Accepted Manuscript Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial Anthony Lequerica, Ph.D., Neil Jasey, M.D., Jaclyn N. Portelli Tremont, M.A., Nancy D. Chiaravalloti, Ph.D. PII:
S0003-9993(15)00423-2
DOI:
10.1016/j.apmr.2015.05.011
Reference:
YAPMR 56212
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 28 January 2015 Revised Date:
20 May 2015
Accepted Date: 20 May 2015
Please cite this article as: Lequerica A, Jasey N, Portelli Tremont JN, Chiaravalloti ND, Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/j.apmr.2015.05.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 1 Pilot Study on the Effect of Ramelteon on Sleep Disturbance
Anthoy Lequerica, Ph.D. 1,2 Neil Jasey, M.D.3 Jaclyn N. Portelli Tremont, M.A.4 Nancy D. Chiaravalloti, Ph.D.1,2
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After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial
Kessler Foundation, West Orange, NJ
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Rutgers, New Jersey Medical School, Department of Physical Medicine and Rehabilitation
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Kessler Institute for Rehabilitation, West Orange, NJ
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Rutgers Robert Wood Johnson Medical School.
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Please send correspondence and reprint requests to: Anthony Lequerica, Ph.D. Kessler Foundation Traumatic Brain Injury Research 1199 Pleasant Valley Way West Orange, NJ 07052 Phone: 973-324-3551 Email: [email protected]
Acknowledgments: The contents of this article were developed under NJ Commission on Traumatic Brain Injury Research Pilot Grant #10-3222-BIR-E-0. The authors have no conflicts of interest to report.
Counts: Title: 89 characters; Abstract: 227 words; Paper: 3000; References: 39; Tables: 1; Figures: 5
ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 1 Pilot Study on the Effect of Ramelteon on Sleep Disturbance
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After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial
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Abstract Objective: To investigate the effect of ramelteon on sleep and daytime functioning among individuals
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with traumatic brain injury (TBI).
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Design: A double blind placebo controlled study with a cross-over design.
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Setting: A research facility attached to an acute rehabilitation hospital.
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Participants: Individuals with TBI (N=13) complaining of sleep difficulties with a Pittsburgh Sleep
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Quality Index score greater than five.
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Interventions: A nightly dosage of ramelteon (8mg) was given over a period of three weeks.
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Main Outcome Measures: An actigraph and daily sleep log were used to measure sleep/wake patterns
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along with a daily sleep log. Daytime functioning was measured after three weeks of treatment using a
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computer-administrated neuropsychological test battery (CNS Vital Signs software) in conjunction with
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subjective questionnaires measuring mood, daytime sleepiness, and fatigue.
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Results: A significant increase in objectively measured total sleep time and a small increase in sleep
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latency were observed after three weeks of treatment compared with placebo. Treatment also showed a
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significant increase in standardized neuropsychological test scores, with a particular improvement on an
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index of executive functioning.
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Conclusions: Preliminary evidence for the effectiveness of 8mg of ramelteon taken nightly over a three
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week period was found in the treatment of sleep difficulties among individuals with TBI. Improvements
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in total sleep time and some aspects of cognitive functioning are discussed.
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Keywords: traumatic brain injury, sleep, cognition
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Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial Sleep disorders are common following TBI[1], with 30%-70% of persons with TBI reporting difficulty sleeping, many of whom meet DSM-IV criteria for Insomnia Syndrome[2]. Commonly
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reported symptoms of sleep abnormalities include both difficulties with falling asleep (sleep initiation)
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and staying asleep (sleep maintenance)[3-5]. Individuals with TBI who report sleep-wake problems also
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report increased anxiety, depression, and fatigue, which have all been associated with increased
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neurobehavioral and cognitive symptoms and poorer occupational outcomes[3, 5-8]. Whereas
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sleep/wake cycle disorders following TBI have historically been underdiagnosed and undertreated, their
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prevalence and implications for recovery and daily functioning have led to a growing awareness among
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health care providers[9,10].
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Various medications used routinely to treat sleep disturbance carry side effect profiles that can affect cognitive functioning. For example, benzodiazepines can have a lagging effect the day after
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medication administration, causing daytime sedation and anterograde amnesia with adverse effects on
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motor and cognitive functioning[11,12]. Tricyclic antidepressants have been used for sleep induction
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despite their negative impact on cognition and the potential to reduce the seizure threshold[13]. They
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have also been shown to prolong the time it takes from sleep onset to enter into rapid eye movement
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(REM) sleep and suppress REM sleep time, which can potentially interfere with certain types of
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memory consolidation[14-16]. Trazodone, a non-tricyclic antidepressant that is often used for insomnia
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has been shown to interfere with sleep-dependent cortical plasticity[17]. In addition, common
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antihistamines used as sleeping pills tend to result in quick development of tolerance[18]. Some of these
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medications carry abuse potential and physical dependence after prolonged usage.
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Ramelteon (TAK-375), FDA approved for treatment of insomnia with sleep onset abnormalities, is a neurohormone that functions as a melatonin receptor agonist targeting the MT1 and MT2 receptors
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located in the suprachiasmatic nucleus of the hypothalamus[21,22], which regulates the circadian
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rhythm of the 24-hour sleep-wake cycle. It is the only medication indicated for long-term treatment of
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insomnia[19,20].
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Unlike other pharmacologic agents such as the benzodiazepines and opiates typically used for
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insomnia, ramelteon has minimal affinity for the receptor sites responsible for addiction, [21,22]. It is
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the first FDA-approved sleep agent showing no evidence of abuse or dependence[23]. Evidence for
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cognitive impairment on the morning following treatment with ramelteon show conflicting results. Some
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studies show cognitive impairment the morning after treatment[24], while others show no significant
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change[25]. The difference in doses and administration protocols in these studies makes it difficult to
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make accurate comparisons. Although it may seem that there are more studies showing cognitive
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impairment resulting from benzodiazepines, it is important to note that ramelteon is relatively newer
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compared to many other sleep agents. Thus, research on this medication is limited. Ramelteon and its
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metabolites have a rather short elimination half-life of 1-3 hours, on average[26]. To date, there are
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approximately 12 randomized clinical trials investigating the efficacy of ramelteon in treating
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insomnia[20,27-35]. After one week of treatment with ramelteon, eight studies found significant
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reductions in subjective sleep latency[20,27,29-31,34-36], and six found significant increases in total
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time asleep[20,27,30,34-36]. These effects of ramelteon have been shown to continue through the fifth
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week of nightly dosages[25].
