Phenomenology, aetiology and treatment of schizophrenia.

Schizophrenia affects up to 1% of the global population. While traditional models focused on dopamine dysfunction, glutamatergic models have become mainstream over the last 15 years, explaining features poorly accounted for by dopamine alone. These models are based on observations that PCP and ketamine induce psychotic symptoms by blocking NMDA-type glutamate receptors. NMDA receptors are widespread, causing information-processing deficits in sensory and subcortical systems as well as higher cortical regions. They also regulate dopamine release, suggesting dopaminergic deficits may be secondary to glutamatergic dysfunction. Agents stimulating glutamatergic transmission, such as glycine-site agonists and glycine transport inhibitors, have shown promise in preclinical studies and are undergoing clinical development, potentially leading to new treatments.

Study at a glance

Abstract

Schizophrenia is a serious mental disorder that affects up to 1% of the population worldwide. Traditional models of schizophrenia have emphasized dopaminergic dysfunction. Over the last 15 years, however, glutamatergic models have become increasingly mainstream, and account for features of the disorder that are poorly explained by dopaminergic dysfunction alone. Glutamatergic models, such as the PCP/NMDA model, are based upon the observation that the psychotomimetic agents phencyclidine (PCP) and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. Because NMDA receptors are located throughout the brain, information-processing deficits are observed not only in higher cortical regions, but also in sensory cortices and subcortical systems. Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction. Agents that stimulate glutamatergic neurotransmission, including glycine-site agonists and glycine transport inhibitors, have shown encouraging results in preclinical studies and are currently undergoing clinical development. Overall, these findings suggest that glutamatergic theories may lead to new conceptualizations and treatment approaches that would not be possible based upon dopaminergic models alone.