Cognitive, motor, and autonomic function among individuals with serotonergic versus isolated rapid eye movement sleep behavior disorder

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a well-recognized prodrome of Parkinson’s disease, Lewy body dementia, and multiple system atrophy. However, it remains unclear whether patients whose RBD was triggered or exacerbated by a serotonergic antidepressant, who are typically younger, are at similar risk for future neurodegenerative disease. This study explores the prevalence of serotonergic RBD (5-HT RBD) and compares neurological function and depression in this group to iRBD patients without selective serotonin reuptake inhibitor (SSRI) use. Participants with self-reported 5-HT RBD were on average younger than those with iRBD and reported greater autonomic dysfunction and depression. Cognitive and motor function scores were not significantly different between groups. The neurological progression of these groups merits further prospective study. Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by vigorous, often violent, dream enactment due to loss of REM sleep atonia. RBD is a known prodrome of alpha-synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy (MSA) [1]. The majority of RBD cases occur spontaneously without exposure to a provoking factor or existing neurodegenerative disorder, known as isolated or idiopathic RBD (iRBD). Three in four patients with iRBD will go on to be diagnosed with a neurodegenerative disease in their lifetime [2]. Many RBD patients report the onset or exacerbation of dream enactment shortly after initiating a serotonergic antidepressant medication, most commonly selective serotonin reuptake inhibitors (SSRIs) [3]. This phenomenon can be termed “serotonergic RBD” (5-HT RBD) and in contrast with iRBD more typically occurs in younger patients [4]. The exact prevalence of 5-HT RBD is unknown, but symptoms of dream enactment have been reported to occur in about 6% of patients who are prescribed antidepressants [5]. Endogenous serotonin, from the raphe nucleus, modulates REM sleep by activating the “REM-Off” pontine nuclei. Therefore, it has been proposed that an increase in serotonergic tone induced by SSRI medications leads to diminished REM sleep atonia and the subsequent dream enactment of 5-HT RBD [6]. Investigators have noted that patients with 5-HT RBD also appear to have prodromal neurodegenerative findings including constipation, anosmia, subtle motor impairments, and color vision abnormalities not explained by serotonergic mechanisms5. Of note, depression is a prodromal symptom of alpha-synucleinopathy [7]. It is unknown whether 5-HT RBD is caused by SSRIs sporadically in otherwise non-predisposed individuals, or if instead, SSRIs unmask existing alpha-synuclein pathology in individuals at high risk for future development of neurodegenerative disease. It is therefore crucial to understand whether patients with 5-HT RBD have similar prodromal features as those with iRBD. Here, we aim to examine the prevalence of 5-HT RBD in a large cohort, comparing patients’ baseline cognitive, motor, and autonomic function, as well as mood, to those with iRBD. This is a cross-sectional analysis to examine the prevalence and demographic characteristics of North American Prodromal Synucleinopathy Study (NAPS) research participants with 5-HT RBD and iRBD. NAPS enrolls patients with RBD and healthy controls at nine clinical centers across the United States and Canada. The RBD group included adults with polysomnogram-confirmed RBD by ICSD-3 criteria. Those with an existing diagnosis of PD, dementia of any type, or MSA, narcolepsy-associated RBD were excluded. All NAPS subjects were evaluated face-to-face by an RBD clinical expert in a structured interview and examination. The 5-HT RBD group was determined by a three-step process: first, as part of the structured face-to-face interview patients were questioned by a NAPS investigator whether their RBD symptoms were triggered or exacerbated by a medication. Second, for each NAPS subject a clinician investigator is specifically asked whether the subject is 5-HT RBD, defined as “…the participant’s RBD was unequivocally and temporally associated with antidepressant medications.” For this study, only individuals triggered by SSRIs were included. Finally, each NAPS case was reviewed and adjudicated by a peer NAPS investigator panel to ensure accurate diagnosis and classification. The medication triggers included fluoxetine, paroxetine, escitalopram, and sertraline. Duration and dosage of SSRI treatment were not captured in this dataset. The iRBD group was identified through the same mechanism; however, indicating that they had never taken antidepressant medications. Individuals with RBD on SSRIs who reported no known relationship to their dream enactment were excluded. This was done as it was the investigator’s suspicion that many of these individuals may have 5-HT RBD but