DEPRESSION IN LATER LIFE:DEPRESSION IN LATER LIFE:IS IT TIME FOR PREVENTION?IS IT TIME FOR PREVENTION?

Charles F. Reynolds Ⅲ,M.D.Charles F. Reynolds Ⅲ,M.D.

Intervention Research Center forIntervention Research Center for

Late-Life Mood DisordersLate-Life Mood Disorders

Department of PsychiatryDepartment of Psychiatry

University of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicine

Support: National Institute of Mental Health , Forest Laboratories, GlaxosmithKlincSupport: National Institute of Mental Health , Forest Laboratories, GlaxosmithKlinc

THE RROSPECT STUDYTHE RROSPECT STUDY

Prevention of Suicide In Primary Prevention of Suicide In Primary

Care Elderly: Collaborative TrialCare Elderly: Collaborative Trial

Cornell

University of Pennsylvania

University of Pittsburgh

Late-life Depression: Late-life Depression: Causes and EffectsCauses and Effects

Disease

Disability

Psychosocial

Stressors

Genetics

Depression

SuicideAnxiolytie Dependence, Alcoholism

Cognitive Impairment DisabilityMedical Symptoms

Health Care Utilization

Mortality

A PUBLIC HEALTH RATIONALE FOR A PUBLIC HEALTH RATIONALE FOR PREVENTIVE TREATMENT OF PREVENTIVE TREATMENT OF

DEPRESSION IN OLD AGEDEPRESSION IN OLD AGE

• Depression in old age Depression in old age

- is common- is common

- has serious health consequences- has serious health consequences

- contributes to global burden of illness - contributes to global burden of illness related related

disabilitydisability

- is a risk factor for suicide- is a risk factor for suicide

- is a relapsing, recurrent, and chronic - is a relapsing, recurrent, and chronic illnessillness

FACTORS CONTRIBUTING TOFACTORS CONTRIBUTING TO RELAPSING CHRONIC ILLNESS COURSE RELAPSING CHRONIC ILLNESS COURSE

IN LATE LIFE DEPRESSIONIN LATE LIFE DEPRESSION

• • Psychosocial factors:Psychosocial factors:

- Role transitions, bereavement, increasing - Role transitions, bereavement, increasing

dependency, interpersonal conflictsdependency, interpersonal conflicts

• • Progressive depletion of psychosocial Progressive depletion of psychosocial resourcesresources

• • Chronic sleep disturbancesChronic sleep disturbances

• • Risk factors for cerebrovascular diseaseRisk factors for cerebrovascular disease

• • Neurodegenerative disordersNeurodegenerative disorders

• • Limited access to adequate treatmentLimited access to adequate treatment

Prevalence of Late-life Depression by Prevalence of Late-life Depression by Health/Independence StatusHealth/Independence Status

0

10

20

30

40

50

60

70

CommunityResidents

Chronically inPrimay CareOutpatients

HospitalizedPatient

Cognitively IntactNursing Home

Patients

Per

cen

t

Data represent a composite of multiple status

Major Depression Depressive Symptoms

Goals Of TreatmentGoals Of Treatment

• Mortality and health care costs

• Depressive symptoms

• Relapse and recurrence

• Quality of life

• Medical health status

NIH consensus Conference on Diagnosis and Treatment of Depression

In Late Life. JAMA. 1992;268:1018

PROSPECT GOAL:PROSPECT GOAL:

• To test the effectiveness of an To test the effectiveness of an intervention in preventing and intervention in preventing and reducing:reducing:

• • Suicidal ideation and behaviorSuicidal ideation and behavior

• • HopelessnessHopelessness

• • Depressive symptomatologyDepressive symptomatology

in a representative sample of older in a representative sample of older patients in primary care.patients in primary care.

BACKGROUND:BACKGROUND:

• The elderly have the highest suicide rates in The elderly have the highest suicide rates in US.US.

• Old white males are at the greatest risk.Old white males are at the greatest risk.• Late life suicide victims typically see their Late life suicide victims typically see their

primary care physicians in the month prior to primary care physicians in the month prior to death.death.

• The majority of older suicide victims have had The majority of older suicide victims have had their first depressive episode in late life.their first depressive episode in late life.

• Although effective treatments exit, depression Although effective treatments exit, depression is often not detected or treated by the primary is often not detected or treated by the primary care physician.care physician.

