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Sequenced Treatment Alternatives to Relieve Depression: STAR*D 

Sequenced Treatment Alternatives to Relieve Depression: STAR*D
Sequenced Treatment Alternatives to Relieve Depression: STAR*D

Eric Lin

, and Pochu Ho

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Subscriber: null; date: 23 October 2019

The theoretical cumulative remission rate [for depression] after four acute treatment steps was 67%.

The STAR*D Investigators1

Research Question:

What are the outcomes and remission rates for depression? What are the long-term outcomes, especially the relapse rates, for patients receiving sequential depression therapies?


The National Institute of Mental Health

Year Study Began:


Year Study Published:


Study Location:

41 outpatient sites providing primary or psychiatric care in the United States.

Who Was Studied:

Individuals 18 to 75 years old referred by their doctors who were already seeking care for nonpsychotic major depressive disorder (MDD) by DSM-IV criteria and had scores of ≥14 on the Hamilton Rating Scale of Depression 17 (HRSD-17).

Who Was Excluded:

Patients with bipolar disorder, psychotic disorders (including depression with psychotic features), anorexia, bulimia, obsessive compulsive disorder, or substance abuse disorders requiring detoxification. Suicidal patients requiring immediate hospitalization. Those who had already attempted an adequate trial of treatments that were utilized in the first two Sequenced Treatment Alternatives to Relieve Depression (STAR*D) treatment steps, or if a STAR*D treatment could not be safely used because of their other health conditions (pregnant or breastfeeding) or medication regimens.

How Many Participants:


Study Overview:

See Figure 27.1 for a summary of the study design. See Figure 27.2 for a summary of the cognitive therapy arm design.

Figure 27.2 Summary of Cognitive Therapy Arm Design

Figure 27.2 Summary of Cognitive Therapy Arm Design

Study Intervention:

Participants with depression were treated in stepwise fashion. Patients who improved after any step could exit treatment and were followed for 12 months. During this follow-up phase, subjects could change treatment regimens but were recommended to continue on their final treatment regimen from the STAR*D study. Those who did not remit (defined in the following discussion) continued to the next treatment step and were randomized to subsequent therapies.

All patients in the study started with citalopram treatment as Step 1. Subsequent treatment steps are shown in Figures 27.1 and 27.2.

Dosing was adjusted using measurement-based care methods and were “vigorously” dosed. As an example, citalopram dosing was determined on an individual basis by clinicians, but was guided by a STAR*D treatment manual and clinical research coordinator monitoring and recommendations.

Quick Inventory of Depressive Symptomatology Self-Report (self-rated; QIDS-SR16) and QIDS (clinician rated; QIDS-C) were recommended at weeks 2, 4, 6, 9, and 12 of treatment. The general recommendation was to start citalopram at 20 mg/day and to increase to 40 mg/day by week 4 and 60 mg/day by week 6. Clinicians were permitted to initiate at lower doses, slow titration, stop titration, or switch the medication (and move the patient to the next step) based on clinical judgment.2


12 months


Primary outcome: “Response rate,” defined as a ≥50% reduction on the QIDS-SR16. Other outcomes: “Remission rate,” defined as a QIDS-SR16 score of ≤5 (corresponds to HRSD-17 ≤7), time to response/remission, relapse rate defined as a QIDS-SR16 score ≥11 (corresponds to HRSD-17 ≥14) during follow-up, and treatment intolerance/exit.


  • Overall, 67% of the patients who started treatment in this study remitted from depression.

  • Patients in later treatment steps demonstrated progressively lower remission rates (p < 0.0001) (Table 27.1).

  • Patients who entered later treatment steps also had higher relapse rates (p < 0.0001).

  • Patients who participated in later treatment steps tended to have a higher number of psychiatric and medical diagnoses and tended to have worse illness burden from their depression.

  • Substantial numbers of patients exited after each step: 20.9% after Step 1, 29.7% after Step 2, and 42.3% after Step 3. Results reported were from an intent-to-treat analysis.

Table 27.1 Summary of STAR*D’s Key Findings


Step 1 (%)

Step 2 (%)

Step 3 (%)

Step 4 (%)

Overall (%)

Remission rate*






Response rate






Intolerance rate






Relapse rate post-treatment






note: STAR*D = Sequenced Treatment Alternatives to Relieve Depression. Pairwise comparisons demonstrated that only Step 1 relapse rate (as monitored during follow-up) was significantly different from the other steps (P < 0.0001).

