolerability profile in elderly populations with MDD Escitalopram produced continued improvement in depressive symptom scores and remission/response rates Kasper et al. Neuropsychobiology 2006; 54: 152–159 50
  51. 51. Study overview Design • Outpatients with MDD, ≥65 years (MADRS ≥22 and ≤40; MMSE ≥22) • 52-week open-label extension study in which patients were treated with escitalopram 10 or 20 mg/day, following an 8-week double-blind lead-in study Assessments – extension study • Adverse events, clinical laboratory tests and physical examination • Changes in MADRS and CGI-S scores • Response rates (≥50% reduction in lead-in study baseline MADRS score) • Remission rates (MADRS ≤12) Demographics – extension study Patients, n Age, years, mean (SD) Gender, women, % MMSE=Mini-Mental State Examination; MADRS=Montgomery-Åsberg Depression Rating Scale 225 74 (6) 82% Kasper et al. Neuropsychobiology 2006; 54: 152–159 51
  52. 52. Tolerability – extension study Completers, n (%) 171 (76.0) Discontinuation, n (%) 54 (24.0) Due to: AEs 20 (8.9) Lack of efficacy 4 (1.8) Non-compliance with study product 1 (0.4) Protocol violation 4 (1.8) Withdrawal of consent 15 (6.7) Lost to follow-up 5 (2.2) Administrative/other reasons 5 (2.2) Kasper et al. Neuropsychobiology 2006; 54: 152–159 52
  53. 53. Tolerability – extension study AEs reported in ≥5% of patients Patients, n (%) Patients with AEs 175 (77.8) Accidental injury 29 (12.9) Rhinitis 19 (8.4) Weight increase 19 (8.4) Arthralgia 18 (8.0) Coughing 18 (8.0) Diarrhoea 16 (7.1) Headache 16 (7.1) Nausea 16 (7.1) Bronchitis 15 (6.7) Hypertension 15 (6.7) Back pain 13 (5.8) Dyspepsia 13 (5.8) Insomnia 13 (5.8) Weight decrease 12 (5.3) Kasper et al. Neuropsychobiology 2006; 54: 152–159 53
  54. 54. Efficacy assessments during extension study – MADRS and CGI-S scores Mean MADRS total score 16 MADRS scores, mean (LOCF): Start extension study: 13.4 End extension study: 8.5 14 12 10 LOCF 8 6 4 2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Treatment week of extension study (OC) CGI-S scores • Start extension study: 2.6; End extension study: 1.6 (OC) • This decrease confirms the clinical relevance of the efficacy results LOCF=Last observation carried forward Kasper et al. Neuropsychobiology 2006; 54: 152–159 54
  55. 55. Response and remission – extension study Response • Start of extension study: 57% of patients were responders • End of extension study: 77% of patients were responders (LOCF) Remission • Start of extension study: 48% of patients were remitters • End of extension study: 72% of patients were remitters (LOCF) Importance of long-term treatment emphasised • Of the 116 non-remitters at extension study entry, 50% achieved remission by last assessment • Of the 97 non-responders at extension study entry, 46% achieved remission by last assessment Response = ≥50% reduction in lead-in study baseline MADRS score Remission = MADRS ≤12 Kasper et al. Neuropsychobiology 2006; 54: 152–159 55
  56. 56. Patients in remission – extension study Percentage of patients in remission 80 70 60 50 40 30 20 10 0 0 1 2 4 8 12 16 20 24 28 32 36 40 44 48 52 Visit week Intent-to treat population; LOCF; Remission = MADRS ≤12 Kasper et al. Neuropsychobiology 2006; 54: 152–159 56
  57. 57. Conclusion • 78% of patients reported AEs • • • • The majority of AEs were considered unrelated to study drug No new types of AEs were reported in extension study The majority of AEs were mild to moderate in intensity Continued exposure to escitalopram provided continued benefit • • Mean MADRS and CGI-S scores, as well as response and remission rates, were better at the end of the extension period Results support the concept that even after remission is attained, further exposure is needed to consolidate remission and allow it to become sustained A favourable tolerability profile, coupled with evidence of sustained efficacy, demonstrate that escitalopram is a valid choice for the long-term treatment of elderly patients suffering from MDD Kasper et al. Neuropsychobiology 2006; 54: 152–159 57
