1. STAR*D Changed Our Working Definition of Treatment Resistance People who are intolerant to drugs regardless of dosage OR People who receive vigorous dosing but receive inadequate benefit (ie, do not remit) Rush AJ, et al. Am J Psychiatry. 2006;163:1905-1917. Either is a treatment failure. 2 failed treatments = treatment resistance

2. STAR*D Level 2 Overview 4 switch options and 3 augment options If someone had a clear medication intolerance or <25% decrease in symptom severity by week 9 on an adequate dose, then that person was encouraged to move to the next treatment level Overall remission rate at Level 2 was 31% 1 in 4 people who switched treatments remitted in Level 2 1 in 3 people who augmented the citalopram treatment remitted in Level 2 It matters less which drug is chosen than how the drug is used No advantages in switching patients in class, out of class, or switching to a dual-action antidepressant Substantial pharmacologic differences in classes of drugs don’t translate into differences in efficacy Rush AJ, et al. N Engl J Med. 2006;54:1231-1242.

3. Remission Rates by Levels 1 By QIDS-SR 16 ≤5 Level 1 1 (3671)37 Level 2 1,2 (1439)31 Switch (789) Augment (650) Level 3 3 (377)14 Switch (235) Augment (142) Level 4 4 (109)13 Level Overall Remitted 1 (To the nearest %) (n) 1. Rush AJ, et al. Am J Psychiatry. 2006;163:1905-1917. 2. Wisnieweski SR, et al. Am J Psychiatry. 2007;164:753-760. 3. Nierenberg AA, et al. Am J Psychiatry. 2006;163:1519-1530. 4. McGrath PJ, et al. Am J Psychiatry. 2006;163:1531-1541. QIDS-SR 16 = Quick Inventory of Depressive Symptomatology, Self-Rated

4. SWITCH OPTIONS Randomized STAR*D Defining Evidence for Protocols—Level 3 AUGMENT OPTIONS Randomized L2 therapy + lithium N = 69 NTP N = 121 Nonremitting or intolerant to first 2 prescribed medications Level 3: Level 3 options: MRT = mirtazapine; NTP = nortriptyline; T 3 = triiodothyronine. Nierenberg AA, et al. Am J Psychiatry. 2006;163:1519-1530. MRT N = 114 L2 therapy + T 3 N = 73 RESULTS: 14% remission rate overall (QIDS-SR 16 <5 at exit) Remission happened, on average, after 9.6 weeks

5. SWITCH OPTIONS Randomized STAR*D Defining Evidence for Protocols—Level 4 Nonremitting or intolerant to any Level 3 therapy Level 4: Level 4 options: TCP = tranylcypromine; VEN-XR = venlafaxine extended release; MRT = mirtazapine. McGrath PJ, et al. Am J Psychiatry. 2006;163:1531-1541. TCP N = 58 VEN-XR + MRT N = 51 RESULTS: 13% remission rate overall (QIDS-SR 16 < 5 at exit)

6. Cognitive Therapy Cognitive therapy (CT) is both an acceptable switch and an acceptable augmentation option in the 2nd step 1 Benefit of CT as augmentation was slower (up to 3 weeks) compared with augmenting with medication 2 If time to response is of the essence, then CT may not be the best option 2 Whether CT responders/remitters fare better in follow-up is to be analyzed 2 CT was not as popular as expected (26% chose it), which limited these results’ statistical power 1 1. Wisniewski SR, et al. Am J Psychiatry. 2007;164:753-760. 2. Thase ME, et al. Am J Psychiatry. 2007;164:739-752.

7. STAR*D-Child Study 1/3 of mothers with major depressive disorder had children with psychiatric symptoms 1 The children’s symptoms eased when maternal depression remitted or at least responded (a 50% drop in symptoms) 1 If the mother remained depressed, 17% of symptom- free children started manifesting Axis I symptoms 1 As the mother improved, so did the child— measurably for 6 months; tapering after that 2 Children of late-remitting mothers showed same improvements 2 1. Weissman MM, et al. JAMA. 2006;295:1389-1398. 2. Pilowsky DJ, et al. Am J Psychiatry. AJP in Advance. June 16, 2008.A1A:1-12.

8. Ancillary Study—Anxious Depression Nelson JC. Am J Psychiatry. 2008;165:297-299. As anxiety symptoms with depression increase The less likely patients are to respond to step 1 and step 2 treatments The more likely they are to experience adverse effects The more likely they are to have greater side effect burden

9. Overall Predictors of Attrition Black race Younger age Higher perceived functioning Black race Less education Greater side effect burden Hispanic ethnicity More Axis 1 comorbidities Immediate attrition if … Later attrition if … >1 MDD episode Older age Lower attrition if … Warden D, et al. Am J Psychiatry. 2007;164:1189-1197.

10. Takeaway Messages from Levels 2–4 People with greater side effect burden prefer switching to a new medication vs augmenting 1,2,3 People most amenable to cognitive therapy have more education and/or a family history of mood disorders 3,4 People with 2 failed treatments will take longer to achieve remission (often 10–14 weeks) 1 Treatment-resistant cases will have greater treatment intolerance and greater side effect burden 5,6,7 T 3 deserves consideration as an augment drug when 2 treatments fail 5 MAOI administration should be left to specialists who have experience using this drug class 7 Despite differences in presumed mechanism of action, patient outcomes did not differ significantly according to which drug(s) they took 1,2,6 1. Rush AJ, et al. Am J Psychiatry. 2006;163:1905-1917. 2. Rush AJ, et al. N Engl J Med. 2006;54:1231-1242. 3. Wisniewski SR, et al. Am J Psychiatry. 2007;164:753-760. 4. Thase ME, et al. Am J Psychiatry. 2007;164:739-752. 5. Nierenberg AA, et al. Am J Psychiatry. 2006;163:1519-1530. 6. Rush AJ. Am J Psychiatry. 2007;164:201-204. 7. McGrath PJ, et al. Am J Psychiatry. 2006;163:1531-1541.

11. Suggested Readings 1. Rush AJ, Trievdi NJ, 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. 2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;54:1231-1242. 3. Wisniewski SR, Fava M, Trivedi MH, et al. Acceptability of second-step treatments to depressed outpatients: a STAR*D report. Am J Psychiatry. 2007;164:753-760. 4. Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication in augmentation and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry. 2007;164:739-752. 5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T 3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163:1519- 1530. 6. Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007;164:201-204. 7. 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. 8. Warden D, Trivedi MH, Davis L, et al. Predictors of attrition during initial (citalopram) treatment for depression: a STAR*D report. Am J Psychiatry. 2007;164:1189-1197. 9. Pilowsky DJ, Wickramaratne P, Tag M, et al. Children of depressed mothers 1 year after initiation of maternal treatment: findings from the STAR*D study. Am J Psychiatry. AJP in Advance June 16, 2008:AiA1-12. 10. Ladsen L. STAR*D study leaders at UT Southwestern test two-drug approach to depression in new CO-MED trial. Press release. July 22, 2008. http://www.eurekalert.org/pub_releases/2008-07/usmc- ssl072108.php. Accessed August 10, 2008.