Abstract
Study Objectives:
Despite its widespread use in patients with isolated rapid eye movement sleep behavior disorder (iRBD), the cognitive effect of clonazepam is uncertain. This study aimed to investigate the effect of cumulative clonazepam on cognitive function in patients with iRBD.
Methods:
Demographic characteristics, baseline cognitive test, and most recent cognitive test information were collected retrospectively. Based on cumulative clonazepam doses, patients were classified into 4 subgroups: group 1, < 365 mg (1 mg × 1 year); group 2, 365 mg to < 1,095 mg (1 mg × 3 years); group 3, 1,095 mg to < 2,190 mg (1 mg × 6 years); and group 4, 2,190 mg or more. Cognitive test scores were calculated as z scores adjusted for age, education, and sex.
Results:
This study included 101 patients with iRBD (63 males). Groups 1, 2, 3, and 4 had 14, 20, 32, and 35 patients, respectively. In within-group comparisons, follow-up Digit Span Backward test and the Trail Making Test A scores decreased in group 3, and follow-up Trail Making Test A and the Trail Making Test B scores decreased significantly in group 4. In the multiple regression analysis to determine influential factors on cognitive decline, cumulative clonazepam dose did not show a significant correlation with any cognitive domain. Follow-up cognitive function showed significant correlation only with baseline cognitive function.
Conclusions:
Memory and executive functions tended to decline in patients with iRBD. However, there was no significant effect of cumulative clonazepam. There was no evidence that long-term use of clonazepam was related to cognitive decline in patients with iRBD.
Citation:
Lee M, Kim TK, Hong JK, Yoon I-Y. Minimal effect of long-term clonazepam on cognitive function in patients with isolated rapid eye movement sleep behavior disorder. J Clin Sleep Med. 2024;20(7):1173–1182.
Keywords: clonazepam, cognitive decline, REM sleep behavior disorder, memory, executive function
BRIEF SUMMARY
Current Knowledge/Study Rationale: Patients with isolated rapid eye movement sleep behavior disorder (iRBD) are prescribed clonazepam for an extended period because symptoms reappear upon discontinuation of the drug. Since iRBD is associated with neurodegenerative diseases, it is clinically important to know whether taking benzodiazepine for an extended period has a negative effect on cognitive decline.
Study Impact: In patients with iRBD, cumulative clonazepam dose did not appear to be associated with cognitive decline when adjusted for other factors that affect cognitive function. This study provides evidence that it is acceptable to maintain long-term clonazepam in patients with iRBD.
INTRODUCTION
Isolated rapid eye movement sleep behavior disorder (iRBD) is characterized by vivid, violent dreams, and dream enactment behaviors while asleep.1 Isolated RBD is considered to be an early stage of α-synucleinopathy such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy.1,2 Treatment of rapid eye movement sleep behavior disorder (RBD) includes pharmacologic treatment and injury prevention. Clonazepam has been used widely since the case report in 1986 showing that clonazepam could improve RBD symptoms.3 In RBD treatment guidelines, the recommended dose of clonazepam is 0.25 to 2.0 mg. However, there is no mention of a recommended period of use.4 As symptoms immediately recur when the drug is discontinued, long-term use of clonazepam is common.5
There have been concerns regarding the use of clonazepam in patients with iRBD due to studies demonstrating that long-term benzodiazepine use can impair various neuropsychological functions and that such impairment persists even after discontinuation.6,7 On the other hand, there are conflicting reports regarding the use of benzodiazepines and cognitive decline for patients who have already had neurodegenerative diseases. One study has shown that the use of benzodiazepines for more than 18 months does not result in cognitive decline in patients with mild to moderate Alzheimer’s disease.8 Another study has shown no difference in cognitive function between patients with RBD taking clonazepam for 4 weeks and a placebo group of patients with RBD who are not taking clonazepam.9
Since iRBD is associated with neurodegenerative diseases and long-term use of clonazepam is inevitable, it is important to know whether clonazepam causes cognitive decline. One study has investigated the sleep structure of patients with RBD after using clonazepam for an average of 2.75 years,10 but it did not investigate the change in cognitive function. Thus, the aim of this study was to determine correlation between cumulative clonazepam dose and cognitive function in patients with iRBD.
METHODS
Participants
Our study included participants who were diagnosed with iRBD between 2003 and 2015 at Seoul National University Bundang Hospital. A sleep specialist made the diagnosis of RBD after a formal interview with participants and a video polysomnography according to the standard criteria of the International Classification of Sleep Disorders, second edition.11 Rapid eye movement (REM) sleep without atonia was defined based on the American Academy of Sleep Medicine (AASM) manual.12 After a baseline neurological examination performed by a neurologist and a neuropsychological examination, those who were free of Parkinsonism or dementia were confirmed as having iRBD. Patients visited the sleep clinic at intervals of 1 month to 1 year. All patients with iRBD were recommended to have an annual neurological examination to determine whether a neurodegenerative disorder had developed. Every 5 years, neurologist and neuropsychological examinations were performed for patients in the cohort. As mild cognitive impairment is prevalent in iRBD, with evidence suggesting that people with mild cognitive impairment can regain normal cognitive functions,13,14 patients with mild cognitive impairment were not classified as phenoconversion cases. Patients with head trauma, cerebrovascular disease, or brain tumors were excluded. Informed consent was obtained from participants according to the Declaration of Helsinki. The Institutional Review Board of Seoul National University Bundang Hospital approved this study (IRB no. B-1907-553-301).
