Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers
4 affiliations
- 1Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD USA
- 2Microarrays and Single-Cell Genomics Core, National Human Genome Research Institute, Bethesda, MD USA
- 3Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD USA
- 4Section on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD USA
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 h with agents being investigated as rapid-acting antidepressants, including (2 R,6 R)-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, (2 R,6 R)-HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from (2 R,6 R)-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. Clinical Trial Registry: www.clinical trials.gov, NCT02484456.
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BibTeX
@article{johnston2026timedependent,
title = {{Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers}},
author = {Jenessa N. Johnston and Gregory H. Jones and Shiyong Peng and Peixiong Yuan and Mani Yavi and Bashkim Kadriu and Ioline D. Henter and Brandi Quintanilla and Abdel Elkahloun and Ruin Moaddel and Anton Schulmann and Nirmala Akula and Mark D. Kvarta and Francis J. McMahon and Carlos A. Zarate},
journal = {Molecular Psychiatry},
year = {2026},
month = jul,
doi = {10.1038/s41380-026-03768-0},
url = {https://doi.org/10.1038/s41380-026-03768-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers
AU - Jenessa N. Johnston
AU - Gregory H. Jones
AU - Shiyong Peng
AU - Peixiong Yuan
AU - Mani Yavi
AU - Bashkim Kadriu
AU - Ioline D. Henter
AU - Brandi Quintanilla
AU - Abdel Elkahloun
AU - Ruin Moaddel
AU - Anton Schulmann
AU - Nirmala Akula
AU - Mark D. Kvarta
AU - Francis J. McMahon
AU - Carlos A. Zarate
PY - 2026
DA - 2026/07/24
JO - Molecular Psychiatry
DO - 10.1038/s41380-026-03768-0
UR - https://doi.org/10.1038/s41380-026-03768-0
AB - 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 h with agents being investigated as rapid-acting antidepressants, including (2 R,6 R)-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, (2 R,6 R)-HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from (2 R,6 R)-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. Clinical Trial Registry: www.clinical trials.gov, NCT02484456.
SN - 1359-4184
SN - 1476-5578
ER -