Lithium augmentation of ketamine increases insulin signaling and antidepressant-like active stress coping in a rodent model of treatment-resistant depression.
Level 5 - mechanism / opinion, no new human data
Preclinical animal model without human clinical data
PubMed 34824208 · doi:10.1038/s41398-021-01716-w
What was done
Male Wistar rats received adrenocorticotropic hormone (ACTH; 100 µg/day i.p. for 14 days) to model antidepressant resistance and were then treated for 2 days with ketamine (10 mg/kg; n = 12), lithium (37 mg/kg; n = 12), ketamine plus lithium (10 mg/kg + 37 mg/kg; n = 12), or vehicle saline (0.9%; n = 12). Behavioral testing included open field and forced swim tests. Prefrontal cortical (PFC) subregions (infralimbic [IL] and prelimbic [PL]) and peripheral blood were collected one hour post-stress. Western blots assessed ERK, mTOR, Akt, and GSK3β levels. Bioenergetics (OCR and ECAR) in anterior PFC tissue and plasma mTOR and insulin levels via ELISA were also analyzed.
What was found
The abstract reports directions of effect and p-values without absolute numerical values. Ketamine plus lithium significantly reduced forced swim immobility time (p < 0.05) and latency to immobility (p < 0.01). Combined treatment increased plasma mTOR (p < 0.01) and insulin (p < 0.001). In the IL PFC, ketamine plus lithium increased phosphorylated-to-total mTOR (p < 0.001) and Akt (p < 0.01) ratios while decreasing ERK; conversely, in the PL PFC, pmTOR/mTOR was reduced and pERK/ERK was elevated. Prefrontal tissue bioenergetics showed no significant alteration in response to BDNF or TNFα.
Why it matters
The findings suggest lithium augmentation may overcome ketamine nonresponsiveness in refractory depression via region-specific PFC mTOR/Akt signaling and peripheral insulin pathway modulation.
Limits
The study is restricted to an animal model in male rats, limiting generalizability to humans and precluding assessment of sex-specific effects. No numerical baseline or endpoint values are reported in the abstract.
Cited by
- supports Lithium improves insulin signaling in the brain.