1. DEPRESSION IN LATER LIFE: IS IT TIME FOR PREVENTION? Charles F. Reynolds Ⅲ,M.D. Intervention Research Center for Late-Life Mood Disorders Department of Psychiatry University of Pittsburgh School of Medicine Support: National Institute of Mental Health, Forest Laboratories, GlaxosmithKlinc

2. THE RROSPECT STUDY Prevention of Suicide In Primary Care Elderly: Collaborative Trial Cornell University of Pennsylvania University of Pittsburgh

3. Late-life Depression: Causes and Effects Disease Disability Psychosocial Stressors Genetics Depression Suicide Anxiolytie Dependence, Alcoholism Cognitive Impairment Disability Medical Symptoms Health Care Utilization Mortality

4. A PUBLIC HEALTH RATIONALE FOR PREVENTIVE TREATMENT OF DEPRESSION 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 related - contributes to global burden of illness related disability disability - is a risk factor for suicide - is a risk factor for suicide - is a relapsing, recurrent, and chronic illness - is a relapsing, recurrent, and chronic illness

5. FACTORS CONTRIBUTING TO RELAPSING CHRONIC ILLNESS COURSE IN LATE LIFE DEPRESSION Psychosocial factors: Psychosocial factors: - Role transitions, bereavement, increasing - Role transitions, bereavement, increasing dependency, interpersonal conflicts dependency, interpersonal conflicts Progressive depletion of psychosocial resources Progressive depletion of psychosocial resources Chronic sleep disturbances Chronic sleep disturbances Risk factors for cerebrovascular disease Risk factors for cerebrovascular disease Neurodegenerative disorders Neurodegenerative disorders Limited access to adequate treatment Limited access to adequate treatment

6. Prevalence of Late-life Depression by Health/Independence Status Percent Data represent a composite of multiple status Major Depression Depressive Symptoms

7. Goals Of Treatment Mortality and health carecosts 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

8. PROSPECT GOAL: To test the effectiveness of an intervention in preventing and reducing: To test the effectiveness of an intervention in preventing and reducing: Suicidal ideation and behavior Suicidal ideation and behavior Hopelessness Hopelessness Depressive symptomatology Depressive symptomatology in a representative sample of older patients in primary care. in a representative sample of older patients in primary care.

9. BACKGROUND: The elderly have the highest suicide rates in US. The elderly have the highest suicide rates in US. Old white males are at the greatest risk. Old white males are at the greatest risk. Late life suicide victims typically see their primary care physicians in the month prior to death. Late life suicide victims typically see their primary care physicians in the month prior to death. The majority of older suicide victims have had their first depressive episode in late life. The majority of older suicide victims have had their first depressive episode in late life. Although effective treatments exit, depression is often not detected or treated by the primary care physician. Although effective treatments exit, depression is often not detected or treated by the primary care physician.

10. PROSPECT’S INTERVENTION: GUIDELINE MANAGEMENT Identification of Diagnosis Physician Education Patient & Family Psycho-Education DEPRESSION SPECIALIST TREATMENT ALGORITHM &

11. FEATURES OF TREATMENT ALGORITHM The algorithm is based on AHCPR Practice Guideline for the Treatment of Depression in Primary Care. The algorithm is based on AHCPR Practice Guideline for the Treatment of Depression in Primary Care. The algorithm is modified for treatment of the elderly at the primary care office. The algorithm is modified for treatment of the elderly at the primary care office. Guidelines use psychopharmacological (SSRI), psychosocial, and other interventions based on individual needs. Guidelines use psychopharmacological (SSRI), psychosocial, and other interventions based on individual needs. Psychiatric consultation is offered in complex cases. Psychiatric consultation is offered in complex cases. The guidelines encompass Acute, continuation, and Maintenance Treatment. The guidelines encompass Acute, continuation, and Maintenance Treatment. The paths address a wide range of syndromes ranging from mild to very severe depression. The paths address a wide range of syndromes ranging from mild to very severe depression.

