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Exploring psychotherapeutic issues and agents in clinical practice

Robert H. Howland, MD, Section Editor

Psychopharmacology

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Part 2: Study Outcomes

Robert H. Howland, MD

AbSTRAcT This article reviews the main outcome findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The study compared the efficacy and tolerability of a range of antidepressant therapies through four sequen- tial levels of treatment with the goal of achieving remission. Remission rates based on the primary outcome measure (Hamilton Rating Scale for De- pression) were 28% (Level 1 citalopram), 17% to 30% (Level 2 treatments), 12% to 25% (Level 3

treatments), and 7% to 14% (Level 4 treatments). For patients not responding adequately to an initial trial of citalopram, subsequent treatment strategies may be effective. When more treat- ment steps are required, however, lower acute remission rates, greater degrees of treatment in- tolerance, and higher relapse rates during follow up are seen. There were few differences among treatments within each level related to efficacy or tolerability, although patients had clear prefer- ences for or against certain treatments.

Journal of Psychosocial nursing • Vol. 46, no. 10, 2008 21

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Psychopharmacology

T he purpose of the Se- quenced Treatment Al- ternatives to Relieve

Depression (STAR*D) study was to compare the efficacy and toler- ability of a range of diverse anti- depressant therapies through four sequential levels of treatment with the goal of achieving re- mission (Rush et al., 2004). The September article (Howland, 2008) described the design of the study. The main outcome find- ings from STAR*D are reviewed in this article.

LeveL 1 TReATMenT From July 2001 through April

2004, the study recruited 4,041 outpatients ages 18 to 75 from 18 primary care and 23 psychi- atric settings (Trivedi, Rush, et al., 2006). A total of 1,127 pa- tients exited the study for vari- ous reasons; analyzable data were available for 2,876 patients who received Level 1 treatment with citalopram (Celexa®). Nearly 80% had chronic or recurrent major depression, and most had various comorbid general medi- cal and psychiatric conditions. Remission rates were 28% (based on the Hamilton Rating Scale for Depression [HAM-D]) and 33% (based on the Quick Inventory of Depressive Symptomatology, Self-Report [QIDS-SR]). The response rate was 47% (based on the QIDS-SR). In STAR*D, remission was defined as an exit score of 7 or less on the HAM-D (primary outcome measure) or a score of 5 or less on the QIDS- SR (secondary outcome mea- sure). Response was defined as a reduction of 50% or greater on the QIDS-SR score from baseline to exit.

These Level 1 response and re- mission rates are similar to those reported in 8-week efficacy tri- als. Patients in primary care and psychiatric settings did not differ in remission or response rates. A

substantial proportion achieving response or remission at study exit did so at or after 8 weeks of treatment. Patients who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates. Longer episodes (Gilmer et al., in press), more concurrent anxiety and substance use disorders (Fava et al., 2008; Howland et al., in press), more general medical disorders, and lower baseline function and qual- ity of life were associated with lower HAM-D remission rates.

Because premature attrition from treatment may lead to worse clinical outcomes and compro- mise the integrity of clinical tri- als, pretreatment predictors of attrition (the 1,127 patients who exited the study) during acute treatment with citalopram were examined (Warden et al., 2007). Attrition was defined as imme- diate (patients who attended a baseline visit only) or later (pa- tients who attended at least one post-baseline visit but dropped out before the 12-week visit). Overall, 1,034 (26%) of the 4,041 enrolled patients dropped out of the acute phase for non- medical reasons. Of these, 34% dropped out immediately, 59% dropped out by week 12, and 7% dropped out after 12 weeks. Im- mediate attrition was associated with younger age, less education, and higher perceived mental health functioning. Later attri- tion was associated with younger age, less education, and African American race. Having had more than one episode of depression was associated with less attrition. Methods to enhance retention in order to achieve remission are needed, especially for those pa- tients at higher risk for attrition.

LeveL 2 TReATMenT At the end of Level 1 treat-

ment, 1,475 patients entered 1-

year naturalistic follow up and 1,439, advanced to Level 2. Be- cause the study allowed patients to exclude specific treatment strategies (as long as sufficient options were left that allowed a randomization between at least two different options), analyses were conducted to identify fac- tors associated with the accept- ability of the Level 2 treatments (Wisniewski et al., 2007). Of the 1,439 patients, only 1% accepted all seven treatments, 3% accepted only cognitive psychotherapy, and 26% accepted cognitive psycho- therapy alone or with medication. Thus, approximately 70% did not want cognitive psychotherapy. Most patients accepted only a switch strategy (48%) or an aug- mentation strategy (41%). Those with higher educational levels or a family history of a mood disor- der were more likely to accept cognitive psychotherapy. Patients in primary care settings and those who experienced a greater side ef- fect burden or a lower reduction in symptom severity with citalo- pram were more likely to accept a switch strategy, rather than an augmentation strategy. Those with better symptom benefit and minimal intolerance with citalo- pram preferred augmentation. Pa- tients with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy.

