Add-On MEmaNtine to Dopamine Antagonism to Improve Negative Symptoms at First Psychosis- the AMEND Trial Protocol

Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multipl...

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Published in:	Frontiers in psychiatry Vol. 13; p. 889572
Main Authors:	Sandström, Katharina O, Baltzersen, Olga B, Marsman, Anouk, Lemvigh, Cecilie K, Boer, Vincent O, Bojesen, Kirsten B, Nielsen, Mette Ø, Lundell, Henrik, Sulaiman, Daban K, Sørensen, Mikkel E, Fagerlund, Birgitte, Lahti, Adrienne C, Syeda, Warda T, Pantelis, Christos, Petersen, Esben T, Glenthøj, Birte Y, Siebner, Hartwig R, Ebdrup, Bjørn H
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 20-05-2022
Subjects:	amisulpride (AMS) antipsychotic-naïve first-episode schizophrenia magnetic resonace imaging (MRI) magnetic resonance spectrography (MRS) memantine neuromelanin (NM) Psychiatry neuromelanin (NM) magnetic resonance spectrography (MRS) memantine randomized controlled (clinical) trial antipsychotic-naïve first-episode schizophrenia amisulpride (AMS) magnetic resonace imaging (MRI) glutamate
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Summary:	Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis. This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine. Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment. The primary endpoint is negative symptom severity. Secondary outcomes comprise: (i) clinical endpoints related to cognition, psychotic symptoms, side effects, and (ii) neurobiological endpoints related to regional glutamate- and neuromelanin levels, and structural brain changes. We hypothesize that add-on memantine to amisulpride will be superior to amisulpride monotherapy in reducing negative symptoms, and that this effect will correlate with thalamic glutamate levels. Moreover, we anticipate that add-on memantine will restore regional white matter integrity and improve cognitive functioning. By combining two licensed, off-patent drugs, AMEND aims to optimize treatment of psychosis while investigating the memantine response. Alongside, AMEND will provide neurobiological insights to effects of dual receptor modulation, which may enable future stratification of patients with first-episode psychosis before initial antipsychotic treatment. [ClinicalTrials.gov], identifier [NCT04789915].
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Antonia Manduca, Roma Tre University, Italy These authors have contributed equally to this work and share first authorship Reviewed by: Clifford Cassidy, University of Ottawa, Canada; Robert McCutcheon, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom; Felice Iasevoli, University of Naples Federico II, Italy This article was submitted to Molecular Psychiatry, a section of the journal Frontiers in Psychiatry
ISSN:	1664-0640 1664-0640
DOI:	10.3389/fpsyt.2022.889572