Evidence map›Paper›PMID 42498781›Full record

ArticleMolecular psychiatry2026

Time-dependent effects of rapid-acting antidepressants in iPSC-derived neurons from treatment-resistant depression and healthy volunteers.

Jenessa N Johnston, Gregory H Jones, Shiyong Peng, Peixiong Yuan, Mani Yavi, Bashkim Kadriu, Ioline D Henter, Brandi Quintanilla, Abdel Elkahloun, Ruin Moaddel and 5 more

Registry-linked trialAbstract read
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In one paragraph

Article in Molecular psychiatry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02484456 (An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101), which is not on this map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02484456 phase2completednot on this map

An Investigation of the Antidepressant Effects of the Glycine Receptor Antagonist AV 101 (4-chlorokynurenine) in Major Depressive Disorder

TypeinterventionalSponsorNational Institute of Mental Health (NIMH)Ran2015 to 2019Enrolled22ConditionsMajor DepressionArmsAV 101 (4-Chlorokynurenine), Placebo Comparator
3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors.

Jenessa N JohnstonExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. jenessa.johnston@nih.gov.ORCID http://orcid.org/0000-0003-2986-3179
Gregory H JonesExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Shiyong PengExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Peixiong YuanExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Mani YaviExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Bashkim KadriuExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-3809-9451
Ioline D HenterExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Brandi QuintanillaExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Abdel ElkahlounMicroarrays and Single-Cell Genomics Core, National Human Genome Research Institute, Bethesda, MD, USA.
Ruin MoaddelLaboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Anton SchulmannSection on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-6323-4969
Nirmala AkulaSection on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Mark D KvartaExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-1093-1648
Francis J McMahonSection on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0002-9469-305X
Carlos A ZarateExperimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

Funding

Glutamatergic Modulators for Rapid & Sustained Antidepressant EffectZIAMH002857 · NIMH · NATIONAL INSTITUTE OF MENTAL HEALTH · PI ZARATE, CARLOS · 2009 to 2025
$55.0M
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) ZIAMH002857U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) NIA z01-AG000297U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) NIH z01-AG000297
6 · The paper itself

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.

Identifiers

PMID42498781

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