Exploring the STAR*D Controversy

Without doubt, the STAR*D trial is one of the most important foundational studies in psychiatry to guide the treatment of unipolar major depression. Despite the significant evolution of pharmacotherapies that have joined our antidepressant armamentarium since STAR*D’s publication in 2006, the broader findings of percent response and remission of patients with depression at each of the 4 steps remain as relevant to us today as they were 18 years ago.

For that reason, I wrote the December 2023 Psychiatric Times cover story, “STAR*D Dethroned?”¹ Shortly thereafter, we received feedback, including a brief commentary, from H. Edmund Pigott, PhD, and colleagues, the authors of the BMJ article² that prompted my cover story. They looked to Psychiatric Times, the voice of psychiatry, to further explain their position and share a dialogue with the original STAR*D authors³ in our forum. Their viewpoints and commentaries are presented exclusively to you, our readers, for your consideration.

New Reflections

Upon reflecting on the 2 commentaries and my original cover story, I read—and, in many cases, reread—numerous publications related to STAR*D. The original rationale and design publication by the STAR*D investigators specifically stated⁴:

The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression [HRSD], administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments.

A satisfactory outcome for research purposes is defined as an HRSD <8. (Note: Participants who begin a level with HRSD <8 will be excluded from analyses.)

In any clinical trial, the primary outcome is the most important data point. In fact, if the primary outcome is not positive, even in the context of several statistically significant secondary outcomes, the trial is considered to have a negative outcome. A review of 4 of the manuscripts extracted from various steps or substeps of STAR*D published in the same journal and year as the summary STAR*D findings all report the primary outcome HRSD results in their abstracts.^5-8

In their commentary, Rush et al stated they chose the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR) to report step-by-step and cumulative remission, rather than the HRSD as “a secondary ‘post hoc’ report, specifically requested by the editor in chief of The American Journal of Psychiatry at that time, with the goal of summarizing the clinical outcomes.” It is a curious request given that the STAR*D analyses published in The American Journal of Psychiatry that same year reported the predefined HRSD primary outcome as the measure of treatment remission. Additionally, the STAR*D 2004 rationale and design publication specified the HRSD blinded assessment as the primary outcome. Thus, it would be peculiar to not use it as the source of data for sequential and cumulative remission in the flagship publication (ie, the 2006 summary study, which remains the face of the STAR*D trial).

Let me be clear: I do not believe that Rush et al intentionally inflated the remission rates by using the QIDS-SR results as their calculation of remission. Rather, in my view, the prespecified primary outcome would have been a more clinically relevant choice.

I agree that the increased utilization of patient-reported outcomes (PROs) has been a welcome addition to more recent clinical trials. However, PROs are commonly reported as secondary outcomes and are rarely reported as the primary outcome in a clinical trial when an objective measure by blinded raters is the preferred assessment. Equally perplexing is the absence of the 16-item clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C16), which was reported to have been assessed by the clinical research coordinators at each clinic visit to assess symptoms experienced during the previous week. Although also a nonblinded secondary outcome, it would have been highly informative to compare the patients’ self-assessment with the clinicians’ assessment at the same visit.

Finally, Maurizio Fava, MD, a coauthor of the original STAR*D report, sent an additional reference for inclusion in their commentary.⁹ The piece is a letter to the editor published in World Psychiatry in February 2024 that reanalyzed the 2006 STAR*D results. The authors utilized the “inverse probability of censoring weighted Kaplan-Meier method” and concluded that the cumulative remission rate “in the original STAR*D paper” is 87.5% rather than the reported 67%. I submit this final reference as an example of why the prespecified primary outcome data in any clinical trial is most significant, and, in fact, primary.

I leave it to you the reader to come to your own conclusions. We welcome all feedback and opinions to further explore this controversial summary STAR*D report.

Dr Miller is Medical Director, Brain Health, Exeter, New Hampshire; Editor in Chief, Psychiatric Times; Staff Psychiatrist, Seacoast Mental Health Center, Exeter; Consulting Psychiatrist, Exeter Hospital, Exeter; Consulting Psychiatrist, Insight Meditation Society, Barre, Massachusetts.

References

1. Miller JJ. STAR*D dethroned? Psychiatric Times. 2023;40(12).

2. Pigott HE, Kim T, Xu C, et al. What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study’s patient-level data with fidelity to the original research protocol. BMJ Open. 2023;13(7):e063095. 

3. 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.

4. Rush AJ, Fava M, Wisniewski SR, et al; STAR*D Investigators Group. Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design. Control Clin Trials. 2004;25(1):119-142.

5. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. 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.

6. Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report. Am J Psychiatry. 2006;163(7):1161-1172.

7. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530; quiz 1665.

8. McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1531-1541.

9. Sakurai H, Noma H, Watanabe K, et al. Cumulative remission rate after sequential treatments in depression: reappraisal of the STAR*D trial data. World Psychiatry. 2024;23(1):156-157.