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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 • National Institute for Mental Health • Bristol-Myers Squibb • Forest Pharmaceuticals • Aspect Medical Systems Disclosures None of my slides and/or handouts contain any advertising, trade names or productgroup messages. Any treatment recommendations I make will be based on clinical evidence or guidelines. Ira Lesser, M.D. Harbor-UCLA Medical Center 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 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 Definitions of Response and Remission % Reduction in Score Remission >75% Response 50% - 74% Partial Response 25% - 49% Nonresponse <25% 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. Staging Treatment Resistance Stage I Inadequate response to 1 monotherapy Stage II Inadequate response to 2 adequate monotherapy trials (different classes) Stage III Stage II resistance plus inadequate response to 1 augmentation trial Stage IV Stage III resistance plus inadequate response to a second augmentation trial Stage IV resistance plus inadequate response to bilateral ECT Stage V Adapted from: Thase ME, Rush AJ. J Clin Psychiatry. 1998;59(suppl 5):5 Souery D et al. Eur Neuropsychopharmacol. 1999;9:83 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 Efficacy vs Effectiveness Randomized Clinical Trials 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 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 Center Dallas, Texas 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” Why Remission Was the End Point Remitters have less disability, better role function, life satisfaction, and less recurrences 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 Median Weeks to Relapse* Following Response 250 231 Weeks 200 150 100 50 68 0 Improved Without Remission (n = 82 ) Remission (n = 155) *Relapse defined as onset of new major depressive episode. Adapted from Judd LL et al. J Affect Disord. 1998;50:97-108. 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 STAR*D Overview - II 14 Regional Centers 41 Clinical Sites 18 Primary Care Settings 23 Psychiatric Care Settings 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 Participants Major depressive disorder Nonpsychotic Representative primary and specialty care practices (nonacademic) Self-declared patients Inclusion Criteria Clinician deems antidepressant medication indicated. 18-75 years of age. Baseline HRSD17 14. Most concurrent Axis I, II, III disorders allowed. Multiple Research Outcomes Symptoms Function Side effect burden Patient and clinician satisfaction Utilization and costs of health care services 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 Level 1 Findings Demographic Baseline Features (N=2876) Age (yrs.) % Female Race % White % African-American % Others % Latino Age Groups 18-30 years 31-50 years 51+ years Education (yrs.) Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 40.8 (13.0) 63.7 75.8 17.6 6.6 13.0 26.2 48.0 25.8 13.4 (3.2) Demographic Baseline Features (N=2876) Education < High School High School < College > College Insurance Private Public None % Primary Care Household Income ($ mo.) Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 % 12.6 62.2 25.2 51.1 14.2 34.7 37.9 Mean (SD) 2358 (3030) Social Baseline Features (N=2876) Marital Status Never Married Married Divorced Widowed Employment Status Employed Unemployed Retired Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 % 28.7 41.7 26.5 3.1 56.2 38.2 5.6 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 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 Majority Had Concurrent Axis I Disorders at Baseline (N=2876) 40 35 34.8 30 % 26.6 25 20 16.5 15 12.9 9.2 10 5 0 0 1 2 3 # Concurrent Axis I Disorders Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 > or = 4 Concurrent Baseline Axis I Disordersa (N=2876) Generalized Anxiety Dis. Obsessive Compulsive Dis. Panic Disorder Social Phobia Posttraumatic Stress Dis. Agoraphobia Alcohol Abuse/Dependence Drug Abuse/Dependence Somatoform Dis. Hypochondriasis Bulimia Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 a % 23.6 14.3 13.1 31.3 20.6 11.8 12.1 7.4 2.4 4.4 13.0 Defined by PDSQ. 