ArticleMolecular psychiatry2018
Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide.
Article in Molecular psychiatry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers.
What it found
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Who cites it
134 citing papers in PubMed, 231 citations in OpenAlex.
- Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2020Trial
- CausalCellInfer: Prioritizing Cell-Type-Specific Disease Associations From Genetically Predicted Transcriptomes in Biobank Cohorts.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis.Molecular psychiatry · 2026Review
- Roles of autophagy in brain homeostasis and disease.Nature neuroscience · 2026Review
- Inhaled sphingosine reduces bronchial Pseudomonas aeruginosa burden during porcine ex vivo lung perfusion and shows tissue delivery in explanted human lungs.Scientific reports · 2026Article
- Hippocampal neuronal progranulin mediates estrogen‑deficiency‑induced affective vulnerability and lysosomal-autophagic dysfunction.Molecular psychiatry · 2026Article
- Metabolomic signatures of SSRI exposure during neural differentiation and correlation of lysophosphatidylcholines with early symptoms of neurodevelopmental disorders.EBioMedicine · 2026Article
- Spatial lipidomic and neuron-specific transcriptomic signatures in the nucleus accumbens reveal phospholipid dyshomeostasis in depression-related maladaptations.Translational psychiatry · 2026Article
- Gut microbiota dysbiosis drives depression-like behavior in adolescent rats via lysine-regulated mTOR autophagy pathway.Translational psychiatry · 2026Article
- From energy metabolism to mood regulation: The rise of lactate as a therapeutic target.Journal of advanced research · 2026Review
- Sphingolipids in Emotional Well-Being.Journal of neurochemistry · 2026Review
- Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- Retrospective analysis of the impact of antidepressants with anti-acid sphingomyelinase activity on survival of patients with glioblastoma.Journal of neuro-oncology · 2026Article
- Autophagy and Neuropsychiatric Disorders: Unraveling Molecular Mechanisms and Signaling Pathways.CNS & neurological disorders drug targets · 2026Review
- Review
- Chronic Stress Disrupts Immune and Endocrine Axis, Inducing Persistent Behavioral Impairments in Male Rats: In Silico and In Vivo Insights.Neurochemical research · 2025Article
- Psychosomatic - psychotherapeutic treatment of stress-related disorders impacts the sphingolipid metabolism towards increased sphingosine and sphingosine-1-phosphate levels.European archives of psychiatry and clinical neuroscience · 2025Article
- Autophagy Modulation by Antidepressants: Mechanisms and Implications.Neurochemical research · 2025Review
- Genome-wide identification of modulators of Chlamydia trachomatis parasitophorous vacuole stability highlights an important role for sphingolipid supply.PLoS biology · 2025Article
- A depression-associated protein FKBP5 functions in autophagy initiation through scaffolding the VPS34 complex.Molecular neurobiology · 2025Article
74 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 3 countries.
Funding
Abstract
Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B. Although treatment with amitriptyline or fluoxetine requires at least 12 days to achieve sphingomyelin accumulation and the subsequent biochemical and cellular changes, direct inhibition of sphingomyelin synthases with tricyclodecan-9-yl-xanthogenate (D609) results in rapid (within 3 days) accumulation of ceramide in the ER, activation of autophagy, and reversal of biochemical and behavioral signs of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioral changes typical of MDD. These findings identify sphingolipid-controlled autophagy as an important target for antidepressive treatment methods and provide a rationale for the development of novel antidepressants that act within a few days.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.