Interpreting Key Trials

The STAR*D study: Treating depression in the real world

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ABSTRACTThe Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut "winner," it does provide guidance on how to start therapy and how to proceed if initial treatment fails.


  • Remission (ie, complete relief from a depressive episode) rather than response (merely substantial improvement) should be the goal of treatment, as it is associated with a better prognosis and better function.
  • Should the first treatment fail, either switching treat mentor augmenting the current treatment is reasonable.
  • For most patients, remission will require repeated trials of sufficiently sustained, vigorously dosed antidepressant medication. Physicians should give maximal but tolerable doses for at least 8 weeks before deciding that an intervention has failed.
  • After two well-delivered medication trials, the likelihood of remission substantially decreases. Such patients likely require more complicated regimens. Given the thin existing database, these patients are best referred to a psychiatrist for more complex treatments.
  • With persistent and vigorous treatment, most patients will enter remission: about 33% after one step, 50% after two steps, 60% after three steps, and 70% after four steps (assuming patients stay in treatment).



Depression can be treated successfully by primary care physicians under “real-world” conditions.

Furthermore, the particular drug or drugs used are not as important as following a rational plan: giving antidepressant medications in adequate doses, monitoring the patient’s symptoms and side effects and adjusting the regimen accordingly, and switching drugs or adding new drugs to the regimen only after an adequate trial.

These are among the lessons learned from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest prospective clinical trial of treatment of major depressive disorder ever conducted. It was funded by the National Institutes of Health and directed by A. John Rush, MD.


Depression, a common and debilitating condition, affects approximately one in eight people in the United States.1 It is expected2 to be the second-leading cause of disability in the world by the year 2020; today, it is the second-leading cause of disability-adjusted life years in those 15 to 44 years old.3

Nevertheless, the available evidence base for treatment is limited, since most participants in clinical trials are recruited by advertisement rather than from representative practices, and they are often selected to have few comorbid disorders, either medical or psychiatric. In addition, those with chronic depression or current suicidal ideation are excluded.1,4 These uncomplicated and “pristine” participants are unlike typical patients seen by primary care physicians or psychiatrists.

Similarly, the protocols used in these trials do not represent usual clinic practice.Patients in clinical trials undergo more assessment and more frequent follow-up than in real-world practice, they have no say in treatment decisions, the doses are fixed, and the patients and physicians are blinded to the intervention. Consequently, how to translate the results of these efficacy trials into practice is unclear.5

Further, even in relatively uncomplicated cases, only about one-half of outpatients with nonpsychotic major depressive disorder initially treated with a single medication or with psychotherapy will experience a clinically significant improvement in symptoms (ie, a response) during the 8 to 12 weeks of acute-phase treatment,6–10 and only 20% to 35% of patients will reach remission,9 the aim of treatment.8,11 The remission rates are even lower in treatment-resistant depression.12 How to manage most patients—those whose depression does not remit with the first, second, or third step of treatment—is unclear.

Accordingly, the overall objective of STAR*D was to develop and evaluate feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression, who were identified prospectively from a pool of patients in a current major depressive episode.13–15 Specifically, STAR*D aimed to determine prospectively which of several treatments is the most effective “next step” for patients who do not reach remission with an initial or subsequent treatment or who cannot tolerate the treatment.


Nearly 10% of all primary care office visits are depression-related.16 Primary care physicians provide nearly half the outpatient care for depressed patients.17 Indeed, primary care physicians log approximately as many outpatient visits for depression as psychiatrists do.18 Medical comorbidity is especially common in primary care settings.19 When to refer to a psychiatrist is not clear.


STAR*D involved a national consortium of 14 university-based regional centers, which oversaw a total of 23 participating psychiatric and 18 primary care clinics. Enrollment began in 2000, with follow-up completed in 2004.

Entry criteria were broad and inclusive

Patients had to:

  • Be between 18 and 75 years of age
  • Have a nonpsychotic major depressive disorder, identified by a clinician and confirmed with a symptom checklist based on the Diagnostic and Statistical Manual, fourth edition revised,20 and for which antidepressant treatment is recommended
  • Score at least 14 on the 17-item Hamilton Rating Scale for Depression (HAMD17)21
  • Not have a primary diagnosis of bipolar disorder, obsessive-compulsive disorder, or an eating disorder, which would require a different treatment strategy, or a seizure disorder (which would preclude bupropion as a second-step treatment).

Dosing recommendations were flexible but vigorous

Medications often were increased to maximally tolerated doses. For example, citalopram (Celexa) was started at 20 mg/day and increased by 20 mg every 2 to 4 weeks if the patient was tolerating it but had not achieved remission, to a maximum dose of 60 mg/day. Treatment could be given for up to 14 weeks, during which side effects22 and clinical ratings23 were assessed by both patients and study coordinators.


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