STAR*D

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission.
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35


An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed. Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.

The Role of L-methylfolate in Depressive Disorders