Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [C-11] AZ10419369 is a novel 5-HT1B receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [C-11]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BPND) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BPND tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BPND was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.