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: HowlandRH@upmc.edu.
The purpose of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study was to compare the efficacy and tolerability of a range of diverse anti-depressant therapies through four sequential levels of treatment with the goal of achieving remission (Rush et al., 2004). The September article (Howland, 2008) described the design of the study. The main outcome findings 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 psychiatric settings (Trivedi, Rush, et al., 2006). A total of 1,127 patients exited the study for various 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 medical 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 measure). Response was defined as a reduction of 50% or greater on the QIDS-SR score from baseline to exit.
These Level 1 response and remission rates are similar to those reported in 8-week efficacy trials. 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 quality of life were associated with lower HAM-D remission rates.
Because premature attrition from treatment may lead to worse clinical outcomes and compromise the integrity of clinical trials, 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 immediate (patients who attended a baseline visit only) or later (patients 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. Immediate attrition was associated with younger age, less education, and higher perceived mental health functioning. Later attrition 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 patients at higher risk for attrition.
Level 2 Treatment
At the end of Level 1 treatment, 1,475 patients entered 1-year naturalistic follow up and 1,439, advanced to Level 2. Because 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 factors associated with the acceptability 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 psychotherapy alone or with medication. Thus, approximately 70% did not want cognitive psychotherapy. Most patients accepted only a switch strategy (48%) or an augmentation strategy (41%). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive psychotherapy. Patients in primary care settings and those who experienced a greater side effect 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. Patients 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 assigned to switch from citalopram to bupropion SR (Wellbutrin SR®), sertraline (Zoloft®), or venlafaxine 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, and 28.2% for venlafaxine. These treatments did not differ significantly with respect to outcomes, tolerability, or adverse events.
In the augmentation arm, 565 patients were continued on citalo-pram and augmented with bupropion SR or buspirone (Buspar®) (Trivedi, Fava, et al., 2006). The bupropion and buspirone groups had similar rates of HAM-D remission (29.7% and 30.1%, respectively), QIDS-SR remission (39% and 32.9%), and QIDS-SR response (31.8% and 26.9%). Bupropion, however, was associated with a greater reduction (from baseline to the end of Level 2) in QIDS-SR scores than was buspirone (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 intolerance (12.5% versus 20.6%).
Also in Level 2, cognitive psychotherapy 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 received cognitive psychotherapy (either alone or in combination with citalopram) had similar response and remission rates compared with those assigned to medication-only strategies. For patients who continued on citalopram, medication augmentation resulted in significantly more rapid remission than did augmentation with cognitive psychotherapy. Among those who discontinued citalopram and switched to cognitive psychotherapy or to medication, there were no significant differences in outcome, although patients who switched to a different antidepressant agent reported significantly more side effects than did patients who received cognitive psychotherapy alone.
Level 3 Treatment
At the end of Level 2 treatment, 427 patients had exited the study and 622 entered into naturalistic follow up. In the switch arm of Level 3, 235 patients were randomly assigned to mirtazapine (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, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-SR response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither 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 randomly assigned to augmentation with lithium (Eskalith®) or thyroid 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 statistically 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 treatment, 165 patients had exited the study and 102 entered naturalistic 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). Remission 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 associated with each of the four levels of treatment have been reported (Rush, Trivedi, Wisniewski, Nierenberg, 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. Altogether, the cumulative remission rate after up to four levels of treatment was 67%. This cumulative remission rate was estimated by assuming that 100 patients began citalopram treatment (Rush, Trivedi, Wisniewski, Nierenberg, et al., 2006). Overall, 36.8 patients 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 remit (leaving 44). In the third level, 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 unremitted after up to four levels of treatment, the theoretical cumulative remission rate is therefore 67%. Obviously, this estimate assumes no dropouts and that those patients 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, respectively. 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 successive levels, respectively. In addition, 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.
Nurses should be familiar with the main outcome findings from the STAR*D study. For patients not responding adequately to an initial antidepressant agent, subsequent treatment strategies may be effective. When more treatment steps are required, however, lower acute remission rates, greater degrees of treatment intolerance, and higher relapse rates during follow-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.
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- Fava, M, Rush, AJ, Wisniewski, SR, Nierenberg, AA, Alpert, JE & McGrath, PJ et al. 2006. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report. American Journal of Psychiatry, 163, 1161–1172. doi:10.1176/appi.ajp.163.7.1161 [CrossRef]
- Gilmer, WS, Gollan, JK, Wisniewski, SR, Howland, RH, Trivedi, MH & 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
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