  58. 58. An open-label trial in 2,050 elderly outpatients with depression treated with escitalopram in a naturalistic setting in Germany Möller et al. Poster presented at the 26th CINP congress Munich, Germany, 2008 58
  59. 59. Objectives and key findings Objectives • To investigate the efficacy and tolerability of escitalopram in the treatment of outpatient depression in patients aged 65 and over in a more clinically relevant, naturalistic setting Key findings • • Length of symptoms and duration of illness are key factors influencing treatment response and remission, which have implications for treatment regimens This study confirmed the efficacy and tolerability of escitalopram treatment in elderly patients in a clinically relevant, naturalistic setting Möller et al. Poster presented at CINP, 2008 59
  60. 60. Study overview Design • 8-week, naturalistic, open-label, multicentre, German trial of outpatients with depression receiving escitalopram treatment* • Subgroup analysis of patients >65 years of age Assessments • Short version of the MADRS scale (svMADRS) – used to assess depression severity1 • CGI-I and CGI-S – used to assess degree of improvement • Response rates (≥50% decrease of svMADRS total score from baseline) • Remission rates (svMADRS total score ≤12) • Group comparisons of old (66–75 years) and old–old (>75 years) patients were conducted Demographics 66–75 years >75 years Total 1,295 755 2,050 Age, years, mean (SD) 70.1 (2.8) 80.9 (4.2) 74.1 (6.2) Gender, women, n (%) 926 (71.6) 601 (79.7) 1,527 (74.6) Patients, n** *Previously published: Möller et al. Pharmacopsychiatry 2007; 40: 53–57 **2,280 patients were enrolled, and 2,050 patents completed 8 weeks of treatment and were included in the analysis; MADRS=Montgomery-Åsberg Depression Rating Scale; CGI-I=Clinical Global Impression – Improvement; CGI-S=Clinical Global Impression – Severity 1. Möller et al Nervenarzt 2007; 78:685–690 Möller et al. Poster presented at CINP, 2008 60
  61. 61. • Decreasing svMADRS total score [mean (SD)]: • • • • Baseline: 31.9 (7.9) Week 8: 14.2 (8.5) Statistically significant (p<0.001) baseline adjusted improvement in svMADRS for patients 66–75 years (18.3) The improvement was lower for patients >75 years (16.8) Adjusted mean change in svMADRS Change in svMADRS score from baseline to Week 8 0 66–75 years (n=1,295) >75 years (n=755) -5 -10 -15 -20 0 2 4 6 8 Treatment week Möller et al. Poster presented at CINP, 2008 61
  62. 62. Response and remission Response • 63.9% of patients were responders • • Positive factors significantly affecting response: • • • • Significantly more patients responded in the 66–75 years group vs the >75 years group (67.5%, n=874 versus 57.7%, n=436; p<0.001) Having a current episode ≤1 month Duration of illness ≤1 year Having a diagnosis of depressive episode or recurrent depressive disorder Negative factors significantly affecting response: • • • • Being male Being older than 75 years Having a diagnosis of bipolar disorder or persistent affective disorder Using psychotropics Remission • 48.6% of elderly patients achieved remission at Week 8 • Factors affecting remission were comparable to those affecting response, with baseline severity as an additional factor influencing remission Response = ≥50% decrease of svMADRS total score from baseline Remission = svMADRS total score ≤12 Möller et al. Poster presented at CINP, 2008 62
  63. 63. CGI-S • Decreasing CGI-S values [mean (SD)]: • • • Baseline: 3.75 (0.76) Week 8: 2.27 (1.04) Statistically significantly greater (p<0.001) baseline-adjusted mean decrease for patients 66–75 years (1.54) than for patients aged >75 years (1.40) CGI-I • 80.3% of patients had symptoms that were much or very much improved (CGI-I ≤2) • Response rate based on CGI-I scores was statistically significantly greater (p=0.011) for patients aged 66–75 years (82.0%) than for patients aged >75 years (77.4%) Adjusted mean change in CGI-S Change from baseline to Week 8 on CGI-S and CGI-I 0 -0.2 66–75 years (n=1,295) >75 years (n=755) -0.4 -0.6 -0.8 -1.0 -1.2 -1.4 -1.6 -1.8 -2.0 0 2 4 6 8 Treatment week Möller et al. Poster presented at CINP, 2008 63
