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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). STAR*D Changed Our Working Definition of Treatment Resistance. Either is a treatment failure. 2 failed treatments = treatment resistance.

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STAR*D Changed Our Working Definition of Treatment Resistance

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

  2. 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 STAR*D Level 2 Overview Rush AJ, et al. N Engl J Med. 2006;54:1231-1242.

  3. Remission Rates by Levels1By QIDS-SR16 ≤5 Overall Remitted1 (To the nearest %) (n) Level Level 11 (3671) 37 Level 21,2 (1439) 31 Switch (789) Augment (650) Level 33 (377) 14 Switch (235) Augment (142) Level 44 (109) 13 QIDS-SR16 = Quick Inventory of Depressive Symptomatology, Self-Rated 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.

  4. L2 therapy + lithium N = 69 L2 therapy + T3 N = 73 MRT N = 114 NTP N = 121 STAR*D Defining Evidence for Protocols—Level 3 Nonremitting or intolerant tofirst 2 prescribed medications Level 3: Level 3 options: SWITCH OPTIONS Randomized AUGMENT OPTIONS Randomized RESULTS: 14% remission rate overall (QIDS-SR16<5 at exit) Remission happened, on average, after 9.6 weeks MRT = mirtazapine; NTP = nortriptyline; T3 = triiodothyronine. Nierenberg AA, et al. Am J Psychiatry. 2006;163:1519-1530.

  5. STAR*D Defining Evidence for Protocols—Level 4 Nonremitting or intolerant to any Level 3 therapy Level 4: Level 4 options: TCP N = 58 VEN-XR+ MRT N = 51 SWITCH OPTIONS Randomized RESULTS: 13% remission rate overall (QIDS-SR16< 5 at exit) TCP = tranylcypromine; VEN-XR = venlafaxine extended release; MRT = mirtazapine. McGrath PJ, et al. Am J Psychiatry. 2006;163:1531-1541.

  6. Cognitive therapy (CT) is both an acceptable switch and an acceptable augmentation option in the 2nd step1 Benefit of CT as augmentation was slower (up to3 weeks) compared with augmenting with medication2 If time to response is of the essence, then CT may not be the best option2 Whether CT responders/remitters fare better in follow-up is to be analyzed2 CT was not as popular as expected (26% chose it), which limited these results’ statistical power1 Cognitive Therapy 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. 1/3 of mothers with major depressive disorder had children with psychiatric symptoms1 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 symptoms1 As the mother improved, so did the child—measurably for 6 months; tapering after that2 Children of late-remitting mothers showed same improvements2 STAR*D-Child Study 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 The less likely patients are to respond to step 1 and step 2 treatments As anxiety symptoms with depression increase The more likely they are to experience adverse effects The more likely they are to have greater side effect burden Nelson JC. Am J Psychiatry. 2008;165:297-299.

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

  10. People with greater side effect burden prefer switching to a new medication vs augmenting1,2,3 People most amenable to cognitive therapy have more education and/or a family history of mood disorders3,4 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 burden5,6,7 T3 deserves consideration as an augment drug when 2 treatments fail5 MAOI administration should be left to specialists who have experience using this drug class7 Despite differences in presumed mechanism of action, patient outcomes did not differ significantly according to which drug(s) they took1,2,6 Takeaway Messages from Levels 2–4 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 • 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. • 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. • 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. • 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. • 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. • Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007;164:201-204. • 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. • 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. • 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. • 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.

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