Glutamate signaling through NMDA receptors is essential for brain computations that support cognition, and its disruption may contribute to schizophrenia. Using ketamine, an NMDA receptor antagonist, the study found that the normal anticorrelation between the default-mode and task-positive brain systems was disrupted during a working memory task. The degree of this disruption predicted task performance and produced schizophrenia-like symptoms. A computational model suggests that cortical disinhibition underlies this effect, linking glutamate's role in large-scale brain organization to cognition and psychiatric symptoms.
NMDA channel blockers can produce antidepressant effects without the psychotomimetic and dissociative side effects seen with ketamine. Using quantitative electroencephalography to align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to ketamine, the antidepressant response was maintained with repeated and intermittent drug administration in placebo-controlled data. This provides a path for developing glutamatergic-based treatments for treatment-refractory mood disorders.