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Despite these promising findings, there have been no studies investigating the use of ramelteon
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following TBI. Yet, many clinicians choose this medication as an option to treat sleep disturbance after
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TBI. Clinical trials on the effect of this substance on sleep disorders among individuals with TBI are
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clearly needed to promote evidence-based practice. The current pilot study was designed to fill this void.
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Method
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Participants
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Participants included 18 persons with TBI at least 1 month prior to enrollment. With regard to inclusion criteria, one of more of the following was required: a GCS5
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minutes, post traumatic amnesia>30 minutes, abnormal neuro-imaging findings after TBI and/or
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evidence of neurologic deficit as a result of TBI. Participants were also required to self- or proxy-report
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problems falling or staying asleep or daytime sleepiness or fatigue with onset after TBI.
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Individuals were excluded if screening blood work revealed abnormal levels of liver enzymes or if they were taking luvox or fluvoxamine or other medication that could potentially interact with
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ramelteon. They were also required to be free of all other known hypnotic agents (i.e., benzodiazepines,
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diphendyramine, zolpidem) for at least two weeks prior to enrollment and throughout their study
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participation. Blood oxygen saturation throughout the first night of participation was recorded using
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pulse oximetry. No participants showed any significant decrease in blood oxygen saturation throughout
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the night that could suggest a sleep-related breathing disorder.
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For this preliminary study, an intended sample size of 20 was determined based on the sample sizes of previous studies of individuals with insomnia which showed relatively large effect sizes.
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However, barriers to participation(Figure 1) and other funding restrictions led to ending the trial with a
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sample size of 18. Participants were randomly assigned to Group 1(n=9) or Group 2(n=9), which
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determined the order in which they would take the treatment and placebo. Five participants dropped out
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of the study due to the time commitment and/or transportation issues. One individual withdrew after
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complaints of headache during the placebo phase. The final N was therefore 13(Group 1 n=8, Group 2
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ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 6 n=5). There were no significant differences between the groups in age, gender, education, or time since
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injury. The groups performed similarly on tests of neuropsychological functioning prior to treatment, as
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well as baseline sleep variables and measures of mood (Table 1). Verification of health status, date of
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injury, and injury severity was achieved via medical record review. See Figure 1 for participant flow.
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Table 1 _______________________________
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Using a double blind, placebo-controlled crossover design, participants were randomly assigned to two
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groups through a computerized random number generator. Participants and all study personnel, with the
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exception of the study coordinator preparing the treatment packets, were blinded regarding group
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assignment. Upon consent, all participants were informed that they would be receiving the active
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ramelteon at some point in the study but that they had a 50% chance of being assigned to either group,
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which determined the order of conditions. Random assignment code for one participant was revealed
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when she complained of migraines so that a decision could be made regarding the need to withdraw her
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from participation. This participant was in the placebo group at the time of headache presentation and
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decided to withdraw from the study.
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Measures
ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 7 Actigraph – The actigraph is an electronic device worn on the wrist of the non-dominant hand
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containing an accelerometer designed to measure movement patterns over an extended period of time.
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This instrument has been shown to be useful in evaluating the effectiveness of various treatments for
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insomnia and other circadian rhythm disorders[37]. The actigraph was worn day and night from the day
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of the first visit through the end of the study. At each follow-up visit, the actigraph data was uploaded
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onto a computer while the participant completed a battery of questionnaires. Variables included
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objective measures of Sleep Onset Latency (oSOL), Number of Awakenings (oNWK), Wake Time
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After Sleep Onset (oWASO), and Total Sleep Time (oTST).
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awakenings, subjective sleep quality, and levels of pain and anxiety experienced overnight. Participants
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were encouraged to keep the log at bedside for easy access before bedtime and upon awakening.
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Participants also documented the number of caffeinated beverages consumed each day. Variables
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included subjective measures of Sleep Onset Latency (sSOL), Number of Awakenings (sNWK), Wake
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Time After Sleep Onset (sWASO), and Total Sleep Time (sTST).
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The Pittsburgh Sleep Quality Index (PSQI) – The PSQI was used to measure sleep disturbance at the initial visit. It measures seven major areas: subjective sleep quality, sleep latency, sleep duration,
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habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over
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the last month. Scoring is based on a scale from 0 to 3 where a global sum greater than or equal to 5
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suggests “poor” sleep. The index has been shown to have good psychometric properties[38].
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The Brunel Mood Scale (BRUMS) is a 24-item scale derived from the Profile of Mood
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States[39]. Respondents rate the degree to which they have experienced various moods (i.e., angry,
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energetic, nervous, unhappy) over the past week using a 5-point scale ranging from “0=not at all” to
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“4=extremely.” The sum of the ratings provides scores in 6 domains: anger, confusion, depressed mood,
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fatigue, tension, and vigor. It has been demonstrated as valid in adults[40, 41]. The BRUMS was
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administered at visits 2-5.
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CNS Vital Signs (CNSVS) – This cognitive testing software measured multiple cognitive domains. The Neurocognitive Index consists of the average of five domain scores: Memory,
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Psychomotor Speed, Reaction Time, Complex Attention, and Cognitive Flexibility. These computer-
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administered subtests have been shown to be psychometrically sound and have proven useful in serial
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cognitive testing[42]. CNSVS was administered at visits 2-5.
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Procedure
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The study consisted of five visits over nine weeks (Figure 2). At the initial visit, participants
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completed the PSQI and a demographic questionnaire. They were examined by a physician, a medical
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history was obtained, and blood was drawn to test liver function. Participants were instructed to make
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sleep log entries once each morning when they awoke and in the evening prior to bedtime. They were
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given an actigraph to wear at all times. Following the initial visit, participants began a one-week
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baseline period, which assessed their sleep patterns before treatment. At the second visit, the
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neuropsychological test battery was administered to obtain a baseline. Participants were given a 3-week
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supply of either 8mg of ramelteon or the placebo for Phase 1 and were instructed to take one pill every
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night within 30 minutes of bedtime. At the end of three weeks, participants received a second blood
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draw and began a two-week washout period, in which they did not take either pill. After this,
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participants were given a 3-week supply of either 8mg of ramelteon or the placebo for Phase 2 and
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instructed to take one pill each night 30 minutes before bedtime. Participants returned for the final visit
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three weeks later for an examination by a physician and a final blood draw. The crossover design
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allowed a within-subject analysis in which each person served as his/her own control.
