McElroy, Susan L.a; Winstanley, Erin L.a; Martens, Briana; Patel, Nick C.b; Mori, Nicolea; Moeller, Diannaa; McCoy, Jessicaa; Keck, Paul E.a
Bipolar disorder is usually characterized by sleep disturbance (Harvey, 2008; Plante and Winkelman, 2008). Such sleep disturbance typically manifests as hyposomnia (reduced need for sleep) during manic and mixed episodes and hyposomnia (insomnia) or hypersomnia during depressive episodes (Harvey, 2008). In addition, sleep may be impaired during the interepisode period and often worsens just before an episode (Harvey, 2008). For example, Harvey et al. (2005) reported that 70% of euthymic bipolar patients reported significant sleep disturbance, and 55% met diagnostic criteria for insomnia.
As sleep disturbance is a core feature of bipolar disorder, and because diurnal rhythm abnormalities occur in bodily functions other than sleep in bipolar disorder, it has been hypothesized that sleep dysfunction and circadian rhythm instability may play a pathogenic role in the illness (Dallaspezia and Benedetti, 2009). Support for this possibility comes from findings that genetic variants in some (though not all) clock genes may be associated with bipolar disorder (Harvey, 2008; Dallaspezia and Benedetti, 2009); sleep loss may be a final common pathway for mania induction (Wehr et al., 1987); and dark therapy may be effective for mania (Barbini et al., 2005).
Melatonin induces circadian-related and sleep-related responses (Arendt and Rajaratnam, 2008; Zawilska et al., 2009). It acts on the central circadian clock to affect the timing of endogenous rhythms under the clock's control, has sleep-promoting properties in day-active animals and humans, and may be effective in primary insomnia and some circadian rhythm sleep disorders (Zawilska et al., 2009; Ferguson et al., 2010). Melatonin secretion abnormalities have been found in patients with bipolar I disorder (Kennedy et al., 1996; Nurnberger et al., 2000). Therefore, in bipolar patients with sleep disruption, the administration of melatonin or an agent that acts in a similar manner (e.g. a melatonin agonist) may be of clinical benefit.
Clinical studies of melatonin in bipolar disorder, however, have been inconsistent. In one 12-week trial in five patients with rapid-cycling bipolar disorder, melatonin had no positive effects on mood or sleep (Leibenluft et al., 1997). Moreover, one patient developed an unentrained sleep-wake cycle after melatonin withdrawal. By contrast, in an open-label 4-week trial in 11 patients with acute bipolar mania in which melatonin (3 mg daily at bedtime) was added to ongoing antimanic treatment, marked improvement in subjective sleep duration was observed concurrent with significant improvement in manic symptoms (Bersani and Garavini, 2000). No randomized, placebo-controlled trial has been published to examine the efficacy and safety of adjunctive treatment with melatonin or a selective melatonin agonist in bipolar disorder, which targets improvement in sleep and mood symptoms.
Ramelteon is a highly selective melatonin MT1/MT2 receptor agonist approved for the treatment of insomnia characterized by difficulty with sleep onset (Miyamoto, 2009; Ferguson et al., 2010). Preclinical and randomized control trials suggest that ramelteon may also be useful for circadian rhythm sleep disorders (Arendt and Rajaratnam, 2008). Ramelteon has low abuse potential, which may be of benefit in bipolar disorder given the condition's high comorbidity with substance use disorders (Merikangas et al., 2007).
We hypothesized that adjunctive ramelteon would improve quality and quantity of sleep in outpatients with bipolar I disorder with mild-to-moderate manic symptoms and sleep disturbance who were receiving pharmacotherapy. In addition, we hypothesized that improvement in sleep disturbance because of ramelteon would be associated with improvement in mood symptoms. We, therefore, conducted a single-center, randomized, parallel-group, double-blind, placebo-controlled clinical trial to assess the efficacy and tolerability of adjunctive ramelteon in outpatients with bipolar I disorder with mild-to-moderate manic symptoms and sleep disturbance.
