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Efficacy of Chronotherapeutic Combination for Major Depressive Episode With Insomnia

NCT07120880

RecruitingPhase 3

Sponsor: Assistance Publique - Hôpitaux de Paris

Conditions: Major Depressive Disorder (MDD) With Insomnia

Interventions: AD + SHR + active LT and extended-release melatonin 2mg, AD + SHR + active LT and placebo melatonin, AD + SHR + placebo LT and extended-release melatonin 2mg, AD + SHR + placebo LT and placebo melatonin

Countries: France

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.

Eligibility overview

Sex: ALL

Age: 18 Years to 65 Years

Healthy volunteers: No

Study type: INTERVENTIONAL

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

Locations (1)

Paris, France