Reviewing the ketamine model for schizophrenia

Introduction

Schizophrenia is described as a disorder of positive symptoms (for example, delusions and hallucinations), negative symptoms (for example, avolition and affective flattening) and cognitive and social dysfunction, with a lifetime prevalence reported here of 0.30-0.66% and a shortened life expectancy of about 12–15 years. Historically the dopamine hypothesis dominated explanations of psychosis, in part because D2 antagonists reduce positive symptoms; however, that hypothesis does not explain negative and cognitive symptoms well and has difficulty accounting for the pattern of cortical hypodopaminergia alongside subcortical hyperdopaminergia. In the past two decades the glutamate hypothesis—rooted in observations that N-methyl-D-aspartate receptor (NMDAR) antagonists such as PCP and ketamine transiently induce schizophrenia-like symptoms—has emerged as an alternative or complementary model that may better address negative and cognitive features and could also account for downstream dopamine abnormalities. Frohlich and Van Horn set out to review the pharmacology and psychotomimetic effects of ketamine, with emphasis on its value as a human experimental model of aspects of schizophrenia. The review examines NMDAR physiology, ketamine’s receptor pharmacology (including non-NMDAR targets), convergent genetic and molecular evidence for NMDAR hypofunction in schizophrenia, and how NMDAR hypofunction could account for dopaminergic and GABAergic dysfunction, abnormal connectivity, altered cortical oscillations and the typical adolescent/early-adult age of onset. The authors frame the ketamine challenge as a tool for studying positive, negative and cognitive symptoms and related circuit and oscillatory abnormalities in acute schizophrenia.