Neurology & Psychiatry · 2006
STAR*D sequenced antidepressant treatment study
Sequenced Treatment Alternatives to Relieve Depression
Before STAR*D, the evidence base for treating major depression beyond a single drug trial was thin. Most antidepressant registration trials lasted eight to twelve weeks, enrolled patients selected for high placebo response, and excluded anyone with significant comorbidity. Real-world patients frequently had partial responses or treatment failures, but clinicians lacked data from representative populations on what to try next or how likely a second or third agent was to succeed. That gap was what the STAR*D investigators set out to fill.
STAR*D enrolled 3,671 outpatients with nonpsychotic major depression from primary care and psychiatric outpatient settings across the United States, deliberately using minimal exclusion criteria to reflect actual clinical populations. A. John Rush designed the sequential protocol, and Madhukar Trivedi led the implementation of measurement-based care, in which clinicians adjusted treatment according to standardized symptom scales at each visit rather than relying on clinical impression alone. Maurizio Fava oversaw the augmentation strategy arms. Patients who did not achieve remission on one treatment could proceed to a next step, which offered either a medication switch or augmentation.
Remission rates fell steeply with each step. At step one, citalopram, roughly 37% of patients achieved remission by QIDS criteria. At step two, approximately 31% of those who had failed step one remitted. Steps three and four each produced remission in around 13 to 14% of the patients who reached them. Cumulative remission approached 67%, meaning that with sufficient persistence, about two-thirds of patients could eventually achieve remission. The critical caveat was durability: patients who required three or four steps to remit had substantially higher relapse rates during follow-up, diminishing the practical benefit of late remission.
The trial's publication in 2006 in the American Journal of Psychiatry carried a message that was sobering and practically useful at the same time. Most depressed patients do not remit on their first antidepressant. Each failed trial reduces the odds of eventual remission and raises the odds of relapse if remission is eventually achieved. This finding changed how clinicians counseled patients at the outset of treatment, providing a realistic rather than optimistic framing for what antidepressant therapy could accomplish. It also validated the use of structured symptom measurement to guide treatment decisions rather than waiting for global clinical impression.
STAR*D's methodology attracted criticism as well. The lack of a placebo arm meant that it was impossible to determine how much improvement was drug-specific. Some statisticians questioned how cumulative remission rates were calculated and whether including partial responders who later achieved remission in the final count overstated the benefit. Later reanalyses suggested the numbers were somewhat less favorable than originally reported. Despite those objections, STAR*D remains the largest and most pragmatic antidepressant effectiveness study conducted and is still cited in treatment guidelines for major depression.
Key People
- A. John Rush — Principal investigator; designed the sequential treatment protocol
- Madhukar Trivedi — Co-investigator; led measurement-based care implementation
- Maurizio Fava — Co-investigator; oversaw augmentation strategy arms
- Harold Pincus — Co-investigator; contributed to design and health services outcomes
Am J Psychiatry. 2006;163(11):1905-1917.
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