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All study procedures were approved by an institutional review board. Written, informed consent was provided by all participants. Study compliance and adverse events were monitored via telephone
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throughout the study. The clinical trial is registered with clinicaltrials.gov (protocol ID:NCT01207050).
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Results
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Study recruitment ran from June 2010 through June 2013, ending due to the completion of external funding. Actigraph variables were averaged over each week of treatment and entered into a 3(Week) x
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2(Treatment) repeated measures ANOVA. This procedure was repeated for subjective data.
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Total Sleep Time (TST)
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For objective TST (oTST), a significant main effect was found for Treatment [F(1,12)=10.67,
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p=0.007,ηp²=0.47] with a significant Treatment x Week interaction [F(2,24)=6.55, p=0.025,ηp²=0.35].
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The main effect for Week was not significant. oTST was significantly greater after Ramelteon compared
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with placebo (Figure 3).
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Post hoc analyses using a Bonferoni correction (p < 0.020) showed the maximum benefit to be at the
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third measurement interval where a significant difference was noted between ramelteon and placebo,
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F(1,12)=9.80, p=0.009,ηp²=0.45. The ANOVA on the subjective TST (sTST) showed no significant
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main effects or interactions, yielding small effect sizes.
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Sleep Onset Latency (SOL)
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For objective SOL (oSOL), significant main effects were noted for Treatment [F(1,12)=9.95,
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p=0.008,ηp²=0.45] and Week [F(2,24)=12.31, p=0.004,ηp²=0.51] with no significant interaction. The
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direction of the Treatment effect was contrary to what has been reported in the literature (Figure 4).
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After the third week on ramelteon, oSOL had increased by just under 5 minutes compared with placebo.
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No significant main effects or interactions were noted for the sSOL, but the effect size for the
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main effect of treatment was large ηp²=0.17, suggesting that a significant effect may be detected with a
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larger sample size (Figure 4).
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Figure 3 About Here ______________________________________
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Carryover Effects for Objective Total Sleep Time and Objective Sleep Onset Latency The difference between effects for each treatment period was assessed with a standard t-test for independent samples using the intra-individual differences between the degree of change between
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conditions for those who received ramelteon before placebo compared with those who received placebo
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before ramelteon. There were no significant differences for oSOL (t=0.06, df=11, p=0.953), nor for
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oTST (t=1.29, df=11, p=0.225). Carryover was also evaluated by insuring the values after the two week
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washout period had returned to baseline levels within the group that received the ramelteon before
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placebo. Using a t-test, this group (n=8) showed no significant differences between baseline values and
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values post-washout period for oSOL (t=-1.06, df=7, p=0.324, nor for oTST (t=0.79, df=7, 0.455). And
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the change from baseline to post washout in this group was comparable to that of the group receiving
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placebo during the same period for oSOL (t=0.08, df=11, p=0.937) and for oTST (t=-0.13, df=11,
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p=0.900).
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Cognitive Functioning
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ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 11 CNSVS cognitive battery was administered multiple times throughout this study. Although the software
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generated alternate versions for each re-testing, participants tended to show an improvement with
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repeated administration. A learning estimate was calculated by subtracting the baseline score (first
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administration) from scores after the washout period (third administration). This showed that
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participants tended to show an average increase in score of approximately six points with no significant
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effect of order of conditions. To control for practice effects, this learning estimate was used as a
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covariate in a repeated measures ANCOVA to evaluate change in cognitive performance as a result of
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treatment. Significant improvement was noted after three weeks on ramelteon compared with placebo
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on the CNSVS neurocognitive index [F(1,10)=7.92, p=0.018,ηp²=0.44] and on the executive functioning
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score [F(1,10)=13.43, p=0.004,ηp²=0.57]. Reaction time [F(1,10)=4.47, p=0.061,ηp²=0.31] and complex
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attention [F(1,10)=2.41, p=0.152,ηp²=0.19] showed a marginally significant effect of ramelteon (Figure
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5). Although none of the other subtests showed any significant change after treatment, it is important to
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note that in 75% of the subscores, the increase in performance while on ramelteon improved the clinical
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impairment category of the participant. For example, after three weeks of treatment with ramelteon,
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memory scores increased from the impaired range to borderline range, psychomotor speed improved
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from the borderline to low average range, and cognitive flexibility improved from the low average to
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average range. These are clinically significant improvements in cognition as categorized by common
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neuropsychological levels of functioning.
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Discussion
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minutes prior to bedtime for three weeks. Average maximum effectiveness was reached after the first
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week of treatment. This is consistent with the literature in non-TBI insomniacs, both in the direction and
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timing of the effect[20,25,27,30,34-36]. Participants tolerated treatment well without serious side effects
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and experienced an improvement in cognitive functioning after 3 weeks of treatment, most notable on a
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composite cognitive index and a measure of executive functioning.
The decrease in subjective sleep latency was similar in direction to values reported in the
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literature, but did not reach significance in this current sample and did not yield a large effect size. In
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contrast, oSOL while showing significant variability across days, showed a statistically significant
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increase on ramelteon that has not been shown in other studies. It is not clear why it took participants
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longer to fall asleep on ramelteon. First, the delay of sleep onset was no more than 5 minutes and did not
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reach this magnitude until week 3 of treatment. This additional time to fall asleep did not appear to be
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clinically significant and did not detract from the overall effect of ramelteon on total sleep time. Second,
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individuals with TBI may respond differently to this medication than healthy persons. It should be noted
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that most participants had at least one week where their oSOL was lower on ramelteon, and 9
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participants (almost 70%) experienced at least 1 week with shorter oSOL on ramelteon. The greatest
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mean increase in oSOL was less than a 5-minute difference from the mean oSOL on placebo.
