Reviewing the ketamine model for schizophrenia

The glutamate hypothesis of schizophrenia, which arose from observations that NMDAR antagonists like ketamine and PCP induce schizophrenia-like symptoms, may explain negative and cognitive symptoms better than the dopamine hypothesis and even account for dopamine dysfunction itself. Ketamine primarily acts at the NMDAR, and genetic and molecular evidence points to NMDAR hypofunction in schizophrenia. This hypofunction can explain connectional and oscillatory abnormalities through weakened excitation of GABAergic interneurons and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience symptom onset in adolescence when synaptic pruning reduces network connectivity below a critical threshold. Ketamine challenge is useful for studying multiple aspects of acute schizophrenia.

Study at a glance

Abstract

The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.