Melatonin + Sleep Intervention for Bipolar Disorder

Overseen By Leslie Swanson, PhD

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if melatonin, a common sleep supplement, combined with a special sleep program (Behavioral Sleep Intervention), can improve sleep and mood in people with bipolar disorder. Participants will receive either melatonin and the sleep program or a placebo and a different sleep program. It suits individuals with bipolar disorder who typically stay up late and experience mild depression symptoms. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that melatonin is generally safe for use. Studies have found that melatonin causes few side effects compared to a placebo. Most people taking melatonin do not experience serious problems. If side effects occur, they are usually mild and may include sleepiness, dizziness, or headaches.

In this trial, melatonin is used alongside a method to improve sleep habits. Participants will take a supplement and work on better sleep routines. Melatonin has been safely used in many studies, even with individuals who have sleep problems, making it a promising option for improving mood and sleep in those with bipolar disorder.

Although this trial is in its early stages, existing safety data on melatonin is reassuring. Based on past research, participants can feel somewhat confident that the risks are low. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments for bipolar disorder?

Researchers are excited about using melatonin combined with a behavioral sleep intervention for bipolar disorder because it offers a novel approach that could complement or enhance current treatments like mood stabilizers and antipsychotics. Melatonin is a hormone that regulates the sleep-wake cycle, which is often disrupted in people with bipolar disorder, potentially helping to stabilize mood by promoting better sleep patterns. The behavioral sleep intervention aims to improve sleep hygiene and habits, providing a holistic approach that addresses underlying sleep issues. This combination might offer a non-invasive, natural adjunct to existing therapies, potentially leading to improved overall management of bipolar disorder symptoms.

What evidence suggests that melatonin plus a behavioral sleep intervention might be an effective treatment for bipolar disorder?

This trial will compare the effects of melatonin with a placebo in participants with bipolar disorder. Research has shown that melatonin can help individuals with psychiatric disorders sleep better, including falling asleep more quickly. Melatonin influences the brain's internal clock, which may also affect mood. Studies suggest that people with bipolar disorder might have lower melatonin levels, impacting mood and sleep. Taking melatonin as a supplement might help reset these rhythms and improve both mood and sleep quality. Although research continues, the way melatonin works offers hope for treating sleep and mood issues in bipolar disorder. ^{3 4 6 7 8}

Who Is on the Research Team?

Leslie Swanson, PhD

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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Plausible therapeutic effects of melatonin and analogs in ... This review seeks to analyze the role of MEL and its agonists in modulating dopamine-related pathophysiological pathways, improving behavioral outcomes, and ...

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Circadian rhythms of melatonin and its relationship with ... These results suggest that circadian rhythms of melatonin are differentiated in depression and bipolar disorder and correlate with anhedonia in depression.

5. biorxiv.org biorxiv.org/content/10.1101/2025.09.03.673928v1.full.pdf

Investigating the role of melatonin in bipolar disorder using ... 34-36 Overall, these results suggest hypomelatoninaemia may directly contribute to biological pathophysiology of BD via an inability to suppress ...

6. ema.europa.eu ema.europa.eu/en/documents/rmp/slenyto-epar-risk-management-plan_en.pdf

Slenyto, INN-melatonin - EMA psychiatric disorders, especially depression, bipolar disorder, autism spectrum disorders, ... Neurim-pooled clinical safety data ...

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Current Insights into the Risks of Using Melatonin as a ... In the analysis of safety data from randomized, placebo-controlled trials, minimal adverse effects were reported with both melatonin and placebo ...

8. kosinmedj.org kosinmedj.org/upload/pdf/kmj-22-142.pdf

Safety issues regarding melatonin use in child and ... Several studies have reported adverse effects of exogenous melatonin use in children and adolescents. A systematic review and meta-analysis on the efficacy and ...