Evaluation of D-Cycloserine Augmentation of Accelerated Transcranial Magnetic Stimulation in Major Depressive Disorder Patients

The primary objective of this study is to evaluate the **antidepressive** effect of augmenting a single day of accelerated transcranial magnetic stimulation (aTMS) with D-cycloserine (DCS) in patients with Major Depressive Disorder (MDD). This investigation is clinically relevant as it aims to enhance the therapeutic efficacy of aTMS, potentially offering a more effective treatment option for individuals suffering from MDD.

Secondary objectives include:

• Investigating the durability of the antidepressive response at 6 months follow-up.
• Assessing the clinical outcomes of augmenting a single day of aTMS with DCS.
• Evaluating the anxiolytic effect of augmenting a single day of aTMS with DCS.
• Determining the antidepressive effect of augmenting a single day of aTMS with DCS according to self-report.
• Investigating the effect of TMSxDCS on cognitive outcomes.
• Assessing the adverse events of augmenting a single day of aTMS with DCS.
• Evaluating the change in quality of life at 6 weeks follow-up.

The clinical trial focuses on individuals diagnosed with **Major Depressive Disorder (MDD)**, specifically targeting those experiencing a current moderate to severe depressive episode. The study population includes both male and female participants aged between 18 and 65 years. Participants are required to have a diagnosis of moderate to severe treatment-resistant depression, having previously tried at least two types of antidepressant medications without achieving sufficient results. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the **antidepressive** effect of augmenting a single day of accelerated transcranial magnetic stimulation (TMS) with D-cycloserine (DCS) in patients diagnosed with **Major Depressive Disorder (MDD)**. This study is a Phase 4, randomized, double-blind, controlled trial. The trial will span approximately two years, with an estimated recruitment start date of May 1, 2025, and an estimated end date of May 31, 2027. Participants will be randomly assigned to receive either the active treatment or a placebo, with the determination of an adequate placebo to ensure blinding to be finalized at a later stage.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a primary diagnosis of MDD, age between 18-65 years, and a history of treatment-resistant depression. Following the screening, participants will attend weekly visits for the first six weeks post-treatment to assess the primary endpoint, which is the percentage reduction from baseline in the **Montgomery-Åsberg Depression Rating Scale (MADRS)** score. Secondary endpoints include assessments at six months follow-up, clinical remission and response rates, and changes in anxiety and depression scores using the GAD-7 and PHQ-9 scales, respectively.

The expected length of participant involvement is approximately six months, with follow-up visits scheduled monthly after the initial six-week period. The end-of-study visit will occur at the six-month mark, where final assessments, including cognitive performance and quality of life measures, will be conducted. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or non-compliance with study procedures. The trial aims to provide valuable insights into the potential benefits of combining TMS with DCS for individuals with MDD, contributing to the understanding and treatment of this condition.

The clinical trial involves the administration of **CYCLOSERINE**, a pharmaceutical agent used to augment transcranial magnetic stimulation for the treatment of depression. **CYCLOSERINE** is provided in the form of a hard capsule, with each capsule containing the active substance **CYCLOSERINE**. The medication is administered orally. The maximum daily dose is 1000 mg, with a total maximum dose of 730,000 mg over the course of the treatment period, which spans up to 24 weeks. The product is manufactured by NEON HEALTHCARE LIMITED and is identified by the marketing authorization number PL 45043/0109. The chemical origin of the active substance is confirmed, and the product is classified under the ATC code J04AB01.

In addition to the experimental treatment, a **placebo** will be utilized to ensure blinding within the study. The determination of the appropriate placebo will be conducted at a later stage, as per the correspondence with the relevant Medical Ethics Review Committee (METC). The placebo will be designed to match the experimental treatment in appearance and administration route to maintain the integrity of the study's blinding process. Further details regarding the placebo's composition and administration will be provided following the amendment process.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the percentage reduction from baseline in the Montgomery-Åsberg Depression Rating Scale (**MADRS**) score, which will be measured weekly for six weeks following treatment. This scale is a validated tool used to quantify the severity of depressive episodes in patients with Major Depressive Disorder (MDD).

Secondary endpoints include several measures: the percentage reduction from baseline MADRS score at a six-month follow-up, clinical remission (defined as a MADRS score of ≤8), and clinical response (defined as a reduction from baseline MADRS score of >50%) at six weeks follow-up. Additionally, the trial will assess the percentage reduction from baseline in the Generalized Anxiety Disorder 7-item (**GAD-7**) score and the Patient Health Questionnaire-9 (**PHQ-9**) score, both measured weekly for the first six weeks post-treatment and monthly for the remainder of six months. Changes in performance on a cognitive test battery will be evaluated at one week follow-up, and side effects will be monitored through a questionnaire administered immediately after treatment. The EQ5D questionnaire will be used to assess quality of life at six weeks follow-up.