The findings from this investigation must be considered preliminary in view of the retrospective analysis, open label treatment, and limited number of subjects. They thus require replication by prospective study of a larger number of subjects. Nevertheless, this report complements our previously reported finding (from a double-blind, prospective study) on the superiority of the MAOI tranylcypromine versus imipramine in the treatment of anergic bipolar depression3
. In that previous investigation, the response rate for subjects who were able to complete at least four weeks of treatment was 81%, which is comparable to the 70% rate of durable recovery found in the present study (in the previous investigation, patients were not considered nonresponders and were excluded from the analysis unless they completed at least four weeks of treatment). Thus, despite the differences in criteria for defining outcome that were utilized in our current and previous investigations, MAOIs emerged in a consistent way as being substantially more effective than conventional reuptake-blocking antidepressants in bipolar depression (notwithstanding that in the current investigation, comparable proportions of MAOI and PAROX subjects were able to complete at least four weeks of antidepressant treatment).
The findings presented here are consistent with a recent report by Nolen and associates10
. Although their findings were based on a small group of subjects and were not statistically significant, they observed during a first trial that 63% of treatment refractory bipolar depressed patients responded to tranylcypromine (n = 8), whereas only 36% responded to lamotrigine (n = 11). Nevertheless, some authors believe that older MAOI such as tranylcypromine should not be recommended for first line use because of the dietary limitations required and the frequency of adverse events11
The irreversible and nonselective MAOI utilized in the present investigation (primarily tranylcypromine, see Methods) may have a therapeutic advantage over newer reversible and selective agents. Silverstone and colleagues12
compared a reversible inhibitor of MAO-A (moclobemide) with imipramine in a randomized, double-blind, parallel group, multicenter study of 156 patients with bipolar depression. Although they did not use a measure of durable recovery, acute response to treatment was similar with moclobemide (46%) or imipramine (53%). Mean score on the 17-item Hamilton Depression Scale after eight weeks of treatment was 13.1 with moclobemide and 9.5 with imipramine, indicating no therapeutic advantage for moclobemide. Lotufo-Neto and associates13
performed a meta-analysis of moclobemide effectiveness, and found that both intention-to-treat and adequate treatment trial data tended to favor nonselective MAOI. However, only four studies were available, and for the one trial in which moclobemide was superior to tranylcypromine, the dosage of this latter drug was clearly subtherapeutic (10-30 mg/day).
Selegiline is an irreversible inhibitor of MAO that at low doses is selective for MAO-B14
. This agent has recently been introduced in a transdermal formulation that conveys some safety advantages, and comparative studies in bipolar depression would be of interest.
An important difference from our previously reported study on MAOIs in bipolar depression is that, unlike the previous work, patients in the present investigation received concomitant mood stabilizer treatment. This more closely reflects the standard of care in clinical practice, although it also raises issues related to the possible confounding influence of the mood stabilizer on antidepressant response. In our current investigation, all subjects were treated with adequate mood stabilizer for at least one month before starting antidepressant, although this was not the case in the STEP-BD adjunctive antidepressant study.
Administration of IPSRT was a possibly confounding factor in this work. However, IPSRT assignment did not differ significantly between the medication groups, and in fact IPSRT and ICM were associated with comparable rates of durable recovery. In the STEP-BD adjunctive antidepressant study, 36% of subjects received intensive psychotherapy and 29% received brief psychoeducation in a concurrent investigation of psychosocial treatments; in that study, augmentation of drug therapy with intensive psychotherapy or brief psychoeducation carried no significant benefit.
As noted previously, the observed rate of durable recovery with PAROX treatment in the present study was 27%. This finding is very similar to the 24% antidepressant recovery rate noted in the STEP-BD adjunctive antidepressant study. In contrast, MAOIs produced significantly higher rates of durable recovery as compared to PAROX, both in an intention-to-treat analysis, and among patients who could complete an adequate treatment trial of at least four weeks duration. MAOIs may offer unique advantages over reuptake-blocking antidepressants for treatment of bipolar depression.