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of 13 participants had an earlier bedtime when taking ramelteon. Of the four who did not show this
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trend, three were individuals who did not show the anticipated response to the treatment in total sleep
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time. Most individuals who responded to the drug as expected (increased TST), tended to go to bed at an
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earlier time while on ramelteon compared with placebo. This alteration of bedtime may be due to the
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drug’s mechanism of action through the regulation of the sleep/wake circadian rhythm.
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Limitations and Future Directions Although this study was somewhat limited in respect to sample size, the main effects were robust to the point where significant findings were detectable. The crossover design, used in other ramelteon
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studies[21,24,36], was employed here to maximize power in a small sample. Although the positive
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findings are relatively robust, marginally significant and nonsignificant findings with medium to large
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effect sizes may require more power to detect the differences through use of a larger sample. In addition,
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as a pilot study, the difficulties with participant recruitment were informative so that barriers to research
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participation can be considered and rectified in future studies. One of the biggest barriers, aside from not
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wanting to take prescription medication for sleep, was the unwillingness to discontinue sleep
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medications currently being used. The two-week pre-baseline washout period, in addition to the nine
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weeks of the study added up to over two months without their usual sleep aid. Future studies may have
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greater success by recruiting potential participants who have more recent injuries or are seeking
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treatment for their sleep difficulties for the first time.
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Ramelteon has been shown to impact clock gene expression in parncreatic cells leading to changes in glucose metabolism even after agonist washout. This raises questions regarding the proper
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amount of time between treatments in the crossover paradigm to avoid carryover effects. Ramelteon
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studies have used washout periods ranging from 3 days to greater than one week[21,24]. The present
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study used a conservative duration of two weeks and did not find evidence of carryover with respect to
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the sleep-related variables of oTST and oSOL. However, additional research with physiological
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variables would be needed to rule out neurochemical or other signs of carryover that are not readily
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expressed behaviorally.
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An additional limitation in the current study was that the information gathered via actigraphy can
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in no way be equated with polysomnography that has the capability of greater accuracy through utility of
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multiple types of data (i.e., EEG, EOG, EMG, EKG) that can also provide information about the
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distribution of various sleep stages throughout the night.
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Clinical considerations should be addressed in future studies. For example, the finding that at least one week of nightly treatment was necessary before any effect was observed should be considered
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when prescribing this medication for inpatients at the acute rehabilitation stage of recovery. Patients
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might ideally be started on ramelteon while at the end of their acute care stay so that they may be
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functioning at their best by the time they reach the rehabilitation setting in order to maximize the impact
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of rehabilitation therapies.
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examine whether the large effect sizes observed here in the absence of statistical significance are
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reliable. Extending the observation period for the group receiving ramelteon during the final treatment
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period could provide additional information after treatment is discontinued so that carryover effects can
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be more thoroughly studied. Information could also be gathered at the end of the trial regarding
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subjective opinions about their experience on the active drug and desire to continue its use. In addition,
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measures that capture the impact of improved cognition on daily functioning are recommended to
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understand how treatment affects social engagement, productivity, and community participation.
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Conclusions
Ramelteon may be a viable treatment option for the treatment of sleep-wake disturbance among
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individuals with TBI. Effects on sleep within this population appear to occur after one week of nightly
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use. This pilot study provides preliminary evidence that sleep related changes from ramelteon may result
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in improved cognitive functioning after three weeks of treatment. Additional studies with larger sample
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sizes are needed to replicate the current findings and perhaps extend to examine how ramelteon may
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affect the distribution of sleep stages among individuals with TBI who have sleep-wake disturbances.
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Table 1. Sample characteristics BRUMS = Brunel Mood Scale, CNSVS = CNS Vital Signs© 2003–2014
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Note : All comparisons between groups at baseline were non-significant
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Figure 1. Participant Flow
474 Figure 2. Study protocol broken down by phase and visit number.
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Note: The study pill was either ramelteon or a placebo, which was determined by their
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randomization number. During the baseline and washout period, participants did not receive
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either study pill.
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Figure 3. Objective Total Sleep Time as a Function of Treatment with Ramelteon.
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Figure 4. Objective Sleep Onset Latency as a Function of Treatment with Ramelteon
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Figure 5. Estimated Marginal Means for Cognitive Test Scores Note: Domains labeled A though D yielded large effect sizes but only A and B showed a significant
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improvement after 3 weeks of treatment with ramelteon. nci=neurocognitive index, ca=complex
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attention, cf=cognitive flexibility, ef=executive functioning, pmrs=psychomotor speed, ps=processing
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speed, rt=reaction time, mem=memory
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M
SD
Placebo First (n=5) M
45.3
19.7
38.2
Years of Education
13.5
2.4
16.0
Time Post Injury (months)
61.1
102.5
63.6
Pittsburgh Sleep Quality Index
12.3
3.6
11.6
Objective Sleep Latency (min)
3.6
2.3
Subjective Sleep Latency (min)
39.2
22.5
M
SD
14.8
42.5
17.7
3.2
14.5
2.9
82.0
62.1
91.5
4.4
12.0
3.7
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Age
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Total (N=13)
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3.5
1.9
23.7
9.8
33.2
19.7
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Objective Total Sleep Time (min)
473.4
99.2
432.5
99.6
457.7
97.4
Subjective Total Sleep Time (min)
418.3
111.3
416.4
126.1
417.6
111.9
6.3
5.8
8.0
2.7
6.9
4.8
6.3
4.3
7.6
3.7
6.8
4.0
6.3
5.4
9.6
4.9
7.5
5.3
8.6
3.6
9.2
4.5
8.9
3.8
6.6
6.7
9.4
5.0
7.7
6.0
4.4
1.6
4.8
4.1
4.5
2.7
75.8
11.4
73.2
39.0
74.8
24.2
BRUMS: Anger BRUMS: Confusion
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CNSVS Neurocognitive Index
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count
%
count
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Mild
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50.0
3
60.0
7
53.8
Moderate-Severe
4
50.0
2
40.0
6
46.2
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BRUMS = Brunel Mood Scale, CNSVS = CNS Vital Signs© 2003–2014 Note : All comparisons between groups at baseline were non-significant
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Figure 2. Study protocol broken down by phase and visit number.
