Ketamine, originally developed as an anesthetic, has emerged as a novel treatment for major depressive disorder (MDD) and treatment-resistant depression (TRD). Its antidepressant properties were discovered serendipitously, leading to FDA approval for TRD and MDD with suicidal ideation. The drug acts primarily as an NMDA receptor antagonist, triggering a paradoxical AMPA-mediated glutamate surge that promotes synaptogenesis and neuroplasticity. Intravenous ketamine and intranasal esketamine differ in dosing, bioavailability, and onset. Common adverse effects include dissociation, sedation, and hypertension. Efficacy studies show mixed-to-positive results, with non-inferiority to established treatments like electroconvulsive therapy. Future research aims to develop predictive markers for personalized medicine.
A meta-analysis of 135 fMRI studies involving 6,391 participants found that youth and adults with major depressive disorder (MDD) show different patterns of brain activation during tasks. Compared to adults with MDD, youth with MDD had distinct activation differences in the subgenual anterior cingulate cortex (sgACC) and dorsolateral prefrontal cortex (dlPFC). After controlling for illness duration, youth showed less activation than adults with shorter-duration MDD in regions like the sgACC. Among adults, those with longer-duration MDD showed less activation in the dlPFC compared to those with shorter-duration MDD. These results suggest that both age and length of illness matter for understanding brain changes in depression.