Mismatch Negativity (MMN) as a Pharmacodynamic/Response Biomarker for NMDA Receptor and Excitatory/Inhibitory Imbalance-Targeted Treatments in Schizophrenia.

Schizophrenia is a major mental disorder that affects approximately 0.5% of the population worldwide. Persistent negative symptoms and cognitive impairments associated with schizophrenia (CIAS) are key features of the disorder and primary predictors of long-term disability. At the neurochemical level, both CIAS and negative symptoms are potentially attributable to dysfunction or dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission within cortical and subcortical brain regions. At present, there are no approved treatments for either CIAS or persistent negative symptoms. Development of novel treatments, moreover, is limited by the lack of biomarkers that can be used translationally across preclinical and early-stage clinical investigation. The present chapter describes the use of mismatch negativity (MMN) as a pharmacodynamic/response (PD/R) biomarker for early-stage clinical investigation of NMDAR targeted therapies for schizophrenia. MMN indexes dysfunction of early auditory processing (EAP) in schizophrenia. In humans, deficits in MMN generation contribute hierarchically to impaired cognition and functional outcome. Across humans, rodents, and primates, MMN has been linked to impaired NMDAR function and resultant disturbances in excitatory/inhibitory (E/I) balance involving interactions between glutamatergic (excitatory) pyramidal and GABAeric (inhibitory) local circuit neurons. In early-stage clinical trials, MMN has shown sensitivity to the acute effects of novel pharmacological treatments. These findings support use of MMN as a pharmacodynamic/response biomarker to support preclinical drug discovery and early-stage proof-of-mechanisms studies in schizophrenia and other related neuropsychiatric disorders.