Time-Dependent Effects of Rapid-Acting Antidepressants in iPSC-Derived Neurons from Treatment-Resistant Depression and Healthy Volunteers.
Jenessa Johnston, Greg Jones, Shiyong Peng, Peixiong Yuan, Mani Yavi, Bashkim Kadriu, Ioline Henter, Brandi Quintanilla, Abdel G Elkahloun, Ruin Moaddel, Anton Schulmann, Nirmala Akula, Mark Kvarta, Francis Mcmahon, Carlos Zarate
Research square February 12, 2026 Peer reviewed DOI: 10.21203/rs.3.rs-8733841/v1 via PubMed
Summary
Induced pluripotent stem cells (iPSCs) from individuals with treatment-resistant depression (TRD) and healthy volunteers were used to model cortical neurons and investigate the effects of rapid-acting antidepressants like ketamine, psilocybin, LSD, and DOI. The study found that while these drugs have different initial targets, they produced highly correlated gene expression changes indicative of shared downstream effects, particularly involving inflammation and cellular growth pathways. Notably, HNK treatment led to specific alterations in excitatory and inhibitory neuron populations.
Study at a glance
| Design | experimental study |
|---|---|
| Population | individuals with treatment-resistant depression and healthy volunteers |
| Key finding | Overall gene expression changes induced by various rapid-acting antidepressants were highly correlated, suggesting shared downstream effects despite differing initial pharmacological targets. |
Abstract
Rapid-acting antidepressants like ketamine and serotonergic psychedelics show promise for treatment-resistant depression (TRD), but the molecular mechanisms that contribute to their therapeutic effects remain unclear. Induced pluripotent stem cells (iPSCs) offer a platform to model human cortical neurons and investigate drug effects in a human-relevant system. Here, iPSCs from individuals with TRD and healthy volunteers (HVs) were differentiated into mature cortical-like neurons and treated for six and 24 hours with agents being investigated as rapid-acting antidepressants, including (2R,6R)-hydroxynorketamine (HNK), psilocybin, lysergic acid diethylamide (LSD), and 2,5-Dimethoxy-4-iodoamphetamine (DOI). Bulk and single-cell RNA sequencing assessed global and cell-type-specific transcriptomic responses. Synaptic proteins were evaluated via Western blotting and immunocytochemistry. To validate translational relevance, transcriptomic results were compared to CSF proteomics from ketamine-treated HVs. Despite differing initial pharmacological targets, overall gene expression across all compounds was highly correlated at matched timepoints compared to vehicle control, suggesting shared downstream effects. Both glutamatergic and serotonergic drugs converged on pathways involving inflammation, mTORC1 signaling, and cellular growth. At the single-cell level, HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from HNK-treated neurons also overlapped with CSF proteomic signatures from ketamine-treated individuals, supporting the model's translational relevance. This study is the first to assess multiple putative rapid-acting antidepressants in parallel using an iPSC-derived neuron model. Both convergent and drug-specific changes in gene expression and pathway enrichment were observed across diverse compounds, supporting the use of human iPSC-derived neurons in antidepressant drug discovery. www.clinicaltrials.gov, NCT02484456.