Clozapine mitigates MK-801-induced mismatch negativity impairment in a rat electroencephalography study: relevance for schizophrenia drug development

Abstract

Treating people with schizophrenia still represents a major challenge for neuropsychiatric drug development companies. While available atypical antipsychotics are mainly effective on positive symptoms of schizophrenia, their effects on cognitive and social-cognitive deficits remain insufficient and poorly characterized. For instance, a modest improvement of cognitive functions has been described following clozapine treatment. Nevertheless, it remains unclear whether this outcome is due to a direct effect on the neural circuits underlying cognition or to an indirect effect mediated by an overall reduction in positive symptoms. To address this question, we sought to measure mismatch negativity (MMN) responses in telemetered rats. MMN constitutes an electroencephalography-based biomarker of sensory, pre-attentional and predictive coding processes, functions whose disruptions highly influence certain aspects of patients' cognitive symptoms. MMN was measured under N-methyl-d-aspartate receptor (NMDAr) pharmacological inhibition by MK-801 (dizocilpine), a model based on the glutamatergic hypothesis of schizophrenia, and we tested whether clozapine could improve MMN under this condition or not. We found that MK-801 dose-dependently reduced the MMN peak amplitude in rats, aligning with the MMN response deficit seen in schizophrenia patients. Strikingly, clozapine was able to mitigate this electrophysiological deficit, an unprecedented observation that has the potential to inspire new treatment strategies aimed towards unaddressed schizophrenia symptoms.