Measurements
Clonazepam exposure
Through a retrospective review of the medical chart, information about clonazepam exposure was collected. The cumulative dose of clonazepam was calculated by summing the doses from the date of the baseline cognitive function test to the date of the last follow-up cognitive function test. Patients with iRBD were divided into 4 groups according to their clonazepam cumulative dose (group 1, < 365 mg; group 2, 365 mg to < 1,095 mg; group 3, 1,095 mg to < 2,190 mg; and group 4, 2,190 mg or more). For example, group 1 would be the equivalent of taking less than 1 mg of clonazepam daily for 1 year, or less than 0.5 mg of clonazepam daily for 2 years. Group 2 included cases with a dosage less than 1 mg per day for a period ranging from 1 to 3 years. Those who had consumed clonazepam less than 1 mg daily for 3 to 6 years were categorized as group 3. Group 4 included those who took more than 1 mg of clonazepam for more than 6 years. The average daily dose of clonazepam was calculated by dividing the cumulative dose by the follow-up duration.
Risk factors
Risk factors for cognitive decline, such as smoking status, alcohol consumption, regular exercise, hypertension, diabetes mellitus, hyperlipidemia, and zolpidem intake history, were investigated based on clinical history. Apnea-hypopnea index (AHI) data were also collected from the video polysomnography. The use of zolpidem included patients who had received at least 1 prescription for zolpidem during their hospital visits.
REM Sleep Behavior Disorder Questionnaire–Hong Kong
The REM Sleep Behavior Disorder Questionnaire–Hong Kong (RBDQ-HK) is a self-report scale having 13 items with a total score of 0 to 100.15 Since the RBDQ-HK was conducted after January 2014, only values measured after that date were collected.
Depression
For evaluating depression in the older persons, the Geriatric Depression Scale (GDS) was used.16 The Revised Korean version of the GDR (GDS-KR) consisted of 30 items as a dichotomy scale. Its total score ranges from 0 to 30 points. The cutoff point for depression with clinical significance was 17 points or more.17
Pittsburgh Sleep Quality Index
The Pittsburgh Sleep Quality Index (PSQI) was used to evaluate the sleep state.18 The questionnaire comprises 19 items in 7 areas. It has a score of a 0–3 scale. If a global score exceeds 5 points, it could be evaluated as clinically meaningful insomnia.
Neuropsychological assessment for cognition
Neuropsychological tests included the Korean Version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet Neuropsychological Assessment Battery (CERAD-K-N),19 the Digit Span Forward test (DSF), the Digit Span Backward test (DSB),20 the Frontal Assessment Battery (FAB),21 the Clock Drawing Test 2 (CLOX2),22 and the Stroop Color and Word Test (SCWT).23 The CERAD-K-N consists of 9 neuropsychological tests, including the Verbal Fluency Test (VFT), the Mini-Mental State Examination–Dementia Screening (MMSE-DS), the Constructional Praxis test (CP), the Word List Recall test (WLR), the Constructional Recall test (CR), the Trail Making Test A (TMT-A), and the Trail Making Test B (TMT-B). Raw scores of each test were transformed into z scores adjusted for age, sex, and education.
Statistical analysis
The Shapiro-Wilk test was performed to confirm the normality of data. All results are presented as mean ± standard deviation for parametric variables or median (interquartile range). For baseline comparison of demographic characteristics, analysis of variance (ANOVA) or Kruskal-Wallis test was used for numerical variables and Pearson’s chi-square or Fisher’s exact test was used for categorical variables. ANOVA or Kruskal-Wallis test was used for comparing baseline cognitive function scores between groups. The paired t test or Wilcoxon signed-rank test was used to examine within-group differences of cognitive function. Repeated-measures analysis of variance (RM ANOVA) was used to confirm group-by-time interaction. Multiple linear regression was used to estimate the relationship between cognitive function and other variables, including cumulative dose of clonazepam. All significance tests were 2-sided and a P value < .05 was considered statistically significant. Bonferroni correction was used for multiple comparison correction. SPSS version 22.0 for Windows (SPSS, IBM Corporation, Armonk, NY, USA) was used for all statistical analyses.
RESULTS
Among 198 patients diagnosed with iRBD in 2003–2015, patients who developed neurodegenerative diseases, those who expired from other causes, those who had central nervous system comorbidity, and those who were lost to follow-up were excluded. A total of 101 (63 males) patients with complete baseline and follow-up cognitive function data were included in the analysis (Figure 1). Information on demographic characteristics of the 4 groups are presented in Table 1. Their average age at diagnosis was 64.3 ± 6.0 years. The minimum cumulative dose was 0 mg (n = 2) and the maximum cumulative dose was 13,476 mg. Each group divided according to cumulative dose included 14, 20, 32, and 35 patients. In group 1, the mean cumulative dose was 185.1 ± 130.0 mg and the median daily dose during the follow-up duration was 0.06 mg (interquartile range, 0.02–0.14 mg). The mean cumulative dose of clonazepam was 823.0 ± 233.1 mg and the median daily dose was 0.35 mg (interquartile range, 0.24–0.50 mg) for group 2. Cumulative doses of clonazepam for group 3 and group 4 were 1,643.5 ± 338.1 mg and 4,168.1 ± 2054.3 mg, while their average daily doses were 0.79 ± 0.21 mg and 1.34 ± 0.37 mg, respectively. The average follow-up period was 7.1 ± 2.4 years. The median follow-up period was 7.6 years (interquartile range, 6.4–10.5 years) for group 4, which was statistically significantly longer than that for groups 2 or 3. The proportion of patients prescribed zolpidem in group 4 reached 34.3%. There was no significant difference in the severity of depression, insomnia, or AHI between groups. The average RBDQ-HK score was 43.7 ± 12.8, showing no statistically significant difference between groups.
Figure 1. Study flow chart.
iRBD = isolated rapid eye movement sleep behavior disorder, Mar = March.
Table 1.
Demographic data of patients with iRBD.
| Group 1 (n = 14) | Group 2 (n = 20) | Group 3 (n = 32) | Group 4 (n = 35) | P | |
|---|---|---|---|---|---|
| Clonazepam total dose (mg) | 185.1 (130.0) | 823.0 (233.1) | 1643.5 (338.1) | 4,168.1 (2054.3) | < .001*** |
| Clonazepam mean dose (per day) | 0.06 (0.02, 0.14) | 0.35 (0.24, 0.50) | 0.79 (0.21) | 1.34 (0.37) | < .001*** |
| Male (%) | 11 (78.6%) | 13 (65%) | 18 (56.3%) | 21 (60%) | .528 |
| Age (y) | 64.3 (8.2) | 65.5 (5.1) | 65.8 (6.4) | 62.1 (4.6) | .059 |
| Education (y) | 14 (12, 16) | 13.7 (4.2) | 16 (12, 16) | 12 (12, 16) | .469 |
| Height (cm) | 167.0 (9.4) | 161.8 (7.9) | 162.8 (8.1) | 164.9 (8.2) | .229 |
| Weight (kg) | 67.5 (14.0) | 63.3 (11.9) | 63.8 (7.9) | 66.2 (9.2) | .510 |
| BMI (kg/m2) | 23.9 (3.0) | 24.0 (3.3) | 24.1 (2.5) | 24.4 (2.9) | .954 |
| Smoking (%) | 2 (14.3%) | 1 (5.0%) | 3 (9.4%) | 3 (8.6%) | .859 |
| Alcohol (%) | 6 (42.9%) | 3 (15.0%) | 7 (28.0%) | 8 (28.6%) | .357 |
| Exercise (h/d) | 0.39 (0.00, 0.93) | 0.54 (0.20, 1.32) | 0.57 (0.24, 1.27) | 0.43 (0.00, 1.00) | .438 |
| Hypertension (%) | 5 (35.7%) | 8 (40.0%) | 13 (40.6%) | 7 (20.0%) | .259 |
| Diabetes mellitus (%) | 4 (28.6%) | 1 (5.0%) | 4 (12.5%) | 4 (11.4%) | .279 |
| Hyperlipidemia (%) | 5 (35.7%) | 7 (35.0%) | 11 (34.4%) | 7 (20.0%) | .489 |
| Zolpidem intake (%) | 1 (7.1%) | 1 (5.0%) | 4 (12.5%) | 12 (34.3%) | .023* |
| Follow-up duration (y) | 6.7 (6.2, 7.6) | 5.8 (5.1, 6.7) | 6.0 (1.2) | 7.6 (6.4, 10.5) | < .001*** |
| GDS | 9.1 (6.1) | 6.1 (4.5) | 7 (2, 11) | 12.3 (8.7) | .080 |
| RBDQ-HK | 41.2 (12.6) | 43.9 (15.1) | 45.2 (12.2) | 42.8 (12.0) | .853 |
| PSQI | 5.2 (3.9) | 5.6 (3.7) | 6.6 (3.9) | 7.5 (4.5) | .938 |
| AHI | 8.4 (9.4) | 9.7 (12.1) | 14.0 (15.2) | 8.8 (12.7) | .353 |
Pearson’s chi-square tests were performed for differences between categorical variables presented as number (%). Parametric data were analyzed by ANOVA and presented as mean (standard deviation). Nonparametric data were analyzed by Kruskal-Wallis test and presented as median (Q1, Q3). P values reaching statistical significance: *P < .05; ***P < .001. AHI = apnea-hypopnea index, ANOVA = analysis of variance, BMI = body mass index, GDS = Geriatric Depression Scale, iRBD = isolated rapid eye movement sleep behavior disorder, PSQI = Pittsburgh Sleep Quality Index, RBDQ-HK = REM Sleep Behavior Disorder Questionnaire–Hong Kong.
