AbstractDopamine D2 (D2R) receptor blockade exerted by antipsychotics is the current standard for the treatment of psychosis. However, the effects on brain structure and function are still under debate. In addition, most studies examining brain changes have been conducted in patients where results are confounded by disease state and trait effects and placebocontrolled designs are difficult to perform for ethical concerns. As a result, disentangling between disease and treatment effects is challenging. Whilst previous studies in healthy volunteers have shown that acute single exposure to D2R antagonism is associated with alterations in brain structure and function, it remains unclear whether these effects are detectable after prolonged D2R blockade. Moreover, structural, and functional Magnetic Resonance Imaging (MRI) findings after antipsychotic administration in humans have rarely been directly linked with pharmacodynamics at D2R. To address all these issues, the present thesis illustrates the results of three studies. The first study tested the association between the main effects of single-dose antipsychotic administration on cerebral perfusion and spatial distribution of D2R across the entire brain, the second investigated changes in brain structure and function after sustained D2R blockade in healthy volunteers and the third examined differences in brain perfusion between non-medicated patients at their first episode of psychosis (FEP) and healthy controls (HC).
Study 1. I analysed Cerebral Blood Flow (CBF) data as assessed with Arterial Spin Labelling (ASL) from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2R antagonists and tested the association of the main effects of the drugs on CBF against non-displaceable binding potential (BPND) [18F]-Fallypride Positron Emission Tomography (PET) normative maps and brain post-mortem microarray mRNA expression data for the DRD2 gene from the Allen Human Brain Atlas (AHBA). For all antipsychotics, CBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures. In addition, the spatial relationship between ΔCBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Study 2. I analysed data from a double-blinded, randomized, crossover, placebo-controlled study in healthy volunteers who received either amisulpride 400mg or a placebo daily for seven days. T1 maps and brain volume estimation were derived from the MP2RAGE sequence. Pseudo-continuous ASL and resting-state multi-echo fMRI sequences were used to assess CBF and functional connectivity respectively. Using the Spearman correlation, I tested the association between drug effects and extrapyramidal symptoms (EPS). In addition, to explore inter-individual variability in drug response, I implemented a pharmacokinetic/pharmacodynamic (PK/PD) framework from pre-clinical studies which modelled plasma drug concentration in a repeated dose regimen, receptor occupancy and brain changes after sustained D2R blockade. No differences were found between amisulpride and placebo conditions in both T1 maps and brain volumes. Amisulpride increased CBF in the striatum and reduced functional connectivity between its sensorimotor subdivision and the primary motor cortex as compared with placebo. The PK/PD model revealed a monotonically increasing relationship between changes in CBF and receptor occupancy as predicted by preclinical models. Finally, a greater reduction in functional connectivity was associated with greater EPS.
Study 3. I examined CBF in FEP free from antipsychotic medication compared to HC. Both absolute and relative-to-global CBF was assessed. I also investigated the association between baseline CBF and treatment response in a partially nested follow-up study. The comparison revealed significantly lower absolute CBF in the frontal cortex and no differences in the basal ganglia. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal, and frontal cortices. No differences were found in relative CBF in the selected region of interest and voxel-wise analysis. Relative frontal CBF was correlated with the percentage change in total Positive and Negative Syndrome Scale (PANSS) after antipsychotic treatment.
My PhD shows that both acute and sustained D2R blockade induces increased CBF in the basal ganglia in healthy volunteers and that the magnitude of the effects reflects the spatial distribution of D2R in the brain and inter-individual variability in D2R occupancy. These findings from experiments inform the negative finding in the clinical study where no difference was found in striatal perfusion between non-medicated FEP and healthy controls, indicating that increased striatal perfusion in psychosis is likely a treatment effect. My PhD also extends previous evidence from single-dose studies to show that sustained blockade of D2R over a week is not associated with changes in brain tissue structure and volume. Finally, the results of my PhD also indicate that D2R blockade also has non-local effects by altering cortico-striatal functional connectivity which could potentially serve as a biomarker for EPS.
|Date of Award
|1 Sept 2023
|Ottavia Dipasquale (Supervisor) & Mitul Mehta (Supervisor)