Buspirone augmentation  One relatively user-friendly strategy is buspirone augmentation. Buspirone is typically a well-tolerated anti-anxiety drug, an azaspirodecanedione and a partial serotonin type 1 (5-HT₁) agonist. Three patients whose depression did not respond to fluoxetine alone showed marked improvement when buspirone was added (Bakish 1991). In an open trial with 8 fluoxetine nonresponders, partial or full response was observed in 7 (87%) when buspirone (10 mg tid) was added (Jacobsen 1991). In a larger open study of 25 depressed patients who had undergone several previous failed treatments and who had not responded to treatment with either fluoxetine or fluvoxamine, it was found that 17 (68%) had marked or complete response when they received buspirone for 3 weeks in addition to their SSRI (Joffe and Schuller 1993). Other studies using 5-15 mg bid of buspirone have shown significant improvement in patients with treatment-resistant depression (Bouwer and Stein 1997; Dimitriou and Dimitriou 1998).

One concern with the use of buspirone augmentation is the need for controlled-trial evidence of efficacy. In fact, in one study, the response rate was very low among depressed patients with refractory depression (Fischer et al. 1998), and the only placebo-controlled study in refractory depression comparing buspirone against placebo augmentation did not reveal any statistically significant difference in response rates between these two treatment groups (51% for buspirone vs. 47% for placebo) (Landen et al. 1998).

Pindolol augmentation  Pindolol augmentation is uncommonly used in the United States for the treatment of resistant depression (Fredman et al. 2000), but it is relatively more popular in Europe and Canada. Pindolol is a β-adrenergic blocker and a serotonin type 1A (5-HT_1A) antagonist. A dosage of 2.5 mg tid has been used in most studies. This agent has generated a lot of interest because it has been shown to accelerate response to SSRIs when combined with SSRIs in some (Blier and Bergeron 1998; Bordet et al. 1998; Perez et al. 1997; Tome et al. 1997; Zanardi et al. 1997) but not all (Berman et al. 1997) studies. A study by Moreno et al. (1997) demonstrated no response among 10 patients with refractory depression, and a study by Perez et al. (1999) showed no difference from placebo in a very short (10-day) trial of augmentation in a refractory depressed population as well, with 5 (12.5%) of 40 patients responding to pindolol augmentation and 5 (12.5%) of 40 responding to placebo augmentation. On the other hand, 11 (65%) of 17 patients with resistant depression who were taking SSRIs responded to pindolol augmentation in another study (Blier and Bergeron 1995), and 6 (60%) of 10 patients who did not respond to one adequate trial of an antidepressant responded to fluoxetine plus pindolol, whereas 1 of 11 responded to fluoxetine alone (Maes et al. 1999). Another issue concerning the use of this augmentation strategy is that Blier and Bergeron (1998) reported the occasional emergence of increased irritability with the use of pindolol in refractory depression.