This study aimed to analyze the effect of ketamine (KT) on Major Depressive Disorder (MDD) symptoms and explore the underlying neural mechanisms from a magnetoencephalographic (MEG) perspective.

Methods: Databases including EBSCO, PubMed, Embase, and Web of Science were searched for studies on MEG observations of KT intervention in MDD patients, covering publications up to June 2024.

Results: In total, 14 RCTs from the United States, involving 351 MDD subjects aged 18-65, were included. The studies, mainly published after 2016 in molecular and biological psychiatry journals, used the DSM-IV criteria for MDD diagnosis. KT was administered at 0.5 mg/kg, with a placebo of 0.9% saline, for a duration of less than 40 minutes. KT significantly improved depression, anxiety, psychotic symptoms, and suicidal ideation, as evidenced by reductions in Montgomery Depression Rating Scale scores. MEG findings indicated the following: 1) AMPA-mediated glutamatergic transmission increase; 2) increased anterior cingulate gyrus (ACC) activation correlating with rapid antidepressant response; 3) prefrontal ACC involvement negatively correlated with symptom improvement during increased working memory load; 4) increased functional connectivity of the anterior striatum; 5) hydroxyketamine levels correlated with gamma power and antidepressant efficacy; 6) baseline gamma power predicted post-dosing gamma power and antidepressant efficacy; 7) decreased connectivity between the amygdala and temporal insula; 8) prefrontal ACC–eft amygdala connectivity negatively correlated with symptom changes; 9) increased δ-α and δ-γ connectivity in responders, and decreased connectivity in non-responders; and 10) fusiform M170 component association with antidepressant effects.

Conclusion: KT improves depression and enhances resting functional connectivity in MDD patients; however, the involved frequency bands are inconsistent and the findings lack reproducibility.