Study participants were outpatients at the Lindner Center of HOPE who were recruited by radio, newspaper, and television advertisements requesting volunteers for a study of a medication for persons with bipolar disorder who had insomnia. Patients were enrolled into the trial if they met the following inclusion criteria: (i) were male or female 18–65 years of age inclusive; (ii) had bipolar I disorder according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) (A.P.A., 2000) criteria as determined by Mini-International Neuropsychiatric Interview (M.I.N.I.) (Sheehan et al., 1998); (iii) were currently experiencing mild-to-moderate manic symptoms [defined as a Young Mania Rating Scale Score (YMRS) (Young et al., 1978) score ≥10 and ≤25]; (iv) had clinically significant sleep disturbance, defined as a Pittsburgh Sleep Quality Index (Buysse et al., 1989) (PSQI) total score greater than 5; (v) were receiving at least one mood stabilizing medication, which may have been lithium, an anticonvulsant with mood-stabilizing properties (e.g. carbamazepine, lamotrigine, oxcarbazepine, or valproate/divalproex), or an atypical antipsychotic (e.g. aripiprazole, clozapine, olanzapine, quetiapine, risperidone, or ziprasidone) for at least 1 week before the baseline; and (vi) were outpatients (i.e. were ambulatory and did not require hospitalization for management of their bipolar symptoms).
The patients were excluded from participating in the study if they: (i) were experiencing clinically significant suicidal ideation, homicidal ideation, or psychotic features; (ii) had a current DSM-IV-TR diagnosis of delirium, dementia, or other cognitive disorder or a lifetime DSM-IV-TR psychotic disorder; (iii) had a DSM-IV-TR substance dependence disorder (except for nicotine dependence) within 6 months of study entry; (iv) had a clinically significant finding on medical history, physical examination, electrocardiogram, or laboratory testing; (v) had a history of allergy or hypersensitivity to ramelteon; or (iv) were taking medications that might interact adversely with ramelteon (e.g. fluvoxamine). Women were excluded if they were pregnant, lactating, or if fertile, not practicing a form of medically accepted contraception.
All psychotropic medications that the patient was taking at study entry were continued unchanged throughout the course of this study, except in instances in which a medication required dose reduction for side effect management. Continued administration of benzodiazepines or sedative hypnotics was allowed only if the patient has been receiving the medication for 2 or more weeks before baseline. Increase in dose of a baseline psychotropic medication or the addition of a new psychotropic medication resulted in patient termination from the protocol.
The institutional review board at the University of Cincinnati Medical Center approved the study protocol, and the study was conducted in compliance with the Declaration of Helsinki. All patients signed approved written informed consent forms after the study procedures had been fully explained and before any study procedures were performed. Patients were enrolled from February 2008 to March 2010.
This was an 8-week, outpatient, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study conducted at the Lindner Center of HOPE. The trial consisted of two phases: a 1-week to 2-week screening period and an 8-week double-blind treatment period. The patients were evaluated at least twice during the screening period and after each week during the 8-week treatment period. They were also evaluated on at least one occasion 1 week after study medication discontinuation.
All study medication was in identical tablets (8 mg of ramelteon or placebo) supplied in numbered containers and dispensed to patients according to a predetermined randomization schedule. Ramelteon was administered at a dose of 8 mg/day about 30 min before bedtime throughout the study.
The patients were randomized to receive ramelteon or placebo in a 1 : 1 ratio according to computer-generated coding. Randomization was balanced by the use of permuted blocks. Allocation concealment was achieved by having the research pharmacy perform the randomization, package the study medication, and maintain the integrity of the blinded information throughout the trial.
