Letters to the Editor

TO THE EDITOR: In an important contribution, Robert M. Berman, M.D., and colleagues (1) concluded that the combination of the selective serotonin reuptake inhibitor (SSRI) fluoxetine with pindolol, a serotonin (5-HT) blocker at 5-HT_1A receptors, conveyed no advantage over treatment with fluoxetine alone in either response time or efficacy. The authors' experience differs from earlier open-label studies of the combination (2, 3), which were themselves based on promising studies in rats (4). We have recently completed a randomized, placebo-controlled, double-blind trial in which pindolol was combined with paroxetine in the treatment of major depression (5). The combination demonstrated both a reduction in latency of the antidepressant action and a possible superior efficacy that was sustained for up to 6 months after the trial's completion.

We were struck by some apparent differences between the two studies in the patient groups that were used. For example, we found that the pindolol-paroxetine combination worked less well for men over 35 years of age and for male and female subjects with a chronic history of dysthymia or depression or who were more severely depressed. We specifically excluded subjects who misused substances. It may be relevant that our patients were reviewed twice weekly during the first 2 weeks of the study and weekly thereafter to permit ascertainment of an early medication response.

These methodological issues apart, other possibilities may explain why Berman et al.'s patients did not show positive results. It is becoming clearer that the 5-HT_1A receptor is subject to genetic polymorphism (6), and such differences may be highlighted by use of a 5-HT_1A receptor blocker. Moreover, the isomer and the mixed enantiomer compositions of pindolol appear to act differently (in rats at any rate [7]) in their activity as partial agonists of 5-HT_1A receptors. Thus, it could be that the isomeric composition differed between the two studies. Finally, although we agree with Berman et al. that there are no a priori reasons to suggest that the absence of an effect is due to the choice of fluoxetine, rather than paroxetine or citalopram, perhaps this requires more examination as well.