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WHAT CAN WE LEARN FROM STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

WHAT CAN WE LEARN FROM STAR*D (Sequenced Treatment Alternatives to Relieve Depression). Ira Lesser, M.D. Chair, Department of Psychiatry Harbor-UCLA Medical Center Professor, Department of Psychiatry and Biobehavioral Sciences Geffen School of Medicine at UCLA. DISCLOSURES. Grant support

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WHAT CAN WE LEARN FROM STAR*D (Sequenced Treatment Alternatives to Relieve Depression)

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  1. WHAT CAN WE LEARN FROM STAR*D(Sequenced Treatment Alternatives to Relieve Depression) Ira Lesser, M.D. Chair, Department of Psychiatry Harbor-UCLA Medical Center Professor, Department of Psychiatry and Biobehavioral Sciences Geffen School of Medicine at UCLA

  2. DISCLOSURES • Grant support • National Institute for Mental Health • Bristol-Myers Squibb • Forest Pharmaceuticals • Aspect Medical Systems

  3. Disclosures • None of my slides and/or handouts contain any advertising, trade names or product-group messages. Any treatment recommendations I make will be based on clinical evidence or guidelines. Ira Lesser, M.D. Harbor-UCLA Medical Center

  4. Focus of Presentation • Discuss consequences of untreated/partially treated depression • Discuss treatment resistant depression • Discuss research approaches to study this, e.g. efficacy vs effectiveness trials • Discuss the STAR*D trial and methodology • Discuss the STAR*D results and implications for clinical practice

  5. Health Burden Of Depression • MDD is common and recurrent and can be disabling • Lifetime prevalence ~ 10-15% • Women are affected more than men • Over 2/3 of people have recurrences • Depressed adults have twice the annual health care costs as non-depressed • World-wide is the 4th most disabling medical condition, climbing to 2nd by 2020

  6. Remission >75% Response 50% - 74% Partial Response 25% - 49% Nonresponse <25% Definitions of Response and Remission % Reduction in Score

  7. Nonremission is Common • 35–45% remission • 10–20% response with residual symptoms • 15% partial response • 25% nonresponse • 7–15% intolerant Depression in Primary Care, Vol. 2. Treatment of Major Depression. Rockville, MD: US Dept. of Health and Human Services, AHCPR Publication No. 93-0550, 1993.

  8. Staging Treatment Resistance Adapted from: Thase ME, Rush AJ. J Clin Psychiatry. 1998;59(suppl 5):5Souery D et al. Eur Neuropsychopharmacol. 1999;9:83

  9. Pharmacological Options After Failure of First Antidepressant • Optimize dose and address adherence • Change to another antidepressant • Same class • Different class • Add a second antidepressant • Add a non-antidepressant • Lithium or other mood stabilizer • Thyroid hormone • Psychostimulant • Atypical antipsychotic

  10. EFFICACY Aims for pure populations Assesess safety and efficacy Co-morbid conditions excluded Rates for MDD response are about 50%, 20-30% remission EFFECTIVENESS Looks for “real world” subjects Assesess effectivenenss Co-morbid conditions are OK Rates for MDD response are low Efficacy vs Effectiveness Randomized Clinical Trials

  11. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Trial Rationale and Design(www.star-d.org) A. John Rush, M.D.University of Texas Southwestern Medical CenterDallas, Texas

  12. Importance of STAR*D • The largest clinical trial of depression ever • Conducted in primary care as well as psychiatric settings • Few exclusion criteria, making it “real world” • Included large numbers of minority patients • Included cognitive therapy • Combined randomization and patient choice • The outcome was “remission” rather than “response”

  13. Why Remission Was the End Point Remitters have less disability, better role function, life satisfaction, and less recurrences

  14. Consequences of Nonremission • Poor function (e.g., work, family) • Poor prognosis (e.g., increased recurrence) • Psychiatric or general medical complications (e.g., substance abuse) • Health service utilization • Death from: • Medical comorbidities • Suicide • Treatment resistance

  15. Median Weeks to Relapse* Following Response 250 231 200 150 Weeks 100 68 50 0 Remission (n = 155) Improved Without Remission (n = 82 ) *Relapse defined as onset of new major depressive episode. Adapted from Judd LL et al. J Affect Disord. 1998;50:97-108.

