Modelling cerebral blood flow and neuroreceptor occupancy in dopamine blocking studies

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated using hemodynamic markers such as Cerebral Blood Flow (CBF) and Cerebral Blood Volume (CBV). However, the relationship between observed hemodynamic effects and the pharmacological action of antipsychotics has not been fully established. Here we wanted to investigate the relationship between the administered repeated dose of amisulpride, an atypical antipsychotic, and the changes in cerebral blood flow in the striatum. To investigate this relationship, we linked the plasma concentration to PET receptor occupancy and ultimately to the Arterial Spin Labelling's (ASL) CBF data from a placebo-controlled study in healthy volunteers, who received a repeated dose of amisulpride. To link the data, we developed a PK/PD framework which, starting from the dose administered, was able to predict the plasma drug concentration after a repeated dose, to predict the receptor occupancy (RO) in the targeted regions of the brain, and finally to link it with changes in cerebral blood flow in the striatum. The results showed a statistically significant monotonically increasing relationship between changes in relative to global CBF and receptor occupancies in the putamen (p-value < 0.001) and caudate regions of the brain (p-value < 0.01). These findings suggest that antipsychotics increase striatal perfusion, with a mechanism possibly mediated by D2 receptors and represent further evidence supporting the hypothesized PK/PD model of antipsychotic effects on CBF measures founded on macaques by 'Sander et al, 2013'.