failed to recognize the relationship between the SSRI and the dream enactment. Participants’ de-identified age, sex, Montreal Cognitive Assessment (MoCA) scores, motor subscore of the unified Parkinson’s disease rating scale (UPDRS), SCales for Outcomes in PArkinson’s disease—Autonomic Dysfunction (SCOPA-AUT) scores, and Patient Health Questionnaire-9 (PHQ-9) scores at their initial study visit were drawn from previously completed, questionnaires that make up the NAPS database. Statistical analysis was performed using GraphPad Prism software. A Mann–Whitney U test was performed to compare group means. Of a total of 450 NAPS participants, 23% reported use of an SSRI medication at baseline. The 5-HT RBD group consisted of 20 participants while the iRBD group consisted of 159 participants. The 5-HT RBD group was significantly younger than the iRBD group (Table 1). There was no significant difference in scoring on MoCA or the motor subsection of UPDRS between groups. The 5-HT RBD group scored significantly higher on SCOPA-AUT compared to iRBD. The 5-HT RBD group had significantly higher scores on PHQ-9 compared to iRBD. 10% of participants in the 5-HT RBD group endorsed suicidal ideation compared to 3.1% of participants in the iRBD group. Cognitive, Motor, Autonomic Function, and Depression in Patients With Self-reported Serotonergic REM Sleep Behavior Disorder (5-HT RBD) and Isolated REM Sleep Behavior Disorder (iRBD) REM, rapid eye movement. The bold values are the P-values of significance (< 0.05). Cognitive, Motor, Autonomic Function, and Depression in Patients With Self-reported Serotonergic REM Sleep Behavior Disorder (5-HT RBD) and Isolated REM Sleep Behavior Disorder (iRBD) REM, rapid eye movement. The bold values are the P-values of significance (< 0.05). In this analysis, we found that SSRI use in the NAPS cohort is common (23%). Both 5-HT RBD and iRBD groups were majority male, which is expected given the male predominance of alpha-synucleinopathies as well as the large number of participants recruited from the Veterans Affairs system. Consistent with existing literature, we found that participants with 5-HT RBD were significantly younger than those with iRBD. We discovered that patients with self-reported 5-HT RBD and iRBD performed similarly on cognitive and motor screening tests, portending that 5-HT RBD patients may also be at risk for future development of neurodegenerative disorders. We recognize a trend towards greater pathology in the cognitive and motor domains for iRBD compared to 5-HT RBD, which is consistent with the finding that participants with 5-HT RBD are significantly younger. From these findings, we conclude that patients with 5-HT RBD are being captured earlier in a prodromal syndrome. Participants with self-reported 5-HT RBD scored significantly higher on SCOPA-AUT compared to iRBD, suggesting a greater burden of autonomic dysfunction in the 5-HT RBD group. This finding can perhaps be explained in part by autonomic side effects associated with SSRI use [8]. It was unsurprising that patients with 5-HT RBD had greater symptoms of depression and suicidal thoughts. Limitations of this analysis include the small sample size in the 5-HT group. We suspect that 5-HT RBD is underreported as patients may have been on SSRI medications for extended periods of time, had subtle dream enactment, or missed the SSRI connection due to lack of bedpartner observation. Another limitation was the lack of available data on the dosage and duration of SSRI treatment. The feasibility of collecting this information is limited by the time-intensive process of the NAPS study, often taking upwards of twelve hours to complete. Given the importance of dosage and duration, we are following up this report with a separate investigation to assess the connection between SSRI dosage and the development of dream enactment among individuals with 5-HT RBD. This is not a causal analysis, and future prospective studies of this cohort are needed to determine if individuals with 5-HT RBD are at increased risk of developing alpha-synuclein-mediated neurodegenerative disease. This cross-sectional analysis was conducted on NAPS data collected at the initial baseline visit. The intention of the NAPS study will be to follow these individuals for years to decades. In future studies, emerging biomarkers such as skin biopsy and seed amplification assays, may be useful to identify synuclein pathology in those with 5-HT iRBD. This preliminary analysis of NAPS participants begins to address a gap in our current understanding as to whether 5-HT RBD exists on a spectrum of neurodegenerative disease progression alongside iRBD or is itself a unique condition. Elucidating this relationship could lead to earlier diagnosis, and in the future, initiation of disease-modifying therapy. This study was supported by NIH NIA 1RO1 AG075101-01A1 and NIH NIA U19AG071754-01.

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