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

Abstract

Objective: Reanalyse the patient-level data set of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study with fidelity to the original research protocol and related publications.

Design: The study was open label and semirandomised examining the effectiveness of up to four optimised and increasingly aggressive, antidepressant therapies in depressed adults. Patients who failed to gain adequate relief from their level 1 trial on the SSRI citalopram could receive up to three additional treatment trials in levels 2-4.

Setting: 41 North American psychiatry and primary care treatment centres.

Participants: 4041 adults screened positive for major depressive disorder. In contrast to most clinical trials, STAR*D enrolled patients seeking care (vs recruited) and included patients with a wide range of common comorbid medical and psychiatric conditions to enhance the generalisability of findings to real-world clinical practice.

Interventions: STAR*D evaluated the relative effectiveness of 13 antidepressants therapies in treatment levels 2-4 for depressed patients who failed to gain adequate benefit from their level 1 medication trial.

Main outcome measures: According to the STAR*D protocol, the primary outcome was remission, defined as a score <8 on the blinded Hamilton Rating Scale for Depression (HRSD). Response was a secondary outcome defined as ≥50% reduction in HRSD scores. STAR*D's protocol specifically excluded all non-blinded clinic-administered assessments from use as research outcome measures.

Results: STAR*D investigators did not use the protocol-stipulated HRSD to report cumulative remission and response rates in their summary article and instead used a non-blinded clinic-administered assessment. This inflated their report of outcomes, as did their inclusion of 99 patients who scored as remitted on the HRSD at study outset as well as 125 who scored as remitted when initiating their next-level treatment. These patients should have been excluded from data analysis. In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria.

Conclusion: STAR*D's cumulative remission rate was approximately half of that reported.

Keywords: Adult psychiatry; CLINICAL PHARMACOLOGY; Depression & mood disorders.

Figure 1

Patient flowchart. *In level 2, 580 patients were randomised to switch medications, 441 to medication augmentation, and 113 to cognitive therapy as either a switch or medication augmentation treatment. In level 2A, 28 patients were randomised to one of two level 2 switch medications. For step 3/level 3 patients, 186 were randomised to medication switch and 111 to medication augmentation. For step 4/level 3 patients, seven were randomised to medication switch and nine to medication augmentation. For step 4/level 4 patients, 90 were randomised to one of two medication/medication combination switch options. **Exit refers to the number of patients who exit the study and do not proceed either to the next treatment level nor enter follow-up. ***Follow-up refers to the number of patients who exit a treatment and enter the 12-month follow-up phase. HRSD, Hamilton Rating Scale for Depression.

Figure 2

Comparison of STAR*D protocol predictions to what occurred. RIAT, Restoring Invisible and Abandoned Trial; STAR*D, Sequenced Treatment Alternatives to Relieve Depression.

Figure 3

STAR*D’s step-by-step cumulative remission rate presented three ways. The step-by-step theoretical remission rates were obtained from the STAR*D summary article where it states: ‘The theoretical cumulative remission rate is 67% (37+19+6+5).’ [Rush AJ et al, p1910]. The HRSD+QIDS SR cumulative remission rate was taken from table 1. It combines the 1089 patients with an exit HRSD score of<8 with the 195 patients who were missing an exit HRSD score but had a final clinic-visit QIDS-SR score of<6. The RIAT Reanalysis cumulative remission rate is based on an exit HRSD score of <8 as the sole measure of remission for the 3110 patients who met STAR*D’s inclusion for data analysis criteria. HRSD, Hamilton Rating Scale for Depression; QIDS-SR, Quick Inventory of Depressive Symptomatology–Self Report; RIAT, Restoring Invisible and Abandoned Trial; STAR*D, Sequenced Treatment Alternatives to Relieve Depression.