In the baseline cognitive test, there was no significant difference in any baseline cognitive test result between groups (Table 2). Baseline and follow-up cognitive function test results of each group are presented in Table 3. In within-group comparison, DSB and TMT-A test scores were decreased significantly from baseline to follow-up cognitive tests in group 3 (DSB: from 0.56 ± 1.24 to 0.00 ± 1.11; P = .004; TMT-A: from 0.99 ± 0.51 to 0.63 ± 0.73; P = .001). In group 4, TMT-A and TMT-B scores were also significantly decreased from baseline to follow-up cognitive tests (TMT-A: from 0.88 ± 0.67 to 0.67 ± 0.56; P = .004; TMT-B: from 0.79 ± 1.10 to –0.08 ± 1.55; P = .001). In RM ANOVA results, time effect was significant for WLR and TMT-A (WLR: F = 11.30, P = .001; TMT-A: F = 2.58, P = .001). The time effect on MMSE-DS score was also significant (F = 14.14, P < .001). No significant group by time interaction was observed for any cognitive test subcategory.
Table 2.
Baseline cognitive function test data of patients with iRBD.
| Group 1 (n = 14) | Group 2 (n = 20) | Group 3 (n = 32) | Group 4 (n = 35) | P | |
|---|---|---|---|---|---|
| Memory | |||||
| DSF | 0.20 (0.97) | 0.12 (0.97) | 0.23 (0.84) | 0.64 (0.81) | .149 |
| DSB | −0.05 (0.68) | 0.29 (1.09) | 0.56 (1.24) | 0.57 (1.41) | .341 |
| WLR | −0.04 (1.00) | 0.32 (0.89) | −0.07 (1.02) | −0.04 (0.81) | .461 |
| CR | 0.28 (0.96) | 0.37 (1.04) | 0.15 (0.89) | −0.02 (0.75) | .412 |
| Visuospatial function | |||||
| CP | 0.30 (0.48) | 0.05 (0.93) | 0.32 (0.53) | 0.28 (0.45) | .579 |
| CLOX2 | 0.27 (0.42) | 0.24 (0.43) | 0.31 (0.45) | 0.14 (0.84) | .070 |
| Executive function | |||||
| TMT-A | 1.05 (0.54) | 0.79 (0.41) | 0.99 (0.51) | 0.88 (0.67) | .179 |
| TMT-B | 0.75 (0.96) | 0.04 (1.68) | 0.81 (1.46) | 0.79 (1.10) | .193 |
| VFT | 0.21 (1.24) | 0.52 (1.05) | 0.63 (1.35) | 0.47 (1.21) | .786 |
| SCWT | −0.07 (1.05) | 0.51 (0.89) | 0.40 (1.04) | 0.32 (0.95) | .396 |
| FAB | 0.28 (0.75) | 0.18 (0.78) | 0.29 (0.68) | 0.38 (0.72) | .723 |
| Global cognition | |||||
| MMSE-DS | −0.92 (1.55) | −0.34 (0.87) | −0.14 (0.92) | −0.76 (1.39) | .111 |
Parametric data were analyzed by ANOVA. Nonparametric data were analyzed by Kruskal-Wallis test. CLOX2 = Clock Drawing Test 2, CP = Constructional Praxis test, CR = Constructional Recall test, DSB = Digit Span Backward test, DSF = Digit Span Forward test, FAB = Frontal Assessment Battery, iRBD = isolated rapid eye movement sleep behavior disorder, MMSE-DS = Mini-Mental State Examination–Dementia Screening, SCWT = Stroop Color and Word Test, TMT-A = Trail Making Test A, TMT-B = Trail Making Test B, VFT = Verbal Fluency Test, WLR = Word List Recall test.
Table 3.
Follow-up cognitive function test data of patients with iRBD.
| Memory | Visuospatial Function | Executive Function | Global Cognition, MMSE-DS | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DSF | DSB | WLR | CR | CP | CLOX2 | TMT-A | TMT-B | VFT | SCWT | FAB | ||
| Group 1 (n = 14) | ||||||||||||
| Pre | 0.20 (0.97) | −0.05 (0.68) | −0.04 (1.00) | 0.28 (0.96) | 0.30 (0.48) | 0.27 (0.42) | 1.05 (0.54) | 0.75 (0.96) | 0.21 (1.24) | −0.07 (1.05) | 0.28 (0.75) | −0.92 (1.55) |
| Post | −0.16 (0.94) | −0.03 (1.08) | −0.63 (1.17) | 0.03 (1.03) | −0.26 (1.02) | 0.22 (0.49) | 0.88 (0.47) | 0.49 (1.11) | 0.17 (0.92) | −0.03 (0.84) | −0.03 (1.23) | −0.07 (1.21) |
| P | .115 | .918 | .065 | .299 | .03 | .465 | .354 | .326 | .878 | .706 | .466 | .006 |