  64. 64. Tolerability • • The majority (>90%) of patients and physicians rated tolerability as good or very good No statistical differences in tolerability assessment between patients 66–75 years and patients >75 years AEs possibly or probably related to treatment 66–75 years >75 years Patients with ≥1 related AE 57 (4.4%) 41 (5.4%) Gastrointestinal disorders 28 (2.2%) 20 (2.6%) General and administration site disorders 6 (0.5%) 3 (0.4%) Nervous system disorders 16 (1.2%) 14 (1.9%) Psychiatric disorders 14 (1.1%) 10 (1.3%) Skin and subcutaneous tissue disorders 3 (0.2%) 4 (0.5%) Möller et al. Poster presented at CINP, 2008 64
  65. 65. Conclusions • • • • Escitalopram treatment was shown to be efficacious and well tolerated in this trial Patients aged 66–75 years achieved slightly better results than patients >75 years Duration of illness and length of current symptoms were significant factors affecting treatment response, suggesting that treatment should be initiated soon after diagnosis Baseline severity of illness was a highly significant factor in achieving remission, reflecting the need for a longer treatment period for severely depressed patients The study population reflected patients seen in real-life clinical practice, and confirmed the efficacy and tolerability of escitalopram seen in controlled clinical trials Möller et al. Poster presented at CINP, 2008 65
  66. 66. Escitalopram for comorbid depression and anxiety in elderly patients: a 12-week, open-label, flexible-dose, pilot trial Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 66
  67. 67. Objectives and key findings Objectives • To assess the efficacy and tolerability of short-term (12 weeks) administration of escitalopram 10–20 mg/day for moderate to marked comorbid depression and anxiety in elderly patients Key findings • • Elderly patients with comorbid anxiety and depression treated with escitalopram (10–20 mg/day) demonstrated statistically significant improvements in both MADRS and HAM-A scores from baseline Significant changes from baseline were also noted in four of eight subscale scores in the SF-36 survey MADRS=Montgomery-Åsberg Depression Rating Scale; HAM-A=Hamilton Rating Scale for Anxiety; SF-36=36-item Short-Form health survey Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 67
  68. 68. Study overview Design • 12 week, open-label, flexible dose, pilot trial • Outpatients, ≥65 years, with moderate to marked comorbid major depressive disorder (MDD; MADRS >22) and generalised anxiety disorder (GAD; HAM-A ≥18) • Treatment with escitalopram (up to 20 mg/day depending on clinical judgement) Endpoints • Primary – changes from baseline in MADRS and HAM-A scores • Secondary – change from baseline in SF-36 subscale scores Demographics Patients, n Age, years, mean (SD) Sex, women, n (%) 20 73.0 (4.8) 6 (30) Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 68
  69. 69. Changes from baseline in MADRS and HAM-A scores after 12 weeks of escitalopram (10–20 mg/day) treatment 20 Mean (SD) change in score * 15 * 10 5 0 MADRS n=20; LOCF (last observation carried forward); *p<0.001 vs baseline; Baseline MADRS score, mean (SD)=29.8 (5.2); Baseline HAM-A score, mean (SD)=23.8 (5.6) HAM-A Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 69
  70. 70. Response rates in MADRS and HAM-A scores after 12 weeks of escitalopram (10–20 mg/day) treatment Percentage of patients responding 70 60 50 40 30 20 10 0 MADRS n=20; LOCF; Response = ≥50% improvement from baseline to endpoint HAM-A Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 70
  71. 71. Quality of life and social functioning before and after 12 weeks of escitalopram treatment Physical functioning * Mental health * Social functioning Role functioning – physical Baseline * Energy/ fatigue Week 12 Pain Role functioning – emotional General health * 0 20 40 60 Mean (SD) SF-36 score n=18; LOCF; *p<0.01 vs baseline based on paired-samples t test 80 0 20 40 60 80 Mean (SD) SF-36 score Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 71
  72. 72. Tolerability Completers, n (%) 17 (85) Discontinuation, n (%) 3 (15) Discontinuation due to AEs, n (%) 2 (10) Discontinuation due to lack of efficacy, n (%) 1 (5) • Two patients withdrew due to adverse events (AEs) • • • Dizziness (n=1, 5%) and somnolence (n=1, 5%) There were no other AEs reported There were no clinically significant changes in laboratory values at endpoint Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 72
  73. 73. Conclusions • Elderly patients with comorbid moderate to marked depression and anxiety treated with escitalopram (10 or 20 mg/day) for 12 weeks showed: • Statistically significant improvement from baseline in MADRS scores • Statistically significant improvement from baseline in HAM-A scores • Numerical improvement in four of eight subscales, and statistically significant improvement in four of eight subscales from the SF-36 survey Escitalopram was associated with significant improvements in the symptoms of depression and anxiety Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209 73
  74. 74. Antidepressive therapy with escitalopram improves mood, cognitive symptoms, and identity memory for angry faces in elderly depressed patients Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 74
  75. 75. Objectives and key findings Objectives • To assess the effects of treatment with escitalopram on affective and cognitive symptoms, and on memory for facial identity in elderly depressed patients compared with healthy age-matched controls Key findings • • Escitalopram treatment had significant benefits for mood, cognitive performance, and memory for negative facial stimuli in elderly depressed patients Escitalopram is effective in decreasing negative bias of depressed patients and may help improve patients‟ dysfunctional social interactions Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 75
  76. 76. Study overview Design • 4-week, single centre, open-label trial • Elderly depressed in-patients (ICD-10; >65 years old) vs healthy, age-matched controls • Treated with escitalopram (up to 20 mg/day depending on clinical judgement) Assessments • GDS – used to assess affect (scores >6 indicate depressive disorder) • MMSE – used to assess cognitive functioning (scores <26 indicate cognitive disturbances) • Emotional facial recognition test – used to investigate memory for facial identity (happy and angry male faces) Demographics Depressed patients Control group 18* 22 Age, years, mean (SEM) 76.2 (1.8) 76.9 (1.8) Gender, women, n (%) 14 (77.8) 16 (72.7) Patients, n *22 patients were enrolled, but 4 withdrew before Week 4 and were excluded from the analysis GDS=Geriatric Depression Scale; MMSE=Mini-Mental State Examination Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 76
  77. 77. GDS and MMSE score from baseline to Week 4 of treatment Baseline Week 4 p-value GDS, Mean (SEM) 9.4 (0.4) 4.7 (0.6) <0.0001 MMSE, Mean (SEM) 26.8 (0.5) 27.9 (0.4) =0.023 Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 77
  78. 78. Identity recognition memory performance Prior to escitalopram treatment • Depressive patients have lower identity recognition memory performance than healthy agematched controls (p=0.038) This difference is mainly due to memory performance on faces with happy expressions (p=0.018) • The control group had a better recognition of identities with happy faces (p=0.046) • This was not the case for depressed patients Depressed d’ (identity recognition) • Control p=0.046 1.5 p=0.018 1.0 0.5 Happy faces Angry faces Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 78
