Add-On Ramelteon in Bipolar I Disorder With Clinically Significant Sleep Disturbance

• Pittsburgh Sleep Quality Index (PSQI) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Pittsburgh Insomnia Rating Scale (PIRS) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

• Young Mania Rating Scale (YMRS) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Inventory of Depressive Symptoms (IDS) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Hamilton Anxiety Scale (HAM-A) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Clinical Global Impressions Scale for Bipolar Disorder (CGI-BP) [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
• Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

The purpose of this research study is to evaluate the safety and efficacy of ramelteon (Rozerem™) as an add-on treatment for sleep problems in patients with bipolar disorder. This study will determine whether or not the addition of ramelteon to ongoing medication(s) for bipolar disorder is useful in improving sleep.

This is a randomized, double-blind, placebo-controlled, parallel-group, single site, 8-week trial of add-on ramelteon in outpatient adults (18-65 years old, inclusive) with lifetime bipolar I disorder, with mild to moderate manic symptoms, and currently experiencing a clinically significant sleep disturbance. Approximately 60 subjects will be screened to obtain 30 subjects who enroll in the 8-week trial. Subjects will be randomized to ramelteon or placebo in a double-blind manner as add-on to current treatment. Any other psychotropic medications that the subject is taking at the initiation of participation in this protocol should be continued unchanged throughout the course of this study, except in instances in which these medications require dose reduction for management of side effects. Efficacy and safety assessments will be performed weekly, and the presence of treatment-emergent adverse events will be monitored and recorded.

• Insomnia
• Bipolar Disorder

• Drug: Ramelteon
  Ramelteon 8mg daily
  Other Name: Rozerem
• Drug: Placebo
  matching placebo for ramelteon 8mg daily

• Active Comparator: Active drug
  Ramelteon - this group receives active drug at a fixed dose of 8mg daily throughout study
  Intervention: Drug: Ramelteon
• Placebo Comparator: Placebo (sugar pill)
  placebo (sugar pill) - this arm receive the fake pill, also know as placebo or the sugar pill
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Subjects must be 18 to 65 years of age, inclusive.
2. Subjects must have lifetime bipolar I disorder as defined by DSM-IV-TR criteria.
3. Subjects' manic symptoms must be mild to moderate in severity, defined as an YMRS score between 10 and 25.
4. Subjects must be currently experiencing a clinically significant sleep disturbance, defined as a PSQI total score > 5.
5. Subjects must be receiving at least 1 mood stabilizing medication, which may include an atypical antipsychotic (e.g., aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone) and/or mood stabilizer/anticonvulsant (e.g, lithium, carbamazepine, valproate/divalproex, lamotrigine, oxcarbazepine) medication for > 1 week prior to baseline. Continued administration of benzodiazepines or sedative-hypnotics will be allowed only if the subject has been receiving the medication for > 2 weeks prior to baseline.
6. Subjects or their legally authorized representative must sign the Informed Consent Document after the nature of the trial has been fully explained.
7. If female, subjects must be: postmenopausal, surgically incapable of childbearing, or practicing medically acceptable effective method(s) of contraception (e.g., hormonal methods, barrier methods, intrauterine device) for at least 1 month prior to study entry and throughout the study.

Exclusion Criteria:

1. Subjects who are experiencing clinically significant suicidal or homicidal ideation.
2. Subjects who are currently experiencing psychotic symptoms.
3. Subjects with a current DSM-IV-TR Axis I diagnosis of delirium, dementia, amnesia, or other cognitive disorders; a DSM-IV-TR diagnosis of a substance dependence disorder within the past 6 months; or, a lifetime DSM-IV-TR psychotic disorder (e.g., schizophrenia or schizoaffective disorder).
4. Subjects with serious general medical illnesses including hepatic, renal, respiratory, cardiovascular, endocrine, neurologic, or hematologic disease as determined by the clinical judgment of the investigator.
5. Subjects with hypo- or hyperthyroidism unless stabilized on thyroid replacement for > 3 months.
6. Subjects with a clinically significant abnormality in their pre-study physical exam, vital signs, EKG, or laboratory studies.
7. Subjects who are allergic to or who have demonstrated hypersensitivity to ramelteon.
8. Subjects who are taking medications that interact with ramelteon (e.g., ketoconazole, fluconazole, fluvoxamine, rifampin).
9. Females who are pregnant or nursing.
10. Subjects who have received an experimental drug or used an experimental device within 30 days.

• Takeda Global Research & Development Center, Inc.
• University of Cincinnati