Tranylcypromine versus venlafaxine plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report.


Patients with treatment-resistant depression in Level 4 of the STAR-D (Sequenced Treatment Alternatives to Relieve Depression) study were randomized to receive either tranylcypromine (an MAOI) or combination venlafaxine plus mirtazapine. Remission rates were low for both groups and not significantly different, however the combination group had fewer side effects and greater symptom reduction. Because treatments were not masked to patients or clinicians, attitudes towards MAOIs may have altered behavior. Combination therapy required two pills, so this may have also created a disproportionate placebo effect.


  • N=109 adults with nonpsychotic major depressive disorder enrolled in the STAR-D study who had not achieved remission with, or were intolerant of, the first three levels of STAR-D treatment were included in this study (STAR-D treatment Level 4). This was 2.7% of participants initially enrolled in the STAR-D trial.
  • As these participants had not achieved remission in the first three levels of treatment, comorbidity was predictably high. 76% of participants who made it to this level had at least one other axis I comorbid disorder, and 19% had at least four.
  • Subjects were randomized to receive either tranylcypromine (n=58) or extended-release venlafaxine plus mirtazapine (n=51). Treatment was not masked to subjects or clinicians (as with the other levels of STAR-D). The tranylcypromine group did a 2-week washout period, which was considered as part of the treatment duration.
  • Primary outcome: remission, defined as a score ≤ 7 on the Hamilton Depression Rating Scale (HAM-D).
  • Secondary outcomes: Quick Inventory of Depressive Symptomatology (QIDS-SR) to determine remission (score ≤ 5) or response (score ≥50% from baseline).


  • Remission and response rates were low for both groups and not significantly different between the two (6.9% for tranylcypromine, 13.7% for venlafaxine plus mirtazapine).
  • Tranylcypromine was associated a significantly higher attrition rate due to intolerance. 29% (n=17) of tranylcypromine patients had less than 4 weeks of treatment, as opposed to 8% (n=4) of the combination patients (P<0.01). It should be noted that 5 patients in the tranylcypromine group dropped out during the washout period, when they were not receiving the drug.
  • Venlafaxine and mirtazapine showed a greater percent reduction in QIDS-SR score than tranylcypromine (-25% vs -6%, P<0.05).


McGrath P. Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report. Am J Psychiatry. 2006;163(9):1531. doi:10.1176/appi.ajp.163.9.1531.

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