Criticisms and Limitations:

The trial was open label and not placebo-controlled, which is particularly relevant for studies of depression given that there is often a substantial placebo effect in depression studies.

Treatment steps were limited to 12 to 14 weeks each; patients who may have remitted with a longer treatment duration were algorithmically pushed into the next step, which may differ from a more flexible real-world practice strategy.

Treatment options did not include many other common options such as electrocardiogram, psychodynamic therapy, or even some of the newer psychotropic medications.

A lower than expected number of patients received the cognitive therapy treatment option perhaps because of the biases with initial recruitment. Moreover, the study excluded suicidal patients and those with common comorbidities including depression with psychotic features, which limits its generalizability. Other studies suggest that those with these more severe symptoms may respond better to treatment.3

Other Relevant Studies and Information:

  • Other studies have found similar rates of response to antidepressants as reported in STAR*D.4,5

  • For patients with unresponsive depression, American Psychiatric Association (APA) guidelines recommend maximizing initial treatments by raising medications to higher doses of medication, switching to other treatment strategies, or augmentation. At the time of its publication, the guidelines stated that there was limited data other than the STAR*D study in recommending a specific switching algorithm.6

Summary and Implications:

The STAR*D trial was a landmark study exploring the natural history of patients receiving a sequential treatment strategy for depression. It showed that 67% of patients treated according to the sequential management strategy utilized in this study remitted. It also demonstrated that patients with depression who fail multiple treatment trials have lower remission rates and higher relapse rates.

Clinical Case: Rates of Remission and Relapse

Case History

A 37-year-old, medically uncomplicated woman is wondering about her chances of “resolving” her major depressive episode after no response from a six-week trial of citalopram. Notably, she complains of dysphoric mood, anhedonia, insomnia, decreased energy, and poor concentration. Per the STAR*D study, what treatment strategies can she try, and what is her expected chance of remitting with this second treatment?

Suggested Answer

The STAR*D study found that 36.8% of patients remit with citalopram as first-line therapy. Of the patients who required another treatment step (Step 2), another 30.6% responded to either a switch to bupropion, sertraline, or venlafaxine or augmentation with buspirone or bupropion or a switch to cognitive therapy or augmentation with cognitive therapy. Her chance at remission is expected to be 30.6% with the described treatment options since she has already failed citalopram treatment. By the STAR*D follow up statistics, she would have a 55.3% chance of relapsing by the end of 12 months from treatment exit.

The patient in the vignette is typical of one that would be included in the STAR*D trial. Based on the patient’s history and preference, the psychiatrist can choose to either augment or switch antidepressants and/or cognitive therapy and should have realistic expectations regarding the likelihood of remission.


1. Gaynes, B. N., Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Spencer, D., & Fava, M. (2008). The STAR*D study: Treating depression in the real world. Cleveland Clinic Journal of Medicine, 75(1), 57–66.Find this resource:

2. Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., . . . Shores-Wilson, K. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. American Journal of Psychiatry, 163(1), 28–40.Find this resource:

3. Fournier, J. C., DeRubeis, R. J., Hollon, S. D., Dimidjian, S., Amsterdam, J. D., Shelton, R. C., & Fawcett, J. (2010). Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA, 303(1), 47–53.Find this resource:

4. Fava, M., Dunner, D. L., Greist, J. H., Preskorn, S. H., Trivedi, M. H., Zajecka, J., & Cohen, M. (2001). Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: An open-label trial. Journal of Clinical Psychiatry, 62(6), 413–420.Find this resource:

5. Thase, M. E., A Entsuah, A. R., & Rudolph, R. L. (2001). Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. British Journal of Psychiatry, 178(3), 234–241.Find this resource:

6. Gelenberg, A. J.Freeman, M. P., Markowitz, J. C., Rosenbaum, J. F., Thase, M. E., Trivedi, M. H., & Van Rhoads, R. S. (2010). APA Practice guideline for the treatment of patients with major depressive disorder (3rd ed.). Washington, DC: American Psychiatric AssociationFind this resource: