Evaluation of Semaglutide's Efficacy in Alleviating Depressive Symptoms in Patients with Major Depressive Disorder and Comorbid Overweight or Obesity

The primary objective of this study is to evaluate the efficacy of the **glucagon-like peptide-1 receptor agonist semaglutide** in alleviating depressive symptoms in patients with major depressive disorder and overweight or obesity. This is measured by the change in depressive symptoms using the 12-item self-report mood questionnaire, Major Depression Inventory (MDI), from week 0 to week 26. The MDI is a validated tool that estimates depression symptom severity, providing clinically relevant insights into the potential therapeutic benefits of semaglutide in this patient population.

Secondary objectives include assessing changes in body weight, as well as evaluating inflammatory, metabolomics, and oxidative stress biomarkers. Additionally, the study aims to measure global functioning, cognition, and quality of life, which are important factors in understanding the broader impact of semaglutide on patients' overall health and well-being.

The clinical trial involves participants diagnosed with **unipolar depression** and **obesity and overweight**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to have a body mass index (BMI) of 27 kg/m² or higher. The trial does not focus on a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria include individuals who have given informed oral and written consent and have been diagnosed with unipolar disorder according to ICD10 or DSM-V criteria. Participants must also have a Hamilton Depression Rating Scale (HDRS-17) score of 13 or higher. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **semaglutide** in alleviating mood symptoms in patients diagnosed with major depressive disorder and who are also overweight or obese. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thereby minimizing bias. The trial will span approximately 26 weeks, with the primary endpoint being the change in depressive symptoms as measured by the Major Depression Inventory (MDI) from baseline to the end of the study.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as a diagnosis of unipolar disorder according to ICD10 or DSM-V, a Hamilton Depression Rating Scale score of 13 or higher, and a body mass index of 27 kg/m² or greater. Following the inclusion visit, participants will be randomly assigned to receive either the active treatment, **semaglutide**, or a placebo, administered via subcutaneous injection. The trial includes several follow-up visits to monitor the participants' progress, assess any changes in depressive symptoms, and evaluate secondary outcomes such as changes in body weight, waist circumference, and biomarkers related to inflammation and oxidative stress.

The expected duration of participant involvement is approximately 26 weeks, with conditions for early termination including significant adverse effects or withdrawal of consent. The end-of-study visit will involve a comprehensive assessment of the primary and secondary endpoints, ensuring a thorough evaluation of the treatment's impact. The trial's design and procedures are meticulously planned to ensure the collection of reliable and valid data, contributing to the understanding of **semaglutide**'s potential benefits in this patient population.

The clinical trial involves the administration of several **experimental medications** and a **non-experimental treatment**. The primary experimental medication is **Wegovy**, which contains the active substance **semaglutide**. This medication is provided in various dosages, including 0.25 mg, 0.5 mg, 1 mg, 1.7 mg, and 2.4 mg, all formulated as a solution for injection in a pre-filled pen. The pharmaceutical form is a solution for injection, and the route of administration is via **subcutaneous injection**. The maximum daily dose for each formulation corresponds to its respective dosage, with a maximum treatment period of 28 days for most formulations, except for the 1.7 mg dosage, which has a maximum treatment period of 18 days. The administration frequency is once weekly. Participant compliance is monitored through regular assessments and adherence checks.

The non-experimental treatment used in this study is a **Saline Solution Basi** 9 mg/ml, which serves as a placebo. This solution is a **sodium chloride** solution for infusion, provided by Laboratórios Basi – Indústria Farmacêutica, S.A. The pharmaceutical form is a solution for infusion, and it is administered via subcutaneous injection. The maximum daily dose is 3.0 ml, with a total maximum dose of 5.0 ml over a treatment period of 4 weeks. This placebo is used to maintain blinding in the trial and to serve as a comparator to the active treatment.

Efficacy in the clinical trial will be assessed primarily through the change in depressive symptoms, as measured by the Major Depression Inventory (MDI). The MDI is a 12-item self-report mood questionnaire that estimates the severity of depression symptoms. Participants will rate the presence of depressive symptoms over the past two weeks. The primary endpoint is the change in MDI scores from baseline (week 0) to the end of the study (week 26).

Secondary efficacy endpoints include changes in body weight, hip and waist circumference, hemoglobin A1c, lean and fat body mass, bone density, and biomarkers related to inflammation and oxidative stress. Additionally, overall functioning, quality of life, perceived stress, and cognitive scores will be evaluated. These parameters will be measured at various timepoints throughout the study to assess the impact of the treatment on these secondary outcomes.

The trial involves the administration of **semaglutide** in the form of a solution for injection in pre-filled pens, with dosages ranging from 0.25 mg to 2.4 mg. The treatment period varies, with a maximum duration of 28 weeks for most dosages. The efficacy assessments will be conducted using validated scales and laboratory tests to ensure accurate and reliable data collection and analysis.