| Group 2 (n = 20) | ||||||||||||
| Pre | 0.12 (0.97) | 0.29 (1.09) | 0.32 (0.89) | 0.37 (1.04) | 0.05 (0.93) | 0.24 (0.43) | 0.79 (0.41) | 0.04 (1.68) | 0.52 (1.05) | 0.51 (0.89) | 0.18 (0.78) | −0.34 (0.87) |
| Post | 0.16 (1.04) | 0.08 (1.14) | 0.21 (0.98) | 0.20 (0.70) | 0.10 (0.92) | 0.45 (0.13) | 0.71 (0.75) | 0.08 (1.58) | 0.10 (0.84) | 0.42 (0.80) | 0.61 (0.83) | −0.14 (1.40) |
| P | .872 | .400 | .555 | .936 | .773 | .042 | .936 | .653 | .08 | .709 | .026 | .435 |
| Group 3 (n = 32) | ||||||||||||
| Pre | 0.23 (0.84) | 0.56 (1.24) | −0.07 (1.02) | 0.15 (0.89) | 0.32 (0.53) | 0.31 (0.45) | 0.99 (0.51) | 0.81 (1.46) | 0.63 (1.35) | 0.40 (1.04) | 0.29 (0.68) | −0.14 (0.92) |
| Post | 0.40 (0.98) | 0.00 (1.11) | −0.53 (0.98) | −0.06 (0.90) | 0.45 (0.47) | 0.40 (0.23) | 0.63 (0.73) | 0.67 (1.19) | 0.65 (1.03) | 0.31 (1.07) | 0.09 (0.84) | 0.08 (0.83) |
| P | .299 | .004* | .022 | .158 | .088 | .022 | .001* | .437 | .918 | .492 | .198 | .175 |
| Group 4 (n = 35) | ||||||||||||
| Pre | 0.64 (0.81) | 0.57 (1.41) | −0.04 (0.81) | −0.02 (0.75) | 0.28 (0.45) | 0.14 (0.84) | 0.88 (0.67) | 0.79 (1.10) | 0.47 (1.21) | 0.32 (0.95) | 0.38 (0.72) | −0.76 (1.39) |
| Post | 0.49 (0.92) | 0.17 (1.15) | −0.27 (0.75) | −0.10 (0.97) | 0.20 (0.65) | 0.27 (0.87) | 0.67 (0.56) | −0.08 (1.55) | 0.31 (1.07) | 0.18 (0.96) | 0.24 (0.80) | −0.25 (1.04) |
| P | .626 | .041 | .069 | .746 | .828 | .017 | .004* | .001* | .407 | .19 | .475 | .025 |
| Group × time effect P | .243 | .334 | .398 | .942 | .038 | .497 | .352 | .035 | .561 | .911 | .106 | .274 |
| Group effect P | .112 | .646 | .096 | .348 | .106 | .653 | .673 | .231 | .453 | .392 | .550 | .219 |
| Time effect P | .420 | .014 | .001* | .139 | .161 | .062 | .001* | .023 | .212 | .407 | .600 | < .001* |
Paired t test or Wilcoxon signed rank test were performed for differences between pre- and post-cognitive functions in each group. Repeated measures analysis of variance (RM ANOVA) was conducted to confirm group by time interaction. P values reaching statistical significance are shown in bold. *The adjusted significance level for multiple comparisons was set to .0042 with Bonferroni correction. CLOX2 = Clock Drawing Test 2, CP = Constructional Praxis test, CR = Constructional Recall test, DSB = Digit Span Backward test, DSF = Digit Span Forward test, FAB = Frontal Assessment Battery, iRBD = isolated rapid eye movement sleep behavior disorder, MMSE-DS = Mini-Mental State Examination–Dementia Screening, SCWT = Stroop Color and Word Test, TMT-A = Trail Making Test A, TMT-B = Trail Making Test B, VFT = Verbal Fluency Test, WLR = Word List Recall test.
Multiple regression analysis was performed to examine which variables were significantly related to follow-up cognitive function (Table 4). There was no correlation between cumulative clonazepam dose and follow-up cognitive function decline in any domain. In addition, when clonazepam cumulative dose was analyzed as a continuous variable without dividing into groups, there was also no significant relationship between clonazepam dose and follow-up cognitive function score. Only baseline cognitive function scores showed significant correlations with follow-up cognitive function scores even after Bonferroni correction, except for CR or FAB.
Table 4.
Correlation between various variables including cumulative dose of clonazepam and cognitive functions in patients with iRBD.
| Memory | Visuospatial Function | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DSF | DSB | WLR | CR | CP | CLOX2 | ||||||||
| β | P | β | P | β | P | β | P | β | P | β | P | ||
| Intercept | 0.32 | .970 | –0.04 | .966 | 0.23 | .791 | 0.91 | .307 | –0.51 | .472 | 0.13 | .762 | |
| Clonazepam total dose | group 1 | ||||||||||||
| group 2 | 0.50 | .108 | 0.17 | .586 | 0.72 | .025 | 0.18 | .578 | 0.41 | .115 | 0.16 | .311 | |
| group 3 | 0.63 | .026 | –0.19 | .522 | 0.18 | .539 | –0.04 | .900 | 0.67 | .006 | 0.11 | .421 | |
| group 4 | 0.46 | .115 | –0.16 | .575 | 0.52 | .077 | –0.11 | .717 | 0.45 | .064 | 0.15 | .296 | |
| BMI | –0.02 | .452 | –0.02 | .603 | –0.02 | .505 | –0.02 | .628 | 0.01 | .667 | –0.00 | .807 | |
| Smoking | 0 | ||||||||||||
| 1 | 0.01 | .975 | –0.08 | .790 | –0.29 | .365 | –0.12 | .712 | 0.17 | .509 | 0.11 | .480 | |
| Alcohol | 0 | ||||||||||||
| 1 | 0.39 | .060 | 0.62 | .004 | 0.22 | .291 | 0.05 | .827 | –0.10 | .593 | –0.12 | .254 | |
| Exercise | 0.00 | .988 | 0.00 | .701 | 0.00 | .696 | 0.00 | .523 | 0.00 | .673 | 0.00 | .327 | |
| Hypertension | 0 | ||||||||||||
| 1 | 0.08 | .678 | –0.55 | .006 | –0.25 | .212 | –0.20 | .336 | –0.06 | .727 | 0.18 | .074 | |
| Diabetes mellitus | 0 | ||||||||||||
| 1 | 0.06 | .824 | 0.13 | .642 | 0.04 | .874 | –0.00 | .993 | –0.15 | .504 | –0.27 | .042 | |
| Hyperlipidemia | 0 | ||||||||||||
| 1 | 0.15 | .465 | 0.55 | .009 | 0.32 | .134 | –0.20 | .346 | 0.05 | .790 | 0.16 | .124 | |
| GDS follow-up | 0.00 | .815 | 0.02 | .266 | –0.05 | .005 | –0.05 | .007 | –0.02 | .227 | 0.01 | .504 | |
| Zolpidem | 0 | ||||||||||||
| 1 | 0.11 | .653 | 0.31 | .221 | 0.06 | .824 | 0.45 | .092 | 0.11 | .609 | –0.14 | .282 | |
| AHI | –0.00 | .484 | 0.00 | .630 | –0.00 | .714 | –0.00 | .588 | –0.00 | .857 | –0.01 | .114 | |
| Baseline cognitive function | 0.61 | < .001* | 0.53 | < .001* | 0.49 | < .001* | 0.19 | .081 | 0.45 | < .001* | 0.60 | < .001* | |
| Executive Function | Global Cognition | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TMT-A | TMT-B | VFT | SCWT | FAB | MMSE-DS | ||||||||
| β | P | β | P | β | P | β | P | β | P | β | P | ||
| Intercept | 0.82 | .138 | –1.11 | .353 | 0.01 | .909 | 0.35 | .608 | 1.51 | .086 | 1.25 | .198 | |
| Clonazepam total dose | group 1 | ||||||||||||
| group 2 | –0.05 | .808 | –0.02 | .970 | –0.23 | .465 | 0.12 | .636 | 0.73 | .024 | –0.29 | .405 | |
| group 3 | –0.26 | .129 | 0.12 | .749 | 0.21 | .473 | 0.10 | .675 | 0.16 | .591 | –0.12 | .724 | |
| group 4 | –0.14 | .419 | –0.63 | .113 | –0.02 | .949 | 0.07 | .759 | 0.31 | .300 | –0.20 | .540 | |
| BMI | –0.01 | .468 | 0.05 | .241 | –0.01 | .690 | –0.02 | .567 | –0.05 | .111 | –0.02 | .542 | |
| Smoking | 0 | ||||||||||||
| 1 | –0.30 | .127 | –0.08 | .853 | –0.27 | .413 | 0.02 | .932 | –0.04 | .910 | –0.19 | .614 | |
| Alcohol | 0 | ||||||||||||
| 1 | 0.06 | .664 | 0.29 | .306 | 0.17 | .421 | 0.19 | .265 | 0.29 | .182 | 0.08 | .741 | |
| Exercise | 0.00 | .864 | 0.00 | .607 | 0.00 | .147 | 0.00 | .393 | –0.00 | .031 | 0.00 | .429 | |
| Hypertension | 0 | ||||||||||||
| 1 | –0.06 | .615 | –0.25 | .356 | –0.06 | .778 | –0.04 | .795 | –0.04 | .844 | –0.07 | .760 | |
| Diabetes mellitus | 0 | ||||||||||||
| 1 | –0.10 | .522 | –0.32 | .382 | –0.06 | .818 | –0.16 | .473 | –0.27 | .318 | 0.01 | .978 | |
| Hyperlipidemia | 0 | ||||||||||||
| 1 | –0.19 | .136 | 0.31 | .263 | 0.19 | .348 | 0.35 | .038 | –0.03 | .870 | –0.27 | .234 | |
| GDS follow-up | –0.02 | .014 | –0.02 | .346 | 0.01 | .734 | –0.02 | .262 | –0.03 | .052 | –0.02 | .389 | |
| Zolpidem | 0 | ||||||||||||
| 1 | 0.20 | .189 | 0.24 | .491 | 0.21 | .426 | 0.02 | .936 | 0.13 | .615 | –0.15 | .611 | |
| AHI | 0.00 | .360 | –0.01 | .634 | 0.01 | .306 | –0.01 | .104 | 0.01 | .376 | –0.01 | .378 | |
| Baseline cognitive function | 0.64 | < .001* | 0.58 | .001* | 0.42 | < .001* | 0.61 | < .001* | 0.25 | .061 | 0.47 | < .001* | |
Multiple linear regression included clonazepam total dose, BMI, smoking status, alcohol consumption, regular exercise, hypertension, diabetes mellitus, hyperlipidemia, GDS, zolpidem intake history, AHI, and baseline cognitive function as covariates. Clonazepam total dose: group 1, < 365 mg; group 2, 365 mg to < 1,095 mg; group 3,1,095 mg to < 2,190 mg; group 4, 2,190 mg or more. P values reaching statistical significance are shown in bold. *The adjusted significance level for multiple comparisons was set to .0042 with Bonferroni correction. AHI = apnea-hypopnea index, BMI = body mass index, CLOX2 = Clock Drawing Test 2, CP = Constructional Praxis test, CR = Constructional Recall test, DSB = Digit Span Backward test, DSF = Digit Span Forward test, FAB = Frontal Assessment Battery, GDS = Geriatric Depression Scale, iRBD = isolated rapid eye movement sleep behavior disorder, MMSE-DS = Mini-Mental State Examination–Dementia Screening, SCWT = Stroop Color and Word Test, TMT-A = Trail Making Test A, TMT-B = Trail Making Test B, VFT = Verbal Fluency Test, WLR = Word List Recall test.
However, a positive correlation trend was observed between follow-up cognitive function and clonazepam dosage, although it was not statistically significant. In the memory domain, the regression coefficient was 0.63 (P = .026) for clonazepam dose less than 2,190 mg in the DSF. The regression coefficient was 0.72 (P = .025) for clonazepam dose less than 1,095 mg in the WLR. In visuospatial function, a clonazepam dose less than 2,190 mg tended to show a positive association with the CP test (β = 0.67, P = .006). In the executive function domain, a clonazepam dose less than 1,095 mg was positively associated with FAB score (β = 0.73, P = .024). Body mass index, smoking, alcohol consumption, and zolpidem intake were not associated with cognitive function. In the DSB, hypertension had a negative association with follow-up cognitive function (β = –0.55, P = .006) without showing statistical significance. Diabetes mellitus was negatively correlated with follow-up cognitive function in CLOX2 (β = –0.27, P = .042) without showing statistical significance. Hyperlipidemia showed positive associations with follow-up cognitive test in DSB (β = 0.55, P = .009) and SCWT (β = 0.35, P = .038). The GDS score was negatively correlated with WLR, CR, and TMT-A scores (WLR: β = –0.05, P = .005; CR: β = –0.05, P = .007; TMT-A: –0.02, P = .014), although it did not reach statistical significance after Bonferroni correction.
DISCUSSION
In this study, we investigated associations between cumulative clonazepam doses and cognitive decline. In groups 3 and 4 with high cumulative clonazepam doses, memory declined in group 3 and executive function declined in both group 3 and group 4. However, in a multiple regression analysis that considered other factors affecting cognitive function, the cumulative clonazepam dose did not show a significant correlation with follow-up cognitive function. Depression tended to show a negative correlation with follow-up cognitive function. However, the correlation was not statistically significant. Baseline cognitive function scores showed positive correlations with follow-up cognitive function scores in all domains of memory, visuospatial function, executive function, and global cognition. It appears that memory and executive functions were compromised in those taking high doses of clonazepam. However, the underlying cognitive function was a more important factor than the cumulative clonazepam dose.
DSB and TMT-A scores decreased in group 3 and TMT-A and TMT-B scores decreased in group 4, indicating that memory and executive function decreased in higher cumulative clonazepam-dose groups. There have been many studies about the effects of benzodiazepine use on cognitive function. However, their results were inconsistent as to whether and which areas of cognitive function were impaired. In 1 systematic review, only 3 out of 14 studies supported an association between long-term benzodiazepine use and cognitive decline.24 One study found that long-term benzodiazepine use has negative effects on memory, processing speed, attention, visuoconstruction, and expressive language.6 However, another study showed a decrease in processing speed without a decrease in memory.25 This discrepancy might be due to the inclusion of heterogeneous patient populations (eg, depression, anxiety disorders, insomnia) and different effects of benzodiazepines on cognitive decline depending on characteristics of patients.26–28 For instance, in patients with panic disorder, long-term benzodiazepine users showed a decline in visual memory.26 Meanwhile, a study on patients with insomnia showed a correlation between the duration of benzodiazepine exposure and decreased executive function, but not in cumulative benzodiazepine doses.27 In another study targeting older people with normal cognitive function, there was no difference in the rate of cognitive decline between nonbenzodiazepine users and benzodiazepine users, although benzodiazepine users were more likely to have depression and low baseline cognitive function scores.28 In the present study, similar to previous research studies, only baseline cognitive function affected follow-up cognitive function decline. In light of these facts, patient characteristics and baseline cognitive function tests are important to evaluate the impact of benzodiazepine on cognitive function.
The association between RBD and cognitive decline has been well documented in previous studies.14,29–32 In previous studies, patients with iRBD showed a decline in memory compared with controls, especially verbal memory.29–31 Some studies have shown that individuals with probable RBD perform worse than participants without RBD in executive function.14,29,31,32 In the present study, RM ANOVA results showed a significant time effect on WLR and TMT-A, which represented a decline in memory function and executive function in patients with iRBD, respectively. However, no significant group by time interaction was observed. Multiple regression analyses further supported this finding. In multiple regression analysis, cumulative clonazepam dose was not associated with cognitive decline. In study by Shin et al9 related to RBD, although it did not target people with Parkinson’s disease, taking clonazepam did not reduce cognitive score based on the Korean Version of the Montreal Cognitive Assessment. Considering these facts, the decline in cognitive function in patients with iRBD might be due to iRBD characteristics themselves rather than clonazepam.
