NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels
The NIMH-funded Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study was conducted to determine the effectiveness of different treatments for people with major depression who have not responded to initial treatment with an antidepressant. This is the largest and longest study ever conducted to evaluate depression treatment.
What were the results?
In most clinical trials of treatment for depression, the measure of success (outcome) is called “response” to treatment, which means that the person’s symptoms have decreased to at least half of what they were at the start of the trial. In STAR*D, the outcome measure was a “remission” of depressive symptoms—becoming symptom-free. This outcome was selected because people who reach this goal generally function better socially and at work, and have a better chance of staying well than do people who only achieve a response but not a remission.
In level 1, about one-third of the participants reached remission and about 10-15 percent more responded, but did not reach remission. Still, these are considered good results because study participants had high rates of chronic or recurrent depression and other psychiatric medical problems.
It took an average of six weeks of treatment for participants to improve enough to reach a response and nearly seven weeks of treatment for them to achieve a remission of depressive symptoms. In addition, participants visited their care providers an average of five to six times. Participants who achieved remission stayed on the treatment for an average of 12 weeks before going on to a 12-month follow-up period.
In the level 2 switch group, about 25 percent of participants became symptom-free. All three of the switch medications performed about the same and were equally safe and well-tolerated. In the add-on group, about one-third of participants became symptom-free. Those who added bupropion experienced less troublesome side effects and slightly more reduction of symptoms than those who added buspirone.
In levels 2 and 3 where participants were allowed to either add-on or switch medications, most participants found only one or the other treatment strategies acceptable. Because most participants did not agree to be randomly assigned to one or the other treatment strategy, the findings of the add-on and switch approaches cannot be compared. It is likely, however, that people being treated in the real world also tend to limit their treatment preferences to switching or adding on medications. In addition, the people in the switch and add-on groups were a little different. The group who chose and were assigned to a switch medication had more problematic side effects while taking the preceding medication (citalopram) than the group who chose and were assigned to an add-on medication.
Level 2 also included cognitive psychotherapy as a switch or add-on treatment. Results for the psychotherapy treatment are not yet available.
In the level 3 switch group, 12 to 20 percent of participants became symptom-free, and the two medications used fared about equally well, suggesting no clear advantage for either medication in terms of remission rates or side effects. In the add-on group, about 20 percent of participants became symptom-free, with little difference between the two treatments. However, the T3 treatment was associated with fewer troublesome side effects than lithium.
In level 4, seven to 10 percent of participants became symptom-free, with no statistically significant differences between the medications in terms of remission, response rates or side effect burden. However, those taking the venlafaxine-XR/mirtazapine combination experienced more of a reduction in depressive symptoms than those taking the tranylcypromine. Also, those who were treated with tranylcypromine were more likely to discontinue the treatment citing side effects as the reason. It is also possible that the dietary restrictions associated with taking an MAOI could have limited its acceptability as a treatment.
In conclusion, about half of participants in the STAR*D study became symptom-free after two treatment levels. Over the course of all four treatment levels, almost 70 percent of those who did not withdraw from the study became symptom-free. However, the rate at which participants withdrew from the trial was meaningful and rose with each level—21 percent withdrew after level 1, 30 percent withdrew after level 2 and 42 percent withdrew after level 3.
What lessons are learned from the results?
For the first time, doctors and people with depression now have extensive data on antidepressant treatments from a federally funded, large-scale, long-term study directly comparing treatment strategies.
Results from level 2 indicate that if a first treatment with one SSRI fails, about one in four people who choose to switch to another medication will get better, regardless of whether the second medication is another SSRI or a medication of a different class. And if patients choose to add a new medication to the existing SSRI, about one in three people will get better. It appears to make some—but not much—difference if the second medication is an antidepressant from a different class(e.g. bupropion) or if it is a medication that is meant to enhance the SSRI (e.g. buspirone). Because the switch group and the add-on group cannot be directly compared to each other, it is not known whether patients are more likely to get better by switching medications or by adding another medication.
Results from level 3 apply to those who do not get better after two medication treatment steps. By switching to a different antidepressant medication, about one in seven people will get better. By adding a new medication to the existing one, about one in five people will get better. Level 3 results also tell us that adding T3 may have some advantages over adding lithium for patients who have tried two other treatments without success.
Finally, for patients with the most treatment-resistant depression, level 4 results suggest that tranylcypromine is limited in its tolerability and that up to 10 percent may benefit from the combination of venlafaxine-XR/mirtazapine.
An overall analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed. In addition, those who become symptom-free have a better chance of remaining well than those who experience only symptom improvement. And those who need to undergo several treatment steps before they become symptom-free are more likely to relapse during the follow-up period. Those who required more treatment levels tended to have more severe depressive symptoms and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level.
These results underscore both the need for a better understanding of how different people respond to different depression treatments, and the challenges in finding broadly effective, short- and long-term depression treatments. Future research may help identify which treatments work for which patients.
What do the STAR*D results mean to people with MDD and their doctors?
The results reiterate the need for high-quality care and attention to the individual needs of patients. Doctors should provide medication at optimal doses, be aware of and offer treatment choices, and maintain diligent monitoring of patients both during treatment and after they become symptom-free so as to avoid relapse.
Like other medical illnesses, depression affects different people in different ways, but a wide range of effective treatments exist. People with depression should not give up if their initial treatment attempts do not result in full benefits. They should continue to work with their doctors to find the best treatment strategy.
In addition, patience is required. While some people may experience benefits in the first six weeks of a treatment strategy, full benefits may not be realized until 10 or 12 weeks have passed. During this time, doctors should work with their patients to adjust dosages so as to find an optimal level, and avoid stopping a treatment prematurely.