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Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels

November 2006

1. What were the goals of the STAR*D trial?

A. The overall goal of the STAR*D trial was to assess the effectiveness of depression treatments in patients diagnosed with major depressive disorder, in both primary and specialty care settings. It is the largest and longest study ever conducted to evaluate depression treatment. Read more about STAR*D

Each of the four levels of the study tested a different medication or medication combination. The primary goal of each level was to determine if the treatment used during that level could adequately treat participants’ major depressive disorder (MDD). Those who did not become symptom-free could proceed to the next level of treatment.

The design of the STAR*D study reflects what is done in clinical practice because it allowed study participants to choose certain treatment strategies most acceptable to them and limited the randomization of each participant only to his/her range of acceptable treatment strategies. No prior studies have evaluated the different treatment strategies in broadly defined participant groups treated in diverse care settings.

2. Who participated in the study?

A. Over a seven-year period, the study enrolled 4,041 outpatients, ages 18-75 years, from 41 clinical sites around the country, which included both specialty care settings and primary medical care settings. Participants represented a broad range of ethnic and socioeconomic groups. All participants were diagnosed with MDD and were already seeking care at one of these sites. No media advertisements were used to recruit participants. Instead, they were referred to the trial by their doctors.

So that results could be generalized to a broad group of real-world patients, most adults with MDD were eligible. People were not eligible for the study if they had not tolerated or did not get well with one or more of the treatments that were part of the first two STAR*D treatment steps, or if a STAR*D treatment could not be safely used because of another medical condition or because they were taking certain other medications. In addition, people with substance abuse disorders that required detoxification, anorexia or bulimia, or obsessive compulsive disorder were not eligible for the study because they required treatments that were not part of STAR*D.

Of the initial 4,041 participants, 1,165 were excluded because they either did not meet the study requirements of having “at least moderate” depression (based on a rating scale used in the study) or they chose not to participate. Thus, 2,876 “evaluable” people were included in level 1 results. Level 2 results include 1,439 people who did not become symptom-free in level 1 and chose to continue. Level 3 results include 377 people, and Level 4 results include 142 people.

3. What were the treatments used in the study?

A. In level 1, participants were given the antidepressant citalopram (Celexa) for 12 to 14 weeks. Those who became symptom-free during this time could move on to a 12-month follow-up period during which the citalopram was continued, and patients were monitored. Those who experienced intolerable side effects or did not become symptom-free during this level could go on to level 2.

Citalopram is representative of the class of antidepressant medications known as selective serotonin reuptake inhibitors (SSRIs). It was chosen as the first treatment because it generally is not associated with troublesome withdrawal symptoms when it is stopped, is easy to administer (once a day), and has been shown to be safe for older adults and medically fragile patients. It does not appear to interact unfavorably with other medications that some participants may have been taking for other medical problems.

Level 2 was designed to help determine an appropriate next treatment step if the first step did not work. Thus, in level 2, participants had the option of switching to a different medication or adding on to their existing citalopram.

Those who joined the “switch” group were randomly assigned to either sertraline (Zoloft), bupropion-SR (Wellbutrin), or venlafaxine-XR (Effexor). These medications were chosen for comparison because they represent three different types of medications. Sertraline is an SSRI, the same class as the citalopram used in level 1. Bupropion belongs to another class of antidepressant medications that work on different neurotransmitters than SSRIs. Venlafaxine is a “dual-action” medication that works on two neurotransmitters at the same time.

Those who joined the “add-on” group were prescribed either the non-SSRI antidepressant bupropion-SR (Wellbutrin), or buspirone (BuSpar), which is not an antidepressant but enhances the action of an antidepressant medication. Participants could also switch to, or add on, cognitive psychotherapy.

As in level 1, those who became symptom-free with their level 2 treatment could continue with that treatment and entered the follow-up period. Those who did not become symptom-free, or who experienced intolerable side effects, could continue on to level 3.

In level 3, which like level 2 was designed to compare medications that are thought to work differently in the brain and produce different results, participants again had the option of either switching to a different medication or adding on to their existing medication. Those who chose to switch their medication were randomly assigned to either mirtazapine (Remeron) — a different type of antidepressant — or to nortriptyline (Aventyl or Pamelor) — a tricyclic antidepressant — for up to 14 weeks. Both work differently in the brain than the SSRIs and other medications used in levels 1 and 2.

In the level 3 add-on group, participants were randomly prescribed either lithium — a mood stabilizer commonly used to treat bipolar disorder — or triiodothyronine (T3) — a medication commonly used to treat thyroid conditions — to add to the medication they were already taking. These medications were chosen because they have been shown to boost the effectiveness of antidepressant medications.

In level 4, participants who had not become symptom-free in any of the previous levels (and therefore considered to have highly treatment-resistant depression) were taken off all other medications and randomly switched to one of two treatments — the monoamine oxidase inhibitor (MAOI) tranylcypromine (Parnate) or the combination of venlafaxine extended release (Effexor XR) with mirtazapine (Remeron). These treatments were chosen for comparison because previous research had suggested that they may be particularly effective in people who had not received sufficient benefit from other medications.

4. How were participant’s doses decided and how was their progress measured?

A. To ensure that every participant had the best chance of recovery with each treatment strategy, a systematic approach called measurement-based care was used. This method requires routine, consistent measurement of symptoms and side effects at each treatment visit with easy-to-use measurement tools. It also involves the use of a treatment manual that describes when and how to modify medication doses and dose adjustments to best tailor them for individual participants so as to minimize side effects, maximize safety, and provide the best chance of therapeutic benefit. This enabled STAR*D practitioners to provide consistent, high-quality care.

STAR*D employed easy-to-use rating tools of symptoms and side effects in a systematic and consistent way. These tools can readily be incorporated into real-world medical and psychiatric settings. Use of this measurement-based care may have caused greater than expected remission rates.

Patients were asked to self-rate their symptoms. The study demonstrated that most depressed patients can quickly and easily self-rate their symptoms and estimate their side effect burden in a very short time. Their doctors can rely on these self-rated tools for accurate and useful information to make informed judgments about treatment. The patients can also use these tools to help manage their illness at home in much the same way that hypertensive patients can measure their own blood pressure.

5. What were the results?

A. 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.

6. What lessons are learned from the results?

A. 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.

7. What do the STAR*D results mean to people with MDD and their doctors?

A. 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.

8. What more will be learned from the STAR*D study and what areas of future research will be influenced by STAR*D?

A. The STAR*D study results published to date provide important information about the effectiveness of current treatments in primary care and specialty settings in real world patients. Subsequent analyses of the STAR*D data include:

  • results of cognitive therapy as a switch and add-on treatment;
  • factors affecting patient preferences in choosing next-step treatments when a first treatment is not successful;
  • comparison of the effectiveness of different treatments in preventing relapse; and
  • factors associated with relapse.

Also, blood samples that were voluntarily collected from more than 1,900 of the STAR*D participants will allow researchers to identify potential biological markers of disease course and treatment response.

The results of STAR*D also underscore the need for more effective treatment strategies and more patient-tailored interventions for the treatment of major depression. Future research topics beyond STAR*D include:

  • developing methods to predict who will respond to which treatment and in what treatment sequence; and
  • evaluating combination medication strategies earlier in the course of treatment compared to single therapy strategies.

For More Information:

Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — Level 1 results, published in American Journal of Psychiatry, January 1, 2006.

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.