The primary outcome measure was change in insomnia as assessed by the 65-item version of the PIRS (Moul et al., 2002). Secondary measures were the YMRS, PSQI, Inventory for Depressive Symptoms (Rush et al., 1986), Clinical Global Impressions Scale modified for Bipolar Illness (CGI-BP) (Spearing et al., 1997), Hamilton Anxiety Rating Scale (Hamilton, 1959), and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (Endicott et al., 1993). All measures were obtained at the baseline (randomization) and weekly thereafter, except the PSQI and Q-LES-Q, which were obtained at the baseline, week 4, and week 8. Response of manic symptoms was defined as a 50% or greater decrease in the baseline YMRS score at treatment endpoint.
The following safety measures were assessed: adverse events, clinical laboratory data, physical examination findings, and vital signs. Hematology parameters, liver function tests, blood chemistries, urinalysis, and drug screen were collected at screening and treatment weeks 4 and 8 (or at premature discontinuation). A physical examination was carried out at screening and week 8 (or at premature discontinuation).
Adherence with study medication was evaluated with returned tablet count. Patients who missed more than or equal to 5 consecutive days of study medication were considered nonadherent and discontinued from the trial.
All statistical analyses were done using Stata SE (version 10.1, College Station, Texas, USA), except for the longitudinal data analysis, which was done using SAS software (version 9.1, Cary, North Carolina, USA). Chi-square, Fisher exact, or t-tests were used to determine statistical differences between the placebo and drug condition on the baseline characteristics, adverse events reported, and reasons for study discontinuation. An intent-to-treat (ITT) analysis was used in which all randomized patients with at least one postbaseline assessment were included. The primary analysis used a longitudinal regression equation to model the mean treatment response during the 8-week treatment period for the primary and secondary outcome measures. The best fitting correlation structure, as determined by the lowest AIC value, was chosen for each independent variable and included unstructured, first-order antedependence and first-order autoregressive. The secondary analysis was an endpoint analysis of the change from the baseline for the ITT sample using last observation carried forward and for patients who completed the 8-weeks of treatment.
All the statistical tests were two-sided, with α=0.05.
Of 64 individuals assessed for eligibility, 43 were not enrolled because they did not meet entry criteria. Twenty-one patients who met entry criteria were randomly assigned to ramelteon (N=10) or placebo (N=11). There were no significant differences between the treatment groups in demographic or clinical variables at the baseline (Table 1). On item 4 of the YMRS, which assesses sleep, the majority of patients (N=19) described sleeping less than normal, either by up to 1 hour (N=1) or more than 1 hour (N=18) (Table 1). Only two patients reported reduced need for sleep. No patient denied the need for sleep. Thus, based on the baseline YMRS ratings, most patients (90%) had insomnia without reduced need for sleep.
Four patients in the ramelteon group and four patients in the placebo group did not complete all 8 weeks of treatment (Fisher exact test, P=1.00). Of the 21 patients who were randomized, one patient withdrew from the study because of an adverse event (sedation with ramelteon), four were withdrawn for protocol violations [two had changes in concomitant psychotropic medications (N=1 on ramelteon and N=1 on placebo), one had a positive urine drug screen (placebo), and one was noncompliant with study medication (ramelteon)], and three were lost to follow-up (N=1 on ramelteon and N=2 on placebo). Nineteen patients (N=9 receiving ramelteon and N=10 receiving placebo) had at least one postrandomization efficacy measure and were included in the ITT analysis. Thirteen (68%) of these patients completed all 8 weeks of treatment (N=6 receiving ramelteon and N=7 receiving placebo).
The primary (longitudinal) efficacy analysis showed that patients receiving ramelteon had a similar rate of reduction in mean total PIRS scores, as did patients receiving placebo (Table 2). They also had similar rates of reduction in YMRS, Inventory for Depressive Symptoms, CGI-BP Mania Severity Scale, CGI-BP Overall Severity Scale, Hamilton Anxiety Rating Scale, PSQI, and Q-LES-Q scores, and significantly worse scores on the quality of life subscale of the PIRS. However, ramelteon-treated patients showed significant improvement on the CGI-BP, Depression Severity Scale.