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 Treatment Outcome: Level 1 (N=2876) 100 90 80 70 60 % 50 47 40 HRSD-17 QIDS-SR-16 27.5 30 20 32.9 10 0 Response Remission 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 Similar Outcomes in Primary and Psychiatric Care Settings (N=2876) 100 90 % 80 QIDS-SR-16 Response 70 HRSD-17 Remission 60 50 40 30 48 46 26.6 28 20 10 0 Primary Care Trivedi et al., Am J Psychiatry 2006;163:28-40 Psychiatric Care 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 Of Ultimate Remitters, 1/2 Remitted by Week 6 52.9% 25.0 22.1 Percent 20.0 n=2,876 19.4 Remission= QIDS-SR16 < 5 14.5 15.0 12.9 12.9 11.4 10.0 10.0 5.0 0.0 2 4 Trivedi et al., Am J Psychiatry, 163(1):28-40, 2006 6 8 Weeks 10 12 >13 Remission vs. Non-Remission: Significant Baseline Differences Female gender Being employed Caucasian (vs. AfricanAmerican) Being married or cohabitating 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 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 Level 2 Findings Level 2 Randomize SER BUP-SR VEN-XR Switch Options CT CIT + CIT + CIT + CT BUP-SR BUS Augmentation Options 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 Level 2 Medication Switch Treatment Outcomes: Level 2 Switch (% remission) 30 HRSD-17 QIDS-SR-16 26.6 25.5 24.8 25.0 21.3 20 17.6 Percent 10 0 BUP-SR SERT (N-239) (N = 238) Rush et al., N Engl J Med 2006;354(12):1231-42 VEN-XR (N = 250) Level 2 Medication Augmentation Treatment Outcomes: Level 2 Augmentation (% remission) 50 HRSD-17 39.0 40 30 QIDS-SR-16 29.7 32.9 30.1 Percent 20 10 0 BUP-SR (N = 279) Trivedi et al., N Engl J Med 2006;354(12):1243-52 BUS (N = 286) 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 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 Level 2 Cognitive Therapy Findings 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 Treatment Outcomes (% Remission) (L-2 CT vs. Med Switch) 40 HRSD-17 QIDS-SR-16 30.6 30 27.9 26.7 25.0 Percent 20 10 0 CT (N = 36) Thase et al., in preparation MED (N = 86) Treatment Outcomes (% Remission) (L-2 CT vs. Med Augment) 40 HRSD-17 QIDS-SR-16 30.8 33.3 33.3 30 23.1 Percent 20 10 0 CT (N = 65) Thase et al., in preparation MED (N = 117) CT Conclusions CT is both an acceptable switch and augmentation option in the second step Benefit of CT as augmentation was slower (up to 3 weeks) compared to augmenting with medication Whether CT responders/remitters fare better in follow-up is to be analyzed CT was not as popular as expected, thus limiting statistical power Level 3 Randomize MRT Switch NTP L-2 Tx + Li L-2 Tx + THY Augmentation Level 3 Treatment Features Medication switch • Mirtazapine mean final dose was 42.1 mg • Nortriptyline mean final dose was 96.8 mg Medication augmentation • Lithium mean final dose was 860 mg • T3 mean final dose was 45 μg Treatment Outcomes: Level 3 Switch (% Remission) 30 HRSD-17 QIDS-SR-16 19.8 20 Percent 12.4 12.3 10 8.0 0 MIRT (N = 114) Fava et al., Am J Psychiatry, in press NTP (N = 121) Treatment Outcomes: Level 3 Augmentation (% remission) 30 HRSD-17 QIDS-SR-16 24.7 24.7 20 15.9 Percent 13.2 10 0 Nierenberg et al., Am J Psychiatry, submitted Lithium Thyroid (N = 69) (N = 73) Summary: Level 3 (switch) Remission rates (<20%) and side effect profiles with nortriptyline and mirtazapine were not different Low remission rates raises