Efficacy and Safety of Memantine Hydrochloride in Adolescents with Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the efficacy of **memantine** compared to placebo in improving manic symptoms in adolescents diagnosed with **Bipolar Disorder**. This is clinically relevant as it aims to determine the potential of memantine as a therapeutic option for managing manic episodes in this population, which could lead to improved treatment strategies and patient outcomes.

Secondary objectives include comparing the effect of memantine versus placebo as a mood-stabilizing agent for adolescents with Bipolar Disorder. This aspect of the study seeks to explore the broader therapeutic benefits of memantine beyond its antimanic effects, potentially offering a comprehensive approach to mood stabilization in affected adolescents.

The clinical trial focuses on adolescents diagnosed with **Bipolar Disorder** (BD), specifically targeting individuals aged 13 to 17 years. The study population includes both male and female participants who meet the standard diagnostic criteria for BD, encompassing Type I, Type II, Cyclothymic Disorder, and Unspecified types, with mild to moderate symptom severity. Participants exhibit current manic, mixed, or hypomanic symptoms, which are not psychotic, as confirmed by expert clinical assessment and structured diagnostic tools. The trial does not involve a vulnerable population. Participants are required to provide assent, with consent obtained from a parent or legal representative. Girls of reproductive potential must have a confirmed negative urine pregnancy test at intake and are required to use adequate contraception throughout the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **efficacy** and safety of **memantine** as an antimanic and mood-stabilizing medication in adolescents diagnosed with **Bipolar Disorder**. This study is a monocentric, randomized, double-blind, placebo-controlled trial. Participants will be randomly assigned to receive either memantine or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial. The trial is expected to last for a total duration of 52 weeks, with the primary endpoint being the improvement of manic symptoms as measured by the mean change in the Young Mania Rating Scale (YMRS) total score from intake to week 12.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as age (13-17 years), a DSM-5 diagnosis of Bipolar Disorder, and specific baseline scores on the YMRS and Clinical Global Impressions-Bipolar (CGI-BP) scale. Following the screening, participants will undergo regular follow-up visits to monitor progress and assess safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the 52-week period, where final assessments will be conducted to evaluate the long-term effects of the treatment.

Participant involvement is expected to last for the entire 52-week duration unless early termination is warranted. Conditions that may lead to early termination include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial aims to provide comprehensive data on the safety and efficacy of memantine in managing manic symptoms in adolescents with Bipolar Disorder, contributing valuable insights into potential treatment options for this population.

The clinical trial involves the administration of **Memantine Accord 10 mg film-coated tablets** as the experimental medication. The active substance in this formulation is **memantine hydrochloride**, a chemical compound classified under the ATC code N06DX01. The pharmaceutical form of the medication is a film-coated tablet, designed for oral administration. Participants in the trial will receive a maximum daily dose of 20 mg, with the total dose not exceeding 7300 mg over the course of the study. The treatment period is set for a maximum of 52 weeks. The tablets are repackaged to maintain blinding of the product during the trial.

The study also includes a **placebo** group, which will receive tablets composed of microcrystalline cellulose PH 102, lactose monohydrated, crospovidone, colloidal anhydrous silica, vegetal magnesium stearate, and a film coating. These placebo tablets are designed to match the appearance of the Memantine Accord tablets to ensure the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients and serves as a comparator to evaluate the efficacy and safety of memantine in treating adolescents with Bipolar Disorder.

The efficacy of memantine as an antimanic and mood-stabilizing medication for adolescents with Bipolar Disorder will be assessed through a series of primary and secondary endpoints. The primary endpoint is the improvement of manic symptoms, which will be measured by the mean change in the Young Mania Rating Scale (YMRS) total score from intake to week 12. This scale is a widely used, validated tool for assessing the severity of manic episodes.

Secondary endpoints include the time-to-dropout from the aripiprazole add-on treatment (AAT) phase, which is defined as the number of days from the start of experimental treatment to the initiation of aripiprazole in the memantine versus placebo arm. Additionally, the response of hypomanic or mixed episodes by week 12 will be evaluated by the percentage of subjects showing a reduction of 50% or more in the total YMRS score after 12 weeks of treatment. Further assessments will include the percentage of subjects completing the 52-week study with remission of symptoms, as measured by a combination of criteria including the Clinical Global Impressions-Bipolar (CGI-BP) improvement score, YMRS score, and Children's Depression Rating Scale-Revised (CDRS-R) score.

Additional efficacy measures will involve the percentage of patients showing improvement at the 52-week mark, with outcomes such as the completion rate of the study and a significant increase in the Children's Global Assessment Scale (C-GAS) score in the memantine group compared to the placebo group. Safety and tolerability will also be monitored by recording all adverse events (AEs) and serious adverse events (SAEs) throughout the trial.