On the basis of a previous report suggesting the effectiveness of the beta-adrenoceptor/5-HT1A antagonist pindolol to accelerate the antidepressant effect of a selective serotonin reuptake inhibitor (SSRI) and to produce a therapeutic effect in drug-resistant depressed patients, these open studies were undertaken to further explore the safety and efficacy of this strategy. In a first study, nine untreated unipolar depressed patients were given the SSRI paroxetine (20 mg/day) together with pindolol (2.5 mg thrice daily). One patient stopped taking pindolol because of increased irritability after 3 days. One week later, seven patients had their Hamilton Rating Scale for Depression Score decreased by more than 50%. In a second study, 19 drug-resistant unipolar depressed patients (9 on paroxetine, 5 on sertraline, 3 on fluoxetine, and 2 on moclobemide) were also given pindolol at the same regimen and were assessed weekly. Two patients (one on sertraline, one on moclobemide) stopped taking pindolol also because of increased irritability after 2 and 3 days, respectively. After 1 week of pindolol addition, 10 patients had a more than 50% decrease of their depression score. By day 14, all of the patients had a score of 10 or less, with the exception of those on sertraline. Improvement was maintained in all patients for at least 28 days on this combination. The results of these studies indicate that pindolol is safe when used in combination with an SSRI or moclobemide. Given the positive results obtained in this second open trial in 28 patients, this treatment strategy should be tested under double-blind conditions to establish its efficacy.