Correcting Circadian Rhythms to Breakthrough in Bipolar Disorder

The purpose of this study is to test whether a dietary supplement (low-dose melatonin) commonly used to treat night owls, administered in conjunction with a behavioral sleep intervention, will help to shift the brain clock earlier and improve mood and sleep in bipolar disorder. Eligible participants will be randomized to receive melatonin plus a behavioral sleep intervention or placebo plus a behavioral sleep placebo.

The hypotheses for this study include:

• Melatonin plus behavioral sleep intervention (compared to placebo plus behavioral sleep placebo) will produce a greater advance of dim light melatonin onset (DLMO), between pre- and post-treatment.
• Melatonin (compared to placebo) will produce a greater reduction in Patient Health Questionnaire-9 score between pre- and post-treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Bipolar Disorder; Delayed Sleep-Wake Phase Disorder
• Intervention / Treatment: Drug: Melatonin; Behavioral: Behavioral sleep intervention; Other: Placebo; Behavioral: Behavioral sleep control

Detailed Description

Ten Participants that competed the randomized trial and were assigned to the placebo group (and meet eligibility) can participate in the open label part of this project. Participants will sign a separate consent for this open label part.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Kelley DuBuc; Phone Number: 734-764-2256; Email: dubuck@umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
      • Contact: Kelley DuBuc; Phone Number: 734-764-2256; Email: dubuck@umich.edu
      • Principal Investigator: Leslie Swanson, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Capable of giving informed consent
• Meet The Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for Bipolar disorder (BD) I or II and are currently enrolled in the Prechter Longitudinal Study of Bipolar Disorder (HUM00000606)
• International Classification of Sleep Disorders (ICSD)-3 diagnosis of Delayed sleep phase disorder (DSPD): (1) have evidence of a delayed phase of the sleep-wake pattern on daily sleep diaries and actigraphy maintained for at least 7 days (e.g., a greater or equal to a 2 hour delay in the timing of habitual sleep episode between work/school and free days); (2) report difficulty falling asleep and difficulty awakening at desired/required times for ≥ 3 months.
• At least mild depressive symptoms on the Patient Health Questionnaire (PHQ)-9 defined by a score ≥5
• Psychotropic medications at stable dose for past month
• Able to download the MyDataHelps mobile application (app), and open app on participants' own phone.
• Willing to abstain from alcohol for the duration of the intervention phase
• Female participants of childbearing potential (i.e., patients are not permanently sterilized (hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or postmenopausal (12 months with no menses without an alternative medical cause) by report) must agree to use a reliable method of contraception from the screening visit until 4 weeks after the study has completed.

Exclusion Criteria:

• Current diagnosis of, or high risk for, a sleep disorder other than DSPD per interview and medical record review (when available) including:

  • Insomnia per DSM-5
  • Sleep-disordered breathing per Snoring, tiredness, observed apnea, blood pressure, body mass index, age, neck circumference, and gender (STOP-BANG)
  • Restless leg syndrome per sleep interview
  • Narcolepsy
  • Suspicion of vasomotor symptoms impacting sleep per interview for women that may be perimenopausal or postmenopausal.
• Risk of current mania (per Young Mania Rating Scale (YMRS) score > 19)
• Suicidal or at high risk for suicide per Columbia Suicide Severity Rating Scale (C-SSRS) guidelines (i.e., presence of any suicidal behavior-suicide attempt, interrupted attempt, abort attempt, or preparatory behavior-in the past 3 months; and/or current active suicidal ideation with any intent), or as determined by the principal investigators.
• Presence of cardiac implantable electronic device, such as defibrillator or pacemaker.

