Melatonin + Sleep Intervention for Bipolar Disorder

Overseen By Kelley DuBuc

Age: 18 - 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Leslie Swanson

Must be taking: Psychotropic medications

Must not be taking: NSAIDs, Beta-blockers

Disqualifiers: Insomnia, Narcolepsy, Psychosis, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that your psychotropic medications (medications affecting mood, perception, or behavior) be at a stable dose for the past month. Additionally, if you are taking medications that may interact with melatonin or interfere with its measurement, you may need to stop or adjust them, but the protocol does not specify which medications these are.

What data supports the effectiveness of the treatment for improving sleep in patients with bipolar disorder?

Research shows that melatonin can improve sleep patterns in people with bipolar disorder by helping them fall asleep earlier and sleep more efficiently. Additionally, cognitive behavioral therapy for insomnia (CBT-I) is effective in treating insomnia, improving sleep quality, and reducing the time it takes to fall asleep. ^{1 2 3 4 5}

Is Cognitive Behavioral Therapy for Insomnia (CBT-I) safe for humans?

Cognitive Behavioral Therapy for Insomnia (CBT-I) is considered a safe and effective treatment for insomnia, with studies showing it improves sleep quality and efficiency without the adverse effects often associated with medication. ^{4 6 7 8 9}

How is the Melatonin + Sleep Intervention treatment for bipolar disorder different from other treatments?

This treatment combines melatonin, a natural hormone that helps regulate sleep, with a behavioral sleep intervention like cognitive behavioral therapy for insomnia (CBT-I), which is unique because it targets both the biological and behavioral aspects of sleep disturbances in bipolar disorder. Unlike many sleep medications, melatonin is well-tolerated and has a low risk of dependence, making it a safer option for long-term use. ^{1 2 5 10 11}

Research Team

Leslie Swanson, PhD

Principal Investigator

University of Michigan

Eligibility Criteria

This trial is for individuals with Bipolar Disorder who also have trouble sleeping at the right times, like night owls. Participants should be interested in trying a dietary supplement and behavioral sleep techniques to improve their mood and sleep patterns.

Inclusion Criteria

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.

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)

My mental health medication dose has been stable for the last month.

Exclusion Criteria

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

I have or might have a sleep disorder that is not DSPD, based on my symptoms and medical history.

Presence of cardiac implantable electronic device, such as defibrillator or pacemaker

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either melatonin plus a behavioral sleep intervention or placebo plus a behavioral sleep placebo for 28 days

4 weeks

Follow-up

Participants are monitored for changes in dim light melatonin onset and depression symptoms

4 weeks

Open-label extension

Participants from the placebo group can opt into receiving melatonin in an open-label format

Treatment Details

Interventions

• Behavioral Sleep Intervention
• Melatonin
• Placebo
• Sleep Hygiene Education Control

Trial Overview The study is testing if taking low-dose melatonin along with learning new sleep behaviors can help people with Bipolar Disorder fall asleep earlier and feel better. Half will get real melatonin; the other half gets a fake pill (placebo), both with behavior training.

Participant Groups

Group I: Melatonin Experimental Treatment 2 Interventions

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.

Group II: Placebo Placebo Group 2 Interventions

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.

Who Is Running the Clinical Trial?

Leslie Swanson

Lead Sponsor

Trials

1

Recruited

50+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Natrol

Collaborator

Trials

1

Recruited

50+

University of Michigan

Collaborator

Trials

1,891

Recruited

6,458,000+

Findings from Research

In a study of 83 euthymic bipolar disorder patients, treatment with 2 mg of exogenous melatonin for three months significantly improved sleep patterns, including increased sleep efficiency and total sleep time.

Patients with delayed sleep-wake phase disorder showed a notable advancement in sleep onset time and a shift towards a more morning-oriented chronotype after melatonin treatment, indicating its potential efficacy for managing sleep issues in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of exogenous melatonin on sleep and circadian rhythm parameters in bipolar disorder with comorbid delayed sleep-wake phase disorder: An actigraphic study. Cruz-Sanabria, F., Faraguna, U., Violi, M., et al.[2023]

Bright light therapy (LT) and sleep deprivation (SD) have shown significant acute antidepressant efficacy in treating bipolar disorder, with SD achieving response rates of up to 59.4% in randomized controlled trials.

Chronotherapeutic treatments, including interpersonal social rhythm therapy (IPSRT) and cognitive behavioral therapy adapted for bipolar disorder (CBTI-BP), are generally safe and well-tolerated, with IPSRT showing response rates of up to 67.4% in studies, indicating their potential as effective adjunctive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. Gottlieb, JF., Benedetti, F., Geoffroy, PA., et al.[2020]

In a clinical case series study of 47 patients with primary insomnia, behavioral treatment led to an average improvement of 43%, indicating significant effectiveness in real-world settings.

Patients experienced a 65% reduction in sleep latency, a 46% decrease in nightly awakenings, a 48% reduction in wake time after sleep onset, and a 13% increase in total sleep time, demonstrating the treatment's substantial impact on sleep quality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral treatment of insomnia: a clinical case series study. Perlis, M., Aloia, M., Millikan, A., et al.[2022]

Cognitive Behavioral Treatment for Insomnia (CBTI) is highly effective, showing significant improvements in various sleep measures across 87 randomized controlled trials involving 3724 patients, with an overall effect size of 0.98 for insomnia severity.

