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Background: 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. Aims: 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. Materials and Equipment: 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. Outcome Measures: 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. Anticipated Results: 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. Perspectives: 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. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04789915]. [ABSTRACT FROM AUTHOR]

BackgroundAntipsychotic 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.AimsThis 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.Materials and EquipmentAntipsychotic-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.Outcome MeasuresThe 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.Anticipated ResultsWe 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.PerspectivesBy 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.Clinical Trial Registration[ClinicalTrials.gov], identifier [NCT04789915].

Background: Many CNS drugs have low bioavailability due to their poor water solubility of extensive first-pass metabolism and hence have less effectiveness., Objective: The present study aims to enhance the solubility and oral bioavailability of poorly watersoluble antipsychotic drug Amisulpride (AMS) through complexation with 2-hydroxypropyl β- cyclodextrin (HPβCD). It has slow and erratic absorption after oral administration., Methods: This report describes the study of the phase solubility diagram, preparation of the inclusion complex and tablet of prepared inclusion complex, characterization of the physico-chemical properties of the inclusion complex and tablet., Results: In-vitro study (100 % drug release in 15 minutes), and in-vivo study of an AL-type (linear type) phase solubility diagram indicated a complex of AMS-HP-β-CD with the constant complex formation of 13245 M-1 at 37°C. The complex formation was confirmed by DSC, IR, and X-ray diffraction. The extent of absorption of the complex was determined in rats and was compared with that of pure drug and the market product. The peak plasma concentration of pure drug was 30.05 ± 1.3 ng/ml (Cmax) at 60 ± 3 min, whereas with the market product the value was 54.85 ± 1.2 ng/ml at 40 ± 1 min and with AMS-HPβCD inclusion complex the value was 79.01 ± 1.5 ng/ml. The AUCtot of the pure drug was 2980.34±3.6, the market product was 7238.73±2.9 and of the inclusion complex was 11871.1±2.8., Conclusion: Pharmacodynamic studies in mice showed improved effectiveness of drug compared to pure drug. The oral bioavailability of AMS was improved from 48% to 78%., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)