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.
A single intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) significantly reduced depressive symptoms in adolescents with major depressive disorder 24 hours later compared with the active placebo midazolam. The treatment effects appeared to persist for 14 days on one depression scale but not another. A greater proportion of participants responded to ketamine during the first three days after infusion (76%) compared with midazolam (35%). Ketamine caused transient dissociative symptoms but no serious adverse events.
Ketamine works as a rapid antidepressant for some but not all patients. In adolescents with treatment-resistant depression, those who had tried fewer antidepressant medications and augmentation treatments, had a shorter current depressive episode, and were currently taking a selective serotonin reuptake inhibitor (rather than a serotonin–norepinephrine reuptake inhibitor) were more likely to experience symptom improvement one and seven days after a single dose of ketamine. These findings are preliminary due to the small sample and multiple analyses, and more research is needed before using such predictors in clinical practice.
In a phase 2b trial, adolescents aged 12 to 17 with major depressive disorder at imminent risk for suicide received either esketamine nasal spray (28, 56, or 84 mg) or a psychoactive placebo (oral midazolam) twice weekly for four weeks, alongside standard care including hospitalization, an antidepressant, and psychotherapy. Pooled esketamine doses (56 and 84 mg) reduced depressive symptoms more than midazolam at 24 hours after the first dose, though individual doses did not reach statistical significance. Suicidality severity improved across all groups. Common side effects included dizziness, nausea, and dissociation.