Abstract
AbstractSeveral attempts have been made to enhance N-methyl-D-aspartate (NMDA) receptor function in schizophrenia, but they have yielded mixed results. Luvadaxistat, a D-amino acid oxidase (DAAO) inhibitor that increases the glutamate co-agonist D-serine levels, is being developed for the treatment of cognitive impairment associated with schizophrenia. We conducted a biomarker study in patients, assessing several endpoints related to physiological outcomes of NMDA receptor modulation to determine whether luvadaxistat affects neural circuitry biomarkers relevant to NMDA receptor function and schizophrenia. This was a randomized, placebo-controlled, double-blind, two-period crossover phase 2a study assessing luvadaxistat 50 mg and 500 mg for 8 days in 31 patients with schizophrenia. There were no treatment effects of luvadaxistat at either dose in eyeblink conditioning, a cerebellar-dependent learning measure, compared with placebo. We observed a nominally significant improvement in mismatch negativity (MMN) and a statistical trend to improvement for auditory steady-state response at 40 Hz, in both cases with 50 mg, but not with 500 mg, compared with placebo. Although the data should be interpreted cautiously owing to the small sample size, they suggest that luvadaxistat can improve an illness-related circuitry biomarker at doses associated with partial DAAO inhibition. These results are consistent with 50 mg, but not higher doses, showing a signal of efficacy in cognitive endpoints in a larger phase 2, 12-week study conducted in parallel. Thus, MMN responses after a short treatment period may predict cognitive function improvement. MMN and ASSR should be considered as biomarkers in early trials addressing NMDA receptor hypofunction.
Publisher
Springer Science and Business Media LLC
Subject
Psychiatry and Mental health,Pharmacology
Reference48 articles.
1. Javitt DC, Zukin SR. Recent advances in the phenciclidine model of schizophrenia. Am J Psychiat. 1991;148:1301–8.
2. Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol. 2002;42:165–79.
3. Chang CH, Lane HY, Tseng PT, Chen SJ, Liu CY, Lin CH. Effect of N-methyl-D-aspartate-receptor-enhancing agents on cognition in patients with schizophrenia: A systematic review and meta-analysis of double-blind randomised controlled trials. J Psychopharmacol. 2019;33:436–48.
4. O’Donnell P, Rosen L, Alexander R, Murthy V, Davies CH, Ratti E. Strategies to Address Challenges in Neuroscience Drug Discovery and Development. Int J Neuropsychopharmacol. 2019;22:445–8.
5. Kleckner NW, Dingledine R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science. 1988;241:835–7.
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