The Augmentation Hypothesis for Improvement of Antidepressant Therapy: is Pindolol a Suitable Candidate for Testing the Ability of 5HT1A Receptor Antagonists to Enhance SSRI Efficacy and Onset Latency?

The development of selective serotonin reuptake inhibitors (SSRIs) provided a major advancement in the treatment of depression. However, these drugs suffer from a variety of drawbacks, most notably a delay in the onset of efficacy. One hypothesis suggests that this delay in efficacy is due to a paradoxical decrease in serotonergic (5-HT) neuronal impulse flow and release, following activation of inhibitory presynaptic 5-HT1A autoreceptors, following acute administration of SSRIs. According to the hypothesis, efficacy is seen only when this impulse flow is restored following desensitization of 5-HT1A autoreceptors and coincident increases in postsynaptic 5-HT levels are achieved. Clinical proof of this principal has been suggested in studies that found a significant augmenting effect when the beta-adrenergic/5-HT1A receptor antagonist, pindolol, was coadministered with SSRI treatment. In this article, we review preclinical electrophysiological and microdialysis studies that have examined this desensitization hypothesis. We further discuss clinical studies that utilized pindolol as a test of this hypothesis in depressed patients and examine preclinical studies that challenge the notion that the beneficial effect of pindolol is due to functional antagonism of the 5-HT1A autoreceptors.