Dose Finding for d-Serine Enhancement of Plasticity in Schizophrenia

In the current issue of Biological Psychiatry, Sehatpour et al. ( 1 Sehatpour P. Iosifescu D.V. De Baun H.M. Shope C. Mayer M.R. Gangwisch J. et al. Dose-dependent augmentation of neuroplasticity-based auditory learning in schizophrenia: A double-blind, placebo-controlled, randomized, target engagement clinical trial of the NMDA glutamate receptor agonist d-serine. Biol Psychiatry. 2023; 94: 164-173 Abstract Full Text Full Text PDF Scopus (5) Google Scholar ) report the results of a placebo-controlled pilot trial that examined the dose response of d-serine administered with auditory training to assess effects on synaptic plasticity in individuals with schizophrenia. This study followed the National Institute of Mental Health Fast-Fail Trials approach that is intended to evaluate a candidate drug’s target engagement before proceeding to larger clinical trials; establishing target engagement ensures that the novel mechanistic hypothesis is tested. The first step in the Fast-Fail Trials funding mechanism, the R61 pilot trial, uses biomarkers to demonstrate engagement of the molecular target. These studies provide a go/no-go signal based on predefined criteria, but because of small sample sizes, statistical significance may not be achieved and hence reliability of results may not be high. SEE CORRESPONDING ARTICLE ON PAGE 164 SEE CORRESPONDING ARTICLE ON PAGE 164 Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serineBiological PsychiatryVol. 94Issue 2PreviewPatients with schizophrenia show reduced NMDA glutamate receptor–dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. Full-Text PDF