Efficacy of a Combination of Chronotherapeutics for the Treatment of Major Depressive Episode (MDE) With Insomnia: a Multicenter, Randomized, 2*2 Factorial, Double-blind, Placebo-controlled Trial

Plain English Summary

Efficacy of Chronotherapeutic Combination for Major Depressive Episode With Insomnia is a Phase 3 clinical trial sponsored by Assistance Publique - Hôpitaux de Paris studying Major Depressive Disorder (MDD) With Insomnia. Tests the effectiveness of light therapy and melatonin in treating depression and insomnia. For adults with major depressive disorder (MDD) and insomnia, aged 18-65. Participation involves taking antidepressants, light therapy, and melatonin for 8 weeks. Alternatives include standard antidepressant therapy and sleep hygiene education. The trial aims to enroll 184 participants.

Official Summary

Major Depressive Disorder (MDD) affects 5% of the global population and is the second leading cause of disability worldwide. Despite the widespread use of antidepressants, 50-60% of patients do not respond adequately after 8 weeks of treatment. Insomnia, present in approximately 85% of individuals with MDD, is a frequent and persistent symptom that contributes to poor treatment outcomes. Targeting insomnia has been shown to enhance both symptom remission and functional recovery. In this context, combined therapeutic strategies are often used to optimize the antidepressant response. Among them, chronotherapeutic approaches, such as light therapy and prolonged-release melatonin, have demonstrated rapid antidepressant effects and are beneficial in regulating sleep and circadian rhythms. Light therapy shows an efficacy comparable to antidepressants and, when used in combination with them, can double treatment effectiveness. Melatonin is also recommended in the management of depression-related insomnia. This multicenter, randomized, double-blind, placebo-controlled trial with a 2x2 factorial design aims to evaluate the efficacy of two chronotherapeutic interventions, 8 weeks of active light therapy and 2 mg of prolonged-release melatonin-administered alone or in combination, on depressive symptom reduction at 8 weeks in adult patients with MDD and comorbid insomnia. The primary outcome is the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 8. All participants will receive antidepressant treatment and sleep hygiene education. This study proposes a novel therapeutic strategy combining pharmacological and non-pharmacological interventions to address both depression and insomnia, with the goal of improving outcomes, especially for the 40% of patients who do not adequately respond to antidepressants alone.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18-65 with MDD and insomnia can join. Those with ophthalmologic conditions or other unstable medical conditions cannot join. Must be able to understand and sign the informed consent form. Women of childbearing potential must use highly effective contraception. This trial is studying Major Depressive Disorder (MDD) With Insomnia, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures the change in depression severity, helping patients understand if their symptoms improve over 8 weeks. The specific primary outcome measures are: Assessment of the efficacy of two chronotherapeutics (LT and extended-release melatonin 2mg), alone or combined, associated to AD on depressive symptoms reduction after 8 weeks of treatment (At baseline (Week 0) and at Week 8). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses the significant treatment gap for patients with MDD and insomnia who do not adequately respond to standard antidepressant therapy. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Major Depressive Disorder (MDD) With Insomnia, where improved treatment options are needed.

Investor Insight

This trial targets a large market, with a high unmet need for effective treatments for MDD and insomnia, and a competitive landscape with limited options. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor if you have MDD and insomnia and if you meet the age and health requirements. Participation involves taking antidepressants, light therapy, and melatonin daily for 8 weeks. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: FACTORIAL
• Masking: DOUBLE
• Enrollment: 184 participants

