Glutamatergic neurotransmission modulators as emerging new drugs for schizophrenia

Schizophrenia is a neurodevelopmental mental disorder whose aetiology includes genetic and environmental factors. Because of its early onset, chronicity and characteristic interference with education, employment and socialisation, this illness represents a tremendous human and economic burden to those who suffer from it, their families and society as a whole. Conventional and atypical antipsychotics, which mainly affect dopaminergic and serotonergic neurotransmission, are currently the cornerstone of schizophrenia treatment. Although the introduction of atypical antipsychotics represents a major development and, overall, antipsychotics are efficacious against psychotic symptoms, there remains a critical unmet need for innovative medications with improved efficacy and tolerability for the negative symptoms and cognitive deficits associated with schizophrenia. These dysfunction domains are reliable predictors of long-term disability and treatment outcome and are presently viewed as crucial targets for new pharmacological treatments of schizophrenia. Within this medication development framework, the modulation of glutamatergic neurotransmission has become the focus of intense research. Glutamate (GLU)-mediated neuronal processes are critical throughout the brain and glutamatergic neurotransmission dysfunctions have been hypothesised to play a crucial role in schizophrenia pathophysiology. Glutamatergic neurotransmission may be modulated at multiple levels, with GLU receptor families and their subtypes representing a modulatory site-rich environment for drug research. Numerous types of neurotransmission modulators, acting at the NMDA, AMPA and metabotropic GLU receptors, and/or affecting GLU synaptic release, are hypothesised to be beneficial for schizophrenia treatment, and are presently in various stages of development. For some of these compounds, preliminary studies have furnished encouraging clinical data. Ongoing and planned research is expected to provide, in the near future, critical information regarding the practical utility and tolerability of glutamatergic approaches for schizophrenia pharmacotherapy.