PROSPECT’S INTERVENTION:PROSPECT’S INTERVENTION:GUIDELINE MANAGEMENTGUIDELINE MANAGEMENT

Identification of Diagnosis

Physician Education Patient & Family Psycho-Education

DEPRESSION SPECIALIST

TREATMENT ALGORITHM&

FEATURES OF TREATMENT ALGORITHMFEATURES OF TREATMENT ALGORITHM

• The algorithm is based on AHCPR Practice Guideline The algorithm is based on AHCPR Practice Guideline for the Treatment of Depression in Primary Care.for the Treatment of Depression in Primary Care.

• The algorithm is modified for treatment of the elderly The algorithm is modified for treatment of the elderly at the primary care office.at the primary care office.

• Guidelines use psychopharmacological (SSRI), Guidelines use psychopharmacological (SSRI), psychosocial, and other interventions based on psychosocial, and other interventions based on individual needs.individual needs.

• Psychiatric consultation is offered in complex cases.Psychiatric consultation is offered in complex cases.

• The guidelines encompass Acute, continuation, and The guidelines encompass Acute, continuation, and Maintenance Treatment.Maintenance Treatment.

• The paths address a wide range of syndromes ranging The paths address a wide range of syndromes ranging from mild to very severe depression.from mild to very severe depression.

SUBJECT SELECTION:SUBJECT SELECTION:

GOALS: GOALS: 1.Obtain a sample representative of practice population 1.Obtain a sample representative of practice population 2.Over-sample patients with depression and the very old 2.Over-sample patients with depression and the very old

DESIGN: DESIGN: Use a stratified , two stage random sampling strategyUse a stratified , two stage random sampling strategy

Total Practice

Age 60-74 Age 75+

50% of

Age 60-74

100% of

Age 75+

CES-D < 11CES-D

> 11

10% 100%

Identify age-eligible, Community dwelling patients

Screen by telephone with CES-D

Results of screen

Interview in person with SCID

PRIMARY CARE PRACTIVESPRIMARY CARE PRACTIVES

SELECTION:SELECTION:

• Primary care practices selected in pairs, similar onPrimary care practices selected in pairs, similar on • • location (urban vs. suburban)location (urban vs. suburban) • • Degree of academic affiliationDegree of academic affiliation • • Ethnic an racial composition of patients Ethnic an racial composition of patients

RANDOMIZATION:RANDOMIZATION:• Within pairs, practices randomly assigned to:Within pairs, practices randomly assigned to: • • low level intervention (“enhanced care”)low level intervention (“enhanced care”) • • high level intervention (“guideline management”)high level intervention (“guideline management”)

New York Philadelphia

Pittsburgh

LONGITUDINAL DESIGN:LONGITUDINAL DESIGN:PATIENT ASSESSMENTSPATIENT ASSESSMENTS

0 244 8 12 16 20

Baselin

e

Follow

-up

Telephon

e Telephon

e Telephon

e Follow

-u

p

Telephone

months

Summary of PROSPECT Data on Sampling and Summary of PROSPECT Data on Sampling and ScreeningScreening 4/1/024/1/02

81,185 patient appointments81,185 patient appointments -- 16,704 sampled for CESD screening-- 16,704 sampled for CESD screening

54.2% were eligible and completed screening54.2% were eligible and completed screening 27.6% refused screening27.6% refused screening 7.5% were ineligible7.5% were ineligible

Of 9,136 CESD’s completed, 1,107(11.4%) screened positive.Of 9,136 CESD’s completed, 1,107(11.4%) screened positive.

Patients who screened positive plus a 5% sample of screened Patients who screened positive plus a 5% sample of screened negative patients were invited to participate in the study.negative patients were invited to participate in the study.

In addition to the sampled patients, 68 patients who were not In addition to the sampled patients, 68 patients who were not sampled were invited to participate in the study.sampled were invited to participate in the study.

Summary of PROSPECT Data on Assessments Summary of PROSPECT Data on Assessments 4/1/024/1/02

1,276 sampled and referred patients have 1,276 sampled and referred patients have completed baseline assessment.completed baseline assessment.

By using a high cut off score on the By using a high cut off score on the CESD(>20),PROSPECT was able to optimize CESD(>20),PROSPECT was able to optimize its specificity(.925).its specificity(.925).

