ArticleCellular and molecular life sciences : CMLS2024
Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms.
Article in Cellular and molecular life sciences : CMLS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 17 citations in OpenAlex.
- Prophylactic esketamine to reduce postpartum depression in primiparae: A multicentre, double-blind, randomised clinical trial.European journal of anaesthesiology · 2026Trial
- The hippocampus as a central hub in ketamine's antidepressant action: from molecules to circuit rewiring.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- Sympathetic activation but not dissociation linked to ketamine's sustained antidepressant effect.Therapeutic advances in psychopharmacology · 2026Article
- Rapid-acting NMDA and GABAergic Modulators in Mood Disorders: From Synaptic Mechanisms to Clinical Practice.Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology · 2025Review
- Review
- Adult hippocampal neurogenesis: New avenues for treatment of brain disorders.Stem cell reports · 2025Review
- A comprehensive review on adaptive plasticity and recovery mechanisms post-acquired brain injury.Neuroprotection (Chichester, England) · 2025Review
- Review
- Adult Hippocampal Neurogenesis as a Therapeutic Target in Fetal Alcohol Spectrum Disorder.Advances in experimental medicine and biology · 2025Review
- Extent and activity of adult hippocampal neurogenesis.Frontiers in neuroscience · 2025Review
- Neuroplasticity and Mechanisms of Action of Acute and Chronic Treatment with Antidepressants in Preclinical Studies.Biomedicines · 2024Review
- Fast-acting antidepressant-like effects of ketamine in aged male rats.Pharmacological reports : PR · 2024Article
- Beyond therapeutic potential: a systematic investigation of ketamine misuse in patients with depressive disorders.Discover mental health · 2024Review
- Jujuboside A Regulates Calcium Homeostasis and Structural Plasticity to Alleviate Depression-Like Behavior via Shh Signaling in Immature Neurons.Drug design, development and therapy · 2024Article
- Pharmacological interventions for alcohol use disorder: novel insights from recent clinical trials.Expert review of clinical pharmacologyReview
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine's rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained - but not the rapid - behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine's sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine's sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine's dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.
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