Serotonin transporter occupancy by the SSRI citalopram predicts default-mode network connectivity

The default mode network (DMN) is an important connectivity hub, and alterations may play a role in the pathophysiology of several neuropsychiatric disorders. Despite the growing body of research on DMN (dys)function, the underlying neurochemical substrate remains to be elucidated. The serotonergic neurotransmitter system has been suggested to play a substantial role in modulating the DMN. Therefore, we investigated the association between serotonin transporter (SERT) occupancy by the selective serotonin reuptake inhibitor citalopram and DMN functional connectivity. Forty-five healthy female volunteers (mean age = 21.6y) participated in a double-dose study. The subjects were randomized to pre-treatment with placebo, a low (4 mg; 'low group') or clinically standard (16 mg; 'high group') oral citalopram dose (corresponding to 0%, ∼40% and ∼80% SERT occupancy, respectively). They underwent [123I]FP-CIT single-photon emission computed tomography (SPECT) imaging to assess SERT occupancy. In addition, resting-state functional magnetic resonance imaging was used to measure DMN connectivity. With non-parametric permutation testing we assessed the association between SERT occupancy and DMN connectivity. We found that SERT occupancy by citalopram was negatively associated with DMN connectivity with a number of cortical regions, including the anterior cingulate cortex (ACC), paracingulate gyrus, postcentral gyrus, superior parietal gyrus and temporal pole. These findings provide further neurochemical evidence that the serotonin system dose-dependently modulates DMN function.