In the secondary (endpoint) efficacy analysis, ramelteon was not associated with significant changes for any outcome variable (Table 3). In addition, there were no significant differences among the treatment groups for antimanic response: four (44%) patients in the ramelteon group and five (50%) patients in the placebo group had a more than or equal to 50% reduction in YMRS score between the baseline and the endpoint (P=1.00).
There were no statistically significant differences among the treatment groups in the incidence of individual adverse events, although the sample size was too small to detect moderate differences in event rates (Table 4). Only one patient, who received ramelteon, discontinued the drug for an adverse event (sedation). No patient receiving ramelteon experienced a serious adverse event. There were no significant changes in vital signs, other physical examination findings, electrocardiogram findings, or laboratory tests, except patients in the ramelteon group had reduced platelet and increased monocyte counts (−51.3 vs. +6.0, P=0.03 and +0.9 vs. −1.1, P=0.05, respectively).
In this randomized, double-blind trial in 21 ambulatory patients with bipolar I disorder, adjunctive ramelteon was not superior to placebo in reducing symptoms of insomnia or mild-to-moderate mania in either the longitudinal or endpoint analysis, a finding contrary to our hypothesis. However, in the longitudinal analysis, findings on the CGI-BP suggested that ramelteon might have decreased depressive symptoms.
Several limitations of this study should be considered. First is that because of the small sample size, the study may have been underpowered to detect important statistically significant treatment effects. Second is that attrition rate was high, with eight (38%) patients withdrawing before study completion, rendering the results heavily depending on assumptions regarding missing data. Third is that the duration of the study may have been too short given ramelteon's delayed onset of effect. Fourth is that the dose (8 mg/day) or timing of administration (30 min before bedtime) of ramelteon may have been inadequate for the study population.
Another limitation is that insomnia was not systematically distinguished from reduced need for sleep using the PSQI or PIRS, as none of these instruments assesses the latter feature of disturbed sleep. Moreover, although the PSQI has been used to measure sleep disturbance in clinical trials in bipolar disorder (Vieta et al., 2006; Endicott et al., 2008), to our knowledge, the PIRS has not. As only two patients reported reduced need for sleep on the YMRS at the baseline, it may be presumed that the majority had insomnia. However, little is known about the sleep disturbance of partially treated bipolar I patients with mild-to-moderate manic symptoms, and the relationship between insomnia and reduced need for sleep in this population. In our experience, patients with manic symptoms can report both insomnia and reduced need for sleep that alternates over different nights within the same week. More research on the phenomenology of sleep disturbance in bipolar disorder, and its treatment implications, is needed.
A related limitation is that because the study required bipolar patients to have mild-to-moderate manic symptoms and sleep disturbance, the results may not generalize to patients with depressive episodes or euthymia and sleep disturbance. Indeed, the negative results observed for ramelteon on sleep and manic symptoms in our study might be because of the drug exerting antidepressant effects in this trial (Micale et al., 2006).
However, hypnotics can cause incident depression. In a review of randomized controlled trials involving 7853 patients, the incidence of depression was significantly greater in hypnotics (2%) than in placebo (0.9%, P<0.002) (Kripke, 2007). This included a 1.335% rate of depression among 3594 ramelteon-treated patients versus 0.008% among placebo-treated patients. Our findings should therefore not lead to the conclusion that ramelteon has antidepressant properties without the appropriately conducted controlled trials.
In summary, in an 8-week trial in outpatients with bipolar I disorder, mild-to-moderate manic symptoms, and sleep disturbance, adjunctive ramelteon 8 mg administered 30 min before bedtime was not superior to placebo in improving insomnia or manic symptoms. However, there was a suggestion that ramelteon might have antidepressant properties in this patient population. Controlled trials of ramelteon in larger groups of bipolar patients with manic symptoms, perhaps using a wider dose range, may still be warranted. In addition, trials of ramelteon in bipolar patients with depression or euthymia and sleep disturbance seem indicated.
This study was funded by Takeda Pharmaceuticals North America, Inc.
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bipolar disorder; insomnia; mania; melatonin; ramelteon
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