Several 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.