Finding the Right Dose: NMDA Receptor–Modulating Treatments for Cognitive and Plasticity Deficits in Schizophrenia and the Role of Pharmacodynamic Target Engagement

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are amongst the leading causes of disability in schizophrenia. Despite this, there are no FDA approved treatments for CIAS, and the development of treatments has been limited by numerous Phase II/III failures of compounds that showed initial promise in small-scale studies. N-methyl-d-aspartate-type glutamate receptors (NMDAR) have been proposed to play an important role in schizophrenia; moreover, NMDAR has a well characterized role in cognition, learning and neuroplasticity. We review prior published clinical trials in CIAS focusing on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We will use this discussion of prior studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in Phase III. A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches.