Assessment of P-glycoprotein Activity in Treatment-Resistant Depression Using [18F]MC225 PET/CT Imaging

The primary objective of this study is to evaluate the involvement of **P-glycoprotein (P-gp)** in treatment-resistant depression (TRD) using PET/CT imaging with **[18F]MC225** as a radiotracer. This will be achieved by comparing P-gp activity in subjects with TRD to those with treatment-responsive depression (DRESP). The assessment will focus on measuring the standardized uptake value (SUV) and volume distribution (VD) of [18F]MC225 in the whole brain. Understanding P-gp's role in TRD is clinically relevant as it may provide insights into the mechanisms underlying resistance to antidepressant treatments and potentially guide the development of more effective therapeutic strategies.

Secondary objectives include assessing P-gp activity by measuring [18F]MC225 SUV and VD in nine volumes of interest (VOIs) per hemisphere. In subjects with TRD, the study will further explore the potential relationship between P-gp activity and clinical characteristics related to illness severity, such as duration of disease, number of episodes, history of attempted suicides, current and previous psychosis, previous drug abuse, and prior pharmacotherapy.

The clinical trial involves participants diagnosed with **depression**, specifically focusing on treatment-resistant depression (TRD) and treatment respondent depression (DRESP). The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have a diagnosis of major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). The trial does not involve a vulnerable population. Participants must have at least five years of education and the capability to complete imaging procedures. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations, such as diet and physical activity, are not specified. The selection criteria include the ability to provide written informed consent and, for TRD subjects, a history of nonresponse to a minimum of two prior antidepressant treatments of adequate dose and duration. The trial aims to assess P-glycoprotein (P-gp) activity using PET/CT imaging with [18F]MC225 as a radiotracer.

The clinical trial is designed to evaluate the involvement of **P-glycoprotein** (P-gp) in treatment-resistant depression (TRD) using a **positron emission tomography** (PET) study with the radiotracer **[18F]MC225**. This trial is a phase IV, randomized, double-blind, controlled study, aiming to compare P-gp activity in subjects with TRD and those with treatment-responsive depression (DRESP). The trial is expected to commence on April 15, 2025, and conclude by April 15, 2027. Participants will be involved for the duration of the study, with the primary endpoint being the assessment of differences in whole-brain standardized uptake value (SUV) and volume distribution (VD) of [18F]MC225 between the two groups.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age between 18 and 65 years, a diagnosis of major depressive disorder (MDD) according to DSM-5, and the ability to complete imaging procedures. Participants must also provide written informed consent. The inclusion visit will be followed by scheduled imaging sessions where the **radiopharmaceutical** will be administered intravenously, with a maximum daily dose of 185 MBq. Follow-up visits will be conducted to monitor the participants' response and any adverse effects. The end-of-study visit will involve a final assessment of the primary and secondary endpoints, including the relationship between [18F]MC225 uptake and clinical parameters related to the severity of depression.

Participant involvement is expected to last throughout the trial duration unless early termination is warranted. Conditions for early termination include the inability to adhere to study protocols, withdrawal of consent, or the occurrence of significant adverse events. The trial will ensure rigorous monitoring to maintain participant safety and data integrity. The study's findings aim to enhance the understanding of P-gp's role in TRD, potentially informing future therapeutic strategies.

The clinical trial involves the administration of the experimental medication **18FMC225_FPG**, which is a **solution for injection**. The active substance in this formulation is **[18F]MC225**, a chemical compound used as a radiotracer. The medication is administered via **intravenous use**. The dosage is set at a maximum of 185 MBq (megabecquerel) per day, with the total dose not exceeding 185 MBq. The treatment period is limited to a single day. The administration of the radiotracer is intended to assess P-glycoprotein (P-gp) activity in the brain using PET/CT imaging, specifically in subjects with treatment-resistant depression (TRD) compared to those with treatment-responsive depression (DRESP).

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 evaluation of P-gp alterations using the radiotracer **[18F]MC225**. Participant compliance with the dosing schedule is monitored to ensure accurate assessment of the radiotracer's uptake and distribution in the brain. The trial aims to provide insights into the role of P-gp in TRD by measuring the standardized uptake value (SUV) volume distribution (VD) of **[18F]MC225** in the whole brain.

Efficacy in this clinical trial will be assessed by evaluating the involvement of **P-glycoprotein (P-gp)** in treatment-resistant depression (TRD) using [18F]MC225 as a radiotracer in PET/CT imaging. The primary endpoint is to assess differences in whole-brain standardized uptake value (SUV) and volume distribution (VD) of [18F]MC225 between subjects with TRD and those with treatment-responsive depression (DRESP). These outcome variables will be computed as the sum of the 18 volumes of interest (VOIs).

Secondary endpoints include assessing differences in SUV and VD of [18F]MC225 in each VOI, both on the right and left hemispheres, between TRD and DRESP groups. Additionally, in TRD subjects, the relationship between [18F]MC225 SUV and VD in the whole brain and clinical parameters related to disease severity, such as duration of disease, number of episodes, and history of psychosis or drug abuse, will be evaluated. The same relationship will be assessed at the level of each VOI, either left or right.