questions about sequential use of single agents after two failed trials, even with different pharmacologic action Summary: Level 3 (augment) Remission rates with switching was modest, at best Remission rates augmenting with Li or Thyroid hormone were not different Questions as to whether lithium was adequately dosed T3 augmentation was better tolerated Level 4 Randomize TCP VEN-XR + MRT Switch Treatment Outcomes: Level 4 (% Remission) 20 HRSD-17 QIDS-SR-16 15.7 13.8 13.7 Percent 10 6.9 0 TCP (N = 58) McGrath et al., Am J Psychiatry, submitted VEN + MIRT (N = 51) Summary: Level 4 Mean doses/day:Tranylcypromine=37mg; Venlafaxine=210mg; Mirtazapine=36mg Dosing was lower than might have been expected Tranylcypromine required a washout and had higher early dropouts Overall remission rates were low, with no difference between treatments VEN-XR/MIRT had some advantages (tolerability) over TCP Remission Rates by Levelsa a Level 1 (2876) 32.9 Level 2 (1439) Switch (789) Augment (650) 30.6 27.0 35.0 Level 3 (377) Switch (235) Augment (142) 13.6 10.3 19.1 Level 4 (109) 14.7 By QIDS-SR16 <5 at level exit Follow-up Findings Follow up Follow up was naturalistic; visits recommended every two months Patient were told to continue what was effective before, but any medication dose change or psychotherapy was allowed Response and remission defined by QIDS-SR score as in acute phase; relapse defined by QIDS-SR > 11 (~ equal to HAM-D of 14) Level 1 Follow-Up 1 0.75 Cumulative 0.5 Probability 0.25 Yes Remission No 0 0 p < 0.0001 Relapse = QIDS-IVR16 > 11 3 6 Months in Follow-Up 9 12 Level 2 Follow-Up 1 0.75 Cumulative 0.5 Probability 0.25 Yes Remission No 0 0 p < 0.0001 Relapse = QIDS-IVR16 > 11 3 6 Months in Follow-Up 9 12 Level 3 Follow-Up 1 0.75 Cumulative 0.5 Probability 0.25 Yes Remission No 0 0 p < 0.0132 Relapse = QIDS-IVR16 > 11 3 6 Months in Follow-Up 9 12 Level 4 Follow-Up 1 0.75 Cumulative 0.5 Probability 0.25 Yes Remission No 0 0 p < 0.1387 Relapse = QIDS-IVR16 > 11 3 6 Months in Follow-Up 9 12 Relapse in Follow-up for Participants Remitting with Different Numbers of Acute Treatment Steps p<.0001 1 Step 2 Steps (N=1085) (N=383) Relapse = QIDS-IVR16 > 11. 3 Steps 4 Steps (N=35) (N=15) Relapse in Follow-up for Participants Not remitting to Different Numbers of Acute Treatment Steps 1 Step 2 Steps 3 Steps 4 Steps (N=388) (N=237) (N=66) (N=34) p<.0001 Relapse = QIDS-IVR16 > 11. Summary: Follow Up Failure to reach remission during acute treatment portends a worse prognosis • Remitters at entry to F/U had better prognosis than those who improved, but did not remit • Relapse rates were higher for those who entered F/U after more acute treatment steps • For those who relapse, mean time to relapse was shorter for those who required >2 steps Conclusions Cumulative remission rate is over 50% with first 2 steps Both within-class and out-of-class switches are equally effective (level 2) The duration of acute treatment needed to see response was 8-10 weeks With careful symptom and medication review results are similar in primary and specialty care Patient preference plays a big role in strategy selection Conclusions Pharmacologic distinctions do not lead to large clinical differences Cognitive therapy is viable switch or augmenting option, though many chose not to partake in it It is important not to change course too quickly nor to give up on multiple sequential strategies Psychosocially disadvantaged patients did more poorly and may need innovative approaches Future Directions Further analyze the cognitive therapy data Report multiple sub-analyses We need newer approaches to the treatment refractory patient Develop new medications and treatment protocols to address non-remission, e.g. should patients with chronic depression be started on