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What to Do After Depressed Patients Fail an SSRI

Either substituting or augmenting with another medication might help a minority of patients.

When an initial medication treatment is unsuccessful for a depressed patient, the psychiatrist might switch to or augment with psychotherapy or another medication. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was set up to compare the effectiveness of seven treatment options (four switches and three augmentations, including cognitive-behavioral therapy). First, 4041 patients with major depression from primary care and psychiatric clinics were enrolled in a 12-week trial of the SSRI citalopram. Of these, 1439 patients did not achieve remission or could not tolerate citalopram and entered the next phase, which used an "equipoise stratified" randomized design to allow for some patient preferences in treatment assignments. The secondary treatments lasted up to 14 weeks.

These two papers report separately on outcomes with the three medication switch strategies and the two medication augmentation strategies in the STAR*D trial (strategies using CBT were excluded). Mood-active psychotropic agents, except anxiolytics and sedative/hypnotics, were proscribed. Subgroups were clinically similar, with each including a mix of chronically and acutely ill subjects (although more switch patients than augmentation patients had citalopram intolerance).

The 727 switch patients received sustained-release buproprion (400 mg/day), sertraline (200 mg/day), or extended-release venlafaxine (375 mg/day). Remission rates on the 17-item Hamilton Rating Scale for Depression (Ham-D-17) and on the 16-item Quick Inventory of Depressive Symptomatology — Clinician Rated (QID-SR-16) were similar for the three conditions (ranging from 18% to 26%). Tolerability was comparable among the groups.

The 565 augmentation patients received buspirone (60 mg) or sustained-release buproprion (400 mg). On the Ham-D-17 and the QID-SR-16, Bupropion and buspirone recipients had similar remission rates (ranging from 30% to 39%). However, bupropion was associated with a significantly greater reduction in QID-SR-16 scores than buspirone (25% vs. 17%) and a significantly lower dropout rate due to intolerance (12% vs. 21%).

Comment: These results from this elegantly designed study suggest that switch strategies differ little in effectiveness and tolerability and that bupropion augmentation is slightly superior to, but more tolerable than, buspirone augmentation. Because the study design used equipoise stratified randomization and most patients elected either to switch or to augment, the researchers could not compare the two strategy types, although their remission rates are similar. Although a minority of these patients failing initial treatment achieved remission with a second strategy, almost half of the original sample remained ill. This argues persuasively for efforts to develop better treatments. Ultimate success might require discovery of genomic predictors of response that allow the identification of patients who are sensitive to agents with particular mechanisms of action.

— Peter Roy-Byrne, MD

Published in Journal Watch Psychiatry April 5, 2006

Citation(s):

Rush AJ et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006 Mar 23; 354:1231-42.

• Original article (Subscription may be required)
• Medline abstract (Free)

Trivedi MH et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006 Mar 23; 354:1243-52.

• Original article (Subscription may be required)
• Medline abstract (Free)