12. SUBJECT SELECTION: GOALS: 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: Use 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 < 11 CES-D > 11 10% 100% Identify age-eligible, Community dwelling patients Screen by telephone with CES-D Results of screen Interview in person with SCID

13. PRIMARY CARE PRACTIVES SELECTION: Primary care practices selected in pairs, similar on Primary care practices selected in pairs, similar on location (urban vs. suburban) location (urban vs. suburban) Degree of academic affiliation Degree 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

14. LONGITUDINAL DESIGN: PATIENT ASSESSMENTS 02448121620 Baseline Follow-upTelephone Follow-up Telephone months

15. Summary of PROSPECT Data on Sampling and Screening 4/1/02 81,185 patient appointments -- 16,704 sampled for CESD screening -- 16,704 sampled for CESD screening 54.2% were eligible and completed screening 54.2% were eligible and completed screening 27.6% refused screening 27.6% refused screening 7.5% were ineligible 7.5% were ineligible Of 9,136 CESD’s completed, 1,107(11.4%) screened positive. Patients who screened positive plus a 5% sample of screened negative patients were invited to participate in the study. In addition to the sampled patients, 68 patients who were not sampled were invited to participate in the study.

16. Summary of PROSPECT Data on Assessments 4/1/02 1,276 sampled and referred patients have completed baseline assessment. By using a high cut off score on the CESD(>20),PROSPECT was able to optimize its specificity(.925). 428(33.5%) met SCID/DSM-IV criteria for major depression 256(20.1%) had treatable minor depression

17. PROSPECT Enrollment Data Total enrollment: 1276 subjects, including 874 white and 347 black 889 women and 365 men Of 1313 patients who signed consent, 329(25.1%) terminated from all participation 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 natural causes Psychiatric hospitalization: 11 Refusal of further participation: 133 Treatment discontinuation due to supervening medical problems or dementia: 332

18. PROSPECT Hypothesis Testing HYPOTHESIS: Compared to usual care, PROSPECT intervention is associated at four months follow-up with a greater reduction in depression, defined by 50% reduction in HDRS scores(“response”) and by absolute change in HDRS scores. TESTING: Mixed effect logistic regression and binary models for binary and continuous outcomes; Radon effects corresponded to the primary care practice

19. PROSPECT 4-Month Outcomes Overall, and at each site, the response rate was greater in intervention versus usual care practices(41.1% versus 27.4%) in unadjusted (p<.028) and adjusted (p<.024) analyses. Overall, and at each site, the response rate was greater in intervention versus usual care practices(41.1% versus 27.4%) in unadjusted (p<.028) and adjusted (p<.024) analyses. Factors that were also significantly associated with response included baseline diagnosis (MDD versus minor), gender, and study site. Factors that were also significantly associated with response included baseline diagnosis (MDD versus minor), gender, and study site. The PROSPECT intervention was associated with a significantly greater decrease in HDRS scores(-7.3 vs – 3.7) in both unadjusted (p<.001) and adjusted (p<.001) analyses. The PROSPECT intervention was associated with a significantly greater decrease in HDRS scores(-7.3 vs – 3.7) in both unadjusted (p<.001) and adjusted (p<.001) analyses.

20. PROSPECT Total Depression Remission Rate Total Depression Remission Rate (202/331 =61.03%) (202/331 =61.03%) Caucasian Caucasian (161/238 =67.65%) (161/238 =67.65%) African American African American (33/73 =45,21%) (33/73 =45,21%)

21. Remission Rates in Depressed Primary Care Elderly: PROSPECT Intervention Practices 94/126(74.6%) subjects who entered treatment remitted 94/126(74.6%) subjects who entered treatment remitted 22/126 dropped out ¹ 22/126 dropped out ¹ ¹ 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)

22. Depression Remission Rates in Primary Care Elderly:PROSPECT Usual Care Practices 23/86 (27%) intention to treat 23/86 (27%) intention to treat 23/58 (40%) completer 23/58 (40%) completer (Reynolds et al., unpublished PROSPECT data, June 2001)

23. Remission Rate in Elderly Depressed Patients: Primary Care Versus Mental Health Sector Primary care: 94/126(74.6%) 1 Primary care: 94/126(74.6%) 1 Specialty Mental Health: 101/129(78%) 2 Specialty Mental Health: 101/129(78%) 2 63/116(54%) 3 63/116(54%) 3 1 PROSPECT (MH59381) 1 PROSPECT (MH59381) 2 Maintenance Therapies in Late-Life Depression(MH43832) 2 Maintenance Therapies in Late-Life Depression(MH43832) 3 Nortriptyline vs Paroxetine(MH52247) 3 Nortriptyline vs Paroxetine(MH52247)

24. PROSPECT Percent with Suicide Ideation(Hamilton Item) Among Depressed Patients(N=135) HDRS Suicide Item

25. PROSPECT Percent with Suicide Ideation(SSI>0) Among Depressed Patients(N=133) SSI>0

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

27. Response, Remission, Recovery, Relapse, Recurrence & Chronicity ‘Normalcy’ Symptoms Syndrome Remission Response Relapse Recovery Recurrence Incomplete recovery Chronicity Treatment phasesAcuteContinuationMaintenance Time Severlty Kupfer,1991 progression to disorder

28. Risk 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%

29. Survival Analysis: Recurrence Rates of Major Depressive Episodes Cumulative Proportion With No Recurrence Weeks in Maintenance Reynolds et al., JAMA 1999; 281(1):39-45.

