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

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.

Remission Rates by Levels1

By QIDS-SR16 ≤5

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

Level Overall Remitted1

(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-SR16 = Quick Inventory of Depressive Symptomatology, Self-Rated

SWITCH OPTIONSRandomized

STAR*D Defining Evidence for Protocols—Level 3

AUGMENT OPTIONSRandomized

L2 therapy + lithium

N = 69

NTPN = 121

Nonremitting or intolerant tofirst 2 prescribed medicationsLevel 3:

Level 3 options:

MRT = mirtazapine; NTP = nortriptyline; T3 = triiodothyronine.

Nierenberg AA, et al. Am J Psychiatry. 2006;163:1519-1530.

MRTN = 114

L2 therapy + T3

N = 73

RESULTS: 14% remission rate overall (QIDS-SR16 <5 at exit)Remission happened, on average, after 9.6 weeks

SWITCH OPTIONSRandomized

STAR*D Defining Evidence for Protocols—Level 4

Nonremitting or intolerant to any Level 3 therapyLevel 4:

Level 4 options:

TCP = tranylcypromine; VEN-XR = venlafaxine extended release; MRT = mirtazapine.

McGrath PJ, et al. Am J Psychiatry. 2006;163:1531-1541.

TCPN = 58

VEN-XR+ MRTN = 51

RESULTS: 13% remission rate overall (QIDS-SR16 < 5 at exit)

Cognitive Therapy 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

1. Wisniewski SR, et al. Am J Psychiatry. 2007;164:753-760. 2. Thase ME, et al. Am J Psychiatry. 2007;164:739-752.

STAR*D-Child Study

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

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.

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

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.

Takeaway Messages from Levels 2–4 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

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.

Suggested Readings1. 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 T3 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.