Level 2 STAR*D: If at First You Don’t Remit...

Norman Sussman, MD, DFAPA

Dr. Sussman is Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

The first results of the Sequenced Alternatives to Relieve Depression (STAR*D) antidepressant study were published in January 2006. This 5-year, NIMH sponsored study looks at the short- and long-term effects of different sequences of medication and/or psychotherapy for the treatment of unipolar depressions that have not responded adequately to an initial standard antidepressant trial.

In the first phase (Level 1), all patients were started on the SSRI citalopram with a mean exit dose of 41.8 mg/day. They were treated for up to 8 weeks. Remission rates were ~30%. The next phase (Level 2) involved patients who did not achieve remission on citalopram, and who could either switch to another antidepressant, or have their citalopram augmented. There is no placebo in this study. Approximately 25% of patients in Level 2 achieved remission, regardless of whether they were switched to venlafaxine-XR, sertraline or bupropion-SR, or augmented with bupropion-SR or buspirone. These results mean that just over 50% of patients can expect to achieve remission after two pharmacologic interventions. Moreover, they suggest that mechanism of action was not a factor in the outcomes.

At first glance these findings might seem disappointing. However, it is important to realize that nearly 80% of those studied had chronic or recurrent major depression and that most also had a number of comorbid general medical and psychiatric conditions. This represents a population that is more ill than subjects enrolled in typical industry-sponsored trials.

Although not statistically significant, some differences among treatments were found. For example, bupropion augmentation was found to have certain advantages, such as “greater reduction in the number and severity of symptoms and fewer side effects and adverse events” than when buspirone was used. Also, patients switched to venlafaxine-XR had about a 7% higher remission rate than those switched to the other antidepressants. Whether these differences are in fact clinically significant is not answered by the study, because it is underpowered despite its large size. While the nearly 3,000 patients in this trial represent a larger sample than in any previous trial, more subjects would have been necessary to answer the questions with certainty. The reason for this is that the investigators expected that the remission rate would be 45%. With only a 30% rate primary outcome, the study cannot really say for certain that no differences might be shown if the number of subjects was larger.