• Presence of chronic psychiatric conditions which may directly influence sleep per interview and medical record review (when available), including:

  • Current illicit drug use
  • Current alcohol or drug abuse
  • History of psychotic disorder

• Presence of unstable chronic medical condition which may directly influence sleep:

  • Chronic pain
  • Thyroid conditions

• Current or history of medical conditions which may be affected by melatonin per self-report and medical record review (when available), such as:

  • Hypertension or hypotension
  • Diabetes Type 1 or Type 2
  • Clotting/bleeding disorders
  • Epilepsy/seizures
  • Autoimmune disorders
  • Conditions requiring immunosuppressive management such as transplant
• Per self-report or medical record review (when available), current use of medications which may have interactions with melatonin (see protocol for more details)
• Current use of medications that may interfere with the measurement of melatonin (Non-steroidal anti-inflammatory drugs if used daily, and beta-blockers, per self-report and medical record review (when available).
• Self-report use of melatonin in the past month.
• Hypersensitivity to melatonin or any other component of the melatonin or placebo product.
• Pregnancy (as determined by dipstick urinary pregnancy test at screening for women of child-bearing potential) or self-report of breastfeeding and/or plan to become pregnant in the next 3 months.
• Self-report of routine night shift work.
• Self-report of past month travel or planned travel during the study across more than one time zone.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Melatonin; Oral medication will be taken for 28 days on the afternoon or evening of the participants first intervention session and continue daily for the remainder of the treatment period.	Drug: Melatonin; Participants randomized to this intervention will take 1 oral pill (0.5 milligrams (mg)) daily. They will attend 4 weekly behavioral sleep intervention sessions with a therapist. In addition, participants will complete questionnaires (MyDataHelp app), monitor sleep, collect saliva samples, and wear the Fitbit Device.; Behavioral: Behavioral sleep intervention; An active intervention that is typically paired with melatonin to maximize treatment effects.
Placebo Comparator: Placebo; Oral medication will be taken for 28 days on the afternoon or evening of the participants first intervention session and continue daily for the remainder of the treatment period.	Other: Placebo; Participants randomized to this intervention will take 1 oral placebo pill daily. They will attend 4 weekly behavioral sleep control sessions with a therapist. In addition, participants will complete questionnaires (MyDataHelp app), monitor sleep, collect saliva samples, and wear the Fitbit Device.; Behavioral: Behavioral sleep control; A behavioral placebo (which does not improve sleep in delayed sleep-wake phase disorder) to control for social/interpersonal effects of behavioral sleep intervention sessions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in time of Dim Light Melatonin Onset (DLMO) baseline (pre-treatment) to 4 weeks (post-treatment)	Onset of melatonin in dim light conditions as measured in saliva (also called DLMO). Time of DLMO is measured in clock time and change in time of DLMO is measured in hours. The change score is calculated as time at 4 weeks minus baseline time. Thus, positive scores indicate a shift towards a later onset of melatonin and negative scores indicate a shift towards an earlier onset of melatonin.	4 weeks (after treatment period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a 9-item self-report scale to screen for symptoms of depression. Items are rated on a 4-point Likert scale from 0 (not at all) to 3 (nearly every day), with total scores ranging from 0 to 27, where higher scores indicate more severe depressive symptoms.	Baseline, 4 weeks (after treatment period)

Collaborators and Investigators

• Sponsor: Leslie Swanson
• Collaborators: National Institute of Mental Health (NIMH); University of Michigan; Natrol
• Investigators: Principal Investigator: Leslie Swanson, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: January 16, 2024
• First Submitted That Met QC Criteria: January 16, 2024
• First Posted (Actual): January 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Melatonin; Placebo; Dim light melatonin onset; Correcting Circadian Rhythms
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Bipolar Disorder; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: HUM00235778; 1R21MH132901-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Additional data collected as part of the study's fundings requirements per the National Institute of Mental Health to be shared to the National Institute of Mental Health Data Archive include the Generalized Anxiety-Disorder 7 item scale; World Health Organization Disability Assessment Schedule 2.0 scale, and the DSM-5 cross cutting assessment. Under the current protocol these data are to be collected to fulfill the National Institute of Mental Health funding requirements but are not included as endpoints or in our analytic plan.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No