Discussion
PD
CORTEX, PATHOPHYSIOLOGY
This study found that clonidine was well tolerated by PD patients, and the results indicate that a phase 3 trial should be conducted. Although the rate of success was not significantly different between groups, patients receiving clonidine had a greater and faster, reduction of the total QUIP-RS score at 8 weeks; it is of note that this phase 2b study was not calibrated to conclude on clonidine efficacy but on the conduct a phase 3 study. Of course, the pathophysiology of ICD in PD being still controversial and complex, we cannot exclude that targeting only the noradrenergic system could be insufficient to suppress ICD [Despite the randomisation, an imbalance was observed between groups for several variables, which, in turn, could have affected the results. Indeed, patients in the clonidine group had higher QUIP-RS total scores at baseline, meaning that they experienced more severe ICD. Moreover, patients in the clonidine groups were less systematically on agonist dopaminergic (78.9% vs 100% in the placebo group), which could, again, reflect more important ICD persisting despite the discontinuation of this treatment. Altogether, we cannot rule out that patients in the clonidine group may present more severe and more difficult to tackle ICD. It was however hard, because of the difficulty of recruiting these patients, to perfectly match them based on ICD score for this early-phase study. Although this could have affected our findings, we hypothesize that the differences of trends in terms of QUP-RS score reduction could have been more pronounced with better matching, which reinforces the need for a larger study to smooth out inter-group differences. In addition, with our mixed-effects model considering this difference, the difference in slopes remains statistically significant between the arms at the 10% alpha threshold (with The precise mechanisms of action of clonidine remain to be elucidated. It could, however, impact ICDs via the modification of noradrenergic transmission affecting, in turn, the inhibitory role of the prefrontal cortex; this lack of inhibitory and executive top-down control is one of the mechanisms of behavioural addictions in PD, in combination with aberrant motivation and reward circuits activations [