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Figure 4. Objective Sleep Onset Latency as a Function of Treatment with Ramelteon
Figure 5. Estimated Marginal Means for Cognitive Test Scores
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S0003-9993(15)00423-2
DOI:
10.1016/j.apmr.2015.05.011
Reference:
YAPMR 56212
To appear in:
ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION
Received Date: 28 January 2015 Revised Date:
20 May 2015
Accepted Date: 20 May 2015
Please cite this article as: Lequerica A, Jasey N, Portelli Tremont JN, Chiaravalloti ND, Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial, ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION (2015), doi: 10.1016/j.apmr.2015.05.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 1 Pilot Study on the Effect of Ramelteon on Sleep Disturbance
Anthoy Lequerica, Ph.D. 1,2 Neil Jasey, M.D.3 Jaclyn N. Portelli Tremont, M.A.4 Nancy D. Chiaravalloti, Ph.D.1,2
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After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial
Kessler Foundation, West Orange, NJ
2
Rutgers, New Jersey Medical School, Department of Physical Medicine and Rehabilitation
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Kessler Institute for Rehabilitation, West Orange, NJ
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Rutgers Robert Wood Johnson Medical School.
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Please send correspondence and reprint requests to: Anthony Lequerica, Ph.D. Kessler Foundation Traumatic Brain Injury Research 1199 Pleasant Valley Way West Orange, NJ 07052 Phone: 973-324-3551 Email: [email protected]
Acknowledgments: The contents of this article were developed under NJ Commission on Traumatic Brain Injury Research Pilot Grant #10-3222-BIR-E-0. The authors have no conflicts of interest to report.
Counts: Title: 89 characters; Abstract: 227 words; Paper: 3000; References: 39; Tables: 1; Figures: 5
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After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial
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Abstract Objective: To investigate the effect of ramelteon on sleep and daytime functioning among individuals
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with traumatic brain injury (TBI).
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Design: A double blind placebo controlled study with a cross-over design.
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Setting: A research facility attached to an acute rehabilitation hospital.
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Participants: Individuals with TBI (N=13) complaining of sleep difficulties with a Pittsburgh Sleep
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Quality Index score greater than five.
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Interventions: A nightly dosage of ramelteon (8mg) was given over a period of three weeks.
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Main Outcome Measures: An actigraph and daily sleep log were used to measure sleep/wake patterns
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along with a daily sleep log. Daytime functioning was measured after three weeks of treatment using a
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computer-administrated neuropsychological test battery (CNS Vital Signs software) in conjunction with
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subjective questionnaires measuring mood, daytime sleepiness, and fatigue.
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Results: A significant increase in objectively measured total sleep time and a small increase in sleep
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latency were observed after three weeks of treatment compared with placebo. Treatment also showed a
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significant increase in standardized neuropsychological test scores, with a particular improvement on an
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index of executive functioning.
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Conclusions: Preliminary evidence for the effectiveness of 8mg of ramelteon taken nightly over a three
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week period was found in the treatment of sleep difficulties among individuals with TBI. Improvements
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in total sleep time and some aspects of cognitive functioning are discussed.
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Keywords: traumatic brain injury, sleep, cognition
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Pilot Study on the Effect of Ramelteon on Sleep Disturbance After Traumatic Brain Injury (TBI): Preliminary Evidence from a Clinical Trial Sleep disorders are common following TBI[1], with 30%-70% of persons with TBI reporting difficulty sleeping, many of whom meet DSM-IV criteria for Insomnia Syndrome[2]. Commonly
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reported symptoms of sleep abnormalities include both difficulties with falling asleep (sleep initiation)
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and staying asleep (sleep maintenance)[3-5]. Individuals with TBI who report sleep-wake problems also
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report increased anxiety, depression, and fatigue, which have all been associated with increased
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neurobehavioral and cognitive symptoms and poorer occupational outcomes[3, 5-8]. Whereas
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sleep/wake cycle disorders following TBI have historically been underdiagnosed and undertreated, their
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prevalence and implications for recovery and daily functioning have led to a growing awareness among
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health care providers[9,10].
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Various medications used routinely to treat sleep disturbance carry side effect profiles that can affect cognitive functioning. For example, benzodiazepines can have a lagging effect the day after
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medication administration, causing daytime sedation and anterograde amnesia with adverse effects on
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motor and cognitive functioning[11,12]. Tricyclic antidepressants have been used for sleep induction
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despite their negative impact on cognition and the potential to reduce the seizure threshold[13]. They
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have also been shown to prolong the time it takes from sleep onset to enter into rapid eye movement
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(REM) sleep and suppress REM sleep time, which can potentially interfere with certain types of
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memory consolidation[14-16]. Trazodone, a non-tricyclic antidepressant that is often used for insomnia
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has been shown to interfere with sleep-dependent cortical plasticity[17]. In addition, common
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antihistamines used as sleeping pills tend to result in quick development of tolerance[18]. Some of these
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medications carry abuse potential and physical dependence after prolonged usage.
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Ramelteon (TAK-375), FDA approved for treatment of insomnia with sleep onset abnormalities, is a neurohormone that functions as a melatonin receptor agonist targeting the MT1 and MT2 receptors
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located in the suprachiasmatic nucleus of the hypothalamus[21,22], which regulates the circadian
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rhythm of the 24-hour sleep-wake cycle. It is the only medication indicated for long-term treatment of
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insomnia[19,20].
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Unlike other pharmacologic agents such as the benzodiazepines and opiates typically used for
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insomnia, ramelteon has minimal affinity for the receptor sites responsible for addiction, [21,22]. It is
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the first FDA-approved sleep agent showing no evidence of abuse or dependence[23]. Evidence for
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cognitive impairment on the morning following treatment with ramelteon show conflicting results. Some
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studies show cognitive impairment the morning after treatment[24], while others show no significant
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change[25]. The difference in doses and administration protocols in these studies makes it difficult to
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make accurate comparisons. Although it may seem that there are more studies showing cognitive
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impairment resulting from benzodiazepines, it is important to note that ramelteon is relatively newer
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compared to many other sleep agents. Thus, research on this medication is limited. Ramelteon and its
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metabolites have a rather short elimination half-life of 1-3 hours, on average[26]. To date, there are
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approximately 12 randomized clinical trials investigating the efficacy of ramelteon in treating
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insomnia[20,27-35]. After one week of treatment with ramelteon, eight studies found significant
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reductions in subjective sleep latency[20,27,29-31,34-36], and six found significant increases in total
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time asleep[20,27,30,34-36]. These effects of ramelteon have been shown to continue through the fifth
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week of nightly dosages[25].
