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. [¹¹C]AZ10419369 is a novel
5-HT(1B) 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 [¹¹C]AZ10419369 at baseline conditions and after
escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) 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.