Face-to-face CBTI treatments with at least four sessions are more effective than shorter or self-help interventions, and the effectiveness of CBTI remains consistent across different patient demographics and comorbid conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis. van Straten, A., van der Zweerde, T., Kleiboer, A., et al.[2022]

In a pilot study involving 11 patients with Bipolar Disorder experiencing insomnia, melatonin (3 mg) significantly improved sleep duration and reduced the severity of manic symptoms over one month, while patients continued their usual antimanic treatments.

Melatonin appears to be an effective add-on therapy for managing sleep disturbances in manic episodes, suggesting it can help stabilize circadian rhythms and improve overall treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin add-on in manic patients with treatment resistant insomnia. Bersani, G., Garavini, A.[2019]

Cognitive behavioral therapy for insomnia (CBTi) is a highly effective non-drug treatment for insomnia, showing comparable efficacy to sleep medications in randomized control trials, with better long-term maintenance of benefits after treatment ends.

Due to its strong empirical support, both the National Institutes of Health and the American Academy of Sleep Medicine recommend CBTi as the standard treatment for insomnia, highlighting its importance in addressing the public health burden of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insomnia and its effective non-pharmacologic treatment. Siebern, AT., Manber, R.[2018]

Cognitive Behavioral Therapy for insomnia (CBTi) is an effective alternative to medication for treating insomnia, which affects up to 30% of adults, and has been shown to improve various sleep-related outcomes such as sleep onset latency and sleep quality.

CBTi includes techniques like sleep hygiene and cognitive therapy, making it a safe and beneficial option for both adults and adolescents, although access to this therapy can be limited by certain barriers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive Behavioral Therapy in the Treatment of Insomnia. Haynes, J., Talbert, M., Fox, S., et al.[2018]

Cognitive Behavioral Therapy for Insomnia (CBT-I) significantly improves sleep quality in adults with insomnia and comorbid medical or psychiatric conditions, based on a review of 23 studies involving 1379 patients.

The treatment leads to substantial reductions in sleep onset latency and wake after sleep onset, with benefits lasting up to 18 months, demonstrating its effectiveness and durability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive behavioral therapy in persons with comorbid insomnia: A meta-analysis. Geiger-Brown, JM., Rogers, VE., Liu, W., et al.[2022]

The Veterans Health Administration developed a digital mental health intervention called Path to Better Sleep (PTBS) to provide accessible cognitive behavioral therapy for insomnia (CBT-I) to veterans, addressing the shortage of trained providers.

Feedback from veteran and spouse evaluation panels significantly influenced the design of PTBS, leading to improvements in user engagement by emphasizing CBT-I efficacy, simplifying content, and incorporating relatable veteran testimonials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Evaluation Panels During the Development of a Digital Intervention for Veterans Based on Cognitive Behavioral Therapy for Insomnia: Qualitative Evaluation Study. Ryan, AT., Brenner, LA., Ulmer, CS., et al.[2023]

Melatonin and its agonists (like ramelteon and tasimelteon) may serve as effective adjunctive treatments for patients with bipolar disorder (BD) by improving sleep quality and potentially preventing mood relapses during remission phases, based on a comprehensive review of existing data.

Melatonin is well tolerated with low dependence potential compared to traditional sleep medications, making it a safer option for managing sleep disturbances in BD, which are often linked to mood episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders. Geoffroy, PA., Etain, B., Franchi, JA., et al.[2019]

A systematic review of 41 studies suggests that prolonged release melatonin (2-10 mg) taken 1-2 hours before bedtime can effectively treat insomnia symptoms in various psychiatric disorders, including mood disorders and schizophrenia.

Immediate release melatonin at doses less than 1 mg may help manage circadian sleep disturbances in neuropsychiatric conditions, indicating its potential as a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. Palagini, L., Manni, R., Aguglia, E., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Effects of exogenous melatonin on sleep and circadian rhythm parameters in bipolar disorder with comorbid delayed sleep-wake phase disorder: An actigraphic study. [2023]

2. Denmark pubmed.ncbi.nlm.nih.gov

The chronotherapeutic treatment of bipolar disorders: A systematic review and practice recommendations from the ISBD task force on chronotherapy and chronobiology. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Behavioral treatment of insomnia: a clinical case series study. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Cognitive and behavioral therapies in the treatment of insomnia: A meta-analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Melatonin add-on in manic patients with treatment resistant insomnia. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Insomnia and its effective non-pharmacologic treatment. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Cognitive Behavioral Therapy in the Treatment of Insomnia. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Cognitive behavioral therapy in persons with comorbid insomnia: A meta-analysis. [2022]

9. Canada pubmed.ncbi.nlm.nih.gov

The Use of Evaluation Panels During the Development of a Digital Intervention for Veterans Based on Cognitive Behavioral Therapy for Insomnia: Qualitative Evaluation Study. [2023]

10. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Melatonin and Melatonin Agonists as Adjunctive Treatments in Bipolar Disorders. [2019]

11. Switzerland pubmed.ncbi.nlm.nih.gov

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. [2021]