STAR*D: The Clinical Trial That Keeps on Giving

Five years after the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study ended, the data and conclusions from this large trial continue to provide valuable insights to clinicians, health care policymakers, and researchers.

In a special section in the November Psychiatric Services, researchers involved in the trial and other experts discussed how the study continues to generate important knowledge for clinical practice and health care policies.

The largest and most comprehensive clinical trial on antidepressant treatments for patients in a community setting, STAR*D was funded by the National Institute of Mental Health (NIMH) and conducted from 2000 through 2004 at 41 primary- and specialty-care centers throughout the United States. The study enrolled nearly 3,000 patients and tested four escalating steps of therapy depending on patients' tolerability and remission in each treatment step.

Treatment began with citalopram, a selective serotonin-reuptake inhibitor (SSRI), followed by an algorithm that incorporated switching and augmentation approaches with an option of cognitive psychotherapy.

The special section includes a review article by Bradley Gaynes, M.D., M.P.H., an assistant professor of psychiatry at the University of North Carolina, and colleagues, who summarized important clinical messages derived from STAR*D results. For example, a majority of patients did not achieve remission on the first SSRI monotherapy and required a second step of treatment. For these patients, either switching to a different treatment or augmentation with an additional treatment as the second-step treatment led to similar remission rates.

Further, different mechanisms of action of antidepressants “do not translate into meaningful clinical differences,” they wrote. This observation runs counter to a previous hypothesis that patients who fail to respond adequately to one SSRI are more likely to respond to an antidepressant acting on receptors other than the serotonin receptor.

Beyond clinical practice, STAR*D has relevance for mental health policies and the direction of future research. Several articles in this collection discussed the study's implications from the perspectives of patients, insurance payers, and researchers.

Like several other large clinical trials sponsored by NIMH, STAR*D has “immense importance for everyday clinical practice and for health care reform,” said Grayson Norquist, M.D., M.S.P.H., the guest editor of the special section and a professor and chair of psychiatry and human behavior at the University of Mississippi Medical Center, in an interview with Psychiatric News. “These trials help us understand how well the current treatments work and whether they are worth paying for.”

Best Care Possible in Primary Care

To patients and mental health advocates, STAR*D has demonstrated the promise and challenge of high-quality depression care. In one of four commentaries in this special section, David Shern, Ph.D., president and chief executive of Mental Health America, and colleague Hazel Moran emphasized the gap between scientific knowledge and its dissemination into practice in the community. They also discussed the need to involve patients and consumers in the design, analysis, and interpretation of clinical research.

In another commentary, Michael Ong, M.D., Ph.D., and Lisa Rubenstein, M.D., Ph.D., outlined the barriers to implementing effective depression care used in STAR*D in the primary-care setting. STAR*D showed that primary-care and specialty-care clinicians achieved similar patient outcomes in the first treatment step. However, the treatment protocols used in STAR*D are difficult to implement within the current health care system and payment structure, Ong and Rubenstein pointed out. Many patients in the community do not have access to the type of treatment that was critical to success in STAR*D, such as frequent visits, care management, and referral to mental health specialists. Insurance coverage often excludes mental health care in primary care settings.

In STAR*D a measurement-based approach ensured the quality of depression care, Norquist emphasized. “Patients were assessed with scales and pushed to the next stage of treatment if they did not respond,” said Norquist. This type of aggressive follow-up and management is not done in most primary-care clinics, he noted. However, he is optimistic that the movement toward performance-based practice and electronic health records will push payers and practitioners toward such measurement-based care systems.

‘Goals Remain Out of Reach’

STAR*D has highlighted the “weak, transient effects of [current] antidepressant treatment,” wrote Thomas Insel, M.D., director of NIMH, and Philip Wang, M.D., Dr.P.H., deputy director of NIMH, in an accompanying commentary. They pointed out that despite the hundreds of millions of prescriptions written for antidepressant drugs each year, “important goals remain out of reach.”

In STAR*D, fewer than 1 in 3 patients achieved remission after 14 weeks on citalopram, the study's first-step antidepressant. However, with one year of multistep treatment, approximately 70 percent of study patients achieved remission.

Nevertheless, Norquist pointed out that many chronic diseases, such as hypertension, diabetes, and cancer, usually require more than one drug or step to achieve the therapeutic goal. “Depression treatment is not much different from other areas of medicine … . We are all constantly struggling to come up with more effective interventions,” he said, noting that the large amount of data collected in STAR*D has provided invaluable evidence for scientific research into the disorder and its treatments and laid groundwork for future discoveries.

In an overview article, Gonzalo Laje, M.D., M.H.Sc., and colleagues, who have been involved in the STAR*D research, summarized some of their findings that could one day help clinicians personalize depression treatment, maximizing effectiveness and minimizing adverse reactions for individual patients.

As crucial as the clinical knowledge and lessons gleaned from STAR*D are for depression treatment, also important is that it and other NIMH-funded clinical trials have led to the organization of a network of facilities that can conduct state-of-the-art clinical research and provide excellent care to patients in the community, according to Norquist. “Through these trials, we built an infrastructure of research and practice,” he said. “As new interventions and technologies come out, such networks could be used to quickly test them.” This infrastructure, he believes, is critical for the future of mental health care and must be maintained through continued funding.

Articles in the special section on the implications of STAR*D can be accessed at <http://psychservices.psychiatryonline.org/cgi/content/short/60/11/1425>.