Finding an Undiscovered Depression Pathway with Ketamine

Access to safe, effective, rapid-acting antidepressants can enhance lives and reduce suicide among patients with treatment-resistant depression or in a crisis.

Ketamine, which can relieve depression even in treatment-resistant individuals, is one current potential being researched. Ketamine has been used as an anesthetic for more than 50 years, although it causes major side effects such as addiction, hallucinations, and delusions. While preclinical studies have indicated that a single dosage of ketamine can have long-term mental health benefits, it is only used as a last option to treat depression.

There are strong reasons to be careful; in addition to the negative side effects, the exact mechanism by which ketamine changes brain chemistry is unknown. New medications might be created to target the positive antidepressant effect of ketamine if the molecular pathways that ketamine modulates in the brain are uncovered. Ketamine therapy increased insulin-like growth factor 1 (IGF-1), a recognized antidepressant brain chemical, according to the study. They didn't know if this had anything to do with previously found ketamine-related antidepressant chemicals such as brain-derived neurotrophic factor (BDNF).

Ketamine (10 and 30 mg/kg) substantially elevated extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 hours, according to in vivo microdialysis. In three distinct behavioral scenarios, infusing an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 minutes before or two hours after ketamine infusion inhibited the antidepressant-like effects of ketamine (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively).

The intra-mPFC infusions of BDNF (100 ng/side) and IGF-1 (50 ng/side) had ketamine-like antidepressant-like effects, which were not prevented by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). In a mouse lipopolysaccharide (LPS)-induced depression paradigm, an intra-mPFC infusion of IGF-1 nAb 2 hours after ketamine prevented the antidepressant-like effects of ketamine. Through mechanistic target of rapamycin complex 1 activation, intra-mPFC IGF-1 infusion caused antidepressant-like effects in LPS-challenged rats.

These findings imply that sustained IGF-1 release in the mPFC, irrespective of BDNF, is required for ketamine's antidepressant-like effects.