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. 2021 Nov 14;11(11):1204. doi: 10.3390/jpm11111204

Table 1.

Studies describing effects of clonazepam in patients with RBD.

Authors, Year [Ref] Study Setting/Design Type of Study Main Findings Level of Evidence (Quality Score)
Schenck et al., 1986 [1] The first description of 4 RBD patients Case series

  • Considerable improvement with clonazepam in 2 patients

 III (NA)
Schenck et al., 1989 [17] Description of a series of 100 patients with sleep-related injuries (33 of the 36 patients with RBD were treated with 0.25–2 mg of clonazepam at bedtime) Observational case series

  • Improvement of sleep-related injuries in the majority of patients treated with clonazepam

 III (NA)
Schenck et al., 1993 [18] Description of a series of 96 RBD patients, 67 of them treated with clonazepam Observational case series

  • “Complete efficacy” of clonazepam in 79% of patients and “partial efficacy” in 13.4% of patients

 II (NA)
Olson et al., 2000 [19] Description of a series of 93 RBD patients, 57 of them treated with clonazepam (38 with available information) Observational case series

  • Clonazepam treatment was “completely successful” in 55.2% of patients, “partially successful” in 31.6% of patients, and “unsuccessful” in 13.1% of patients

 II (NA)
Ferri et al., 2013 [20] Comparison of CGI-S, RBDSS, and atonia index using video-PSG recording in 15 RBD patients under clonazepam treatment and 42 untreated patients Observational case-control study

  • Patients treated with clonazepam showed a lower rate of stage shifts, higher sleep efficiency, a lower percentage of wakefulness after sleep onset and of sleep stage 1, an increased percentage of sleep stage 2, and improvement in CGI-S but similar RBDSS and atonia index

 III (NA)
McCarter et al., 2013 [21] Description of a series of 45 RBD patients (60% reported RBD-associated injury before treatment); 18 of them were treated with clonazepam Retrospective cohort study

  • RBD VAS, RBD injuries, and falls from the bed improved significantly with clonazepam (less than with melatonin); 22% of patients discontinued clonazepam because of side-effects

 II (NA)
Ferri et al., 2013 [22] Comparison of RBDSS, atonia index, and NREM sleep instability using video-PSG recording in 15 iRBD patients, 13 narcolepsy/RBD patients, and 18 normal controls. Re-evaluation of iRBD patients was conducted 2.75 ± 1.62 years after treatment with 0.5–1 mg of clonazepam Longitudinal follow-up study

  • RBD patients showed increased slow transient and decreases fast transient EEG events, reduced atonia index during REM sleep, and increased atonia index during NREM sleep

  • Long-term therapy with clonazepam decreased WASO, increased slow-wave sleep and sleep stage 2, decreased sleep stages 1 and 2 instability, and decreased the duration of EEG transients, without modifying chin tone

 II (NA)
Fernández-Arcos et al., 2016 [23] Description of a series of 203 RBD patients, 167 of them treated initially with clonazepam Observational case series

  • Clonazepam treatment was “completely successful” in 55.1%.

 II (NA)
Li et al., 2016 [24] Clinical (including modified RBDQ-3M) before and 28.8 ± 13.3 months after the initiation of treatment with clonazepam in 39 iRBD patients Longitudinal follow-up study

  • “Treatment response” (complete elimination of sleep-related injuries and potentially injurious behaviours) in 66.7% of patients.

  • Significant reduction of disturbing dreams with violent and frightening content.

  • An increase in REM-related EMG activities was observed at follow-up.

  • Less optimal treatment outcomes were associated with comorbid obstructive sleep apnoea and earlier onset of RBD

 III (NA)
Ferri et al., 2017 [25] 29 drug-naïve iRBD patients, 14 iRBD patients treated with clonazepam, and 21 controls.Quantitative measurement of power spectra values of each REM sleep EEG spectral band using REM sleep EEG Observational case-control study

  • The normalized power values a less pronounced REM-related decrease of power in all bands with frequency <15 Hz and an increase in the beta band (that was negatively correlated with muscle atonia) in drug-naïve iRBD patients, compared with controls.

  • iRBD patients treated with clonazepam showed a partial return of all bands <15 Hz toward the control values

 II (NA)
Shin et al., 2019 [26] 40 patients with PD and clinically diagnosed RBD treated with 0.5 mg/day of clonazepam at bedtime (n = 20) or placebo (n = 20) Assessment of CGI-I, KESS, PDSS, KV-MoCA, and UPDRS. Four-week, randomized, double-blind, placebo-controlled trial

  • CGI-I score showed an improvement in RBD symptoms in patients treated with clonazepam that did not significantly differ from that of patients under placebo

  • Secondary outcomes (KESS, PDSS, KV-MoCA, and UPDRS) did not significantly differ between the clonazepam and placebo groups

 I (>50%)
Sunwoo et al., 2020 [27] Assessment of “treatment response” (“presence or absence of any improvement in dream-enacting behaviours or unpleasant dreams after treatment”) in 123 iRBD patients treated with clonazepam (n = 40), melatonin (n = 56), and clonazepam-associated with melatonin (n = 27) Retrospective review of medical records

  • Ninety-six patients (78.0%) reported improvement in their RBD symptoms during a mean follow-up period of 17.7 months

  • RBDQ-KR, PSQI, SCOPA-AUT, and KVSS scores, as well as frequency or excessive daytime sleepiness, did not differ significantly between responders and non-responders

  • Depression was significantly more frequent in non-responders

 II (NA)
Lee et al., 2021 [28] Assessment of “treatment response” (complete cessation of disruptive behaviours that may result in sleep-related trauma) in 171 PSG-confirmed RBD patients treated with clonazepam alone (n = 147) or in combination with other drugs (n = 24; 18 carbamazepine, 3 zolpidem, and 1 melatonin) Retrospective review of medical records of patients with follow-up longer than 18 months (57.9 + 35.6 months)

  • One-hundred and fifty-five patients (90.6%) showed a positive response to the treatment positively, with an average dose of clonazepam of 1.01 + 0.49 mg at the last visit

  • 24 patients experienced side effects of clonazepam (13 drowsiness, 6 dry mouth, 3 constipation, 1 erectile dysfunction, and 1 cloudiness)

  • Earlier age at onset and at diagnosis and the presence of comorbid periodic limb movement during sleep were associated with poor treatment response

 II (NA)

CGI-I, clinical global impression-improvement; CGI-S, clinical global impression-severity; EEG, electroencephalography EMG, electromyography; iRBD, idiopathic or isolated REM sleep behaviour disorder; KESS, Korean Epworth Sleepiness Scale; KV-MoCA, Korean Version of the Montreal Cognitive Assessment; KVSS, Korean version of the sniffin’ stick; NA, not applicable; NREM, non-rapid eye movements; PD, Parkinson’s disease; PDSS, Parkinson’s Disease Sleep Scale; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index; RBD REM, sleep behaviour disorder; RBDQ-KR, RBD Questionnaire-Korean version; RBDQ-3M, modified RBD Questionnaire; RBDSS, RBD severity score, REM, rapid eye movements; SCOPA-AUT, Scales for Outcomes in Parkinson’s Disease Autonomic; SWS, slow-wave sleep; UPDRS, Unified Parkinson’s Disease Rating Scale; VAS, visual analogue scale; WASO, wake after sleep onset.