Glutamatergic model psychoses: prediction error, learning, and inference

Neuropsychopharmacology. 2011 Jan;36(1):294-315. doi: 10.1038/npp.2010.163. Epub 2010 Sep 22.


Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects' previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

Publication types

  • Review

MeSH terms

  • Animals
  • Bayes Theorem
  • Cognition / drug effects
  • Cognition / physiology
  • Excitatory Amino Acid Antagonists / adverse effects
  • Glutamic Acid / physiology*
  • Humans
  • Learning / drug effects
  • Learning / physiology
  • Models, Neurological*
  • Psychoses, Substance-Induced / metabolism*
  • Psychoses, Substance-Induced / physiopathology*
  • Psychotic Disorders / metabolism*
  • Psychotic Disorders / physiopathology*
  • Receptors, Glutamate / physiology*


  • Excitatory Amino Acid Antagonists
  • Receptors, Glutamate
  • Glutamic Acid