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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 1: Study Design
Robert H. Howland, MD
This article describes the design of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The main study objective was to compare the efficacy and tolerability of various antidepressant therapies through four sequential treatment levels. To maximize the generalizability of the results, broad inclusion and minimal exclusion criteria were used to recruit patients with major depression from a large number of real-world settings. The goal of treatment was to achieve full remission. A measurement-based care system was used to guide and optimize treat- ment at each level. Patients were treated for up to
12 weeks at each level (with an optional week 14 visit, if needed). All patients started with citalopram at Level 1. The three subsequent levels of treatment options were randomized and open label, and pa- tients could accept or decline treatments as long as sufficient options were left that allowed randomiza- tion between at least two different options. For any treatment level, patients who reached full remission, and those with satisfactory response, could continue the same treatment during 1-year naturalistic follow up. Patients who did not reach full remission were encouraged to enter subsequent levels.
AbSTRAcT
Journal of Psychosocial nursing • Vol. 46, no. 9, 2008 21
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Psychopharmacology
T he goal of antidepressant therapy should be the absence of significant
depressive symptoms, an out- come referred to as full remission (Rush, Kraemer, et al., 2006). On the basis of typical results of most controlled antidepressant trials, approximately 50% of patients will have a significant treatment response (defined as a 50% or greater decrease in depressive symptoms) with an initial medication. However, in such controlled trials, only 25% to 33% will have attained full remission. A significant propor- tion of depressed patients are left with residual symptoms, despite an adequate initial an- tidepressant drug therapy. What is the best next step treatment for these patients (Howland & Thase, 1999)? The Sequenced Treatment Alternatives to Re- lieve Depression (STAR*D) study was conducted to answer this question. In this article, I will describe the overall design of the STAR*D study. Next month, I will review the main outcome findings from STAR*D.
DeSign of THe STAR*D STuDy
The STAR*D study, funded by the National Institute of Mental Health, is the largest prospective, randomized anti- depressant treatment trial ever conducted in patients with major depressive disorder, in- volving more than 4,000 adult patients from real-world clini- cal settings (Rush et al., 2004). The treatment goal in STAR*D was to achieve clinical remis- sion. The main objective of the study was to determine which treatments are most effective af- ter nonremission or intolerance to an initial serotonin reuptake inhibitor (SRI) antidepressant
medication (Level 1 treatment with citalopram [Celexa®]). This objective was accomplished by sequentially investigating a se- ries of three subsequent levels of randomized treatments to achieve remission.
STAR*D was conducted across the United States at 18 primary care and 23 psychiatric settings that serve public and private sector patients. Clinical research coordinators (CRCs) at each site assisted patients and clinicians in protocol imple- mentation and the collection of clinical measures. A central pool of research outcome asses- sors (ROAs), not located at any clinical site, conducted tele- phone interviews to obtain pri- mary outcomes data.
STAR*D enrolled treatment- seeking patients who visited these clinics rather than soliciting symptomatic volunteers through advertising or other typical re- search recruitment procedures. To maximize the generalizabil- ity of the results, broad inclusion and minimal exclusion criteria were used. Patients with a base- line score of 14 or greater on the 17-item Hamilton Rating Scale for Depression (HAM-D) were enrolled if their treating clini- cians determined that outpatient treatment with an antidepressant medication was appropriate.
Exclusion criteria included bipolar disorder; psychotic symptoms or disorders; current primary diagnosis of obsessive- compulsive disorder, anorexia nervosa, or bulimia; general medical conditions contraindi- cating medications used in the first two treatment levels of the study; substance dependence requiring inpatient treatment; or a clear history of nonre- sponse or intolerance (during the current depressive episode)
to any medication used in the first two treatment levels of the study. Patients who were pregnant, breast-feeding, or in- tending to conceive during the 9 months subsequent to study entry were also excluded. Thus, the study permitted nonpsy- chotic, nonbipolar outpatients with most kinds of comorbid psychiatric and general medi- cal conditions, including active substance abuse or suicidality, to be enrolled as long as outpa- tient treatment was considered clinically appropriate.
