דיכאון בגיל מבוגר

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CipralexLate life depression

The good life has no age

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A broad selection of slides

• The set contains slides that will be of interest to different audiences: nurses, pharmacists, general practitioners, geriatricians and psychiatrists

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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

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Introduction

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Introduction

Depression in older people is

• often missed• under recognised• untreated

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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

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“It is not enough to add years to one’s life…one must also add life to those years”

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Epidemiology

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Prevalence of depression in late life

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

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40

Community elders1,2 Primary care3,4 Nursing homes2

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Major depression Minor depression

5%

15%

10%

20%

15–30%

25–40%

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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.

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Encourage help-seeking

behaviour

Reduce stigma

Raise disease awareness

Broader goals of depression treatment should not be forgotten

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What is different about late life depression?

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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

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• 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.

Ciechanowski et al. 2000 Arch Intern Med 2000 160(21):3278-3285.

The extensive impact of depression

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• Altered pharmacokinetics and pharmacodynamics• End-organ physiological changes• Coexisting medical conditions• Cognitive decline• Polypharmacy• Social isolation

Factors affecting prognosis and pharmacotherapy

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• 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

Specific risk factors for depression in late life

Cole & Dendukuri (Am J Psychiatry 2003; 160:1147–1156) 2003

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What is the added effect of depression on the

well-being of a patient who also suffers from a

chronic medical condition?

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Poorer mean health scores with comorbidity

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

19Gallegos-Carrillo et al. J Psychosom Res 2009; 66: 127–135

Quality of life in older adults with and without depressive symptoms and chronic diseases

Without depressive symptoms and without chronic diseases

Without depressive symptoms and with ≥2 chronic diseases

With depressive symptoms and without chronic diseases

With depressive symptoms and with ≥2 chronic diseases

Physical functioning

Physical role

Bodilypain

General health

Vitality Social functioning

Emotionalrole

Mental health

Physical component summary

Mental component summary

GDS-15 ≤5 (n=795)

GDS-15 >6 (n=290)

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HRQOL scales and summary scores, SF-36

HRQOL: Health related quality of life GDS: Geriatric Depression Scale

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Depression is often associated with anxiety in the elderly

Lenze et al. Am J Psychiatry 2000; 157: 722–728

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45

50

Per

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Primary care patients with MDD

(n=36)

Psychiatric setting outpatients with MDD

(n=40)

Psychiatric setting inpatients with MDD

(n=40)

One or more anxiety disorders during lifetime

Two or more anxiety disorders during lifetime

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Fatality from suicide increases with age

WHO, 2000

5–14 15–24 75+65–7455–6445–5435–4425–34

Age group (years)

Rat

e (p

er

100

000)

Male

Female

0

60

50

40

30

20

10

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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): 572–5812 Lenze et al. Dialogues Clin Neurosci 2008; 10(4): 419–430

3 Vannoy et al. Am J Geriatr Psychiatry 2007; 15(12): 1024–1033

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Population ageing

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The demographic transition

The increasing proportion of elderly will impact upon the burden of diseases

The UN estimates that the number of 80–89-year olds will increase 5-fold from 2000–2050

Ag

e

80

60

40

20

10 05 5 10Percentage

FemaleMale

1950

Population pyramids


2000


2050

60+

0–59

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Populations are ageing across the world

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

0

1.0

2.0

3.0

4.0

5.0

4.5

3.5

2.5

1.5

0.5

World total Africa Asia Europe Latin America

& Caribbean

Northern America

Oceania

Per

cen

tag

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2002 2025

Percent of the population aged ≥80 years

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The average age is increasing

World Population Prospects: The 2006 Revision United Nations Population Division

Evolution of the population of Europe by broad age groups

0255075

100125150175200225250275300325350375400425450475

1950

1955

1960

1965

1970

1975

1980

1985

1990

1995

2000

2005

2010

2015

2020

2025

2030

2035

2040

2045

2050

Mil

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15–59 0–14

60+

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Life expectancy is increasing

*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

US Department of Commerce, Bureau of the Census

Past and projected female and male life expectancy at birth (US, 1900–2050)

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Yea

rs o

f li

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1900* 1910* 1920* 1930* 1940 1950 1960 1980 19901970 2000 2010 2020 2030 2040 2050

Projection

Female

Male

84.3

79.7

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Life expectancy – 65 does not necessarily mean that life is coming to an end …

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

National Vital Statistics Reports, 2007 (Volume 56; Number 9)

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

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Screening and diagnostic tools

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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)

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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)

3. Almeida et al. Int J Geriat Psychiatry 14, 858-865 (1999)

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Geriatric Depression Scale 15 items

• Answers ticked indicate depression, and each score one point

• 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

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

3. Do you feel that your life is empty? Yes No

4. Do you often get bored? Yes No

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 No

7. Do you feel happy most of the time? Yes No

8. Do you often feel helpless? Yes No

9. Do you prefer to stay at home, rather than going out and doing new things? Yes No

10. Do you feel you have more problems with memory than most? Yes No

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 No

13. Do you feel full of energy? Yes No

14. Do you feel that your situation is hopeless? Yes No

15. Do you think that most people are better off than you are? Yes No

Total score 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)

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Treatment

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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

Treatment phases

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What key factors influence our selection of antidepressants for the late life population ?

