Reviewing the ketamine model for schizophrenia

• Published in: Journal of psychopharmacology (Oxford) Vol. 28; no. 4; p. 287
• Main Authors: Frohlich, Joel, Van Horn, John D
• Format: Journal Article
• Language: English
• Published: United States 01.04.2014
• Subjects: Age of Onset; Animals; Dopamine - metabolism; gamma-Aminobutyric Acid - metabolism; Humans; Ketamine - pharmacology; Phencyclidine - pharmacology; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Schizophrenia - genetics; Schizophrenia - physiopathology; Schizophrenic Psychology; N-methyl-D-aspartate receptor; Ketamine; schizophrenia; glutamate
• DOI: 10.1177/0269881113512909

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.