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Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — Level 2 results, published in New England Journal of Medicine · March 23, 2006

March 23, 2006

1. What was the goal of second level of the STAR*D study?

A. The nationwide STAR*D study, whose goal was to assess the effectiveness of adequately delivered treatments in “real world” outpatients who have major depressive disorder (MDD), included four levels of treatment (see Background Questions and Answers on the STAR*D Study and the NIMH introduction to STAR*D). All participants began at Level 1 and were treated with the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI). If they did not achieve satisfactory outcomes, participants could go on to successive levels in an attempt to determine the best next steps after the first treatment did not work. Therefore, the goal of Level 2 of the STAR*D study was to find out which next step treatments are most effective for the participants who did not become symptom-free (i.e., did not achieve remission) or could not tolerate initial treatment with citalopram in Level 1.

2. Who participated in the Level 2 STAR*D study?

A. In the Level 1 study, participants were evaluated for their depression outcomes from treatment with citalopram. Approximately one-third of those participants reached remission and if they chose to stay in the study, they continued on citalopram and entered a citalopram follow-up phase. Approximately two-thirds did not achieve a remission, and were eligible to enter Level 2. A total of 1,439 people chose to participate in Level 2.

3. What treatments were available in Level 2?

A. Level 2 of the study offered seven different treatments; four options “switched” the study participants from citalopram to a new medication or talk therapy, and three options “augmented” citalopram treatment by adding a new medication or talk therapy to the citalopram they were already receiving. A unique feature of the STAR*D study was that participants who were enrolled in Level 2 were asked whether it would be equally acceptable to them to receive a treatment “switch” or a treatment “augmentation,” or would they accept only one or the other of these approaches. This is the way people with depression are currently treated in real-world settings. Also unique to a research study, but not unique to real world practice settings, participants were offered not only medication but also cognitive therapy (a form of psychotherapy) as part of the package of treatments available to be “added” or “switched to”.

When participants were offered these seven treatment options, only 21 of the 1,439 participants said that all of the choices were equally acceptable and allowed themselves to be randomized to a medication augmentation, a medication switch, a cognitive therapy augmentation, or a cognitive therapy switch. All of the rest of the participants identified an unacceptable treatment and chose to limit the range of treatment options to which they would accept randomization.

Thus, due to the way the participants’ choices were distributed, 51 percent of the participants who entered Level 2 of STAR*D (727/1,439) agreed to treatments that included a switch to a different medication and were randomly assigned to receive “medication switch”; these are the participants whose data are examined in the “switch” paper. Similarly, 39 percent (565/1,439) of the participants who entered Level 2 agreed to treatments that included adding another medication to the citalopram they were already receiving and were randomly assigned to receive “medication augmentation”; these are the participants whose data are examined in the “augment” paper. (The remaining 147 of the 1,439 participants in Level 2 were randomly assigned to “switch” to cognitive therapy alone or to “augment” their citalopram with cognitive therapy. These participants are not included in the Level 2 medication outcome analyses described here.)

The main results of the Level 2 treatments are reported in two articles in the March 23, 2006 issue of the New England Journal of Medicine. One article focuses on the outcomes for those participants who received the “switch” medication treatments and the other focuses on those who received one of the “augment” medication treatments.

4. What is the “switch” treatment study?

A. In the switch treatment study, after stopping their citalopram, a total of 727 adult outpatients from among the 18 primary care and 23 psychiatric care clinical STAR*D settings were given one of three widely used medications: bupropion-SR (bupropion), sertraline, or venlafaxine-XR (venlafaxine), for up to 14 weeks. As in Level 1, medications were given by practitioners, using guidelines based on measurement of symptoms and side effects at each treatment visit. There was careful monitoring of the treatment in the study to ensure that the correct doses were given to people for a long enough time to be sure that participants had the best possible chance of benefiting from the medication. The primary outcome of the switch study was remission, the virtual absence of depressive symptoms (symptom-free). The same outcome measure was used in the Level 1 citalopram portion of the study.

5. What were the results of the “switch” study?

A. About one in four of the 727 people who participated in the switch study became symptom-free, and this was about the same in each of the three medication groups. All three medications were equally safe and well tolerated. No switch medication was significantly more effective than another and no switch medication worked more quickly than another. The number of side effects or serious problems, such as hospitalization, did not differ among the three medications.

6. What is the most important thing learned from the “switch” treatment study?

A. These results indicate that any of the three switch medications is a useful second step in the treatment of people with major depressive disorder who do not become symptom- free after initial treatment with an antidepressant.

It is worth emphasizing that all three of the medications used in the switch study were well tolerated by all participants. Sertraline is an SSRI, which inhibits serotonin reuptake. This is the same class of medication as the SSRI citalopram used in the first treatment step and is therefore a “same class switch.” Bupropion represents a medication from a different class, one that does not appear to have any direct effect on serotonin, and is referred to as an “out of class switch.” Venlafaxine is a medication that acts on two neurotransmitters, inhibiting both serotonin and norepinephrine reuptake, and is referred to as a “dual action” agent. Although it has been a common assumption that a within-class switch after one antidepressant medication does not work well or might not be as effective as another approach, these findings suggest that any of these three approaches are reasonable choices. Finally, the dual action medication, venlafaxine, was not any more effective as a second step treatment than the other medications.