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Despite these promising findings, there have been no studies investigating the use of ramelteon
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following TBI. Yet, many clinicians choose this medication as an option to treat sleep disturbance after
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TBI. Clinical trials on the effect of this substance on sleep disorders among individuals with TBI are
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clearly needed to promote evidence-based practice. The current pilot study was designed to fill this void.
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Method
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Participants
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Participants included 18 persons with TBI at least 1 month prior to enrollment. With regard to inclusion criteria, one of more of the following was required: a GCS5
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minutes, post traumatic amnesia>30 minutes, abnormal neuro-imaging findings after TBI and/or
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evidence of neurologic deficit as a result of TBI. Participants were also required to self- or proxy-report
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problems falling or staying asleep or daytime sleepiness or fatigue with onset after TBI.
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Individuals were excluded if screening blood work revealed abnormal levels of liver enzymes or if they were taking luvox or fluvoxamine or other medication that could potentially interact with
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ramelteon. They were also required to be free of all other known hypnotic agents (i.e., benzodiazepines,
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diphendyramine, zolpidem) for at least two weeks prior to enrollment and throughout their study
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participation. Blood oxygen saturation throughout the first night of participation was recorded using
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pulse oximetry. No participants showed any significant decrease in blood oxygen saturation throughout
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the night that could suggest a sleep-related breathing disorder.
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However, barriers to participation(Figure 1) and other funding restrictions led to ending the trial with a
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sample size of 18. Participants were randomly assigned to Group 1(n=9) or Group 2(n=9), which
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determined the order in which they would take the treatment and placebo. Five participants dropped out
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of the study due to the time commitment and/or transportation issues. One individual withdrew after
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complaints of headache during the placebo phase. The final N was therefore 13(Group 1 n=8, Group 2
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injury. The groups performed similarly on tests of neuropsychological functioning prior to treatment, as
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well as baseline sleep variables and measures of mood (Table 1). Verification of health status, date of
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injury, and injury severity was achieved via medical record review. See Figure 1 for participant flow.
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Figure 1 _______________________________ Design.
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Using a double blind, placebo-controlled crossover design, participants were randomly assigned to two
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groups through a computerized random number generator. Participants and all study personnel, with the
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exception of the study coordinator preparing the treatment packets, were blinded regarding group
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assignment. Upon consent, all participants were informed that they would be receiving the active
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ramelteon at some point in the study but that they had a 50% chance of being assigned to either group,
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which determined the order of conditions. Random assignment code for one participant was revealed
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when she complained of migraines so that a decision could be made regarding the need to withdraw her
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from participation. This participant was in the placebo group at the time of headache presentation and
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decided to withdraw from the study.
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_____________________________ Figure 2 _____________________________
Measures
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containing an accelerometer designed to measure movement patterns over an extended period of time.
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This instrument has been shown to be useful in evaluating the effectiveness of various treatments for
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insomnia and other circadian rhythm disorders[37]. The actigraph was worn day and night from the day
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of the first visit through the end of the study. At each follow-up visit, the actigraph data was uploaded
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onto a computer while the participant completed a battery of questionnaires. Variables included
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objective measures of Sleep Onset Latency (oSOL), Number of Awakenings (oNWK), Wake Time
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After Sleep Onset (oWASO), and Total Sleep Time (oTST).
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Sleep Log – A sleep log recorded the participant’s reported bedtime, wake-up time, number of
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awakenings, subjective sleep quality, and levels of pain and anxiety experienced overnight. Participants
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were encouraged to keep the log at bedside for easy access before bedtime and upon awakening.
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Participants also documented the number of caffeinated beverages consumed each day. Variables
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included subjective measures of Sleep Onset Latency (sSOL), Number of Awakenings (sNWK), Wake
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Time After Sleep Onset (sWASO), and Total Sleep Time (sTST).
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The Pittsburgh Sleep Quality Index (PSQI) – The PSQI was used to measure sleep disturbance at the initial visit. It measures seven major areas: subjective sleep quality, sleep latency, sleep duration,
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habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction over
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the last month. Scoring is based on a scale from 0 to 3 where a global sum greater than or equal to 5
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suggests “poor” sleep. The index has been shown to have good psychometric properties[38].
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States[39]. Respondents rate the degree to which they have experienced various moods (i.e., angry,
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energetic, nervous, unhappy) over the past week using a 5-point scale ranging from “0=not at all” to
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“4=extremely.” The sum of the ratings provides scores in 6 domains: anger, confusion, depressed mood,
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fatigue, tension, and vigor. It has been demonstrated as valid in adults[40, 41]. The BRUMS was
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administered at visits 2-5.
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CNS Vital Signs (CNSVS) – This cognitive testing software measured multiple cognitive domains. The Neurocognitive Index consists of the average of five domain scores: Memory,
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Psychomotor Speed, Reaction Time, Complex Attention, and Cognitive Flexibility. These computer-
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administered subtests have been shown to be psychometrically sound and have proven useful in serial
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cognitive testing[42]. CNSVS was administered at visits 2-5.
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Procedure
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completed the PSQI and a demographic questionnaire. They were examined by a physician, a medical
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history was obtained, and blood was drawn to test liver function. Participants were instructed to make
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sleep log entries once each morning when they awoke and in the evening prior to bedtime. They were
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given an actigraph to wear at all times. Following the initial visit, participants began a one-week
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baseline period, which assessed their sleep patterns before treatment. At the second visit, the
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neuropsychological test battery was administered to obtain a baseline. Participants were given a 3-week
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supply of either 8mg of ramelteon or the placebo for Phase 1 and were instructed to take one pill every
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night within 30 minutes of bedtime. At the end of three weeks, participants received a second blood
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draw and began a two-week washout period, in which they did not take either pill. After this,
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participants were given a 3-week supply of either 8mg of ramelteon or the placebo for Phase 2 and
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instructed to take one pill each night 30 minutes before bedtime. Participants returned for the final visit
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three weeks later for an examination by a physician and a final blood draw. The crossover design
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allowed a within-subject analysis in which each person served as his/her own control.
