Melatonin therapy for REM sleep behavior disorder: a critical review of evidence

Abstract

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia associated with dream enactment often involving violent or potentially injurious behaviors during REM sleep that is strongly associated with synucleinopathy neurodegeneration. Clonazepam has long been suggested as the first-line treatment option for RBD. However, evidence supporting melatonin therapy is expanding. Melatonin appears to be beneficial for the management of RBD with reductions in clinical behavioral outcomes and decrease in muscle tonicity during REM sleep. Melatonin also has a favorable safety and tolerability profile over clonazepam with limited potential for drug-drug interactions, an important consideration especially in elderly individuals with RBD receiving polypharmacy. Prospective clinical trials are necessary to establish the evidence basis for melatonin and clonazepam as RBD therapies.

Keywords: Calmodulin; Drug therapy; Melatonin; Parasomnia; REM sleep behavior disorder.

Conflict of interest statement

Conflict of interest statement: The authors IR McGrane and JG Leung have no conflicts of interest to disclose, regarding, but not limited to: place of employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications, grants, or other funding.

Copyright © 2014 Elsevier B.V. All rights reserved.

Figures

Figure 1. Speculative Mechanism of Action of Melatonin in RBD

A. Normal REM sleep physiology. The sublaterodorsal nucleus (SLD) and magnocellular reticular formation (MCRF) nucleus send projections to the anterior horn cell (AHC) neurons in the spinal cord, with the GABAergic +/− glycinergic effects on the AHC exerting inhibitory influences (thereby suppressing AHC activity) and resulting in normal EMG atonia. B. REM sleep behavior disorder. In RBD associated with neurodegenerative disease, the SLD and/or MCRF are presumed to undergo neuronal loss such that their projections on the AHC ultimately have decreased effects. Other projections from brainstem, diencephalic and telencephalic structures maintain their excitatory influences on the AHC (for simplicity, these projections are not shown here), resulting in increased EMG tone +/− the behavioral aspects of RBD. C. REM sleep behavior disorder treated with exogenous melatonin. Melatonin may decrease the electrophysiologic and behavioral manifestations of RBD by potentiating the action of GABA on GABAA receptors on the AHC. Melatonin also may decrease calmodulin, which subsequently may modulate cytoskeletal structure and nicotinic acetylcholine receptor expression in skeletal muscle cells. The encircled plus symbols represent excitatory influences; the encircled minus symbols represent inhibitory influences, and their relative size represents the degree of the influences. The symbol M represents melatonin, with the encircled plus symbols representing the potentiation of GABA on the GABAA receptors on the AHC. The symbol CaM represents calmodulin.