Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a 7-year nationwide clinical trial designed to evaluate the efficacy of different medications in patients who did not respond to an initial antidepressant. Rush et al. (2006) evaluated acute and long-term treatment outcomes in patients who participated in the STAR*D trial and identified differences in response and remission rates and time to remission across patients who received up to four sequential treatment steps.

- Chris Lambert, FNP

What do the results of this study mean for a practicing NP?

"The STAR*D study gives nurse practitioners a large-scale framework to reference for sequential antidepressant treatment strategies as well as important information about response and remission rates for patients at each treatment step."

NP Psych Navigator contributors are paid consultants of AbbVie Inc.

Although the goal of treating major depressive disorder is to achieve remission, most patients require several different therapies to achieve this goal. Symptom reduction as measured by validated scales indicates a response to treatment; however, remission is a brief period of time where patients do not present any clinically relevant symptoms.2,3

Challenges to treatment response include lack of efficacy, as patients typically only achieve about a 50% response rate, in addition to treatment resistance, and intolerable side effects. Measurement-based care including symptom and side-effect monitoring at each visit can help guide dose adjustments to ensure an adequate dose and duration of medication is reached. However, depending on the efficacy response achieved at this stage, sequential treatments, or steps, may be needed to help improve the chance of achieving remission.2,3

Why was this research needed?

The STAR*D trial was designed to comprehensively evaluate how patients with nonpsychotic major depressive disorder responded to four stratified treatment steps. This analysis evaluated data to determine differences between patients who required more treatment steps and those who required fewer steps. The authors also looked at response, remission rates, time to remission, and long-term outcomes.2

This study provides important insights on how applying a multistep, measurement-based care approach can affect long-term outcomes in patients requiring additional treatments to help them achieve remission.2

What did the researchers do?

The authors performed an analysis of data from the STAR*D trial. Of the people enrolled in the trial, 3,671 patients were included in this analysis.2 The trial was conducted across 41 sites that provided primary or psychiatric care. Participants met the DSM-IV criteria for nonpsychotic major depressive disorder, and were 18-75 years of age, not pregnant, and not breastfeeding. Those with comorbid mental health conditions or those whose medications were contraindicated with the study treatments were excluded from the analysis.2

Assessment of response to treatment at each step was determined using standard scales that evaluate depression symptoms. The 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) was used as the primary measurement tool to evaluate acute and long-term outcomes. Treatment response was defined as ≥50% QIDS-SR16 reduction, and remission was defined as QIDS-SR16 ≤5; time to remission (in weeks) was defined as the time from starting treatment to the first point of reaching QIDS-SR16 ≤5.2

Additional information on patient health was collected regarding depressive symptoms, cumulative illness, side effects, function, quality of life, overall health, and work and social life.2

See flowchart below that outlines each treatment step (Figure 1):

Patients who achieved remission or did not achieve remission but adequately benefited were allowed to enter a follow-up phase of the trial where they continued taking the medication they responded to across the 12 months, with visits every 2 months.

What were the main results of the study?

In the acute phase of the study, patients who received only the first step of treatment (n= 3,671) had the highest remission rate of 32.9% based on QIDS-SR16 scores compared to those who received additional steps. Those who received Step 2 (n=1,439) had a 30.6% remission rate; there was a 13.6% remission rate for Step 3 (n=390) and 14.7% for Step 4 (n=123).2 Participants who required additional steps were more likely to have a greater burden of illness, as well as comorbid mental health and medical conditions; additionally, these groups had high treatment intolerance rates. Time to remission ranged from 5.4 to 7.4 weeks across the four treatment steps of those who responded to treatment. In addition, mean time to response ranged from 6.5 to 8.3 weeks across treatment steps, and response rates ranged from 48.6% in Step 1 to 16.3% in Step 4 (Figure 2).2

Patients who had not received prior treatment before starting on Step 1 (42.7%) for their current depressive episode had a higher remission rate than those who had been previously treated (35.6%); however, there was no difference in rates at Step 2.2

Based on these findings, the authors developed theoretical estimates of cumulative remission rates, assuming that no one dropped out of the trial and that those who exited the trial had consistent remission rates. These estimates determined that the cumulative rate would be 67%.2

Of the 1,475 patients who entered the follow-up phase of the study, those who received later steps of treatment had worsening depression and were less likely to be in remission; they also had higher relapse rates. Patients who had remitted prior to entering follow-up had a better prognosis.2

Many participants dropped out of the study across the first two treatment steps (Step 1: 20.9%; Step 2: 29.7%); after Step 3, those rates went up to 42.3%. Therefore, follow-up and efforts to retain patients in care are critically important to help patients with depression achieve remission, especially those with high relapse rates, high illness burden, and those who are earlier in their treatment plan.2

Why are these results potentially important?

The original STAR*D trial was the largest and longest study to thoroughly analyze treatment response to several different medications for patients with depression.4 No other study has evaluated the scope of treatments and effects of switching medications on response and remission rates in a diverse population representing real-world clinical practice.4 A key finding of the follow-up phase of this analysis is that even if remission is achieved at later steps of treatment, it is associated with a better prognosis and helps improve overall patient function.2 Providers should also keep in mind the benefits of a current therapy when considering a change, as well as potential side-effect burden with the start of a new medication that could impede the chance of achieving remission.2

Although these data are quite impactful and can be broadly applied to the mental health field, there are several limitations to keep in mind. The trial design allowed for the use of many treatment options with different mechanisms of action; however, patients did not receive every possible treatment or combination. Additionally, since this study was published, there are far more medications available for depression that were not evaluated in this trial. It is also possible that a greater number of patients would have achieved remission had they been treated for a longer period of time.2

In addition, the QIDS-SR16, which is based on patient self-reporting, was used as the primary outcome measure rather than a clinician-rated scale. Furthermore, the trial was not blinded, so both the participants and clinicians knew which medications were administered, and a placebo group was not included for comparison. Lastly, it is important to note that the number of patients who exited the study could have impacted the results reported.2

What's next?

This analysis can provide essential information to healthcare providers on how patients with depression respond to different treatments and gives guidance on how to manage patients with depression who do not achieve remission after initial treatment.4

This study also sheds light on the heterogeneity of depression, highlighting the importance of evaluating treatment history and course of illness when determining the best treatment approach.2

Additional research is needed to better understand how patients respond to newer classes of medications. Insights into methods that could help predict when and how a patient might respond to a particular therapy or combination would be greatly beneficial to providers.4

The authors declared no conflict of interest. This summary was prepared independently of the study’s authors. The content presented here is provided for educational purposes only. It is not intended as, nor is it a substitute for medical care or advice. Healthcare professionals should use their clinical judgment when reviewing educational resources on NP Psych Navigator. 


  1. National Institute of Mental Health. “Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — Background.”

  2. Rush AJ, Trivedi MH, 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(11):1905-1917.
  3. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
  4. National Institute of Mental Health. “Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels.”  

This resource is intended for educational purposes only and is intended for US health care professionals. Health care professionals should use independent medical judgment. All decisions regarding patient care must be handled by a health care professional and be made based on the unique needs of each patient. 

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