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Key factors influencing selection

• Overall efficacy

• Safety and tolerability

• Potential to interact

• Control of co-morbid anxiety

• Healthcare costs

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Antidepressant usage increases with age

Smith & Tett. Drugs Aging 2009; 26 (2): 113–122

120

100

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00–4 5–14 15–24 25–34 35–44 45–54 55–64 65–74 75–84 ≥85

Age (years)

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DD

/100

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2003

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2006

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An inappropriate imbalance?

SSRIs

TCAs

SNRIs

Other

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80

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100

Per

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35–44 ≥65

Age groups (years)

Smith & Tett. Drugs Aging 2009; 26 (2): 113–122

SSRIs = Fluvoxamine, fluoxetine, escitalopram, paroxetine, citalopram and sertralineTCAs = Dothiepin and amitriptyline; SNRIs = Venlafaxine; Other = Mirtazapine

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Cipralexin late life depression

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Escitalopram prevents relapse in older patients with major depressive disorder

Gorwood et al.

Am J Geriatr Psychiatry 2007; 15: 581–593

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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

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Study design

Period IAcute treatment

(12-week, open label)

Period IIContinuation treatment(24 weeks, double-blind)

W12 W36 W37

Escitalopram fixed dose (10 or 20 mg)

PlaceboTAPER

TAPERRelapseMADRS 22 or lack of efficacy

Remitters onlyMADRS 12

Escitalopram 10 or 20 mgFlexible dose for the first 6-week

n=405

n=152

n=153

W0W-1

Run in

MADRS 22

RelapseMADRS 22 or lack of efficacy

W13


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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

Gender, women, n (%) 313 (77) 119 (78) 121 (79)

MADRS=Montgomery-Åsberg Depression Rating Scale; MMSE=Mini-Mental State Examination CGI-I=Clinical Global Impression – Improvement; CGI-S=Clinical Global Impression – Severity

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Kaplan-Meier analysis of relapse over 24 weeks


• 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

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Treatm ent w eek

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Escitalopram

Placebo

p<0.001 vs placebo (log-rank test)Hazard ratio for time to relapse: 4.44Number needed to treat: 5

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Secondary outcome measures

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

• 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

Response rates (≥50% reduction in MADRS score; CGI-I ≤2)

Res

po

nse

ra

te (

%)

Study week

*** *** *** *** ***

50

60

70

80

90

100

12 13 14 16 20 24 28 32 36

MADRS escitalopram (n=152)

MADRS placebo (n=153)

CGI-I escitalopram (n=152)

CGI-I placebo (n=153)

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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%


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Tolerability improves over time


≥ 1 AE DizzinessHeadacheNausea Diarrhoea

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40

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60 Open-label escitalopram (n=405)

Taper escitalopram (n=152)

Taper placebo (n=153)

Week 2 to completionescitalopram (n=130)

Week 2 to completion placebo(n=91)

*

Taper = 2-week dose adjustment period following randomisation to double-blind treatment*Patients tapering from escitalopram to placebo

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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

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Escitalopram in the long-term treatment of Major Depressive Disorder in elderly patients

Kasper et al.

Neuropsychobiology 2006; 54: 152–159

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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

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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 225

Age, years, mean (SD) 74 (6)

Gender, women, % 82%

MMSE=Mini-Mental State Examination; MADRS=Montgomery-Åsberg Depression Rating Scale

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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)


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Tolerability – extension study

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)


AEs reported in ≥5% of patients

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

CGI-S scores• Start extension study: 2.6; End extension study: 1.6 (OC)• This decrease confirms the clinical relevance of the efficacy results


Treatment week of extension study (OC)

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MADRS scores, mean (LOCF):Start extension study: 13.4End extension study: 8.5

LOCF

LOCF=Last observation carried forward

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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

Kasper et al. Neuropsychobiology 2006; 54: 152–159Response = ≥50% reduction in lead-in study baseline MADRS scoreRemission = MADRS ≤12

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Patients in remission – extension study

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Kasper et al. Neuropsychobiology 2006; 54: 152–159Intent-to treat population; LOCF; Remission = MADRS ≤12

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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

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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 congressMunich, Germany, 2008

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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

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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

*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

66–75 years >75 years Total

Patients, n** 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)

1. Möller et al Nervenarzt 2007; 78:685–690


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Change in svMADRS score from baseline to Week 8

• 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)


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Treatment week

66–75 years (n=1,295)>75 years (n=755)

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Response and remission

Response• 63.9% of patients were responders

• 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)

• Positive factors significantly affecting response: • 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

Möller et al. Poster presented at CINP, 2008Response = ≥50% decrease of svMADRS total score from baselineRemission = svMADRS total score ≤12

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Change from baseline to Week 8 on CGI-S and CGI-I

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%)


0 2 4 6 8-2.0

-1.6

-0.4

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GI-

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Treatment week

66–75 years (n=1,295)

>75 years (n=755)-0.2

-1.0

-0.6

-0.8

-1.8

-1.2

-1.4

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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

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%)


AEs possibly or probably related to treatment

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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

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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

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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

Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209MADRS=Montgomery-Åsberg Depression Rating Scale; HAM-A=Hamilton Rating Scale for Anxiety; SF-36=36-item Short-Form health survey

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 20

Age, years, mean (SD) 73.0 (4.8)

Sex, women, n (%) 6 (30)

69

Changes from baseline in MADRS and HAM-A scores after 12 weeks of escitalopram (10–20 mg/day) treatment


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)

MADRS HAM-A0

5

10

15

20

Mea

n (

SD

) ch

ang

e in

sco

re

*

*

70

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

n=20; LOCF; Response = ≥50% improvement from baseline to endpoint Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209

MADRS HAM-A0

10

40

50

70

Per

cen

tag

e o

f p

atie

nts

res

po

nd

ing

20

30

60

71

Quality of life and social functioning before and after 12 weeks of escitalopram treatment

n=18; LOCF; *p<0.01 vs baseline based on paired-samples t test Mohamed et al. Am J Geriatr Pharmacother 2006; 4: 201–209

Role functioning –

emotional

Role functioning –

physical

Social functioning

Physical functioning

0 20 40 60 80

Mean (SD) SF-36 score

*

*

0 20 40 60 80

Mean (SD) SF-36 score

*

*

Baseline

Week 12

Generalhealth

Pain

Energy/fatigue

Mental health

72

Tolerability

• 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

Completers, n (%) 17 (85)

Discontinuation, n (%) 3 (15)

Discontinuation due to AEs, n (%) 2 (10)

Discontinuation due to lack of efficacy, n (%) 1 (5)


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

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

75


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

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

Patients, n 18* 22

Age, years, mean (SEM) 76.2 (1.8) 76.9 (1.8)

Gender, women, n (%) 14 (77.8) 16 (72.7)

*22 patients were enrolled, but 4 withdrew before Week 4 and were excluded from the analysisGDS=Geriatric Depression Scale; MMSE=Mini-Mental State Examination

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

78

Identity recognition memory performance

Prior to escitalopram treatment• Depressive patients have lower identity recognition memory performance

than healthy age-matched 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


d’ (

iden

tity

rec

og

nit

ion

)

Control

0.5

1.0

1.5

Happy faces Angry faces

Depressed

p=0.018

p=0.046

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


81

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

82

Drug interactions

83

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)

Spina et al. Clin Therapeutics 2008; 30 (7): 1206–1227

84

Health economics

85

5 10 15 20 25 30 35

Calcium antagonists

Erythropoietins

Oral anti-diabetics

Anti-epileptics

All other Antineoplastics

Antidepressants and moodstabilisers

Antipsychotics

Antiulcerants

Cholesterol and triglycerideregulators

Depression alone is costly

Global drug costs by therapy area1

1. IMS Knowledgelink 2. Berto P et al. 2000. The Journal of Mental Health Policy and Economics. 3: 3-10.

World sales ($US dollars)

12 month period to Q2 2008

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Dir

ec

t C

os

ts (

%)

Drugs

Consultations

Hospital admissions

Other

Depression treatment: cost distribution2

A B C D E F G STUDY

86

Escitalopram vs citalopram – healthcare costs in the late life population

Wu et al. Curr Med Res Opin 2008; 24 (9): 2587–2595

Comparison of 6-month healthcare costs per patient by sensitivity analysis

Citalopram

Escitalopram

5,000

10,000

15,000

20,000

25,000

Co

st (

$)

0Total

drug costTotal medical

costTotal

healthcare costs

p=0.049

p<0.001p<0.001

18,94519,899

1,756 1,547

9,855

11,604

87

Conclusion

88

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

89

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.

דיכאון בגיל מבוגר

Health & Medicine

introduction depression

ageing depression

prevalence of depression

cipralex late life depression

inevitable depression

late life populationwittchen

geriatric depression

depression cole dendukuri