Table 1 Clinical trials of NMDAR antagonists showing positive and promising potentials for the treatment of ischemic stroke or AD/ADRD
Drug name | Primary disease target | Trial phase | Year of study or report | Participates | Finding or outcome measurement | Comments | References |
|---|---|---|---|---|---|---|---|
AD, MCI and Dementia Trials | |||||||
Memantine (MEM) | Moderate and severe AD | Phase 3 | 2003 | 369 | MEM showed significant cognition benefits in moderate and severe AD patients | Received FDA approval in 2003 as a symptomatic treatment for advanced AD | |
MEM | Mild to moderate Vascular dementia | Phase 3 | 2002 | 288–321 | MEM 10 mg/day X 28 weeks improved cognition with no deterioration in global functioning and behavior. | A multicenter trial in France | [298] |
MEM | Mild to moderate AD | ? | 2007 | 403 | MEM 10 mg twice/day X 24 weeks improved language and some aspects of memory (ADAS-cog scores) | A post hoc analysis of a randomized, double-blind, placebo-controlled trial in France | [297] |
MEM | Mild to moderate AD | ? | 2008 | 470 | MEM 20 mg/day X 24 weeks was safe and tolerable; MEM significantly improved ADAS-cog and CIBIC-plus scores at weeks 12 and 18, and numerical superiority at week 24 on both scales. | A double-blind, placebo-controlled trial in Europe | [300] |
MEM | Moderate AD | Pilot trial | 2007 | 36 | MEM 20 mg/day X 52 weeks showed less decline in glucose metabolism in all brain areas than patients on placebo. The loss of hippocampal volume was substantially smaller (2.4% vs. 4.0%). | A randomized, double-blind, placebo-controlled pilot study | [294] |
MEM | Mild to moderate AD | ? | 2006–2008 | 167 | MEM 10 mg twice/day X 24 weeks reduced agitation as measured by the NPI compared to donepezil. | Post hoc analysis of a multi-sited, double-blind clinical trial in China | [296] |
MEM | Mild cognitive impairment (MCI) | ? | 2017 | 75 | MEM 5–20 mg/day X 48 weeks improved cognitive and other behavioral performance in multiple tests. Single-photon emission computed tomography (SPECT) scan showed correlations with functional performance. | The initial MEM dose was 5 mg once daily and increased weekly by 5 mg/day in divided doses to a total dosage of 20 mg/day. | [299] |
MN-08 (Memantine nitrate derivative) | Healthy adults | Phase 1 | 2023 | 16 | To assess the safety and tolerability of MN-08 for 6.5 consecutive days in healthy subjects | Ongoing | ClinialTrials.gov; ID: NCT05660863 |
MN-08 (Memantine nitrate derivative) | Alzheimer’s disease | Phase 2 | 2023 | ? | Potential functional benefits of improving cognition | Ongoing | [359] |
Lithium | MCI | Phase 2 | 2007 | 80 | Long-term (2-year) lithium attenuated cognitive and functional decline in amnestic MCI, and modified AD-related CSF biomarkers; well tolerable and showed no impairment to renal function | See published reports for more information | |
Lithium | MCI | Phase 4 | 2017–2024 | 80 | To delineate whether lithium has anti-dementia properties in older adults who have mild cognitive impairment and are at risk of becoming demented. | Ongoing | ClinicalTrials.gov ID:NCT03185208 |
Stroke Trials | |||||||
MEM | Chronic poststroke aphasia | Phase 3 | 2009 | 28 | Significantly short and long-term functional improvements and even greater effects combined with constraint-induced aphasia therapy (CIAT). | See published report for more information | [363] |
MEM | Stroke | Phase 1 | 2014 | 20 | Safety, drop-out rates, feasibility, and establishment of effect sizes | No publication identified | Clinicaltrials.gov; ID: NCT02144584 |
MEM | Mild to moderate cerebral thromboembolic stroke | Phase 3 | 2014 | 53 | Combined with standard treatment resulted in a remarkably improved neurological function. | See published report for more information | [364] |
MEM | Intracerebral Hemorrhage (ICH) stroke | ? | 2015 | 64 | Early administration of memantine to ICH patients resulted significant improvement of long-term motor function and functional independence. | See published report for more information | [365] |
MEM | Ischemic stroke | Phase 3 | 2015 | 47 | Functional outcomes including NIHSS and mRS 7–21 days after ischemic stroke | No publication identified | ClinicalTrials.gov; ID: NCT02535611 |
MEM | Ischemic stroke | ? | 2021 | 77 | Reduction of serum MMP-9; significantly improved NIHSS and BI during and after inpatient hospital care | See published report for more information | [366] |
NEU2000 GluN2B selective NMDAR antagonist | Ischemic stroke; for patients subjected to endovascular thrombectomy less than 8 h from symptom onset | Phase 2 | 2018 | ? | The trial is to examine the safety and efficacy on tissue damage and clinical outcomes | Multicenter, randomized, double-blinded, placebo-controlled trial (high and low doses) | [367]; The report describes the trial protocol, no trial outcome reported yet. |
Ketamine | Ischemic stroke | Phase 1 and 2 | 2015–2018 | 50 | To determine neuroprotection of ketamine combined with tPA in acute ischemic stroke | No publication identified | ClinicalTrials.gov; ID: NCT02258204 |
Ketamine | Subarachnoid Hemorrhage | Phase 2 and 3 | 2016–2021 | 50 | To test the efficacy of ketamine in protecting the brain following aneurysm repair operation | No publication identified | ClinicalTrials.gov; ID: NCT02636218 |
Ketamine | Ischemic stroke/depression | Phase 1 | 2020–2022 | 21 | To assess the effect and safety of transmucosal ketamine in treatment of post-stroke depression | No publication identified | ClinicalTrials.gov; ID: NCT04876066 |
Ketamine | Ischemic stroke | Phase 2 and 3 | 2023–2025 | 120 | To assess the efficacy and side effects of intravenous ketamine against excitotoxicity | No publication identified | ClinicalTrials.gov; ID: NCT03223220 |
Lithium | Stroke risk in bipolar patients | Retrograde Meta-analysis | 2001–2011 | 1,250 | Chronic lithium treatments significantly reduced risk of stroke in patients with bipolar disorder. | Completed | |