In the switch arm of Level 2, 727 patients were randomly as- signed to switch from citalopram to bupropion SR (Wellbutrin SR®), sertraline (Zoloft®), or ven- lafaxine XR (Effexor XR®) (Rush, Trivedi, Wisniewski, Stewart, et al., 2006). Remission rates based on the HAM-D and the QIDS- SR, respectively, were 21.3% and 25.5% for bupropion, 17.6% and 26.6% for sertraline, and 24.8% and 25% for venlafaxine. QIDS- SR response rates were 26.1% for bupropion, 26.7% for sertraline,

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Psychopharmacology

and 28.2% for venlafaxine. These treatments did not differ signifi- cantly with respect to outcomes, tolerability, or adverse events.

In the augmentation arm, 565 patients were continued on citalo- pram and augmented with bupro- pion SR or buspirone (Buspar®) (Trivedi, Fava, et al., 2006). The bupropion and buspirone groups had similar rates of HAM-D re- mission (29.7% and 30.1%, re- spectively), QIDS-SR remission (39% and 32.9%), and QIDS-SR response (31.8% and 26.9%). Bu- propion, however, was associated with a greater reduction (from baseline to the end of Level 2) in QIDS-SR scores than was bus- pirone (25.3% versus 17.1%), a lower QIDS-SR score at the end of Level 2 (8 versus 9.1), and a lower dropout rate due to intoler- ance (12.5% versus 20.6%).

Also in Level 2, cognitive psy- chotherapy was compared with medication augmentation and switch strategies (Thase et al., 2007). Patients were randomly assigned to either augmentation of citalopram with cognitive psychotherapy (n = 65) or with medication (n = 117) or switch to cognitive psychotherapy (n = 36) or to another antidepressant agent (n = 86). Patients who re- ceived cognitive psychotherapy (either alone or in combina- tion with citalopram) had simi- lar response and remission rates compared with those assigned to medication-only strategies. For patients who continued on citalopram, medication augmen- tation resulted in significantly more rapid remission than did augmentation with cognitive psychotherapy. Among those who discontinued citalopram and switched to cognitive psycho- therapy or to medication, there were no significant differences in outcome, although patients who switched to a different antide- pressant agent reported signifi-

cantly more side effects than did patients who received cognitive psychotherapy alone.

LeveL 3 TReATMenT At the end of Level 2 treat-

ment, 427 patients had exited the study and 622 entered into natu- ralistic follow up. In the switch arm of Level 3, 235 patients were randomly assigned to mirtazap- ine (Remeron®) or nortriptyline (Pamelor®) (Fava et al., 2006). For mirtazapine, remission rates were 12.3% and 8% based on the HAM-D and QIDS-SR, respec-

tively. For nortriptyline, remis- sion rates were 19.8% and 12.4%, respectively. QIDS-SR response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Nei- ther response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events.

In the augmentation arm of Level 3, 42 patients were ran- domly assigned to augmentation with lithium (Eskalith®) or thy- roid hormone (triiodothyronine, T3 [Cytomel®]) (Nierenberg et al., 2006). Remission rates based on the HAM-D were 15.9% for lithium and 24.7% for T3, but the difference was not statisti- cally significant. Lithium was more frequently associated with

side effects. More patients taking lithium left treatment because of side effects (23.2% versus 9.6%).

LeveL 4 TReATMenT At the end of Level 3 treat-

ment, 165 patients had exited the study and 102 entered natural- istic follow up. For the last level of STAR*D, 109 patients were randomly assigned to switch to tranylcypromine (Parnate®) or to venlafaxine XR plus mirtazapine (McGrath et al., 2006). Remis- sion rates based on the HAM-D were not significantly different

between the two treatment groups (6.9% for tranylcypromine, 13.7% for venlafaxine plus mirtazapine). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance.

AcuTe AnD Long-TeRM ouTcoMeS

The overall acute and longer term treatment outcomes associ- ated with each of the four levels of treatment have been reported (Rush, Trivedi, Wisniewski, Nie- renberg, et al., 2006). Using the QIDS-SR to define remission, the overall acute remission rates were 36.8%, 30.6%, 13.7%, and 13% for the first, second, third, and fourth levels, respectively.

The overall acute remission rates were 36.8%, 30.6%, 13.7%, and 13% for the first, second, third, and fourth levels, respectively.

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Psychopharmacology

Altogether, the cumulative remis- sion rate after up to four levels of treatment was 67%. This cumula- tive remission rate was estimated by assuming that 100 patients be- gan citalopram treatment (Rush, Trivedi, Wisniewski, Nierenberg, et al., 2006). Overall, 36.8 pa- tients would achieve remission in Level 1, leaving 63 to proceed to the next level. In Level 2, 30.6% (19) of these 63 patients would re- mit (leaving 44). In the third lev- el, 13.7% (6) of these 44 patients would remit (leaving 38). In the fourth level, 13% (5) of these 38 patients will remit. Because 33 patients (33%) are left unremit- ted after up to four levels of treat- ment, the theoretical cumulative remission rate is therefore 67%. Obviously, this estimate assumes no dropouts and that those pa- tients who exited the study would have had the same remission rates as those who stayed in the study.