  16. STAR*D Overview - I • Duration: 7 years (October 1999 - September 2006) • Funding: National Institute of Mental Health • National Coordinating Center, UT Southwestern Medical Center, Dallas • Data Coordinating Center, Pittsburgh

  17. STAR*D Overview - II • 14 Regional Centers • 41 Clinical Sites • 18 Primary Care Settings • 23 Psychiatric Care Settings

  18. Overall Aim of STAR*D • Define preferred treatments for patients who failed one SSRI • All subjects begin on citalopram • Doses are maximized • Remitters enter follow-up • If no remission, go to level 2 and subsequent levels

  19. Participants • Major depressive disorder • Nonpsychotic • Representative primary and specialty care practices (nonacademic) • Self-declared patients

  20. Inclusion Criteria • Clinician deems antidepressant medication indicated. • 18-75 years of age. • Baseline HRSD17 14. • Most concurrent Axis I, II, III disorders allowed.

  21. Multiple Research Outcomes • Symptoms • Function • Side effect burden • Patient and clinician satisfaction • Utilization and costs of health care services

  22. Clinical Procedures • Open treatment with randomization • Symptoms/side effects measured at each clinical visit • Clinicians guided by algorithms/supervision • Dose adjustments”mandatory” to achieve remission (QIDS-C16) • Education for all patients

  23. Level 1 Findings

  24. Demographic Baseline Features(N=2876) Age (yrs.) 40.8 (13.0) % Female 63.7 Race % White 75.8 % African-American 17.6 % Others 6.6 % Latino 13.0 Age Groups 18-30 years 26.2 31-50 years 48.0 51+ years 25.8 Education (yrs.) 13.4 (3.2) Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  25. Demographic Baseline Features(N=2876) Education % < High School 12.6 High School < College 62.2 > College 25.2 Insurance Private 51.1 Public 14.2 None 34.7 % Primary Care 37.9 Mean (SD) Household Income ($ mo.) 2358 (3030) Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  26. Social Baseline Features(N=2876) Marital Status % Never Married 28.7 Married 41.7 Divorced 26.5 Widowed 3.1 Employment Status Employed 56.2 Unemployed 38.2 Retired 5.6 Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  27. Clinical Baseline Features(N=2876) % Recurrent Depression 75.7 Onset age < 18 yrs. 37.8 Positive Family History of Depression 55.5 History of Attempted Suicide 17.9 Current MDE > 24 months 25.3 Anxious Depression 53.2 Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  28. Clinical Baseline Features(N=2876) Mean (SD) HRSD17 (ROA) 21.8 (5.2) QIDS-SR16 16.2 (4.0) Age at First Onset (yrs.) 25.3 (14.4) # of MDEs 6.0 (11.4) Length of Current MDE (mos.) 24.6 (51.7) Length of Illness (yrs.) 15.5 (13.2) Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  29. Majority Had Concurrent Axis I Disorders at Baseline(N=2876) % # Concurrent Axis I Disorders Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  30. Concurrent Baseline Axis I Disordersa(N=2876) % Generalized Anxiety Dis. 23.6 Obsessive Compulsive Dis. 14.3 Panic Disorder 13.1 Social Phobia 31.3 Posttraumatic Stress Dis. 20.6 Agoraphobia 11.8 Alcohol Abuse/Dependence 12.1 Drug Abuse/Dependence 7.4 Somatoform Dis. 2.4 Hypochondriasis 4.4 Bulimia 13.0 a Defined by PDSQ. Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  31. Treatment and Symptom Outcomes (n=2876) • Response (without remission) • 50% decrease in baseline QIDS-SR16 • Remission • HAMD17< 7 • QIDS-SR16< 5 • Citalopram • Dose (at level exit): 41.8 mg (S.D. 16.8) • Duration: 10.0 weeks (S.D. 4.2) Trivedi et al., Am J Psychiatry 2006;163:28-40