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All study procedures were approved by an institutional review board. Written, informed consent was provided by all participants. Study compliance and adverse events were monitored via telephone
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throughout the study. The clinical trial is registered with clinicaltrials.gov (protocol ID:NCT01207050).
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Results
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Study recruitment ran from June 2010 through June 2013, ending due to the completion of external funding. Actigraph variables were averaged over each week of treatment and entered into a 3(Week) x
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2(Treatment) repeated measures ANOVA. This procedure was repeated for subjective data.
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Total Sleep Time (TST)
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For objective TST (oTST), a significant main effect was found for Treatment [F(1,12)=10.67,
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p=0.007,ηp²=0.47] with a significant Treatment x Week interaction [F(2,24)=6.55, p=0.025,ηp²=0.35].
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The main effect for Week was not significant. oTST was significantly greater after Ramelteon compared
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with placebo (Figure 3).
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Post hoc analyses using a Bonferoni correction (p < 0.020) showed the maximum benefit to be at the
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third measurement interval where a significant difference was noted between ramelteon and placebo,
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F(1,12)=9.80, p=0.009,ηp²=0.45. The ANOVA on the subjective TST (sTST) showed no significant
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main effects or interactions, yielding small effect sizes.
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Sleep Onset Latency (SOL)
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For objective SOL (oSOL), significant main effects were noted for Treatment [F(1,12)=9.95,
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p=0.008,ηp²=0.45] and Week [F(2,24)=12.31, p=0.004,ηp²=0.51] with no significant interaction. The
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direction of the Treatment effect was contrary to what has been reported in the literature (Figure 4).
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After the third week on ramelteon, oSOL had increased by just under 5 minutes compared with placebo.
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No significant main effects or interactions were noted for the sSOL, but the effect size for the
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main effect of treatment was large ηp²=0.17, suggesting that a significant effect may be detected with a
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larger sample size (Figure 4).
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Figure 3 About Here ______________________________________
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Carryover Effects for Objective Total Sleep Time and Objective Sleep Onset Latency The difference between effects for each treatment period was assessed with a standard t-test for independent samples using the intra-individual differences between the degree of change between
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conditions for those who received ramelteon before placebo compared with those who received placebo
249
before ramelteon. There were no significant differences for oSOL (t=0.06, df=11, p=0.953), nor for
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oTST (t=1.29, df=11, p=0.225). Carryover was also evaluated by insuring the values after the two week
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washout period had returned to baseline levels within the group that received the ramelteon before
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placebo. Using a t-test, this group (n=8) showed no significant differences between baseline values and
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values post-washout period for oSOL (t=-1.06, df=7, p=0.324, nor for oTST (t=0.79, df=7, 0.455). And
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the change from baseline to post washout in this group was comparable to that of the group receiving
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placebo during the same period for oSOL (t=0.08, df=11, p=0.937) and for oTST (t=-0.13, df=11,
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p=0.900).
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Cognitive Functioning
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ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 11 CNSVS cognitive battery was administered multiple times throughout this study. Although the software
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generated alternate versions for each re-testing, participants tended to show an improvement with
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repeated administration. A learning estimate was calculated by subtracting the baseline score (first
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administration) from scores after the washout period (third administration). This showed that
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participants tended to show an average increase in score of approximately six points with no significant
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effect of order of conditions. To control for practice effects, this learning estimate was used as a
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covariate in a repeated measures ANCOVA to evaluate change in cognitive performance as a result of
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treatment. Significant improvement was noted after three weeks on ramelteon compared with placebo
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on the CNSVS neurocognitive index [F(1,10)=7.92, p=0.018,ηp²=0.44] and on the executive functioning
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score [F(1,10)=13.43, p=0.004,ηp²=0.57]. Reaction time [F(1,10)=4.47, p=0.061,ηp²=0.31] and complex
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attention [F(1,10)=2.41, p=0.152,ηp²=0.19] showed a marginally significant effect of ramelteon (Figure
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5). Although none of the other subtests showed any significant change after treatment, it is important to
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note that in 75% of the subscores, the increase in performance while on ramelteon improved the clinical
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impairment category of the participant. For example, after three weeks of treatment with ramelteon,
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memory scores increased from the impaired range to borderline range, psychomotor speed improved
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from the borderline to low average range, and cognitive flexibility improved from the low average to
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average range. These are clinically significant improvements in cognition as categorized by common
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neuropsychological levels of functioning.
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Discussion
ACCEPTED MANUSCRIPT Ramelteon and Sleep in Brain Injury 12 The current study showed a significant increase in total sleep time when 8mg of ramelteon was taken 30
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minutes prior to bedtime for three weeks. Average maximum effectiveness was reached after the first
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week of treatment. This is consistent with the literature in non-TBI insomniacs, both in the direction and
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timing of the effect[20,25,27,30,34-36]. Participants tolerated treatment well without serious side effects
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and experienced an improvement in cognitive functioning after 3 weeks of treatment, most notable on a
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composite cognitive index and a measure of executive functioning.
The decrease in subjective sleep latency was similar in direction to values reported in the
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literature, but did not reach significance in this current sample and did not yield a large effect size. In
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contrast, oSOL while showing significant variability across days, showed a statistically significant
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increase on ramelteon that has not been shown in other studies. It is not clear why it took participants
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longer to fall asleep on ramelteon. First, the delay of sleep onset was no more than 5 minutes and did not
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reach this magnitude until week 3 of treatment. This additional time to fall asleep did not appear to be
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clinically significant and did not detract from the overall effect of ramelteon on total sleep time. Second,
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individuals with TBI may respond differently to this medication than healthy persons. It should be noted
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that most participants had at least one week where their oSOL was lower on ramelteon, and 9
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participants (almost 70%) experienced at least 1 week with shorter oSOL on ramelteon. The greatest
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mean increase in oSOL was less than a 5-minute difference from the mean oSOL on placebo.
