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After Two Failed Trials for Major Nonpsychotic Depression, What’s Next?

Despite further results from Star*D, more guidance is needed.

Data from the major study, Sequenced Treatment Alternatives to Relieve Depression (STAR*D), may eventually provide guidance for treating major depression when initial efforts fail to produce remission, not just symptom relief. In the first study wave, 4041 "real world" patients with major depression, many with comorbidities, received open-label citalopram for 12 weeks (remission rate, 28%). The second wave involved nonresponders or those intolerant to citalopram (see Journal Watch Psychiatry Apr 5 2006). Participants switched to sertraline, bupropion, or venlafaxine (with statistically indistinguishable remission rates of 18%–25%) or augmented with bupropion or buspirone (remission rate, 30%; bupropion had significantly better symptomatic improvement and tolerability). Patients could also switch to, or add, CBT (unpublished results).

The researchers now report on the third STAR*D wave, in which 235 patients with intolerance or inadequate response to medication in the two previous waves were randomized to mirtazapine (60 mg/day) or nortriptyline (200 mg/day) for up to 14 weeks. At 12 weeks, completion rates were 33% for mirtazapine and 31% for nortriptyline. Remission rates were 12% and 20%, respectively. Tolerability of the drugs did not differ.

Comment: STAR*D results substantiate and reinforce — and have not much changed — the way many clinicians practice. As an editorialist notes, most clinicians might think of medication choices other than those permitted here, as there are multiple ways to switch, combine, or augment treatments. The study lacked a placebo arm, and at least some remissions might have been due to "spontaneous" improvement and healing from depression. Still, the remission rates (though relatively low) might signify that after two failed trials, some patients can achieve remission with different medication strategies. (Nortriptyline might have achieved superiority with a larger sample and increased power.)

These results are unlikely to convince many clinicians to embrace mirtazapine or nortriptyline exclusively. And, we lack clinical or biologic markers to help us predict treatment response. More guidance, please. . . .

— Joel Yager, MD

Published in Journal Watch Psychiatry July 17, 2006

Citation(s):

Fava M et al. A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: A STAR*D report. Am J Psychiatry 2006 Jul; 163:1161-72.

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

Menza M. STAR*D: The results begin to roll in. Am J Psychiatry 2006 Jul; 163:1123-5.

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