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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\u2009h with agents being investigated as rapid-acting antidepressants, including (2\u2009\n                    <jats:italic>R<\/jats:italic>\n                    ,6\u2009\n                    <jats:italic>R<\/jats:italic>\n                    )-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\u2009\n                    <jats:italic>R<\/jats:italic>\n                    ,6\u2009\n                    <jats:italic>R<\/jats:italic>\n                    )-HNK showed distinct cell-type specific alterations: upregulation in excitatory neurons and concomitant downregulation of inhibitory neuron populations. Differentially expressed genes from (2\u2009\n                    <jats:italic>R<\/jats:italic>\n                    ,6\u2009\n                    <jats:italic>R<\/jats:italic>\n                    )-HNK-treated neurons also overlapped with CSF proteomic signatures from ketamine-treated individuals, supporting the model\u2019s 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.\n                    <jats:bold>Clinical Trial Registry<\/jats:bold>\n                    :\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.clinical\" ext-link-type=\"uri\">www.clinical<\/jats:ext-link>\n                    trials.gov, NCT02484456.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03768-0","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:12:51Z","timestamp":1784873571000},"page":"7157-7169","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2986-3179","authenticated-orcid":false,"given":"Jenessa N.","family":"Johnston","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory H.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peixiong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mani","family":"Yavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3809-9451","authenticated-orcid":false,"given":"Bashkim","family":"Kadriu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioline D.","family":"Henter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandi","family":"Quintanilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel","family":"Elkahloun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruin","family":"Moaddel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6323-4969","authenticated-orcid":false,"given":"Anton","family":"Schulmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmala","family":"Akula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1648","authenticated-orcid":false,"given":"Mark D.","family":"Kvarta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9469-305X","authenticated-orcid":false,"given":"Francis J.","family":"McMahon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Carlos A.","family":"Zarate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"3768_CR1","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1176\/ps.2009.60.11.1439","volume":"60","author":"BN Gaynes","year":"2009","unstructured":"Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. 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The contributions of the NIH authors are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. Drs. Zarate and Moaddel are listed as co-inventors on a patent for the use of (2\u2009\n                      R\n                      ,6\u2009\n                      R\n                      )-hydroxynorketamine, (\n                      S\n                      )-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (\n                      R,S\n                      )-ketamine in the treatment of depression and neuropathic pain and as co-inventors on a patent application for the use of (2\u2009\n                      R\n                      ,6\u2009\n                      R\n                      )-hydroxynorketamine and (2\n                      S\n                      ,6\n                      S\n                      )-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. They have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Kvarta holds and receives royalties from a patent for the use of negative modulators of GABA receptors containing \u03b15 subunits as rapid-acting antidepressants, with rights assigned to the University of Maryland, Baltimore. Dr. Kadriu is presently employed full-time and holds shares in Bristol Myers Squibb. He was previously employed by Johnson & Johnson and Jazz Pharmaceuticals, where he maintains share ownership. All other authors have no conflict of interest to disclose, financial or otherwise.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}