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of 13 participants had an earlier bedtime when taking ramelteon. Of the four who did not show this
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trend, three were individuals who did not show the anticipated response to the treatment in total sleep
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time. Most individuals who responded to the drug as expected (increased TST), tended to go to bed at an
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earlier time while on ramelteon compared with placebo. This alteration of bedtime may be due to the
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drug’s mechanism of action through the regulation of the sleep/wake circadian rhythm.
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Limitations and Future Directions Although this study was somewhat limited in respect to sample size, the main effects were robust to the point where significant findings were detectable. The crossover design, used in other ramelteon
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studies[21,24,36], was employed here to maximize power in a small sample. Although the positive
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findings are relatively robust, marginally significant and nonsignificant findings with medium to large
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effect sizes may require more power to detect the differences through use of a larger sample. In addition,
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as a pilot study, the difficulties with participant recruitment were informative so that barriers to research
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participation can be considered and rectified in future studies. One of the biggest barriers, aside from not
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wanting to take prescription medication for sleep, was the unwillingness to discontinue sleep
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medications currently being used. The two-week pre-baseline washout period, in addition to the nine
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weeks of the study added up to over two months without their usual sleep aid. Future studies may have
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greater success by recruiting potential participants who have more recent injuries or are seeking
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treatment for their sleep difficulties for the first time.
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Ramelteon has been shown to impact clock gene expression in parncreatic cells leading to changes in glucose metabolism even after agonist washout. This raises questions regarding the proper
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amount of time between treatments in the crossover paradigm to avoid carryover effects. Ramelteon
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studies have used washout periods ranging from 3 days to greater than one week[21,24]. The present
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study used a conservative duration of two weeks and did not find evidence of carryover with respect to
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the sleep-related variables of oTST and oSOL. However, additional research with physiological
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variables would be needed to rule out neurochemical or other signs of carryover that are not readily
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expressed behaviorally.
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An additional limitation in the current study was that the information gathered via actigraphy can
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in no way be equated with polysomnography that has the capability of greater accuracy through utility of
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multiple types of data (i.e., EEG, EOG, EMG, EKG) that can also provide information about the
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distribution of various sleep stages throughout the night.
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Clinical considerations should be addressed in future studies. For example, the finding that at least one week of nightly treatment was necessary before any effect was observed should be considered
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when prescribing this medication for inpatients at the acute rehabilitation stage of recovery. Patients
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might ideally be started on ramelteon while at the end of their acute care stay so that they may be
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functioning at their best by the time they reach the rehabilitation setting in order to maximize the impact
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of rehabilitation therapies.
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Additional research is needed with larger sample sizes to replicate the current findings and
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examine whether the large effect sizes observed here in the absence of statistical significance are
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reliable. Extending the observation period for the group receiving ramelteon during the final treatment
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period could provide additional information after treatment is discontinued so that carryover effects can
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be more thoroughly studied. Information could also be gathered at the end of the trial regarding
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subjective opinions about their experience on the active drug and desire to continue its use. In addition,
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measures that capture the impact of improved cognition on daily functioning are recommended to
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understand how treatment affects social engagement, productivity, and community participation.
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Conclusions
Ramelteon may be a viable treatment option for the treatment of sleep-wake disturbance among
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individuals with TBI. Effects on sleep within this population appear to occur after one week of nightly
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use. This pilot study provides preliminary evidence that sleep related changes from ramelteon may result
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in improved cognitive functioning after three weeks of treatment. Additional studies with larger sample
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sizes are needed to replicate the current findings and perhaps extend to examine how ramelteon may
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affect the distribution of sleep stages among individuals with TBI who have sleep-wake disturbances.
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Table 1. Sample characteristics BRUMS = Brunel Mood Scale, CNSVS = CNS Vital Signs© 2003–2014
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Note : All comparisons between groups at baseline were non-significant
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Figure 1. Participant Flow
474 Figure 2. Study protocol broken down by phase and visit number.
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Note: The study pill was either ramelteon or a placebo, which was determined by their
477
randomization number. During the baseline and washout period, participants did not receive
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either study pill.
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Figure 3. Objective Total Sleep Time as a Function of Treatment with Ramelteon.
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Figure 5. Estimated Marginal Means for Cognitive Test Scores Note: Domains labeled A though D yielded large effect sizes but only A and B showed a significant
486
improvement after 3 weeks of treatment with ramelteon. nci=neurocognitive index, ca=complex
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attention, cf=cognitive flexibility, ef=executive functioning, pmrs=psychomotor speed, ps=processing
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M
SD
Placebo First (n=5) M
45.3
19.7
38.2
Years of Education
13.5
2.4
16.0
Time Post Injury (months)
61.1
102.5
63.6
Pittsburgh Sleep Quality Index
12.3
3.6
11.6
Objective Sleep Latency (min)
3.6
2.3
Subjective Sleep Latency (min)
39.2
22.5
M
SD
14.8
42.5
17.7
3.2
14.5
2.9
82.0
62.1
91.5
4.4
12.0
3.7
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Age
SD
Total (N=13)
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3.5
1.9
23.7
9.8
33.2
19.7
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Objective Total Sleep Time (min)
473.4
99.2
432.5
99.6
457.7
97.4
Subjective Total Sleep Time (min)
418.3
111.3
416.4
126.1
417.6
111.9
6.3
5.8
8.0
2.7
6.9
4.8
6.3
4.3
7.6
3.7
6.8
4.0
6.3
5.4
9.6
4.9
7.5
5.3
8.6
3.6
9.2
4.5
8.9
3.8
6.6
6.7
9.4
5.0
7.7
6.0
4.4
1.6
4.8
4.1
4.5
2.7
75.8
11.4
73.2
39.0
74.8
24.2
BRUMS: Anger BRUMS: Confusion
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CNSVS Neurocognitive Index
count
%
count
%
count
%
Mild
4
50.0
3
60.0
7
53.8
Moderate-Severe
4
50.0
2
40.0
6
46.2
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BRUMS = Brunel Mood Scale, CNSVS = CNS Vital Signs© 2003–2014 Note : All comparisons between groups at baseline were non-significant
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Figure 2. Study protocol broken down by phase and visit number.
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Figure 4. Objective Sleep Onset Latency as a Function of Treatment with Ramelteon
Figure 5. Estimated Marginal Means for Cognitive Test Scores
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