Background
Antipsychotics affect the brain's dopamine system, and the drugs reduce delusions, hallucinations, and disorganized thinking, which are cardinal symptoms of psychotic disorders. However, negative symptoms, e.g., anhedonia, avolition, and social withdrawal, as well as cognitive deficits, are not sufficiently treated. Memantine is used to treat Alzheimer's disease and affects the brain's glutamate system.
Aim
The main aim is to reduce negative symptoms. Secondary outcomes are cognition, psychotic symptoms, and side effects.
Method
AMEND is a 12-week, double-blind, placebo-controlled, randomized clinical trial (RCT) testing the effects of add-on memantine to initial antipsychotic treatment in never-treated patients with first-episode psychosis. Glutamate levels in the brain will be measured before and after 12 weeks using ultra-high field strength (7 Tesla) magnetic resonance imaging (MRI).
Participants
Antipsychotic-free, first episode psychosis patients aged between 18-45 years and fulfilling the diagnostic criteria of schizophrenia, persistent delusional disorder, acute and transient psychotic disorders, schizoaffective disorder, other non-organic psychotic disorders, and unspecified non-organic disorders. Exclusion criteria are any prior use of antipsychotic medication, treatment with antidepressant medication within 7 days prior to the inclusion, current substance dependence or substance abuse in any period up to 3 months prior to referral, and allergies to amisulpride- or memantine tablets. Healthy controls aged between 18-45 years with no current or previous mental disorder, and no first-degree relatives with a known major psychiatric disorder. Exclusion criteria are lifetime substance abuse or dependence, and lifetime treatment with antidepressants. Exclusion criteria for both patients and healthy controls are head injury with more than 5 minutes of unconsciousness (lifetime), severe physical illness, and any MRI contradictions.
Perspectives
We hypothesize that add-on of memantine to aripiprazole 1) will be superior to reducing negative symptoms and this effect will correlate with reduced glutamate levels in the thalamus after 12 weeks, 2) will exert the most pronounced effect in patients, who display higher baseline thalamic glutamate levels than HC, and this subgroup of patients will also experience better total symptom control, and 3) will improve domains of cognition, and specifically that effects on working memory, set-shifting, and attention will be predicted by initial glutamate levels in the thalamus and anterior cingulate cortex (ACC). AMEND will apply rational drug repurposing to optimize the treatment of patients experiencing their first psychotic episode.
Update
AMEND has included the planned number of participants, and the inclusions has been closed. We are now analysing the data and will update when the results of the trial are ready.
Contact
M.D. Olga Bengård Baltzersen, Ph.d. student, e-mail: olga.bengaard.baltzersen@regionh.dk
Funding
The AMEND study is financed by: Lundbeck Foundation Ascending Investigator grant, Journal nr. R344-2020-931; DKK 4,999,812/4 years (Granted to sponsor Bjørn H. Ebdrup).
Publications
Sandström KO & Baltzersen OB et al. Add-On MEmaNtine to Dopamine Antagonism to Improve Negative Symptoms at First Psychosis- the AMEND Trial Protocol. Front Psychiatry. 2022 May 20;13:889572. doi: 10.3389/fpsyt.2022.889572. PMID: 35669271; PMCID: PMC9163784.
Link: https://pubmed.ncbi.nlm.nih.gov/35669271/