Efficacy and Safety of Daridorexant in Patients With Major Depressive Disorder and Insomnia

Efficacy and Safety of Daridorexant in Patients With Major Depressive Disorder (MDD) and Insomnia: Double-blind, Randomized, Controlled Trial

The goal of this clinical trial is to evaluate the efficacy and safety of Daridorexant in major depressive disorder (MDD) patients with comorbid insomnia. The main questions to answer are:

1. Does Daridorexant improve the severity of insomnia as measured by the Insomnia Severity Index (ISI)?
2. Does Daridorexant have an impact on depressive symptoms?

In order to address these questions, researchers will compare Daridorexant with a placebo to evaluate its impact on both insomnia and MDD-related symptoms.

Participants will:

• Receive Daridorexant or placebo for a duration of three months
• Complete a Sleep Diary and other questionnaires assessing sleep and depressive symptoms.
• Undergo polysomnography to obtain objective measurements of sleep parameters.

Insomnia is an extensively studied condition, yet its interactions with major depressive disorder (MDD) remain insufficiently understood. This study aims to evaluate the efficacy and safety of Daridorexant in MDD patients with comorbid insomnia. The primary objective is to determine whether Daridorexant improves the severity of insomnia, as measured by the Insomnia Severity Index (ISI), while assessing its impact on depressive symptoms will be considered the secondary objective. A prospective, double-blind, randomized, multicenter, placebo-controlled trial will be conducted in major depressive disorder outpatient clinic of the psychiatry department. Eligible patients will be randomized to Daridorexant versus placebo. Neither participants nor investigators will be aware of the treatment allocation. Standardized procedures for blinding and emergency unblinding will be implemented across all centers. The main outcome will be the improvement of Insomnia Severity Index (ISI) but additionally total sleep time, wake after sleep onset time, sleep latency and sleep efficiency will be measured. Data collection will include the Pittsburgh Sleep Quality Index (PSQI), depressive symptoms measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), suicidal thoughts measured by the MINI-Neuropsychiatry Scale, quality of life measured by EuroQol, Dysfunctional Beliefs and Attitudes about Sleep (DBAS) and Polysomnography at baseline and 3 months. The study aims to demonstrate improvements in patient's subjective experience of insomnia, and additionally objective quantifiable improvements of objective sleep measurements via polysomnography, without an associated increase in depressive symptoms.

Inclusion Criteria:

• Age Range: 18-99 years old.

• Patients with a current major depressive episode according to DSM-5, in a stable phase (defined as at least 4 weeks without significant changes in antidepressant treatment and no psychiatric hospitalizations in the previous 8 weeks) and with moderate or greater severity, as indicated by a total score of

  • 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS).

• Insomnia disorder confirmed according to DSM-5

  • Insomnia Severity: Insomnia Severity Index (ISI) score = o >15.

  • Medication Stability defined by :

    • Stable doses of antidepressants, mood stabilizers, or antipsychotics for at least 1 month prior to baseline (T0).
    • Melatonin, Benzodiacepines, sedative antidepressants or sedative antipsychotics use for insomnia should follow a wash out protocol described below.

• Informed Consent: Ability and willingness to provide written informed consent.

• Acceptance of Protocol Requirements: Agreement to adhere to all scheduled visits, treatment plans, and study procedures.

Exclusion Criteria:

• Other Current Psychiatric Disorders: Any current psychiatric disorder other than major depressive disorder (e.g., active psychotic disorders, mania, hypomania, acute schizophrenia, schizoaffective disorder).
• Use of Non-Permitted Sleep Medications: Concurrent use of melatonin, benzodiazepines, sedative antidepressants or sedative antipsychotics use for insomnia not allowed by the protocol and unwillingness to follow the slow- taper schedule constitutes an exclusion criterion.
• No concurrent sleep medications at least 30 days prior to baseline. Exclusion criteria if the patient has withdrawal symptoms and/or sleep disturbances measured by BWSQ prior to baseline.
• Uncontrolled Severe Medical Conditions: Any condition that could interfere with study procedures, safety, or outcome measures (e.g., unstable cardiovascular, respiratory, neurological, or endocrine disorders).
• Pregnancy or breastfeeding
• Cognitive Impairments: Significant impairments that prevent the comprehension or completion of study questionnaires or procedures.
• Hypersensitivity: Known allergy or hypersensitivity to daridorexant or any of its excipients.
• Specific Sleep Disorders: Sleep apnea or hypopnea index ≥ 15 events/hour (based on American Academy of Sleep Medicine criteria) or any event associated with oxygen saturation < 80% (as measured by polysomnography).
• Periodic limb movement index ≥ 15 events/hour (as measured by polysomnography). Restless legs syndrome, circadian rhythm sleep-wake disorders, REM behavior disorder, or narcolepsy.
• Concomitant Use with Moderate and potent CYP3A4 Inhibitors: Prohibited due to potential drug interaction (refer to protocol section 4.5 for specifics).
• Moderate and severe hepatic Impairment: Any hepatic condition deemed unsafe for daridorexant use.
• Relapse or Worsening of the Main Diagnosis: Relapse of depression whose severity precludes continued participation according to the investigator's judgment.
• Substance Use Disorder: History of substance use disorder without sustained remission. Exception: past sedative abuse may be permissible if remission criteria are clearly met, as determined by the investigator.
• Excessive Caffeine Intake: Daily consumption of >400 mg of caffeine (e.g., >4 standard cups of coffee).
• High-Risk Alcohol Consumption: Alcohol intake above recommended risk thresholds in accordance with the guidelines of the Spanish Ministry of Health: i.e., >4 standard drinks/day (>40g/d) for men, >2 standard drinks/day (>20g/d) for women.