Differential occupancy of somatodendritic and postsynaptic 5HT_1A receptors by pindolol: A dose-occupancy study with [¹¹C]WAY 100635 and Positron Emission Tomography in humans

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT_1A receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT_1A autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT_1A receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [¹¹C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 ± 29% on scan 2, 38 ± 26% on scan 3, and 64 ± 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 ± 5% on scan 2, 12 ± 3% on scan 3, and 42 ± 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT_1A autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT_1A agents in this application.