7. What is the “augmentation” treatment study?

A. In the augmentation treatment study, 565 participants from among the STAR*D primary care and psychiatric care clinics continued taking the citalopram they were already taking for the treatment of their depression and one of two medications, either bupropion-SR (bupropion) or buspirone, was added to their treatment, for up to 14 weeks. The participants in each of these two groups were similar to each other when they entered this study in terms of age, severity of illness or number of other psychiatric problems; however, the group given citalopram plus bupropion had a slightly shorter time since the beginning of their first episode of major depression. Therefore, any difference in results would not be due to differences in the groups of people receiving the different medications. As in the Level 1 and “switch” study, medications were given by practitioners, based on careful guidelines and close monitoring of symptoms and side effects at each treatment visit, to be sure that the right medication doses were given and for a long enough time, so that participants had the best possible chance of benefiting from the medication.

8. What were the results of the “augmentation” study?

A. About one-third of the 565 participants in the augmentation study became symptom-free (achieved remission) when a second medication was added to citalopram. Although the percentage of people with remission and the amount of time it took them to become somewhat better or symptom-free were about the same with both medications, there were some advantages of bupropion over buspirone. Participants receiving bupropion had a slightly better outcome in terms of reduction of symptoms, severity of symptoms, and tolerability of side effects.

9. What is the most important thing learned from the results of the “augmentation” study?

A. As with the switch study, these results are relevant to people being treated in usual care settings. Buspirone is a medication that enhances SSRI (serotonin) activities and is not generally used as a single medication treatment for depression. Bupropion is a medication that has no direct effect on the serotonin neurotransmitter, but instead blocks reuptake of dopamine and norepinephrine, two other neurotransmitters; bupropion is often used as a single medication treatment for depression. These findings recommend augmentation of SSRIs with either bupropion or buspirone to achieve symptom remission in patients who do not achieve remission with a first step SSRI, with some slight benefits for citalopram augmented with bupropion. Moreover, these results suggest that augmentation medications (i.e., treatment combinations) might be useful earlier in treatment, perhaps even at the first treatment step, so that more people can become symptom-free faster. It is a question that remains to be tested.

10. Can the switch and augmentation treatment approaches be directly compared so that we know which is the best next step treatment for people with depression who do not respond to initial treatment?

A. No. Most participants in the STAR*D study found it acceptable to receive only a switch or only an augmentation approach. Treatments can only be compared directly if people have agreed to be randomly assigned to any of the treatments being compared. The findings of the augmentation and switch approaches cannot be compared directly with each other because too few people accepted randomization to both approaches. Also, the two groups of people in the switch and augment studies were a little different. The group who chose and were assigned to a switch medication had more problems with side effects with the first step medication than the group that chose and were assigned to an augmentation medication. It is likely, however, that people being treated in the real world also tend to limit their preferences to medication switches or augmentations.

11. How do the results of the Level 2 studies inform the care practitioners provide for the treatment of depression?

A. The knowledge available to guide treatment choices for people with depression is greatly enhanced by the STAR*D findings. For the first time, doctors and people with major depressive disorder will have extensive information on antidepressant treatments from a single, large, long-term study directly comparing the drugs to each other. We can now say that by switching to a different antidepressant medication after treatment failure with an SSRI, about one in four people will get better; and switching to antidepressant medications with the same or different mechanisms of action as the SSRI appears equally effective. We also now know that after treatment failure with an SSRI, by adding a new medication to the mix, about one in three people will get better; and we know that it makes some, but not a lot of difference whether the added medication is another antidepressant from a different class or a non-antidepressant that enhances the first SSRI. Practitioners, however, do not yet know how to predict which patient will do better with switching and which with augmentation because the effectiveness of the two strategies was studied in two different groups and cannot be directly compared to each other.

Clinicians will need additional information to help them decide, with their patients, which strategy to choose (augmenting or switching), and within a strategy, which medication to choose for which patient. Further analysis of the STAR*D clinical data, coupled with genetic data, may provide additional information to help individualize treatments and maximize improvement in patients with depression. Moreover, the data are already yielding valuable clues for future research directions in the use of combination medication strategies earlier in the course of treatment.

12. Is there an overall message to depressed patients and their families?

A. Yes. Just as in the treatment of other general medical conditions, even if the first-step treatment does not result in full benefit, a range of second-step treatments is available and they are effective. So it is important to work with your provider (clinician) and to stay in treatment, and not to give up. In addition, these results indicate that for some patients, while early benefits may occur with these treatments within the first 3 to 6 weeks, the full benefits that can be achieved may not be realized until 10 to 12 weeks. During this time it seems important to adjust the dose as tolerated and to not prematurely stop treatment. The results of the studies show that 50 percent of people with depression can get better within the two treatment steps using this approach.