Serotonin (5-HT) selective reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors are thought to have a delayed onset of antidepressant action attributable in part to the decrease in firing activity of 5-HT neurons they produce upon treatment initiation. As cell body 5-HT1A autoreceptors desensitize, 5-HT neuronal firing is restored. The agent pindolol, through its 5-HT1A receptor blocking property, has been shown to prevent the initial decrease in firing of rat 5-HT neurons associated with SSRI treatment. Four open-label studies put into evidence a significant acceleration of the antidepressant effect of SSRIs when combined with pindolol. Four of five placebo-controlled studies have confirmed this observation. Controlled trials indicate that a greater rate of response may be obtained by combining pindolol from the beginning of the SSRI treatment. The strategy of adding pindolol to the regimen of SSRI-resistant patients also appears to produce a therapeutic effect in a significant proportion of patients.