Discussion
PD-RBD, ’ RBD, PD, central nervous depression, treatment-resistant iRBD, RBD movements, heterogeneous, RBD, treatment-resistant RBD, injuries, RBD symptoms
LITTLE
This trial did not demonstrate superiority of SXB over placebo for improving RBD symptoms in treatment-resistant iRBD and PD-RBD. However, SXB resulted in significant improvements across all subjective outcomes of RBD activity, which was not seen with placebo. Eight out of ten patients receiving SXB had reductions in episode frequency above the placebo mean of 15%. Subjective response was supported by objective reduction of RBD movements observed on video-PSG. Taken together, these findings suggest that SXB may be an effective therapy for severe, treatment-resistant RBD, but due to an inconsistent response and a large placebo effect, statistical significance was not reached.Two participants (17%) receiving SXB could not tolerate side effects, another two reported no benefit or paradoxical worsening despite receiving a 9 g dose. The latter two patients were both in their 50 seconds and had a diagnosis of iRBD. Correlation analysis shows that younger age was associated with worse treatment responses. It is also possible that those participants’ RBD phenotype differed from the rest of the group. As biomarkers of phenotypic progression in synucleinopathy are being developed [There is currently no validated method to objectively monitor outcomes in RBD [Little is known about the mechanism of action of SXB in RBD. Given its short half-life and duration of action, SXB is usually recommended to be taken twice per night, however, we opted in this study to have the flexibility of single dosing for promoting patient adherence and for exploring differential effect compared to double dosing. The literature on efficacy in RBD is limited to six patients with iRBD and one with PD-RBD [AEs occurred in 75% and serious AEs in 42% of patients receiving SXB, leading two participants to discontinue therapy. As expected, non-serious AEs were more frequent (58%) with SXB than placebo (17%). Neither PD nor age correlated with frequency or severity of AEs. This low tolerability contrasts with prior studies in PD [Limitations of this study include the small sample size and large variability in the data. The large benefit observed in the placebo arm was not expected. A new sample size calculation reveals that 65 patients per arm would be required to detect statistical differences between interventions using a parallel arm design, and that 38 patients would be required in a crossover design. Prior RCTs monitoring episode frequency reported a similar placebo effect [Other possible limitations are related to the difficulty to control for confounding effects of clonazepam and melatonin. The study design gave careful consideration to safety and efficacy parameters. Discontinuing all treatments in participants with uncontrolled RBD, as it can lead to severe exacerbation of RBD symptoms and injuries to patients and their bed partners, was not a viable option. However, the concomitant use of clonazepam and SXB can potentially lead to central nervous depression. To maintain adequate level of safety for patients and their partners and adequately evaluate SXB, patients were required to reduce clonazepam treatment by tapering down to the lowest possible dose and discontinue, when possible, while any non-sedative RBD treatment would be maintained during the study, including melatonin. The majority of participants in this study were treated with melatonin, with no difference between groups. There are no known pharmacological interactions between melatonin and SXB, thus low concern about a potential bias.The strengths of this study are that it is the first double-blind, placebo-controlled study to systematically evaluate the effects of SXB on RBD, the individualized titration scheme, use of RBD logs not just reporting episode frequency but informing on their severity, and objective measure of RBD activity per video-PSG.Our results suggest that although SXB could plausibly be an effective therapy in severe RBD, heterogeneous and unpredictable responses may limit its use until more research is conducted. A significant within-group effect was observed on objective RBD activity per video-PSG. To the best of our knowledge, the present study is the second one implementing recommendations from the IRBDSG on video analysis for measuring outcomes in RBD [