  32. Treatment Outcome: Level 1(N=2876) HAMD-17=17-item Hamilton Rating Scale for Depression QIDS-SR-16=16-item Quick Inventory of Depressive Symptomatology – Self-Report Trivedi et al., Am J Psychiatry 2006;163:28-40

  33. Similar Outcomes in Primary and Psychiatric Care Settings(N=2876) % Trivedi et al., Am J Psychiatry 2006;163:28-40

  34. Remission vs. Non-remission • Remitters stayed in treatment longer (12 vs. 9.3 weeks) • Remitters stayed on final dose longer (6.6 vs. 4.4 weeks) • Remitters had less side effect burden

  35. Of Ultimate Remitters,1/2 Remitted by Week 6 52.9% n=2,876 Remission= QIDS-SR16< 5 Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006

  36. Female gender Being employed Caucasian (vs. African-American) Being married or co-habitating Being more educated Having private insurance Having less medical problems Having less psychiatric co-morbidities Lower baseline severity Better baseline physical and mental function Greater life satisfaction Shorter current episode Remission vs. Non-Remission: Significant Baseline Differences

  37. Summary: Level 1 • Over one-third of patients have been depressed for >2 years and 2/3 have concurrent GMCs • About 1/3 will remit • Response occurs in ~1/2 AFTER 6 weeks • Measurement Based Care is feasible and works • Studies of remission require longer study periods than 8 weeks • When protocol-based care is given, results are equivalent in primary and specialty care

  38. Level 2 Findings

  39. Randomize CIT +CT CIT +BUP-SR CIT +BUS SER BUP-SR VEN-XR CT Level 2 SwitchOptions AugmentationOptions

  40. Acceptability of Treatment Options • 41% chose only to have medication switch • 30% chose only to have medication augmentation • 11% chose to have any augmentation (meds or CBT) • 7% chose to have any switch (meds or CBT) • 1.4% chose to have any available option

  41. Level 2 Medication Switch

  42. Treatment Outcomes: Level 2 Switch(% remission) (N-239) (N = 238) (N = 250) Rush et al., N Engl J Med2006;354(12):1231-42

  43. Level 2 Medication Augmentation

  44. Treatment Outcomes: Level 2 Augmentation(% remission) (N = 279) (N = 286) Trivedi et al., N Engl J Med2006;354(12):1243-52

  45. Summary: Level 2 (switch) • Mean doses/day: bupropion=282.7mg; sertraline=135mg; venlafaxine=193mg • ~ 25% achieve remission after switching to another antidepressant • No significant differences among various antidepressants in achieving remission: changing class of medication did not make a difference • Intolerance to citalopram did not predict intolerance to sertraline • Perhaps venlafaxine dose too low

  46. Summary: Level 2 (augment) • Mean doses/day: bupropion=267mg; buspirone=41mg • ~ 30% achieve remission augmenting citalopram, with no absolute difference between treatments • Citalopram plus bupropion led to greater degree of improvement across subjects • Bupropion was better tolerated

  47. Level 2 Cognitive Therapy Findings

  48. Cognitive Therapy Arm • Certification process for CT therapists • Session twice weekly for weeks 1-4, then once weekly for remaining 8 weeks (16 visits) • If there was response without remission, could offer additional 8 sessions • 469/1439 (26%) of those eligible chose CT as a possible option • 65 switched to CT; 36 augmented with CT

  49. Treatment Outcomes (% Remission)(L-2 CT vs. Med Switch) (N = 36) (N = 86) Thase et al., in preparation

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