Siegel JS, Palanca BJA, Ances BM, Kharasch ED, Schweiger JA, Yingling MD, Snyder AZ, Nicol GE, Lenze EJ, Farber NB. Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology (Berl). 2021 Apr;238(4):1157-1169. doi: 10.1007/s00213-021-05762-6. Epub 2021 Jan 22. PMID: 33483802; PMCID: PMC7969576.
Highlights:
· In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion.
· Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27).
· Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8).
Results and Conclusion:
· A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.
· Prolonged ketamine infusion induced persistent improvements in depression severity
Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change.