Intolerance was defined as the proportion of patients exiting a level because of side effects. The overall intolerance rates were 16%, 19%, 26%, and 34% for each of the four levels, respec- tively. The QIDS-SR was also used to define relapse during 1- year long-term naturalistic follow up. Patients who required more treatment steps had higher relapse rates during the naturalistic follow up phase: 40%, 55%, 65%, and 71% after each of the four succes- sive levels, respectively. In addi- tion, at each level, lower relapse rates were found among patients who were in remission at follow- up entry than among those who were not in remission.

concLuSion Nurses should be familiar with

the main outcome findings from the STAR*D study. For patients not responding adequately to an initial antidepressant agent, subse- quent treatment strategies may be effective. When more treatment

steps are required, however, lower acute remission rates, greater de- grees of treatment intolerance, and higher relapse rates during fol- low-up treatment are seen. There were relatively few differences among treatments with respect to efficacy or tolerability, although patients had clear preferences for or against certain treatments.

RefeRenceS Fava, M., Rush, A.J., Alpert, J.E., Balasub-

ramani, G.K., Wisniewski, S.R., Car- min, C.N., et al. (2008). Difference in treatment outcome in outpatients with anxious versus nonanxious depression: A STAR*D report. American Journal of Psychiatry, 165, 342-351.

Fava, M., Rush, A.J., Wisniewski, S.R., Nie- renberg, A.A., Alpert, J.E., McGrath, P.J., et al. (2006). A comparison of mirtazapine and nortriptyline follow- ing two consecutive failed medication treatments for depressed outpatients: A STAR*D report. American Journal of Psychiatry, 163, 1161-1172.

Gilmer, W.S., Gollan, J.K., Wisniewski, S.R., Howland, R.H., Trivedi, M.H., Miyahara, S., et al. (in press). Does the duration of index episode affect the treatment outcome of major depressive disorder? A STAR*D report. Journal of Clinical Psychiatry.

Howland, R.H. (2008). Sequenced Treat- ment Alternatives to Relieve Depres- sion (STAR*D). Part 1: Study design. Journal of Psychosocial Nursing and Men- tal Health Services, 46(9), 21-24.

Howland, R.H., Rush, A.J., Wisniewski, S.R., Trivedi, M.H., Fava, M., Davis, L.L., et al. (in press). Concurrent anxi- ety and substance use disorders among outpatients with major depression: Clinical features and effect on treatment outcome. Drug and Alcohol Dependence.

McGrath, P.J., Stewart, J.W., Fava, M., Trive- di, M.H., Wisniewski, S.R., Nierenberg, A.A., et al. (2006). Tranylcypromine versus venlafaxine plus mirtazapine fol- lowing three failed antidepressant medi- cation trials for depression: A STAR*D report. American Journal of Psychiatry, 163, 1531-1541.

Nierenberg, A.A., Fava, M., Trivedi, M.H., Wisniewski, S.R., Thase, M.E., Mc- Grath, P.J., et al. (2006). A comparison of lithium and T(3) augmentation fol- lowing two failed medication treatments for depression: A STAR*D report. American Journal of Psychiatry, 163, 1519-1530.

Rush, A.J., Fava, M., Wisniewski, S.R.,

Lavori, P.W., Trivedi, M.H., Sackeim, H.A., et al. (2004). Sequenced Treat- ment Alternatives to Relieve Depres- sion (STAR*D): Rationale and design. Controlled Clinical Trials, 25, 119-142.

Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., War- den, D., et al. (2006). Acute and longer- term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. American Journal of Psychiatry, 163, 1905-1917.

Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Stewart, J.W., Nierenberg, A.A., Thase, M.E., et al. (2006). Bupropion-SR, ser- traline, or venlafaxine-XR after failure of SSRIs for depression. New England Journal of Medicine, 354, 1231-1242.

Thase, M.E., Friedman, E.S., Biggs, M.M., Wisniewski, S.R., Trivedi, M.H., Luther, J.F., et al. (2007). Cognitive therapy ver- sus medication in augmentation and switch strategies as second-step treat- ments: A STAR*D report. American Journal of Psychiatry, 164, 739-752.

Trivedi, M.H., Fava, M., Wisniewski, S.R., Thase, M.E., Quitkin, F., Warden, D., et al. (2006). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine, 354, 1243-1252.

Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A., Warden, D., Ritz, L., et al. (2006). Evaluation of outcomes with citalopram for depression using mea- surement-based care in STAR*D: Im- plications for clinical practice. American Journal of Psychiatry, 163, 28-40.

Warden, D., Trivedi, M.H., Wisniewski, S.R., Davis, L., Nierenberg, A.A., Gaynes, B.N., et al. (2007). Predictors of attrition during initial (citalopram) treatment for depression: A STAR*D report. American Journal of Psychiatry, 164, 1189-1197.

Wisniewski, S.R., Fava, M., Trivedi, M.H., Thase, M.E., Warden, D., Niederehe, G., et al. (2007). Acceptability of sec- ond-step treatments to depressed out- patients: A STAR*D report. American Journal of Psychiatry, 164, 753-760.

Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.

Dr. Howland acknowledges grant support from the National Institute of Mental Health.

Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: [email protected].

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