The glutamate hypothesis of schizophrenia

The dopamine hypothesis has guided schizophrenia research for decades and represents the prime explanation model for the current pharmacotherapy. However, several lines of evidence indicate that a dysfunction of the glutamate system plays a major role in the pathobiology of schizophrenia. Pharmacological challenges with NMDA receptor antagonists mimic schizophrenic psychopathology including negative symptoms and cognitive dysfunction as well as alterations in cerebral perfusion. Animal experiments indicate delayed neuronal degeneration after exposition to NMDA receptor antagonists showing similarities with histological abnormalities in schizophrenia. New techniques for in vivo measurement of cerebral glutamate have provided experimental evidence for abnormal glutamate levels in schizophrenia. Evidence for glutamate dysfunctions in schizophrenia is complementary to the dopamine hypothesis, because both systems are closely connected and interact in a complex way. Recently, novel therapeutic agents acting via glutamatergic mechanisms have been found to improve positive and negative symptoms in schizophrenia in a clinically relevant dimension which may constitute a new era of pharmacotherapy beyond dopamine receptor antagonism.