428(33.5%) met SCID/DSM-IV criteria for 428(33.5%) met SCID/DSM-IV criteria for major depressionmajor depression

256(20.1%) had treatable minor depression256(20.1%) had treatable minor depression

PROSPECT Enrollment DataPROSPECT Enrollment Data

Total enrollment: 1276 subjects, including 874 white and 347 blackTotal enrollment: 1276 subjects, including 874 white and 347 black889 women and 365 men889 women and 365 men

Of 1313 patients who signed consent, 329(25.1%) terminated from all participation Of 1313 patients who signed consent, 329(25.1%) terminated from all participation in the study(including 28 prior to completing the baseline interview).in the study(including 28 prior to completing the baseline interview).

Mortality: 49 PROSPECT subjects have died, 1 by suicide (gun shot) and 48 by Mortality: 49 PROSPECT subjects have died, 1 by suicide (gun shot) and 48 by natural causesnatural causes

Psychiatric hospitalization: 11Psychiatric hospitalization: 11

Refusal of further participation: 133Refusal of further participation: 133

Treatment discontinuation due to supervening medical problems or dementia: 332Treatment discontinuation due to supervening medical problems or dementia: 332

PROSPECT Hypothesis TestingPROSPECT Hypothesis Testing

HYPOTHESIS:HYPOTHESIS:Compared to usual care, PROSPECT intervention is Compared to usual care, PROSPECT intervention is

associated at four months follow-up with a greater associated at four months follow-up with a greater reduction in depression, defined by 50% reduction reduction in depression, defined by 50% reduction in HDRS scores(“response”) and by absolute in HDRS scores(“response”) and by absolute change in HDRS scores.change in HDRS scores.

TESTING:TESTING:Mixed effect logistic regression and binary models forMixed effect logistic regression and binary models forbinary and continuous outcomes;binary and continuous outcomes;Radon effects corresponded to the primary care Radon effects corresponded to the primary care

practicepractice

PROSPECT 4-Month OutcomesPROSPECT 4-Month Outcomes

• Overall, and at each site , the response rate was Overall, and at each site , the response rate was greater in intervention versus usual care greater in intervention versus usual care practices(41.1% versus 27.4%) in unadjusted practices(41.1% versus 27.4%) in unadjusted (p<.028) and adjusted (p<.024) analyses.(p<.028) and adjusted (p<.024) analyses.

• Factors that were also significantly associated Factors that were also significantly associated with response included baseline diagnosis (MDD with response included baseline diagnosis (MDD versus minor), gender, and study site.versus minor), gender, and study site.

• The PROSPECT intervention was associated with a The PROSPECT intervention was associated with a significantly greater decrease in HDRS scores(-7.3 significantly greater decrease in HDRS scores(-7.3 vs –3.7) in both unadjusted (p<.001) and vs –3.7) in both unadjusted (p<.001) and adjusted (p<.001) analyses.adjusted (p<.001) analyses.

PROSPECTPROSPECT

• Total Depression Remission RateTotal Depression Remission Rate

• • (202/331 =61.03%)(202/331 =61.03%)

• CaucasianCaucasian

• • (161/238 =67.65%)(161/238 =67.65%)

• African AmericanAfrican American

• • (33/73 =45,21%)(33/73 =45,21%)

Remission Rates in Depressed Primary Care Remission Rates in Depressed Primary Care Elderly: PROSPECT Intervention PracticesElderly: PROSPECT Intervention Practices

• 94/126(74.6%) subjects who entered treatment 94/126(74.6%) subjects who entered treatment remittedremitted

• 22/126 dropped out 22/126 dropped out ¹¹¹ ¹ Reasons for attrition:

death(n=1)

Relocation(n=2)

medical problem(n=1)

severe psychiatric complications(n=4)

treatment refusal(n=12)

other(n=2)

(Reynolds et al., unpublished PROSPECT data, June 2001)

Depression Remission Rates in Depression Remission Rates in Primary Care Primary Care

Elderly:PROSPECT Elderly:PROSPECT Usual Care PracticesUsual Care Practices

• 23/86 (27%) intention to treat23/86 (27%) intention to treat

• 23/58 (40%) completer23/58 (40%) completer

(Reynolds et al., unpublished PROSPECT data, June 2001)

