Introduction The severity of REM sleep without atonia, a prodromal biomarker for synucleinopathy-related neurodegenerative disorders, is influenced by selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine retake inhibitor (SNRI) use. This study investigates whether SSRI/SNRIs similarly impacts the severity of Non-REM hypertonia (NRH), a biomarker independently associated with patients broadly characterized with presumed Parkinsonian-spectrum disorders (PSD). Methods In this multi-center study, the relationship between NRH and SSRI/SNRIs was evaluated in PSD patients [Lewy Body/Parkinson Disease Dementia (DLB/PDD=16), Parkinson Disease (PD=16), isolated REM sleep behavior disorder (iRBD=19), and progressive supranuclear palsy (PSP=12)], and non-PSD subjects [Alzheimer Disease (AD=22), mild cognitive impairment (MCI=35), and normal cognition (NC=61)]. Studies were conducted with the Sleep Profiler in all participants. NRH was auto-detected based on persistently elevated electromyographic (EMG) power relative to delta, theta, and sigma bands. Abnormal-NRH was based on a threshold of >5% of sleep time, and weight-averaged by sleep time, in the 75% of studies with two-nights of data. Statistical analyses included multiple logistic regression, Fisher Exact, and Mann-Whitney U tests. Results Across all 181 records, 38% had abnormal-NRH and 24% used SSRI/SNRIs (P Conclusion Abnormal non-REM hypertonia exhibited a very strong association with Parkinsonian-spectrum disorder diagnoses (odds-ratio=14.0) and a relatively weaker association with selective serotonin reuptake inhibitor or serotonin-norepinephrine retake inhibitor use (odds-ratio=2.4), suggesting a finding that reflects an interactive, rather than causal inference. Support (If Any) NIA grants R44AG050326, R44AG054256, P30AG62677 and R34AG56639.