Table 3.

Future research questions in the field of RBD therapies pertaining to the major themes of this review

Theme	Research questions/areas
1. Screening/diagnosis	• Should subjective or objective measures of RBD be used to dictate therapies or recruitment into trials? • Can we validate and compare automated scoring tools for RSWA across different populations? • What is the utility of innovative technologies including home-monitoring devices, smartphone applications, wearables, etc., in the diagnosis and screening of RBD?
2. Symptomatic therapy	• How do current symptomatic therapies perform in randomized-controlled trials? • Can we refine our molecular understanding (including specific neuromodulatory receptors) of REM-atonia circuitry to help inform therapies? • Do compounds addressing novel aspects of the REM sleep circuitry (such as orexinergic and galanergic pathways) have therapeutic potential for REM atonia and RBD symptoms? • Are specific combinations of treatment (informed by theoretical or empirical data) more effective than monotherapy for RBD?
3. Subgroups of RBD	• Are there genetic, imaging, biochemical, clinical, and PSG markers that discriminate between different RBD subtypes? • Do subgroups of RBD respond differently to different therapies? • Can we use precision medicine to match specific therapies to different RBD patients?
4. Antidepressants and RBD	• Do antidepressants directly induce RBD or unmask a biological predilection to RBD? • Can we predict who will develop RBD using an antidepressant? • Can we separate the contribution of the antidepressant from that of the underlying psychiatric disorder to risk of RBD? • What is the exact risk of neurodegeneration across different demographic subgroups who develop RBD in the context of antidepressants?
5. Monitoring response to treatment	• What is the optimal method of measuring response to therapy for assisting in titration of therapy? • Are there reliable objective biomarkers of disease severity for RBD? • Is there a role for home-monitoring devices in measuring response to therapy?
6. Disease-modifying trials in iRBD	• What inclusion/exclusion criteria should be used to select patients into disease-modifying trials in iRBD? • What biomarkers that should be used to stratify risk of neurodegeneration in iRBD patients? • Should we use enriched populations of patients with iRBD (e.g., those with heterozygous mutations) for disease-modifying treatments initially? • What is the optimal timing for commencing disease-modifying therapies in iRBD patients? • Should we use novel compounds or repurposed medications for initial clinical trials in iRBD? • What is the role of exercise in iRBD?
7. Disclosure of risk of neurodegeneration	• Should disclosure depend on iRBD subtype (i.e., young antidepressant user versus older non-antidepressant user) • What are the responses of patients to disclosure of risk in iRBD? • What are the economic and health implications of disclosure/non-disclosure of risk of neurodegeneration in iRBD? • What behaviors (e.g., lifestyle, diet, exercise, future planning) are affected by disclosure of risk?