Remission Rate in Elderly Depressed Remission Rate in Elderly Depressed Patients:Patients:

Primary Care Versus Mental Health SectorPrimary Care Versus Mental Health Sector

• Primary care: 94/126(74.6%) Primary care: 94/126(74.6%) 11 • Specialty Mental Health: 101/129(78%) Specialty Mental Health: 101/129(78%) 22

63/116(54%) 63/116(54%) 33

11 PROSPECT (MH59381) PROSPECT (MH59381)

22 Maintenance Therapies in Late-Life Depression(MH43832) Maintenance Therapies in Late-Life Depression(MH43832)

33 Nortriptyline vs Paroxetine(MH52247) Nortriptyline vs Paroxetine(MH52247)

PROSPECTPROSPECTPercent with Suicide Ideation(Hamilton Item)Percent with Suicide Ideation(Hamilton Item)

Among Depressed Patients(N=135)Among Depressed Patients(N=135)

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

Baseline 4 months 5 months 12 months

Control

Intervention

HD

RS

Su

icid

e

Item

PROSPECTPROSPECTPercent with Suicide Ideation(SSI>0)Percent with Suicide Ideation(SSI>0)Among Depressed Patients(N=133)Among Depressed Patients(N=133)

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

Baseline 4 months 5 months 12 months

Control

Intervention

SS

I>0

PROSPECT SignificancePROSPECT Significance

PROSPECT seeks to test the effectiveness of PROSPECT seeks to test the effectiveness of its intervention in older primary care its intervention in older primary care patients whose clinical and demographic patients whose clinical and demographic characteristics suggest high risk for characteristics suggest high risk for suicide.suicide.

Response, Remission, Recovery, Response, Remission, Recovery, Relapse,Relapse,

Recurrence & ChronicityRecurrence & Chronicity

‘Normalcy’

Symptoms

Syndrome

Remission

ResponseRelapse

Recovery

Recurrence

Incomplete

recovery

Chronicity

Treatment phases

Acute Continuation

MaintenanceTime

Severl

ty

Kupfer,1991

pro

gre

ssion

to

diso

rder

Risk of RecurrenceRisk of Recurrence

• Angst,1990 75%Angst,1990 75%

• Ernst & Angst,1992 80-90%Ernst & Angst,1992 80-90%

• Kessler, 1994 80-90%Kessler, 1994 80-90%

• Prien,1984 80%Prien,1984 80%

• Lee & Murray, 1988 95%Lee & Murray, 1988 95%

• Frank & Kupfer,1990 80%Frank & Kupfer,1990 80%

Survival Analysis: Recurrence Rates of Major Depressive Survival Analysis: Recurrence Rates of Major Depressive EpisodesEpisodes

Cu

mu

lati

ve P

rop

ort

ion

Wit

h N

o

Recu

rren

ce

Weeks in Maintenance

Reynolds et al., JAMA 1999; 281(1):39-45.

Social Adjustment ScaleSocial Adjustment Scale

-30

-25

-20

-15

-10

-5

0

5

10

Med

ian

%

ch

an

ge

groupPlanned contrast, F (1.46)=7.15, r=0.18, p=0.01

Lenze, Dew et al., American Journal of Psychiatry,2002

Survival Analysis: Recurrence Survival Analysis: Recurrence Rates Rates

of Major Depression Episodeof Major Depression EpisodeC

um

ula

tive P

rop

ort

ion

Wit

h N

o R

ecu

rren

ce

Weeks in Maintenance

Reynolds et al., JAMA 1999; 281(1);39-45

Survival Analysis: Recurrence Survival Analysis: Recurrence Rates Rates

of Major Depression Episodeof Major Depression EpisodeC

um

ula

tive P

rop

ort

ion

Wit

h N

o R

ecu

rren

ce

Weeks in Maintenance

Reynolds et al., JAMA 1999; 281(1);39-45

Survival Analysis – Time to Relapse/Recurrence Survival Analysis – Time to Relapse/Recurrence on Paroxetine/Nortriptyline Continuation on Paroxetine/Nortriptyline Continuation

PharmacotherapyPharmacotherapy

Months in continuation Treatment

Cu

mu

lati

ve P

rop

ort

ion

Wit

h N

o R

ecu

rren

ce

Bump.Mulart et al., Depression and Anxiety 13:38-44,2001

Time to Recurrence of Major Depressive Episodes in Time to Recurrence of Major Depressive Episodes in MTLD-Ⅱ: Preliminary DataMTLD-Ⅱ: Preliminary Data

