Evaluation of Memantine Hydrochloride as an Adjunct to Aripiprazole in Reducing Negative Symptoms in First Episode Psychosis: A Randomized Controlled Trial

The primary objective of the AMEND trial is to evaluate the efficacy of **memantine hydrochloride** as an add-on treatment to initial antipsychotic therapy in patients experiencing their first episode of psychosis. The focus is on reducing negative symptoms such as anhedonia, avolition, and social withdrawal, which are not adequately addressed by standard antipsychotic medications. This is clinically relevant as these negative symptoms significantly impact the quality of life and functional outcomes in patients with psychotic disorders.

Secondary objectives include assessing changes in cognition, psychotic symptoms, and side effects. Additionally, the study aims to measure **glutamate** levels in the brain before and after 12 weeks using an ultra-high field strength (7 Tesla) magnetic resonance scanner. These secondary outcomes are important for understanding the broader effects of memantine on brain function and symptomatology in psychosis.

The clinical trial involves participants diagnosed with **first episode psychosis**, including conditions such as schizophrenia, persistent delusional disorder, and schizoaffective disorder, as classified under ICD-10 codes F20.x, F22.x, F23.x, F24.x, F25.x, F28, and F29. The study population comprises both male and female subjects, aged between 18 and 45 years, who are legally competent. Participants are required to be antipsychotic-free, as defined by the study's exclusion criteria. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet, physical activity, and habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the effects of **memantine hydrochloride** as an add-on treatment to initial antipsychotic therapy in patients experiencing a first episode of psychosis. The trial aims to assess the reduction in negative symptoms over a 12-week period. Participants will be randomly assigned to receive either memantine or a placebo, with both the participants and the researchers blinded to the group assignments to ensure unbiased results. The trial will involve oral administration of the study medication, with memantine being administered at a maximum daily dose of 20 mg.

The study will commence with an inclusion (screening) visit to confirm eligibility based on criteria such as being antipsychotic-free, having a first episode of psychosis, and meeting specific diagnostic criteria for psychotic disorders. Eligible participants will be between the ages of 18 and 45 and must be legally competent. Following the screening, participants will undergo baseline assessments, including the Positive and Negative Syndrome Scale (PANSS) and the Brief Negative Symptom Scale (BNSS), to establish initial symptom levels.

Throughout the 12-week trial, participants will attend regular follow-up visits to monitor treatment effects, side effects, and any changes in cognition, clinical measures, and glutamate levels in selected brain regions. These visits will also include assessments of the PANSS positive and total scores, as well as exploratory endpoints such as quality of life and brain metabolite levels. The end-of-study visit will occur at the conclusion of the 12-week treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last for the entire 12-week duration of the trial. However, conditions that may lead to early termination from the study include significant adverse effects, withdrawal of consent, or non-compliance with study procedures. The trial is anticipated to start recruitment in May 2024 and is estimated to conclude by May 2028. This study is categorized as a Phase 3 trial, focusing on the translational use of memantine for a new indication in the treatment of negative symptoms associated with first episode psychosis.

The clinical trial involves the administration of **memantine hydrochloride**, a chemical compound used as an experimental medication. Memantine hydrochloride is provided in an oral pharmaceutical form, identified by the code PHF00082MIG. The maximum daily dosage is 20 mg, with a total maximum dose of 290 mg over the treatment period. The administration route is oral, and the treatment duration is set for a maximum of 12 weeks. Memantine hydrochloride is primarily used to target the brain's glutamate system, aiming to reduce negative symptoms in patients with first episode psychosis.

In addition to memantine hydrochloride, the trial includes the use of **aripiprazole**, another chemical compound, as a non-experimental treatment. Aripiprazole is also administered orally, with a pharmaceutical form identified by the code PHF00169MIG. The maximum daily dose for aripiprazole is 30 mg, with a total maximum dose of 2200 mg over the 12-week treatment period. Aripiprazole is an antipsychotic that affects the brain's dopamine system, aiming to reduce delusions, hallucinations, and disorganized thinking, which are cardinal symptoms of psychotic disorders.

The study also employs a placebo in the form of coated tablets designed to match the appearance of memantine tablets, available in 10 mg and 20 mg dosages. These placebo tablets serve as a control to evaluate the efficacy of the experimental treatment. The placebo is administered orally, and its use is integral to maintaining the double-blind nature of the trial. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily through the reduction of negative symptoms in patients with first episode psychosis. The primary endpoint is defined as the change in negative symptoms measured by the Positive and Negative Syndrome Scale (PANSS) negative symptoms score from baseline to week 12. This assessment will be supplemented by scores from the Brief Negative Symptom Scale (BNSS).

Secondary endpoints include changes in cognition, specifically focusing on working memory, set-shifting, and attention, as well as changes in PANSS positive and total scores. Additional clinical measures will evaluate the level of functioning and side effects. Biomarker analysis will involve measuring **glutamate** levels in five pre-selected brain regions: thalamus, anterior cingulate cortex (ACC), hippocampus, dorsolateral prefrontal cortex (DLPFC), and basal ganglia.

Exploratory endpoints will investigate associations between clinical data, quality of life, and brain metabolites in other regions, such as the ACC. Structural measures, including hippocampus subfields and basal ganglia quantification, will also be explored. Interactions between baseline brain metabolite levels and brain structure in patients and healthy controls will be examined. The trial is designed as a 12-week, double-blind, placebo-controlled, randomized clinical trial (RCT) to test the effects of add-on memantine to initial antipsychotic treatment.