Melatonin Versus Placebo for Bipolar Disorder (M-bipolar RCT)

Melatonin Versus Placebo for Bipolar Disorder - a Double Blinded Randomised Controlled Trial

The objective with this study is to conduct a 6-month RCT comparing effects of add-on melatonin versus add-on placebo on mood stabilisation and other critical patient outcomes in patients with BD and to test whether principal effects are antimanic, antidepressant and/or prophylactic against relapse

Study Overview

• Status: Recruiting
• Conditions: Bipolar Affective Disorder
• Intervention / Treatment: Drug: Melatonin; Drug: Placebo

Detailed Description

Sleep abnormalities are common in all phases of bipolar disorder (BD) and constitute core symptoms of both depression and mania also during remitted phases and despite treatment.

Melatonin is a key circadian hormone, that expresses a robust circadian rhythm and acts as an important endogenous modulator of the circadian timing system of sleep and may thus improve sleep and stabilize BD per se. Nevertheless, sleep in general and melatonin specifically is critically understudied in BD reflecting a central key knowledge gap within psychiatry. The investigators want in a 6-month randomized placebo-controlled trial (RCT) to compare effects of add on melatonin versus add on placebo on mood stabilisation and other critical patient outcomes in patients with BD.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lars Kessing; Phone Number: +45 38647081; Email: lars.vedel.kessing@regionh.dk

Study Locations

• Denmark
  • Frederiksberg, Denmark, 2000
    • Recruiting
    • Mental Health Center Copenhagen, Copenhagen Affective Research Center (CADIC)
    • Contact: Lars Vedel Kessing; Phone Number: +45 38647081; Email: lars.vedel.kessing@regionh.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Bipolar disorder with diagnosis confirmed by SCAN interview
• Age 18 - 70 years
• The participants must be able to read and understand the participant information in their native language and consent (English and Danish)
• Habile (i.e able to give informed consent)

Exclusion Criteria:

• Past intolerance to melatonin (allergic reactions)
• Impaired renal or hepatic function (defined by GFR <60 ml/min and/or ALAT over allowed reference value)
• Women who are pregnant, breastfeeding or planning pregnancy in near future.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Melatonin; 100 BD patients will receive 6 mg melatonin every evening. Patients, clinicians and researchers will be blinded.	Drug: Melatonin; Oral: Melatonin capsule 6 mg, 1 capsule/day
Placebo Comparator: Placebo; 100 BD patients will receive placebo. Patients, clinicians and researchers will be blinded.	Drug: Placebo; Oral Placebo capsule, 1 capsule/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mood stabilization	Mood stabilization will be measured by a mood instability score reflecting the daily variability in self-monitored mood collected via the Monsenso system. Patients score their daily mood on a 9-point scale (-3 to +3); scores between -0.5 to 0.5 reflect normal variations, whereas scores of +1, +2 or +3 correspond to mildly, moderately, and severely increased mood and scores of -1, -2 or -3 correspond to mildly, moderately, and severely decreased mood. According to our established methodology, for each participant, we will estimate a mood instability score. Estimates of instability will be based on reading obtained via the Monsenso system which will prompt patients to complete daily mood ratings.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep	Change in sleep measured by change from baseline on the Pittsburgh Sleep Quality Index (min. value = 0; max. value = 21 with higher scores indicating poorer sleep quality) on 3 months visit and 6 months visit	6 months
Depression	The clinical rating of depression is assessed using the Hamilton Rating Scale for Depression, 6 items (HAM-D6), (min. value=0; max. value = 22 with higher scores reflecting more severe depression )	Changes between baseline, 3 months and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mania/hypomania	The clinical rating of (hypo)mania is assessed using the Young Mania Rating Scale (YMRS) (Min. value = 0; max. value = 60 with higher values reflecting more manic symptoms) [Clinically rated observer-based difference in scores over the 6 months trial, measured at baseline, 3 months and 6 months]	Changes between baseline, 3 months and 6 months
Functioning	Functioning is assessed using the Functional Assessment Short Test (FAST) (Min. value = 0, max. value = 72 with higher values reflecting poorer function).	Changes between baseline, 3 months and 6 months
Perceived stress	Assessed using Cohen's Perceived Stress Scale (PSS), a 10-item questionnaire. (Min. value = 0; max. value = 40, with higher values reflecting increased stress level)	Changes between baseline, 3- and 6 months
Cognition	Assessed using the self-administered questionnaire, Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) (Min. value = 0; max. value = 48, the higher the score, the higher the number of subjective complaints)	Changes between baseline and 6 months
Non-response to standard mood stabilizing treatment	Non-response to standard mood stabilizing treatment, where standard treatment is defined as lithium or lamotrigine. If one of the following situations occurs after treatment allocation, the date is registrered as "non-response to treatment" defined as: Add-on of a second mood stabilizer (lithium or lamotrigine) in addition to the initial mood stabilizer (lithium or lamotrigine); Add-on of an antidepressant; Add-on of quetiapine > 100 mg/day or another antipsychotic drug The patient will continue the trial follow-up in case of non-response	6 months
Chronotype	Assessed using the Morningness-Eveningness questionnaire (MEQ). (Min. value 16, max. value 86. A value of 41 or below indicate an "evening type". Value of 59 or above indicate a "morning type". Values between 42-58 indicate an "intermediate type")	6 months

Collaborators and Investigators

• Sponsor: Lars Vedel Kessing
• Investigators: Principal Investigator: Lars Kessing, University hospital Bispebjerg and Frederiksberg Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: March 1, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Melatonin; Mental disorders; Bipolar disorder; Mood disorder; Bipolar and related disorders
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Bipolar Disorder; Mood Disorders; Mental Disorders; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Tryptamines; Melatonin
• Other Study ID Numbers: EUCT2025-523549-92-00; Grant ID: 10.46540/00004B (Other Grant/Funding Number: Danmarks Frie Forskningsfond (DFF))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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