Pindolol augmentation of antidepressant response

Abstract

Pindolol, a partial ß-adrenoceptor/5-HT 1A receptor antagonist was first used to accelerate the onset of action of antidepressant drugs in 1994. Since then, it has been used in more than a dozen controlled trials to examine whether it can reduce the lag to clinical improvement, and/or improve the clinical response in treatment-resistant patients. A recent metaanalysis concluded that pindolol accelerates the antidepressant response but does not increase the effectiveness of SSRIs in unresponsive patients. Several studies have examined the pharmacology of pindolol to clarify the neurobiological basis of its clinical action. Pindolol was initially used due to its ability to block 5-HT1A receptor-mediated responses and to enhance the neurochemical effects of SSRIs. In transfected cells, however, pindolol is a weak (20-25%) partial agonist at 5-HT1A receptors and, as such, its actions greatly depend on the system used. In line with this, other reports have also shown that pindolol can reduce serotonergic cell firing when given alone. Positron emission tomography (PET) scan studies have shown that pindolol displays a preferential occupancy of pre- vs. postsynaptic 5-HT1A receptors, although the overall occupancy is lower than desirable, which suggests that higher doses (e.g., 15 mg/day) may be more effective than the currently used 7.5 mg daily dosage. However, given the complex pharmacology of pindolol, it is hoped that new developments in this field can proceed through the use of a) selective and silent 5-HT1A receptor antagonists in combination with SSRIs, or b) dual action agents (SSRI + 5-HT1A receptor blockers).