two medications simultaneously? What about combination medication and psychotherapy approaches? The STAR*D Study Investigators National Coordinating Center University of California, Los Angeles A. John Rush, MD Andrew Leuchter, MD Madhukar H. Trivedi, MD Ira Lesser, MD Diane Warden, PhD, MBA Ian Cook, MD Melanie M. Biggs, PhD Daniel Castro, MD Kathy Shores-Wilson, PhD University of California, San Diane Stegman, RNC Diego Michael Kashner, PhD, JD Sidney Zisook, MD Data Coordinating Center Ari Albala, MD Stephen R. Wisniewski, PhD Timothy Dresselhous, MD G.K. Balasubramani, PhD Steven Shuchter, MD James F. Luther, MA Terry Schwartz, MD Heather Eng, BA. Northwestern University University of Alabama Medical School, Chicago Lori Davis, MD William T. McKinney, MD William S. Gilmer, MD The STAR*D Study Investigators University of Kansas, Wichita New York State Psychiatric and Clinical Research Institute and Columbia Institute College of Physicians and Sheldon H. Preskorn, MD Surgeons, New York Ahsan Khan, MD Frederic M. Quitkin, MD Massachusetts General Patrick J. McGrath, MD Hospital, Boston Jonathan W. Stewart, MD Jonathan Alpert, MD Harold Sackeim, PhD Maurizio Fava, MD University of North Carolina, Andrew A. Nierenberg, MD Chapel Hill University of Michigan, Ann Arbor Robert N. Golden, MD Elizabeth Young, MD Bradley N. Gaynes, MD Michael Klinkman, MD Sheila Marcus, MD The STAR*D Study Investigators Laureate Healthcare System, The University of Texas Tulsa Southwestern Medical Jeffrey Mitchell, MD Center, Dallas William Yates, MD Mustafa M. Husain, MD University of Pittsburgh Michael Downing, MD Medical Center, Pittsburgh Diane Stegman, RNC Michael E. Thase, MD Laurie MacLeod, RN Edward S. Friedman, MD Vanderbilt University Medical Virginia Commonwealth University, Richmond Center, Nashville Susan G. Kornstein, MD Steven Hollon, PhD Richard Shelton, MD Robert K. Schneider, MD Pharmaceutical Industry Support STAR*D medications were provided gratis by Bristol-Myers Squibb Company, Forest Pharmaceuticals Inc., GlaxoSmithKline, King Pharmaceuticals, Organon Inc., Pfizer Inc., and Wyeth-Ayerst Laboratories. References Rush AJ, Fava M, Wisniewski SR et al: Sequenced Treatment Alternatives to Treat Depression (STAR*D): rationale and design. Control Clin Trials 2004; 25:119-142 Trivedi MH, Rush AJ, Wisniewski SR et al: Evaluation of outcomes with citaloprram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 2006; 163:1-13 Rush AJ, Trivedi M, Wisniewski SR et al: Bupropion-SR, sertraline, or Venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006;354:1231-42 Trivedi MH, Rush AJ, Wisniewski SR et al: Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006;354:1243-1252 References Fava M, Rush AJ, Wisniewski SR et al: A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry 2006;163:1161-1172 Insel T: Beyond efficacy: the STAR*D Trial. Am J Psychiatry 2006; 163:5-7 Nierenberg AA, Fava M, Trivedi MH et al: A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry 2006;163:1519-1530 McGrath PJ, Stewart JW, Fava M et al: Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: A STAR*D report. Am J Psychiatry 2006:163:1531-1541 References Rush AJ, Trivedi MH Wisniewski SR et al: Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-1917 Rubinow DR: Treatment strategies after SSRI failure—good news and bad news. N Engl J Med 2006;354:1305-1307 Valenstein M: Keeping our eyes on STAR*D. Am J Psychiatry 2006;163:1484-1486 Menza M: STAR*D: the results begin to roll in. Am J Psychiatry 2006; 163:1123-1125 Nelson CJ: The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry 2006;163:1864-1866 Rush AJ: STAR*D: What have we learned? Am J psychiatry 2007;164:201-204Insel T: Beyond efficacy: the STAR*D Trial. Am J Psychiatry 2006; 163:5-7