Surv

ival D

istr

ibuti

on

Fu

nct

ion

Weeks from Randomization

Mean Time to Recurrence of Major Mean Time to Recurrence of Major DepressiveDepressive

Episodes in MTLD-Ⅱ: Preliminary DataEpisodes in MTLD-Ⅱ: Preliminary Data

ParoxetinParoxetinee

(n=52)(n=52)

77 weeks77 weeks

PlaceboPlacebo

(n=43)(n=43)

43 weeks43 weeks

Maintenance Therapies in Late Life Depression:Maintenance Therapies in Late Life Depression:Optimizing and Maintaining Cognitive FunctioningOptimizing and Maintaining Cognitive Functioning

N=200 N=50

Cit+DONN=70-80

Cit+PBON=70-

80

Elderly Depressed Subjects

Elderly Non-Depressed

Treatment with CIT

8 Weeks: With Venlat if HRSD<30%

12 weeks: With Ven if HRSD>10

Response:HRSD 17<=10

Treatment up to 2 years

Cognitive Assignment:

T1: Post-depression treatment

T2: 3 Months

T3: 12 months

T4: 24 months

POSSIBLE APPROACHES TO PRIMARY POSSIBLE APPROACHES TO PRIMARY PREVENTION OF DEPRESSION PREVENTION OF DEPRESSION

IN OLD AGE IN OLD AGE

APPROACHES TO PRIMARY APPROACHES TO PRIMARY PREVENTION --RATIONALEPREVENTION --RATIONALE

• Certain groups of elderly persons are at high risk for Certain groups of elderly persons are at high risk for developing new onset or recurrent depression:developing new onset or recurrent depression:

- Bereavement- Bereavement

- Care giving- Care giving

- Chronic insomnia- Chronic insomnia

- Medically ill- Medically ill

۰۰ Especially myocardial infarction, stroke, high Especially myocardial infarction, stroke, high cerebrovascular risk burden, macular degeneration, cerebrovascular risk burden, macular degeneration, osteoarthritis, cancerosteoarthritis, cancer

- Early dementia- Early dementia

- Early signs of depression- Early signs of depression

HOPE: Risk Reduction HOPE: Risk Reduction With ACE InhibitionWith ACE Inhibition

-40

-35

-30

-25

-20

-15

-10

-5

0

CVD death Nor MI Stroke CABG/PTCA New-onsetdiabetes

*P<.0001

↑P=.002

The HOPE Study Investigation. N Engl J Med. 2000:342:145-153

%

25%*

20%*

31%*

16%*

32%*

What is practiced?What is practiced?

Geriatric depression is linked to:Geriatric depression is linked to:

• increased utilization of health care increased utilization of health care servicesservices

• More frequent use of multiple medicationsMore frequent use of multiple medications

• Longer hospital staysLonger hospital stays

• Increased demands on nursing home timeIncreased demands on nursing home time

• Under treatment in primary careUnder treatment in primary care

TYPES OF APPROACHES TO PRIMARY TYPES OF APPROACHES TO PRIMARY PREVENTION-OPPORTUNITIESPREVENTION-OPPORTUNITIES

FOR PREVENTIONFOR PREVENTION

• Pharmacotherapy or cognitive behavioral therapy Pharmacotherapy or cognitive behavioral therapy of chronic insomniaof chronic insomnia

• Problem solving therapy or CBT for patients with Problem solving therapy or CBT for patients with chronic medical disorders and disabilitychronic medical disorders and disability

• Social rhythm therapy for recently bereaved Social rhythm therapy for recently bereaved elderlyelderly

• Information, affective self-management, stress Information, affective self-management, stress management, and education in health sleep management, and education in health sleep practices for Alzheimer care giverspractices for Alzheimer care givers

What is known?What is known?

• Geriatric depression responds well to Geriatric depression responds well to treatment.treatment.

• There is a relatively low rate of treatment There is a relatively low rate of treatment resistance to adequate treatment.resistance to adequate treatment.

• Maintenance therapies work to prevent Maintenance therapies work to prevent recurrence.recurrence.

• There is much treatment response There is much treatment response variability.variability.