In neurons derived from induced pluripotent stem cells of five women with treatment-resistant depression (average age 40.2 years), both the glycoprotein reelin and the ketamine metabolite (2R,6R)-hydroxynorketamine increased expression of several synaptic proteins (GluA1, PSD-95, Dab1, Synapsin I, and p-ERK) within one hour, with effects declining by 24 hours. Gene expression changes were similar for both compounds, though only reelin upregulated mTORC1 signaling. The findings suggest that iPSC-derived neurons may serve as a useful in vitro model for studying treatment-resistant depression and testing potential therapeutics.
Rapid-acting antidepressants such as ketamine and psychedelics share common downstream effects on gene expression in human cortical neurons, despite targeting different initial receptors. Using stem cells from people with treatment-resistant depression and healthy volunteers, neurons were treated with several compounds. After 6 and 24 hours, gene activity was highly correlated across all drugs, converging on pathways related to inflammation, mTORC1 signaling, and cell growth. One compound, HNK, increased gene activity in excitatory neurons and decreased it in inhibitory neurons. These gene changes matched protein changes in spinal fluid from people given ketamine, supporting the model's relevance for studying antidepressant mechanisms.