Nevertheless, it is noteworthy that a trend toward improvement in cognitive function was observed despite high cumulative doses of clonazepam. Multiple regression analysis did not find evidence of cognitive decline across all cognitive function domains, although it did find increasing trends in memory, visuospatial function, and executive function domains. First, this might be due to the practice effect. Since practice effects are common in patients with mild cognitive impairment or dementia, these changes in scores might be due to practice effects.33 However, considering that the average test interval was 7 years, practice effect was insufficient to explain the positive association between cognitive function and cumulative doses of clonazepam. Rather, MMSE-DS score in RM ANOVA showed a practice effect properly, as it was a screening test more widely used for dementia screening. Second, the improvement in sleep quality after clonazepam treatment might offset the cognitive damage. Although it is known that insomnia in patients with iRBD does not predict neurodegeneration, insomnia in patients with iRBD is common, with a prevalence ranging from 29.9% to 48.7%.34,35 Although the effect of clonazepam on REM sleep behavioral indicators, such as the atonia index, has not been proven in many cases,10,36 clonazepam has shown favorable effects on sleep, such as increased sleep efficiency, increased stage 2 sleep, decreased stage 1 sleep, and decreased wake after sleep onset.10,37 It is well known that sleep deprivation, fatigue, and sleepiness are associated with cognitive decline.38–41 Long-term use of clonazepam might have helped cognitive function by improving nighttime sleep quality while minimizing daytime sleepiness by long-term medication adjustment. Meanwhile, the GDS score tended to be associated with cognitive decline in memory and executive function subdomains. Several previous studies have revealed a link between depression and cognitive decline.42,43 Although this trend was not statistically significant, the present study results suggest that a patient’s characteristics, such as depression, had more influence on cognitive function than the cumulative clonazepam dose itself.
This study has several limitations. First, there was no iRBD control group who did not take clonazepam. However, patients in group 1 had long since discontinued the medication or were taking a very low dose of clonazepam. Thus, group 1 might not differ significantly from a drug-naive group. Second, the dose of clonazepam prior to hospital visit was not considered. However, results were unlikely to be affected by the previous medication since there were only 4 patients who were taking clonazepam before their hospital visit. In addition, clonazepam was taken for a relatively short period of time. Third, patients developing neurodegenerative diseases were excluded from the analysis because there was no available follow-up cognitive test. Follow-up studies are needed to examine whether phenoconversion, including dementia, is more common in groups with higher cumulative doses. Last, quantitative evaluation of other substances that can affect cognitive function was not performed. Although zolpidem usage and alcohol consumption were investigated, their doses were not evaluated.
Despite these limitations, to the best of our knowledge, this is the first study that examines cognitive decline according to cumulative doses of clonazepam in patients with iRBD. Results of our study revealed a slight decrease in executive function in patients with higher cumulative clonazepam doses, although there was no significant decline in cognitive function when other factors were adjusted. Based on findings of this study, clinicians can be confident that long-term use of clonazepam in patients with iRBD does not result in cognitive decline. Further research is needed to determine whether long-term clonazepam use will increase the risk of conversion from iRBD to neurodegenerative disease.
ACKNOWLEDGMENTS
The authors thank all participants who helped with this study.
Authors’ contributions: M.L.: statistical analysis, visualization, writing—original draft; T.K.K.: data curation, statistical analysis, and review; J.K.H.: conceptualization, data curation, methodology, funding acquisition, investigation; I.-Y.Y.: conceptualization, funding acquisition, investigation, projection administration, supervision, writing—review and editing. All authors read and approved the manuscript.
Datasets of the current study are available from the corresponding author upon reasonable request.
ABBREVIATIONS
- AHI
apnea-hypopnea index
- ANOVA
analysis of variance
- CLOX2
clock drawing test 2
- CP
Constructional Praxis test
- CR
Constructional Recall test
- DSB
Digit Span Backward test
- DSF
Digit Span Forward test
- FAB
Frontal Assessment Battery
- GDS
Geriatric Depression Scale
- iRBD
isolated rapid eye movement sleep behavior disorder
- MMSE-DS
Mini-Mental State Examination–Dementia Screening
- RBD
rapid eye movement sleep behavior disorder
- RBDQ-HK
REM sleep behavior disorder questionnaire–Hong Kong
- REM
rapid eye movement
- RM ANOVA
repeated measures analysis of variance
- SCWT
Stroop Color and Word Test
- TMT-A
Trail Making Test A
- TMT-B
Trail Making Test B
- WLR
Word List Recall test
DISCLOSURE STATEMENT
All authors have seen and agree with the contents of the paper. Work for this study was performed at Seoul National University Bundang Hospital. This study was funded by a grant (grant no. 02-2019-0039) from the Seoul National University Bundang Hospital (SNUBH) Research Fund, Republic of Korea. The authors report no conflicts of interest.
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