MeASuReMenT-bASeD cARe
The success of translating clinical trials research findings to real-world practice has been lim- ited, primarily because strategies effective in clinical trials have not been sufficiently studied in routine clinical care among pa- tients with psychiatric and gen- eral medical comorbidities. The STAR*D study required that the dosage and duration of antide- pressant medication treatment be optimal, while accommodat- ing the flexibility necessary to ensure patient safety, given the wide range of comorbid general medical and psychiatric disorders allowed in the trial.
The study used a measure- ment-based care (MBC) ap- proach and an automated feed- back system to ensure adequate and safe antidepressant treat- ment delivery suitable for both clinical research and routine practice (Trivedi et al., 2007). Ratings of depressive symptom severity and side effect frequen- cy, intensity, and burden were obtained at each treatment visit by CRCs using the MBC sys- tem, which guided medication dosage adjustments and treat- ment duration, documented cli-
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Psychopharmacology
nician adherence to treatment recommendations, and pro- vided prompt feedback to cli- nicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side effect burden, as well as the dosage and duration of antide- pressant agents at each critical decision point during the acute phase treatment.
Feedback was provided at the point of care by the CRCs, assist- ed by Web-based reports following each treatment visit. During Lev- el 1 treatment with citalopram, for example, more than 85% of treatment encounters were con- sistent with study recommenda- tions. Most deviations from treat- ment recommendations occurred late in treatment and were often justifiable. The MBC system was found to be feasible and effective in busy primary care and psychiat- ric settings.
fouR TReATMenT LeveLS Throughout the four levels
of STAR*D, a diverse range of antidepressant treatments were chosen for comparison of their efficacy and tolerability (Rush et al., 2004). At each of the four levels, the highest tolerated medication dosage (within the usual clinical dosage range for each drug) necessary to achieve remission was used, guided by the MBC system. Patients were treated for up to 12 weeks at each level (with an optional week 14 visit, if needed). All patients started with citalopram at Level 1 (Trivedi, Rush, et al., 2006). After Level 1, the three subsequent levels of treatment options were randomized and open label (i.e., not blinded or placebo controlled). Similar to clinical practice, however, pa-
tients could accept or decline particular treatments as long as sufficient options were left that allowed a randomization be- tween at least two different op- tions (Wisniewski et al., 2007).
Patients who did not remit or were intolerant to citalopram could enter Level 2. This level was the most clinically and sci- entifically important phase of STAR*D, because patients were randomly switched from citalo- pram to one of four alternatives (Rush, Trivedi, et al., 2006), or they continued to take citalo-
pram and were augmented with one of three additional treat- ments (Trivedi, Fava, et al., 2006). The four switch options were to bupropion SR (Well- butrin SR®), sertraline (Zoloft®), venlafaxine XR (Effexor XR®), or cognitive psychotherapy. The three augmentation options were adding bupropion SR, bus- pirone (Buspar®), or cognitive psychotherapy. For those pa- tients having inadequate benefit from switching to or augmenting with cognitive psychotherapy (Thase et al., 2007), the next step (Level 2A) was a switch
to bupropion SR or venlafaxine XR. Level 2A ensured that all patients entering Level 3 had received two different pharma- cotherapy trials.
Patients without adequate benefit from Level 2 or 2A treat- ment were advanced to Level 3, where they were randomly switched from their Level 2/2A medication (Fava et al., 2006), or their Level 2/2A medication was augmented (Nierenberg et al., 2006). The two Level 3 switch options were to mirtazapine (Re- meron®) or nortriptyline (Pa-
melor®). The two Level 3 aug- mentation options were adding lithium (Eskalith®) or thyroid hormone (triiodothyronine, T3 [Cytomel®]). Finally, at Level 4, patients were randomly switched to tranylcypromine (Parnate®) or to the combination of venla- faxine XR plus mirtazapine (Mc- Grath et al., 2006).
cLinicAL ASSeSSMenTS The HAM-D scale was the
primary research outcome ob- tained by ROAs using tele- phone-based structured inter- views in English or Spanish.
