Clinical and Research News
For Nonremitting Depression, Add Rather Than Switch
Psychiatric News
Volume 41 Number 8 page 42-56

A pair of new reports from the team crunching the data gathered during the National Institute of Mental Health's STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study show that more than half of all patients originally enrolled achieved remission with the second antidepressant they tried.

The companion reports, published in the March 23 New England Journal of Medicine, detail findings from the study's level 2, which followed patients who did not achieve remission while taking citalopram (Celexa) during STAR*D's level 1 protocol (Psychiatric News, January 20).

One-third of the 2,876 patients who entered level 1 of the study achieved remission—the near absence of any depressive symptoms—and an additional 10 percent to 15 percent were deemed responders.

However, when level 1 results were announced, the question left hanging in the air was, What do you do with the remaining two-thirds of patients who do not achieve remission with their first antidepressant? With the release of the two level 2 reports, clinicians are closer to answering that question.

"These findings provide important treatment options to mental health clinicians and millions of Americans who struggle with treatment-resistant depression," Elias Zerhouni, M.D., director of the National Institutes of Health, said in a press release.

"If the first treatment attempt fails, patients should not give up," added Thomas Insel, M.D., director of the National Institute of Mental Health. "By remaining in treatment and working closely with clinicians to tailor the most appropriate next steps, many patients may find the best single or combination treatment that will enable them to become symptom free."

STAR*D, Insel noted, is "the largest trial ever done on depression." The $35 million, six-year study was designed to address the question of "how to successfully treat people who've not sufficiently recovered after the first [antidepressant medication]." And in each level of the four-stage study, Insel emphasized, "the goal was to find treatments that help people get well, not just get better."


"The major message from level 2 of STAR*D," A. John Rush, M.D., professor and vice chair of research in psychiatry at the University of Texas/Southwestern Medical Center in Dallas, said during a conference call for the media announcing study results, "is that depressive symptoms can be eliminated—that is, symptomatic remission can be achieved in over 50 percent of people who receive two treatment steps. One-third get well after the first step. And results from this second step show that about 30 percent of the two-thirds who are left [with significant symptoms] get well with the second step. So the second step is nearly as effective as the first one."

That message, said Rush, who is the principal author on one of the New England Journal of Medicine reports, is an important one for patients and their clinicians. "It is important to not give up if the first treatment fails or causes [intolerable] side effects."

Treatment in level 2 of STAR*D—a real-world effectiveness trial—was offered to all patients who did not experience remission during level 1 of the study, either because of lack of efficacy or because of intolerable side effects. The 1,439 eligible patients who did not experience remission during level 1 were offered seven treatment options within two arms of the study. Patients were educated on the options and asked which options were acceptable to them.

The first arm of level 2 involved patients discontinuing the citalopram taken in level 1 of the study and switching to one of three antidepressant medications (bupropion-SR, sertraline, or venlafaxine-XR) or to cognitive therapy.

The second arm involved patients continuing the citalopram through level 2 and augmenting the drug with a second (bupropion-SR or buspirone) or with cognitive therapy.

Only a few participants (21 out of 1,439, or 1.5 percent) said that all of the choices were equally acceptable to them and gave consent to researchers to assign them randomly to one of the seven possibilities. Each of the remaining patients identified at least one of the possible treatments as being unacceptable and therefore limited the possible treatments to which researchers could randomly assign them.


A total of 727 patients entering level 2 (51 percent) chose options that included switching to a different medication. Some 565 patients (39 percent) chose options that included augmenting the citalopram they were already taking. The remaining 147 patients (10 percent) chose options involving cognitive therapy. (Results of the cognitive therapy options will be presented in a future report.)

Rush and his coauthors reported that 25.5 percent of the patients switched from citalopram to bupropion-SR achieved remission by the end of the 12 weeks of level 2 treatment, compared with 26.6 percent of those switched to sertraline, and 25.0 percent of those switched to venlafaxine. Rush and his team found no statistically significant differences in efficacy, safety, or tolerability between the groups switched to the three medications.

"No one medication was clearly better," Rush said. "Even though these three treatments differ in how we believe they work in the brain—that is, they have different pharmacologic mechanisms of action—which treatment is used [as the second-step choice] may be less important than [ensuring] that the drugs be used diligently and appropriately with proper dose adjustments and careful measurement of symptoms and side effects."

Importantly, Rush added, "Doctors should know that they should not give up on a treatment after four weeks—which is currently common practice." Nearly one-third of patients who achieved remission during level 1 or 2 of STAR*D, Rush explained, did so after four or six weeks of medication at adequate therapeutic doses. Average doses of the three medications at the end of level 2 (week 12) were 283 mg/day of bupropion-SR, 136 mg/day of sertraline, and 194 mg/day of venlafaxine-XR.

The second arm of level 2, the augmentation study, found that both medications were effective when added to concurrent citalopram therapy. However, those results, reported by Madhukar Trivedi, M.D., a professor of psychiatry at the University of Texas/Southwestern Medical Center, showed one drug slightly edged out the other.

While both combinations produced roughly similar results as far as patients achieving remission (39 percent with citalopram plus bupropion-SR, compared with 32.9 percent with citalopram plus buspirone; not a statistically significantly difference), patients who received citalopram augmented by bupropion-SR experienced statistically significantly greater reductions in depressive symptoms over the 12 weeks of the level 2 study, significantly lower overall depression ratings at week 12, and fewer adverse effects leading to discontinuation of the drug combination.

"Further research is clearly called for," Rush concluded," because we have to better learn how to match the individual treatments to individual patients, and we have to learn how to predict what is the better treatment from the outset."

Both STAR*D reports and an accompanying editorial can be accessed at<http://content.nejm.org/content/vol354/issue12/index.shtml>. Patient self-report tools are posted at<www.star-d.org>.

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