Beyond Efficacy: The STAR☆D Trial

Abstract

Psychiatrists have a range of treatments to offer patients with depression. Randomized controlled trials have demonstrated the efficacy of tricyclic antidepressants, SSRIs, cognitive behavior therapy, and interpersonal therapy. For each of these interventions, one can say with some confidence that at least 40% of a cohort with depression will show statistically significant reductions in unbiased ratings of depression. This information, while entirely commendable in the world of research, is far from satisfactory in the world of practice where an individual clinician needs to make treatment decisions to help an individual patient. The practical questions that the clinician might ask include: For this specific patient, what is the best of the available treatments? What magnitude of response can my patient realistically expect in 4 or 6 weeks? And what should I do if my patient is not sufficiently better in this period: continue or switch treatments? If the first treatment does not work, what is the next best option? Trivedi and colleagues have addressed these questions in a landmark study, part of which is published in this issue of the Journal. Their results from the first phase of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial signify a new approach to clinical trials as part of an NIMH effort to support research with direct, practical value to clinicians. These trials, variously called “practical trials” or “effectiveness trials,” differ from traditional efficacy trials in several ways (1,2). Whereas traditional efficacy trials have strict inclusion criteria, usually compare a drug against placebo, and limit outcome to rating scales, effectiveness trials include a broad spectrum of patients (including suicidal patients in depression trials), compare active treatments rather than active treatment against placebo, and focus on real-world outcomes such as measures of functioning. In addition, these new trials often test effectiveness with self-declared patients in primary care settings where most depressed patients receive treatment. Traditional efficacy trials generally study symptomatic volunteers recruited via advertisements, and the setting is either in academic health centers or commercial clinical research organizations. The STAR*D trial enrolled 4,041 outpatients with nonpsychotic depression at 23 psychiatric and 18 primary care sites. All patients began with a 12-week course of the SSRI citalopram, administered according to a treatment manual that allowed individualized management of doses within a preplanned schedule. The STAR*D trial focused specifically on achieving remission from depression rather than partial improvement. Phase 1 examined this first 12 weeks of treatment to identify those who achieved remission. Among the patients who did not achieve remission or could not tolerate citalopram, Phase 2 compared several different strategies that entailed either replacing citalopram with a different treatment or augmenting citalopram with an additional treatment, including cognitive therapy. Those without sufficient improvement were offered up to two additional levels of treatment. Those who achieved an adequate response were followed for 1 year to evaluate long-term outcomes with these various treatments.