The STAR*D study...is the largest prospective, randomized antidepressant treatment trial ever conducted in patients with major depressive disorder, involving more than 4,000 adult patients.
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Psychopharmacology
Secondary outcomes were based on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) scale, obtained at baseline and at each treatment visit by the CRCs. 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 base- line to exit. Side effects were assessed at each visit using the self-report Frequency, Intensity, and Burden of Side Effects Rat- ings (FIBSER) scale.
Through the MBC system, QIDS-SR and FIBSER data from each visit were used to guide treatment decisions. For any level of treatment, patients who reached full remission, and those with a satisfactory re- sponse, could continue the same treatment during 1-year natu- ralistic follow up. Patients who did not reach full remission were encouraged to enter subsequent levels. Patients could discon- tinue treatment before 12 weeks if intolerable side effects war- ranted a medication change, if an optimal dosage increase was not possible (because of side ef- fects or by patient choice), or if significant depressive symptoms were still present after 9 weeks despite maximum tolerated dos- ages. These patients were eligi- ble to enter subsequent levels.
concLuSion For patients not respond-
ing adequately to an initial SRI antidepressant medication, the STAR*D study was designed to
investigate the effectiveness of a sequential series of next-step treatments guided by an MBC system. Nurses should be famil- iar with the design of STAR*D because the study compared a diverse assortment of antidepres- sant therapies in real-world clini- cal settings. The main outcome findings from STAR*D will be reviewed in next month’s article.
RefeRenceS Fava, M., Rush, A.J., Wisniewski, S.R.,
Nierenberg, A.A., Alpert, J.E., Mc- Grath, P.J., et al. (2006). A compari- son of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report. American Journal of Psychiatry, 163, 1161-1172.
Howland, R.H., & Thase, M.E. (1999). What to do with SSRI nonresponders? Journal of Practical Psychiatry and Be- havioral Health, 5, 216-223.
McGrath, P.J., Stewart, J.W., Fava, M., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., et al. (2006). Tranylcypromine versus venlafax- ine plus mirtazapine following three failed antidepressant medication tri- als 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., McGrath, P.J., et al. (2006). A com- parison of lithium and T(3) augmen- tation following two failed medica- tion 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., Sack- eim, H.A., et al. (2004). Sequenced Treatment Alternatives to Relieve Depression (STAR*D): Rationale and design. Controlled Clinical Trials, 25, 119-142.
Rush, A.J., Kraemer, H.C., Sackeim, H.A., Fava, M., Trivedi, M.H., Frank, E., et al. (2006). Report by the ACNP task force on response and remission in major depressive disorder. Neuro- psychopharmacology, 31, 1841-1853.
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). Cog- nitive therapy versus medication in augmentation and switch strategies as second-step treatments: A STAR*D report. American Journal of Psychiatry, 164, 739-752.
Trivedi, M.H., Fava, M., Wisniewski, S.R., Thase, M.E., Quitkin, F., War- den, 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., Gaynes, B.N., Stewart, J.W., Wisniewski, S.R., War- den, D., et al. (2007). Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR*D measurement-based care. Neuropsychopharmacology, 32, 2479- 2489.
Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A., Warden, D., Ritz, L., et al. (2006). Evaluation of outcomes with citalopram for depres- sion using measurement-based care in STAR*D: Implications for clinical practice. American Journal of Psychia- try, 163, 28-40.
Wisniewski, S.R., Fava, M., Trivedi, M.H., Thase, M.E., Warden, D., Niederehe, G., et al. (2007). Accept- ability of second-step treatments to depressed outpatients: 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, Pennsyl- vania.
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.
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