  79. 79. Identity recognition memory performance Depressed patients after escitalopram treatment • No improvement in identity recognition memory for happy faces • Improvement in identity recognition memory for angry faces • • Before treatment the mean d‟ was 0.46 ( 0.13) After treatment mean d‟ was 0.62 ( 0.1, p=0.05) • Individual improvement in GDS or MMSE scores did not significantly correlate with changes in identity recognition performance Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 79
  80. 80. Conclusions • • • Antidepressant therapy with escitalopram improved mood and overall cognitive performance Elderly depressed patients have not only affective and overall cognitive symptoms, but also deficits in facial identity recognition memory Antidepressant therapy with escitalopram improved the memory for negative facial stimuli (angry faces), but not memory for positive stimuli (happy faces) Escitalopram seems to be effective in decreasing the negative bias of depression, and may improve patients’ maladaptive social interactions Savaskan et al. Int J Neuropsychopharmacol 2008; 11: 381–388 81
  81. 81. Drug interactions 82
  82. 82. Metabolism of antidepressants – an important consideration in late life Second generation antidepressant Enzymes involved in biotransformation Isozymes inhibited Bupropion CYP2B6 CYP2D6 (moderate) Citalopram CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak) Duloxetine CYP2D6 and CYP1A2 CYP2D6 (moderate) Escitalopram CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak) Fluoxetine CYP2D6, CYP2C9, CYP2C19, and CYP3A4 CYP2D6 (strong), CYP2C9 (moderate), CYP2C19 (weak to moderate), CYP3A4 (weak to moderate), CYP1A2 (weak) Fluvoxamine CYP1A2 and CYP2D6 CYP1A2 (strong), CYP2C19 (strong), CYP2C9 (moderate), CYP3A4 (moderate), CYP2D6 (weak) Mirtazapine CYP2D6, CYP1A2, and CYP3A4 None known Nefazodone CYP3A4 CYP3A4 (strong), CYP2D6 (weak) Paroxetine CYP2D6 and CYP3A4 CYP2D6 (strong), CYP1A2 (weak), CYP2C9 (weak), CYP2C19 (weak), CYP3A4 (weak) Reboxetine CYP3A4 CYP2D6 (weak) Sertraline CYP2C9, CYP2C19, CYP2D6, and CYP3A4 CYP2D6 (weak to moderate), CYP1A2 (weak), CYP2C9 (weak), CYP2C19 (weak), CYP3A4 (weak) Venlafaxine CYP2D6 and CYP3A4 CYP2D6 (weak) 83 Spina et al. Clin Therapeutics 2008; 30 (7): 1206–1227
  83. 83. Health economics 84
  84. 84. Depression alone is costly Global drug costs by therapy area1 Depression treatment: cost distribution2 100% Cholesterol and triglyceride regulators 90% Antiulcerants 80% 70% Antidepressants and mood stabilisers 60% Direct Costs (%) Antipsychotics All other Antineoplastics Anti-epileptics Oral anti-diabetics Erythropoietins 50% 40% 30% 20% 10% Calcium antagonists 0% 5 10 15 20 25 30 35 A B C D E F G STUDY World sales ($US dollars) 12 month period to Q2 2008 Drugs Hospital admissions Consultations Other 1. IMS Knowledgelink 2. Berto P et al. 2000. The Journal of Mental Health Policy and Economics. 3: 3-10. 85
  85. 85. Escitalopram vs citalopram – healthcare costs in the late life population Comparison of 6-month healthcare costs per patient by sensitivity analysis Escitalopram 25,000 p<0.001 Citalopram 19,899 20,000 Cost ($) p<0.001 18,945 15,000 11,604 9,855 10,000 5,000 p=0.049 1,756 1,547 0 Total drug cost Total medical cost Total healthcare costs Wu et al. Curr Med Res Opin 2008; 24 (9): 2587–2595 86
  86. 86. Conclusion 87
  87. 87. Conclusions • Safety and tolerability, efficacy, potential to interact and healthcare costs are key criteria for selecting an antidepressant in this population • Dispelling myths and raising disease awareness is of particular importance • Accurate screening and diagnosis is crucial for optimal management of depressive patients • Escitalopram is effective and well tolerated in the late life depressed patients – both in acute and continuation treatment 88
  88. 88. Final thought In 1890, Vincent van Gogh painted this picture. Seen by some as symbolizing the despair and hopelessness felt in depression. Van Gogh himself suffered from depression and committed suicide later that same year. 89

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