STAR*D Dethroned?

Publication
Article
Psychiatric TimesVol 40, Issue 12

Since 2006, STAR*D stands out as an icon guiding treatment decisions of major depressive disorder. But what if it is broken?

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In the treatment of major depressive disorder (MDD), the acronym STAR*D stands out as a beacon guiding treatment decisions since 2006 when a series of publications reported the results from this massive, $35 million National Institute of Mental Health (NIMH)–funded research study.

Recently, a provocative and well-researched publication in the BMJ reanalyzed the original raw data obtained from the NIMH and challenged the conclusions of the STAR*D publications.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) was a prospective study that began with 4041 adults diagnosed with a current major depressive episode who were treated in 41 participating psychiatric and primary care treatment clinics. These patients entered the treatment protocol, which included up to 4 consecutive pharmacological regimens, called steps, lasting 12 to 14 weeks each, with the primary outcome of achieving remission predefined as a score < 8 on the blinded Hamilton Rating Scale for Depression (HRSD).1,2

The BMJ authors of the new review performed a rigorous analysis of the interpretation of the STAR*D data, which they concluded reveals significant violations of the original submitted research protocol.3 The STAR*D investigators concluded that, “The overall cumulative remission rate [of all 4 steps] was 67%.”4 The BMJ authors concluded that, “In contrast to the STAR*D-reported 67% cumulated remission rate after up to 4 antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria.” Hence, they concluded that, “STAR*D’s cumulative remission rate was approximately half of that reported.”

For us in psychiatry, if the BMJ authors are correct, this is a huge setback, as all of the publications and policy decisions based on the STAR*D findings that became clinical dogma since 2006 will need to be reviewed, revisited, and possibly retracted.

STAR*D Design

Unlike most clinical trials, which enroll patients who volunteer and are usually recruited for participation, the STAR*D patients were invited to participate after screening positive for MDD during routine medical or psychiatric treatment. Additionally, patients with multiple comorbidities, including psychiatric, medical, and substance use disorders, were allowed to participate (with a few exceptions). Significantly, there was no placebo control group, which is a large deviation from most clinical trials that usually follow a double-blind, placebocontrolled design.

FIGURE. Treatments by Step in Sequenced Treatment Alternatives to Relieve Depression

FIGURE. Treatments by Step in Sequenced Treatment Alternatives to Relieve Depression

The Figure summarizes the treatment interventions in the 4 steps of the study.4 At the present time, there have been more than 100 peer-reviewed publications related to the STAR*D trial. For the interested reader, references are listed that review each of the steps and the results.4-10

Why Was the STAR*D Data Reanalyzed?

In 2015, the first author of the BMJ article published a paper alleging protocol violations in the STAR*D data, which appeared to result in elevated remission rates for each of the 4 steps of STAR*D.11 A request to reanalyze the STAR*D data set by an independent team of researchers was initiated.

In 2018, the first and fourth authors of the BMJ article collaborated with University of Connecticut researchers to reanalyze the STAR*D level 1 data provided by the NIMH.12 They concluded that the STAR*D reported remission and response rates were significantly inflated.

In 2013, the Restoring Invisible and Abandoned Trials (RIAT) initiative began, the purpose of which was to request that funders or investigators of unpublished or misreported studies publish or correct these studies.13

In 2019, after the authors of the STAR*D declined a request to reanalyze their data adhering to the research protocol as initially reported, the RIAT Support Center funded the BMJ authors to reanalyze STAR*D. The BMJ authors received a STAR*D Data Use Certificate issued by the NIMH Data Archive Data Access Committee and performed the reanalysis, which led to their recent publication.

Protocol Violations of STAR*D Data

The BMJ article authors published a comprehensive list of criticisms of the STAR*D investigators’ report, which can be reviewed in their manuscript.3 Two violations of the rationale and design of the STAR*D study defined in the original publication by the STAR*D research team1 merit mentioning.

The background and rationale for the STAR*D study publication2 specifically states,

“The STAR*D ensures that only participants who are treatment-resistant or intolerant enter each subsequent treatment level.”