30. Social Adjustment Scale Median % change group Planned contrast, F (1.46)=7.15, r=0.18, p=0.01 Lenze, Dew et al., American Journal of Psychiatry,2002

31. Survival Analysis: Recurrence Rates of Major Depression Episode Cumulative Proportion With No Recurrence Weeks in Maintenance Reynolds et al., JAMA 1999; 281(1);39-45

32. Survival Analysis: Recurrence Rates of Major Depression Episode Cumulative Proportion With No Recurrence Weeks in Maintenance Reynolds et al., JAMA 1999; 281(1);39-45

33. Survival Analysis – Time to Relapse/Recurrence on Paroxetine/Nortriptyline Continuation Pharmacotherapy Months in continuation Treatment Cumulative Proportion With No Recurrence Bump.Mulart et al., Depression and Anxiety 13:38-44,2001

34. Time to Recurrence of Major Depressive Episodes in MTLD- Ⅱ : Preliminary Data Survival Distribution Function Weeks from Randomization

35. Mean Time to Recurrence of Major Depressive Episodes in MTLD- Ⅱ : Preliminary Data Paroxetine(n=52) 77 weeks Placebo(n=43) 43 weeks

36. Maintenance Therapies in Late Life Depression: Optimizing and Maintaining Cognitive Functioning N=200N=50 Cit+DON N=70-80 Cit+PBO N=70-80 Elderly Depressed SubjectsElderly 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

37. POSSIBLE APPROACHES TO PRIMARY PREVENTION OF DEPRESSION IN OLD AGE

38. APPROACHES TO PRIMARY PREVENTION --RATIONALE Certain groups of elderly persons are at high risk for developing new onset or recurrent depression: Certain groups of elderly persons are at high risk for developing new onset or recurrent depression: - Bereavement - Bereavement - Care giving - Care giving - Chronic insomnia - Chronic insomnia - Medically ill - Medically ill ۰ Especially myocardial infarction, stroke, high cerebrovascular risk burden, macular degeneration, osteoarthritis, cancer ۰ Especially myocardial infarction, stroke, high cerebrovascular risk burden, macular degeneration, osteoarthritis, cancer - Early dementia - Early dementia - Early signs of depression - Early signs of depression

39. HOPE: Risk Reduction With ACE Inhibition *P<.0001 ↑ P=.002 The HOPE Study Investigation. N Engl J Med. 2000:342:145-153 % 25%* 20%* 31%* 16%* 32%*

40. What is practiced? Geriatric depression is linked to: increased utilization of health care services increased utilization of health care services More frequent use of multiple medications More frequent use of multiple medications Longer hospital stays Longer hospital stays Increased demands on nursing home time Increased demands on nursing home time Under treatment in primary care Under treatment in primary care

41. TYPES OF APPROACHES TO PRIMARY PREVENTION-OPPORTUNITIES FOR PREVENTION Pharmacotherapy or cognitive behavioral therapy of chronic insomnia Pharmacotherapy or cognitive behavioral therapy of chronic insomnia Problem solving therapy or CBT for patients with chronic medical disorders and disability Problem solving therapy or CBT for patients with chronic medical disorders and disability Social rhythm therapy for recently bereaved elderly Social rhythm therapy for recently bereaved elderly Information, affective self-management, stress management, and education in health sleep practices for Alzheimer care givers Information, affective self-management, stress management, and education in health sleep practices for Alzheimer care givers

42. What is known? Geriatric depression responds well to treatment. Geriatric depression responds well to treatment. There is a relatively low rate of treatment resistance to adequate treatment. There is a relatively low rate of treatment resistance to adequate treatment. Maintenance therapies work to prevent recurrence. Maintenance therapies work to prevent recurrence. There is much treatment response variability. There is much treatment response variability.