One in five outpatients seeking care for their major depression experiences episodes lasting two years or more, and chronic depressive episodes are associated with socioeconomic disadvantage and racial/ethnic minority status (Gilmer et al., 2005). These and other findings are emerging from recent reports on the first 1,500 enrollees in one of the largest depression treatment studies ever conducted, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project.
A seven-year, $34.8 million project, STAR*D is funded by the National Institute of Mental Health under a contract with the University of Texas (UT) Southwestern Medical Center at Dallas (the national coordinating center for the project). The study involves 4,041 patients (18 to 75 years of age) diagnosed with nonpsychotic major depression as determined by having a score of greater than or equal to 14 (moderate severity) on the 17-item Hamilton Depression Rating Scale (HAM-D-17).
At the American Psychiatric Association's annual meeting last year, project director, A. John Rush Jr., MD, professor and vice chairman for research in psychiatry at UT Southwestern, said the project's objective is to identify "the preferred treatments in treatment-resistant depression."
"We are looking for the next best step treatments for depressions not responding satisfactorily," he explained, adding that remission rather than response is the goal (Rush, 2005).
Now nearing completion, the study involved four possible treatment levels lasting up to 12 weeks, with an option to go to 14 weeks if symptom ratings were close to remission, Rush said. Level 1 entailed an adequate trial (in terms of dose and duration) with citalopram (Celexa), a selective serotonin reuptake inhibitor. Patients who did not achieve remission or could not tolerate citalopram were eligible to participate in a series of randomizations with options.
In the Equipoise Stratified Randomized Design (ESRD), "We allowed patients to choose whether they would like to receive augmentation or switch [treatments]," Rush said.
Options at Level 2 were bupropion SR (Wellbutrin SR), sertraline (Zoloft), venlafaxine XR (Effexor XR) or cognitive therapy (CT) as monotherapies, or CT, bupropion SR or buspirone (BuSpar) as augmenting agents.
Those patients without remission after two adequate trials with antidepressants could proceed to Level 3. Options at Level 3 were mirtazapine (Remeron) or nortriptyline (Aventyl, Pamelor) as monotherapies, or augmentation with lithium (Eskalith, Lithobid) or a thyroid hormone (T3).
If no remission was achieved after Levels 1, 2 and 3, patients could participate in Level 4, which meant switching to tranylcypromine (Parnate), a non-hydrazine reversible monoamine oxidase inhibitor, or to a combination of venlafaxine XR and mirtazapine. Patients remitting at any level proceeded into a 12-month naturalistic follow-up phase.
As of press time, Rush told Psychiatric Times that enrollment is complete for STAR*D, but there are 10 patients still in follow-up. He expects the findings on the first treatment strategy (Level 1) with citalopram to be published this month in the American Journal of Psychiatry.
Secondary goals of the project as outlined by Rush included identifying predictors and baseline moderators of response or remission; creating an infrastructure for ancillary studies, such as defining the effect of alcohol and drug abuse on treatment outcomes for major depressive disorder (MDD); and simplification of outcome measures for use in subsequent trials.
The STAR*D is remarkable for its scope, coordination and "real world" approach, said William S. Gilmer, MD, the first author of a preliminary STAR*D report on chronic depression (Gilmer et al., 2005).
The STAR*D infrastructure included the national coordinating center in Dallas, a data coordinating center in Pittsburgh and 14 regional centers across the United States, each of which supervised two to four clinical sites providing primary or specialty care. Nearly half of the clinical sites (18 of 41) were primary care settings. Clinicians at all the sites used identical assessment and therapeutic procedures as defined by the STAR*D protocol. In addition to the HAM-D-17, some other baseline assessments were the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rating (QIDS-C16), 30-item Inventory of Depressive Symptomatology-Clinician Rating (IDS-C-30), 14-item Cumulative Illness Rating Scale (CIRS), the Work and Social Adjustment Scale (WSAS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ).
Of the 4,041 enrollees in the study, two-thirds were female, Rush said, and there was a good representation of racial and ethnic minorities. Among the participants, 17% were African-American; 2%, Asian; 73%, Caucasian; and 8%, other. Twelve percent of the enrollees classified themselves as Hispanic (University of Texas Southwestern Medical Center at Dallas, 2004).
"One of the very important things about this study and what makes it so unique is that these are real patients being given care in the community. They are not receiving treatment in tertiary care clinics," said Gilmer, associate professor of psychiatry and behavioral science at Northwestern University's Fineberg School of Medicine.
Gilmer, who is clinical director of the Asher Center for the Study and Treatment of Depressive Disorders, explained that he is involved in several studies evaluating investigational treatments, and "typically those studies developed or supported by the pharmaceutical industry have multiple exclusions. They often exclude anybody who has any comorbid psychiatric illness or who has any significant medical illness."
Exclusion criteria in STAR*D, Gilmer added, was kept to a minimum to ensure that the findings generalized to clinical practice. For example, many of the STAR*D patients have medical illnesses, such as cancer or cardiac disease, or psychiatric comorbidities.
At APA, Rush noted that patients enrolled in STAR*D "turned out to be a much more severe chronic and recurrent sample than we had anticipated." The average HAM-D-17 score was 20, and more than 80% of the participants had chronic or recurrent depression.
Patients also had clear views as to whether they wanted to be switched to a different antidepressant or take an augmenting drug and whether they wanted to receive or exclude CT.
1. Gilmer WS, Trivedi MH, Rush AJ et al. (2005), Factors associated with chronic depressive episodes: a preliminary report from the STAR-D project. Acta Psychiatr Scand 112(6):425-433.
2. Hollon SD, Shelton RC, Wisniewski S et al. (2005), Presenting characteristics of depressed outpatients as a function of recurrence: preliminary findings from the STAR*D clinical trial. J Psychiatr Res Oct. 20 [Epub ahead of print].
3. Husain MM, Rush AJ, Sackeim HA et al. (2005), Age-related characteristics of depression: a preliminary STAR*D report. Am J Geriatr Psychiatry 13(10):852-860.
4. Marcus SM, Young EA, Kerber KB et al. (2005), Gender differences in depression: findings from the STAR*D study. J Affect Disord 87(2-3):141-150.
5. Rush AJ (2005), An update on the STAR*D trial. Symposium 9C. Presented at the 158th annual meeting of the American Psychiatric Association. Atlanta; May 23.
6. Rush AJ, Zimmerman M, Wisniewski SR et al. (2005), Comorbid psychiatric disorders in depressed outpatients: demographic and clinical features. J Affect Disord 87(1):43-55.
7. University of Texas Southwestern Medical Center at Dallas (2004), STAR*D Participant News 3(3):1.
8. Zisook S, Rush AJ, Albala A et al. (2004), Factors that differentiate early vs. later onset of major depression disorder. Psychiatry Res 129(2):127-140.