The BMJ authors found that 125 patients included in the STAR*D remission analysis had met the prespecified HRSD less than 8 remission score before entry into the next step of treatment. These patients should have been excluded from the analyses.

Highly significant, the STAR*D protocol specifically predefined the primary outcome of achieving remission as a score less than 8 on the blinded HRSD. The requirement of the raters being blinded to the patients’ study status—at treatment-level entry, treatment-level exit, and follow-up—was deemed to be an important element of the study design. The STAR*D protocol “specifically excluded all non-blinded clinic-administered assessments from use as research outcome measures.”3

However, in the 2006 STAR*D summary publication, which calculated the cumulative remission rate after all 4 steps as 67%, the primary outcome measure was the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR), a score reported by the patient, was clearly not blinded and has all the inherent bias of any patient self-report scale.4 The authors of this STAR*D summary publication justify this change in depression scale protocol by stating that the QIDS-SR and the HRSD “outcomes are highly related” and justify this statement with 8 references,5-10,14,15 all of which were authored by these same STAR*D investigators.

Concluding Thoughts

Beginning in 2015, the authors of the BMJ article identified what appeared to be protocol violations in the STAR*D data that questioned the results, most importantly, the percentage of remission from depression at each of the 4 steps. They persevered in their inquiry to establish whether the STAR*D data and conclusions are accurate as published or if a reanalysis was required.

Their recent article documents this process, which culminated in their reanalysis of the raw STAR*D data provided to them by the NIMH, which funded and sponsored the STAR*D. This reanalysis concludes that when the data were analyzed in accordance with the prespecified protocol as published before the start of the clinical study, the previously reported 67% cumulative remission during the 4 steps of STAR*D is significantly overinflated and the actual cumulative remission rate is 35%.

STAR*D has become a foundational reference study for understanding treatment expectations with the use of antidepressant medications, ranging from monotherapy to various augmentation strategies not approved by the US Food and Drug Administration (FDA). Significantly, STAR*D has informed a narrative that the best chance of achieving a treatment response or remission from a major depressive episode occurs with the first 2 antidepressant trials.

Beyond these initial trials, even with more aggressive treatments such as augmentation with lithium or T3, or prescribing a monoamine oxidase inhibitor, the chance of response and remission significantly drops. The BMJ article’s reanalysis reports an even poorer remission than previously defined as early as the first antidepressant trial.

Since 2006, novel agents have entered the antidepressant armamentarium with FDA approvals: 4 monoamine-based monotherapy antidepressants, 5 atypical antipsychotics approved as augmentation for partial responders, intranasal esketamine approved for treatment-resistant depression, and an (oral) N-methyl-D-aspartate receptor antagonist approved as an antidepressant monotherapy. No significant studies currently exist to help us understand whether these additions have improved outcomes beyond what we learned from STAR*D.

In my clinical opinion, it is urgent for the field of psychiatry to reconcile the significant differences in remission rates for patients with MDD as published in the original STAR*D article in 2006 with the reanalysis just published in the BMJ article this year. Finally, we must continue to aggressively pursue novel treatments for depression of all types including antidepressants, neuromodulation, and psychotherapies as well as early screening, increased access, improvement of psychosocial risks, and additional funding.

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

2. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am. 2003;26(2):457–494.

3. 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.

4. 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.

5. 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.

6. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354(12):1231-1242.

7. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.

8. 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.

9. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T3 augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.

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

11. Pigott HE. The STAR*D trial: it is time to reexamine the clinical beliefs that guide the treatment of major depression. Can J Psychiatry. 2015;60(1):9-13.

12. Kirsch I, Huedo-Medina TB, Pigott HE, Johnson BT. Do outcomes of clinical trials resemble those “real world” patients? a re-analysis of STAR*D antidepressant data. Psychol Conscious. 2018;5(4):339-345.

13. Doshi P, Dickersin K, Healy D, et al. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ. 2013;346:f2865.

14. Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573-583.

15. Rush AJ, Trivedi MH, Carmody TJ, et al. Self-reported depressive symptom measures: sensitivity to detecting change in a randomized, controlled trial of chronically depressed, nonpsychotic outpatients. Neuropsychopharmacology. 2005;30(2):405-416.


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