Interventions

• PROCEDURE: AD + SHR + active LT and extended-release melatonin 2mg — Patients will receive an SSRI antidepressant (e.g., Fluoxetine, Sertraline, Paroxetine, Escitalopram) or SNRI (e.g., Venlafaxine, Duloxetine) antidepressant (as clinically appropriate), combined with sleep hygiene education, daily morning LT (10,000 lux for 30 minutes between 7-8 a.m. using the Dayvia Slim Style 3 lamp), and 2 mg of extended-release melatonin taken one hour before bedtime, all for a duration of 8 weeks.
• PROCEDURE: AD + SHR + active LT and placebo melatonin — Patients will receive an SSRI or SNRI, sleep hygiene instructions, daily morning bright LT (10,000 lux, 30 cm, 30 min, 7-8 a.m., using Dayvia Slim Style 3 lamps), and placebo melatonin taken one hour before bedtime, all for a duration of 8 weeks.
• PROCEDURE: AD + SHR + placebo LT and extended-release melatonin 2mg — Patients will receive an SSRI or SNRI, sleep hygiene instructions, daily placebo light exposure (\<10 lux, 30 cm, 30 min, 7-8 a.m., using Dayvia Slim Style 3 lamps in non-therapeutic mode), and 2 mg of extended-release melatonin taken one hour before bedtime, all for a duration of 8 weeks.
• PROCEDURE: AD + SHR + placebo LT and placebo melatonin — Patients will receive an SSRI or SNRI, sleep hygiene instructions, daily placebo light exposure (\<10 lux, 30 cm, 30 min, 7-8 a.m., using Dayvia Slim Style 3 lamps), and oral placebo melatonin taken one hour before bedtime, all for a duration of 8 weeks.

Primary Outcomes

• Assessment of the efficacy of two chronotherapeutics (LT and extended-release melatonin 2mg), alone or combined, associated to AD on depressive symptoms reduction after 8 weeks of treatment (At baseline (Week 0) and at Week 8)

Secondary Outcomes

• Assessment of the efficacy of chronotherapeutics, combine or alone, on depressive symptoms evolution (Weeks 1, 4, 8, and Month 3)
• Determination of the rate of therapeutic response to chronotherapeutics at each follow-up visit (Weeks 1, 4, 8, and Month 3)
• Determination of the rate of remission in depressive symptoms (Weeks 4, 8, and Month 3)
• Evaluation of the impact of chronotherapeutics on subjective sleep (Weeks 1, 4, 8, and Month 3)
• Evaluation of the impact of chronotherapeutics on circadian rhythm (Weeks 1, 4, 8, and Month 3)

Full Eligibility Criteria

Inclusion Criteria:

1. Adults aged between 18 and 65 years (to avoid the risk of cataract associated with light therapy) with a diagnosis of a major depressive episode (MDE) in the context of unipolar depression (according to DSM-5 criteria).
2. Diagnosis of comorbid insomnia with the MDE, defined by difficulty initiating sleep, and/or maintaining sleep, and/or early morning awakenings with daytime consequences, occurring at least three times per week (according to DSM-5 and ICSD-3, in line with European guideline recommendations).
3. Outpatients or inpatients treated for MDE in one of the psychiatric departments of the study centers, or in the sleep medicine department, for a minimum treatment duration of 8 weeks.
4. Patients not currently receiving antidepressant treatment for the current MDE (previous use of antidepressants is allowed, provided treatment was stopped at least one month prior to study participation).
5. A MADRS score ≥ 20 (clinician-rated), indicating at least a moderate-intensity depressive episode.
6. An ISI score ≥ 8 (clinician-rated), indicating at least mild and clinically significant insomnia.
7. No exposure to light therapy in the month prior to inclusion.
8. Ability to understand and sign the informed consent form.
9. Use of highly effective contraception for women of childbearing potential.

Exclusion Criteria:

1. Individuals under legal guardianship or deprived of liberty
2. Ophthalmologic conditions (e.g., cataract, glaucoma, age-related macular degeneration) or diseases affecting the retina (e.g., retinitis pigmentosa, diabetes, herpes, etc.)
3. The following disorders (according to DSM-5): schizophrenia and other psychotic disorders; bipolar disorder, particularly (hypo)manic episodes (YMRS score ≥ 12); other unstable mental disorders
4. Other unstable general medical conditions
5. Pregnant or breastfeeding women
6. Hypersomnia with prolonged total sleep time secondary to the depressive episode, according to ICSD-3 criteria
7. Current depressive episode already being treated with an antidepressant
8. Presence of a high suicidal risk, as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS, score ≥ 4)
9. Ongoing melatonin treatment at the time of inclusion

Trial Locations

• Hôpital Bichat-Claude Bernard, Paris, France

Frequently Asked Questions

Related Conditions

• Major Depressive Disorder (MDD) with insomnia, sleep disorders, circadian rhythm disorders, anxiety disorders, bipolar disorder

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