STAR*D Trial Summary
Core Design and Purpose
The STAR*D trial was a landmark, multisite, prospective study of 4,041 adults with major depressive disorder that sequentially tested treatment alternatives when patients failed to achieve remission, demonstrating that most patients require multiple treatment steps and that no single medication strategy is clearly superior to others. 1, 2
The trial enrolled patients aged 18-75 from both primary and specialty care settings with broadly inclusive criteria, specifically excluding only those with psychotic features or prior inadequate response to protocol treatments during the current episode. 1 This real-world design made it the largest practical clinical trial ever conducted for depression treatment without pharmaceutical company support. 3
Sequential Treatment Structure
Level 1: Initial Treatment
- All 4,041 participants began with citalopram (an SSRI) managed by clinic physicians following an algorithm-guided protocol over 12 weeks. 1
- Only 28-37% of patients achieved remission with first-line citalopram, with 50% of these remissions occurring within 6 weeks. 4
- Patients most likely to remit were white women who were employed, had higher education/income, and shorter episode duration. 4
- Higher baseline depression severity paradoxically predicted lower likelihood of remission, contradicting conventional assumptions. 4
Level 2: First Alternative Strategy
Patients without adequate response were randomized to either switching or augmentation strategies:
Switch options (4 choices): 1, 5
- Sertraline (another SSRI): 27% remission
- Bupropion-SR: 26% remission
- Venlafaxine-XR (dual-action): 25% remission
- Cognitive therapy: 31% remission
Augmentation options (3 choices, added to citalopram): 1, 5
- Bupropion-SR: 39% remission
- Buspirone: 33% remission
- Cognitive therapy: 31% remission
Critical finding: No statistically significant differences existed between within-class switches, out-of-class switches, or dual-action agents. 4, 5 However, bupropion-SR augmentation showed significantly better tolerability than buspirone (12.5% vs 20.6% discontinuation due to adverse events, P < 0.001). 4, 6
Level 2A: Cognitive Therapy Non-Responders
Patients who received cognitive therapy at Level 2 without improvement could switch to venlafaxine or bupropion. 1
Level 3: Second Alternative Strategy
Switch options (2 choices): 1, 5
- Mirtazapine: 8% remission
- Nortriptyline: 12% remission
Augmentation options (2 choices, added to primary antidepressant): 1, 5
- Lithium: 13% remission
- T3 (triiodothyronine): 25% remission
T3 demonstrated better tolerability and ease of use compared to lithium, though remission rates were substantially lower than earlier levels. 5
Level 4: Third Alternative Strategy
Switch options (2 choices): 1, 5
- Tranylcypromine (MAOI): 14% remission
- Venlafaxine-XR plus mirtazapine combination: 16% remission
The combination treatment had fewer adverse effects and avoided the washout period and dietary restrictions required for tranylcypromine. 5
Key Findings and Clinical Implications
Remission Rates Decline Sharply
- Remission rates dropped substantially after two failed treatments, with patients requiring more than two well-delivered treatments characterized as treatment-resistant. 5
- However, if patients remained in treatment through all four steps, approximately 67% eventually achieved remission. 5
- Times to remission did not substantially lengthen in later treatment steps. 5
Importance of Achieving Full Remission
Patients who achieved remission had dramatically lower relapse rates compared to those with only partial response: 5
- Step 1: 34% vs 59% relapse
- Step 2: 47% vs 68% relapse
- Step 3: 42% vs 76% relapse
- Step 4: 50% vs 83% relapse
Switch vs. Augmentation Strategies
- Both switching and augmenting appeared reasonable when initial treatment failed, though direct comparison was not possible due to study design. 2, 5
- Higher remission rates with medication augmentation at step 2 (39% and 33%) compared to switching (25-27%) suggest augmentation may be preferable for patients with partial response and good tolerability. 7, 5
- The 2023 American College of Physicians guidelines explicitly cite STAR*D to support that various switch and augmentation strategies show similar efficacy, allowing clinician and patient preference to guide selection. 4
Treatment Resistance Predictors
Poorer outcomes were associated with: 5
- Minority status and socioeconomic disadvantage
- More axis I and III comorbid conditions
- Lower baseline function and quality of life
- Anxious and melancholic features
- Chronicity of depression
Critical Limitations
Absence of Placebo Control
STAR*D did not include placebo arms, making it impossible to determine how many patients would have remitted without active treatment or with alternative therapies. 4 This fundamental design flaw prevents definitive conclusions about absolute effectiveness versus natural course or placebo response. 4
Lower Than Expected Remission Rates
Initial remission rates (28%) and one-year remission rates (70%) were substantially lower than anticipated, suggesting that current antidepressant treatments fall short of adequate efficacy standards. 3 This reveals that the bar for antidepressant effectiveness has been set far too low. 3
Generalizability Concerns
- Most trials were explanatory rather than pragmatic, with average depression scores in the moderate-to-severe range. 8
- The study enrolled patients from real-world settings but excluded those with prior inadequate response to protocol treatments, potentially limiting applicability. 1
Guideline Integration
The 2023 American College of Physicians systematic review incorporating STAR*D data found no significant differences between switching and augmentation strategies overall, establishing that clinician and patient preference should guide selection. 4 STAR*D demonstrated that comorbid anxiety and depression severity do not significantly affect comparative efficacy of switch or augmentation strategies, simplifying treatment algorithms. 4