Patients with treatment-resistant depression (TRD) show elevated levels of the pro-inflammatory cytokine interleukin-6 compared to healthy controls, supporting the immune hypothesis of depression. Analysis of 41 cytokines, chemokines, and growth factors in blood samples from 26 healthy controls and 33 unmedicated TRD patients revealed a unique pattern of increased inflammatory mediators, chemokines, and colony-stimulating factors. Following a single intravenous infusion of ketamine (0.5 mg/kg), several cytokines showed transient changes, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response, suggesting novel treatment targets for TRD patients with dysregulated immune functioning.
In a small randomized clinical trial, repeated doses of ketamine improved PTSD symptoms more than midazolam. Brain scans showed that symptom improvement was linked to increased communication between the ventromedial prefrontal cortex and amygdala when viewing emotional faces, especially in those who received ketamine. Ketamine-related improvement was also predicted by decreased activity in the dorsal anterior cingulate during emotional conflict and increased resting-state connectivity between the ventromedial prefrontal cortex and anterior insula. Further analysis indicated that ketamine specifically strengthened the prefrontal cortex's ability to inhibit amygdala responses to threatening social cues, suggesting a normalization of brain circuits involved in fear regulation.