Conversion to Parkinsonism and Dementia in REM-Sleep Behavior Disorder Using the Chronobiotic Melatonin

Abstract

ABSTRACTBackgroundIsolated REM sleep behavior disorder (iRBD), a reliable prodromal stage marker of α-synucleinopathies like Parkinson’s disease or Lewy body dementia, offers an early window for disease-modifying intervention. Current treatments of iRBD, including the two level B therapies with clonazepam and melatonin, are considered symptomatic. However, numbers of reported patients treated with melatonin are low and whether melatonin has disease-modifying potential is unclear.MethodsThis single-center, prospective cohort study included 206 consecutive patients diagnosed with iRBD until January 2020. Thirty-nine patients had applied mixed treatments on the advice of the referring physician, 167 had administered melatonin according to our chronobiotic protocol (low dose, ≥ 6 months, always-at-the-same-clock-time, between 10 and 11 pm - corrected for chronotype), which differs from existing melatonin prescriptions. Clinical examination to determine phenoconversion was performed from October 2018 to August 2020. To evaluate generalizability, we compared factors such as neuropsychological and neuromotor performance, olfactory ability, neurovegetative behavior, and dopamine transporter density in our patients with those reported for other cohorts. Primary outcome was phenoconversion to clinical synucleinopathy, assessed using Kaplan-Meier analysis. Secondary outcomes were changes in cognitive and motor performance, and in RBD-symptom severity, analyzed using mixed models.ResultsRBD characteristics were comparable to those in other published cohorts, including frequency of phenoconversion in our patients with mixed treatments (10/39; follow-up 3.1±2.1 years). In contrast, long-term melatonin-treated patients rarely converted (4/167; follow-up 4.2±3.1 years; hazard-ratio 0.07, 95% CI, 0.02-0.22, p<0.001). Neuromotor and neuropsychological performance did not decline, improved in some domains. Symptom severity gradually improved over the first 4 weeks of treatment (Clinical Global Impression Severity: 5.7 vs. 3.0) and remained stable over years, also in those patients who had stopped melatonin intake after 6 months. The initial response was slower in patients with melatonin suppressing (beta blockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequate timing of melatonin intake.ConclusionClock-timed melatonin treatment in patients with iRBD appears to be associated with a marked reduction in the development of parkinsonism and dementia as well as with an improvement in neuromotor, cognitive, and specific RBD symptoms. Findings suggest that melatonin treatment may have disease-modifying effects in synucleinopathies. The fact that melatonin is available anywhere at low cost provides the perspective of immediate clinical application in patients at risk for clinical synucleinopathy. On the other hand, clock-time dependency challenges existing prescription guidelines for melatonin. Melatonin should be acknowledged as the darkness signal to circadian clock-work rather than a hypnotic.