Efficacy of Melatonin and Low-Dose Quetiapine Versus Placebo in Patients with Psychiatric Disorders and Comorbid Insomnia: A Randomized Clinical Trial

The primary objective of this randomized clinical trial is to evaluate the **efficacy** of melatonin, low-dose quetiapine, and placebo as augmentation to treatment as usual in patients with psychiatric disorders and comorbid chronic insomnia. This is clinically relevant as it aims to determine the most effective adjunctive treatment option for improving sleep and overall management of psychiatric conditions, which can significantly impact patient outcomes and quality of life.

Secondary objectives include examining the effects of melatonin or low-dose quetiapine on:

• Global symptom severity
• Sleep quality
• Psychosocial functioning
• Subjective well-being

The clinical trial involves participants diagnosed with **psychiatric disorders** and comorbid chronic insomnia, as classified under ICD-10 codes F20-F69, F84, and F90-F95. The study population includes both male and female subjects aged 18 to 64 years. Participants are required to have a current or previous diagnosis of a mental or behavioral disorder, with specific conditions for those diagnosed under F84 and F90, necessitating a prior treatment period with melatonin. Additionally, participants must report sleep difficulties occurring at least three times per week over the preceding three months and have an Insomnia Severity Index score of 11 or higher. Women of childbearing potential are required to have a negative pregnancy test at baseline and must use highly effective contraception measures. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **efficacy** of **melatonin**, low-dose **quetiapine**, and placebo in patients with psychiatric disorders and comorbid insomnia. This study is a randomized, double-blind, controlled trial, aiming to assess the augmentation of treatment as usual with these interventions. The trial is expected to run from September 2023 to February 2026, with a maximum treatment period of six months for each participant. Participants will be randomly assigned to receive either melatonin, quetiapine, or a placebo, all administered orally in the form of film-coated tablets.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as age (18 to 64 years), a diagnosis of a psychiatric disorder according to ICD-10 codes F20-F69, F84, F90-F95, and self-reported sleep difficulties. Women of childbearing potential must have a negative pregnancy test and use effective contraception. Following the screening, participants will attend regular follow-up visits to monitor insomnia severity using the Insomnia Severity Index (ISI) and other secondary endpoints, including clinical global impression and subjective sleep quality. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participant involvement is expected to last up to six months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with the study protocol. The primary endpoint is the change in insomnia severity, while secondary endpoints include measures of psychosocial functioning and subjective well-being. This trial aims to provide valuable insights into the management of insomnia in patients with psychiatric disorders, potentially influencing future therapeutic strategies.

The clinical trial involves the administration of **Melatonin** in the form of **Melatonin Orifarm 3 mg film-coated tablets**. The active substance, melatonin, is of chemical origin. The tablets are administered orally, with a maximum daily dose of 9 mg and a total maximum dose of 378 mg over the treatment period. The treatment duration is set for a maximum of 6 weeks. The tablets are encapsulated in lactose-containing gelatin capsules to facilitate administration. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another experimental treatment in the trial is **Quetiapine**, provided as **Quetiapin Sandoz 25 mg film-coated tablets**. The active substance, quetiapine, is also of chemical origin. These tablets are administered orally, with a maximum daily dose of 150 mg and a total maximum dose of 6300 mg over the treatment period. Similar to the melatonin tablets, the quetiapine tablets are encapsulated in lactose-containing gelatin capsules. The treatment period is also set for a maximum of 6 weeks, and participant adherence to the dosing regimen will be closely monitored.

The trial also includes a **placebo** group, which will receive **starch and lactose-containing gelatin capsules**. These capsules do not contain any active pharmaceutical ingredient and serve as a comparator to evaluate the efficacy of the experimental treatments. The placebo capsules are designed to match the appearance of the active treatment capsules to maintain blinding in the study. The administration route and treatment duration for the placebo group are consistent with those of the active treatment groups.

The efficacy of the trial will be assessed by evaluating both primary and secondary endpoints. The primary endpoint is the severity of **insomnia**, which will be measured using the Insomnia Severity Index (ISI). This validated scale will provide a quantitative measure of insomnia symptoms, allowing for a standardized assessment of treatment impact.

Secondary endpoints include several measures to provide a comprehensive evaluation of treatment effects. These are the Clinical Global Impression (CGI) scale, which assesses overall clinical change; subjective sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI); psychosocial functioning, evaluated using the Personal and Social Performance Scale (PSP); and patient-reported subjective well-being, assessed with the WHO-5 well-being index. These tools will collectively offer insights into the broader impact of the treatments on patients' quality of life and functioning.

Data collection will occur at specified intervals throughout the trial, with assessments scheduled at baseline and at subsequent timepoints to monitor changes over time. The analysis will involve comparing the efficacy of melatonin, low-dose quetiapine, and placebo as augmentation to treatment as usual in patients with psychiatric disorders and comorbid chronic insomnia. The trial is designed to ensure rigorous evaluation of the interventions' effectiveness in improving insomnia and related outcomes.