Of the 4 levels of treatment in the study, level 4 included a switch to the MAOI tranylcypromine or to a combination of 2 antidepressants, mirtazapine(Drug information on mirtazapine) and venlafaxine. Response and remission rates were found to be nonsignificantly greater in the antidepressant combination group than in the tranylcypromine group. The remission rate for the combined antidepressants was 14%, while it was only 7% for tranylcypromine. The response rate for the combination of antidepressants was 24% compared with only 12% for tranylcypromine. There were significantly fewer trial dropouts in the antidepressant combination group than in the tranylcypromine group. In the 21 patients with atypical depression, there was no significant difference in response rates between the two groups. The mean dose for tranylcypromine was 36.9 mg and the mean dose for the antidepressant combination was 210.3/95.2 mg. All in all, this was a disappointing outcome for MAOIs.
However, a comment by Wingo and Ghaemi 16 highlights the fact that of the patients randomized to the tranylcypromine group, 41% had entered the study because of previous medication intolerance in other STAR*D trials, while only 22% of patients who were randomized to the combination antidepressant group had a similar medication intolerance. This could very well account for the increased dropout rate for tranylcypromine and the relatively poor response.
Professor Phillip Cowan, a prominent psychopharmacologist from the University of Oxford, reports his personal favorable experience with the use of tranylcypromine. Although the wait is well worth it, he notes the practical problem of using an MAOI in refractory depression—the need for a prolonged washout period to avoid possible serotonin syndrome. The wait is 2 weeks when switching from an SSRI and 5 weeks when switching from fluoxetine(Drug information on fluoxetine). This interim period requires close follow-up with symptomatic management only.
Recent guidelines and recommendations
Two recent articles report on recommendations for an algorithm-guided treatment for depression, similar to that in the STAR*D trial. Spijker and Nolen17 compared a Dutch algorithm for the treatment of depression with 4 other guidelines, including those from the Texas Medication Algorithm Project (TMAP), the Canadian Network for Mood and Anxiety Treatments (CANMAT), the Royal Australian and New Zealand College of Psychiatrists (RANZCP), and the STAR*D study.
The RANZCP guideline does not mention MAOIs at all. However, the Dutch algorithm recommends tranylcypromine as a step-4 treatment and as a step-2 treatment for atypical depression. TMAP and CANMAT guidelines recommend MAOIs as an option in step 3.
A German study used a 10-step algorithm that involves antidepressant monotherapy, lithium(Drug information on lithium) augmentation, combined lithium and MAOI therapy, and finally ECT.18 Steps 7 and 8 of the algorithm comprise MAOI combined with lithium. In this single-center prospective study, algorithm-guided therapy was demonstrated to produce significantly better outcomes and less frequent medication changes than treatment as usual.
This algorithm uses lithium augmentation followed by lithium monotherapy. If this is unsuccessful, the next step includes the use of an MAOI (tranylcypromine) at 20 mg/d in combination with lithium. If that fails, then 40 mg/d of tranylcypromine combined with lithium is used. The researchers suggest that a better response may have been achieved with a higher dosage of tranylcypromine than the maximum 40 mg/d recommended in this algorithm. This is similar to the concerns for the STAR*D trial in which a mean dose of 36.9 mg of tranylcypromine was used.
A recent article by Fawcett19 reflects the personal opinion of another experienced and well-respected psychopharmacologist. Because of limited numbers of patients available for clinical trials, guidance is often dependent on the personal experience of opinion leaders. In his experience, many patients with treatment-resistant depression may reach remission when given a course of MAOI treatment. Fawcett considers a full course of treatment to be at least 6 weeks at the maximum tolerated dose. He also comments on the relative safety of MAOIs. In over 40 years, he had only 1 case of hypertension with headache induced by diet, which was managed in the office with thioridazine(Drug information on thioridazine).
Fawcett highlights the nature of treatment-refractory depression and the misery to which it condemns its victims. While acknowledging some increased risk, he feels that there is still a good chance of “resurrecting a life devastated by depression or even saving a life.” He discusses 7 patients from his personal practice with recalcitrant depression who were treated with MAOIs—6 of the patients had symptom remission. Three of the 6 patients were given additional augmentation with stimulants. Fawcett provides sage advice: “Before initiating an MAOI, I ask myself, ‘if this patient is unlucky enough to have a serious adverse reaction as a result of the MAOI, can I honestly say that the MAOI was fully indicated?’” In retrospect, he found the answer to be a resounding “yes.”