Comparative Study of Cerebral Neuroinflammation in Major Depressive Disorder Using 18F-DPA-714 PET Imaging

The primary objective of this study is to compare **neuroinflammation** distribution patterns, as assessed by PET imaging, among three groups: patients with Major Depressive Disorder (MDD), patients in remission from MDD for at least 8 weeks while still receiving antidepressant treatment, and control subjects matched by age and gender. This comparison is clinically relevant as it may enhance understanding of the role of neuroinflammation in depressive disorders and inform potential therapeutic strategies.

Secondary objectives include:

• Comparing PET data on neuroinflammation distribution across the experimental, pathological control, and control groups.
• Correlating depressive symptoms, evaluated using the Montgomery and Asberg Depression Scale (MADRS) and the Columbia-Suicide Severity Rating Scale (CSSRS), with neuroinflammation across the groups.
• Correlating neuroinflammation with MRI parameters for functional and structural integrity across the groups.
• Correlating neuroinflammation with biological markers of neuroinflammation, such as cytokines, across the groups.
• Comparing proteomic markers between the three groups of subjects.
• Measuring the correlation between the volume of distribution of TSPO assessed by PET, MRI markers, biological markers of peripheral inflammation, and proteomic markers in the three groups.

The clinical trial involves participants diagnosed with **depressive disorder**. The study population includes both male and female subjects, aged between 18 and 60 years. Participants are divided into three groups: an experimental group with patients currently meeting the criteria for major depressive disorder (MDD) as per DSM-5, a pathological control group consisting of individuals who have had MDD but are in remission for at least 8 weeks and are still on antidepressant treatment, and a control group without any prior neurological or psychiatric disorders. The trial population was selected based on specific inclusion criteria, such as the requirement for the experimental group to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score greater than 20, and for the pathological control group to have a MADRS score less than 10. Participants in the control group must have a C-reactive protein level below 5 mg/L. All participants must provide written consent and demonstrate the ability to understand instructions and information related to the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to investigate **depressive disorder** by comparing the cerebral neuroinflammation patterns among three distinct groups: patients currently experiencing a major depressive episode (MDD), patients in remission from MDD, and healthy control subjects. This study employs a **randomized**, **double-blind**, and **controlled** methodology to ensure the reliability and validity of the results. The trial is expected to span from December 2018 to January 2026, with participant involvement lasting up to one year, depending on individual circumstances and adherence to the study protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and specific diagnostic requirements. Following successful screening, participants will be randomly assigned to one of the study groups. The primary endpoint is the assessment of TSPO density through the cerebral distribution volume of the tracer **18F-DPA-714**. Secondary endpoints include evaluations using psychometric scales, imaging markers, and biological markers of peripheral inflammation.

Study visits will include baseline assessments, periodic follow-up visits to monitor progress and collect data, and an end-of-study visit to conclude participation. The inclusion visit will confirm eligibility, while follow-up visits will ensure compliance with the study protocol and monitor any adverse events. The end-of-study visit will involve final assessments and debriefing. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or choose to withdraw consent.

The trial's rigorous design and comprehensive assessment strategy aim to provide valuable insights into the neuroinflammatory processes associated with depressive disorder, potentially informing future therapeutic approaches.

The clinical trial involves the use of the experimental medication **18F-DPA-714**, which is a **solution for injection**. The active substance in this medication is **N,N-diethyl-(2-(4-(2-(18F)fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidine-3-yl)acetamide**, also known by its synonyms **BAY 85-8102** and **DPA-714 F-18**. This compound is of chemical origin and is administered via **intravenous administration**. The maximum daily dose and total dose for the treatment period is 370 MBq (megabecquerels), with the treatment period limited to a single day. The pharmaceutical form of the medication is a solution specifically designed for injection, and it is not a pediatric formulation. The medication is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the administration of the experimental medication **18F-DPA-714**. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to assess the distribution pattern of neuroinflammation in patients with major depressive disorder (MDD) compared to those in remission and control subjects, with the primary outcome being the comparison of TEP data among these groups.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoint focuses on the **TSPO density**, which will be evaluated by measuring the cerebral distribution volume of the tracer [18F]DPA-714 in the experimental group compared to the control group. This assessment aims to determine the distribution pattern of neuroinflammation in patients with Major Depressive Disorder (MDD) during a major depressive episode.

Secondary endpoints include a broader evaluation of TSPO density across three groups: experimental, control, and pathological control. Additionally, psychometric scales will be utilized to assess the clinical state of subjects, including the Depression scale (MADRS), Anhedonia Scale (SHAPS), Psychomotor Slowing Scale (Widlocher scale), Suicide Risk Rating Scale (CSSRS), and BAS Anxiety Rating Scale (Brief Scale for Anxiety). Imagery markers will be analyzed using structural MRI to quantify cortical atrophy, diffusion MRI to measure microstructural integrity, T2* relaxometry to assess intracerebral iron content, and resting functional MRI to evaluate the connectivity strength of the default mode network.

Furthermore, concentrations of biological markers of peripheral inflammation, specifically TNF alpha and IL6, will be measured. Proteomics will also be conducted to identify plasma proteins and quantify their relative abundances. These comprehensive assessments will be conducted at specified timepoints throughout the trial to ensure a thorough evaluation of the treatment's efficacy.