Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology and Hepatology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Ophthalmology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
ASH 2024 Annual Meeting 2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Podcast | Sexual health in older age

Dr Holly Thomas helps us unpack the needlessly taboo subject of sex and sexual health in women of older age.

Listen now
ADVANCED SEARCH
Log in
Top
European Archives of Psychiatry and Clinical Neuroscience

Open Access 05-03-2025 | Post Traumatic Stress Disorder | Original Paper

Psychosomatic - psychotherapeutic treatment of stress-related disorders impacts the sphingolipid metabolism towards increased sphingosine and sphingosine-1-phosphate levels

Authors: Franziska Werner, Fabian Schumacher, Christiane Mühle, Werner Adler, Caterina Schug, Eva Schäflein, Eva Morawa, Burkhard Kleuser, Johannes Kornhuber, Yesim Erim, Cosima Rhein

Published in: European Archives of Psychiatry and Clinical Neuroscience

Login to get access

Abstract

Objective

Chronic stress is a risk factor for developing stress-induced mental disorders like major depression and post-traumatic stress disorder. Low-grade inflammatory processes seem to mediate this association. The sphingolipid metabolism with its most important lipid messengers ceramide and sphingosine-1-phosphate (S1P) was shown to play an important role in the pathophysiology of affective disorders and inflammation.

Method

We conducted an exploratory trial to investigate the effect of intensive psychosomatic - psychotherapeutic treatment of stress-induced disorders on the biological level. Before and after eight weeks of treatment, blood plasma of 67 patients was analyzed for sphingolipid levels and their metabolizing enzymes. Symptom severity of depression (PHQ-9), anxiety (GAD-7), and somatization (PHQ-15) was assessed in parallel.

Results

During psychosomatic - psychotherapeutic treatment, symptom severity of depression, anxiety, and somatization decreased significantly. Levels of the stress molecule cortisol decreased upon treatment. Enzymatic activities of secreted acid sphingomyelinase (S-ASM) and neutral sphingomyelinase (NSM) increased significantly upon treatment, as well as of neutral ceramidase (NC). Regarding the lipid level, the molar ratio of ceramide species Cer16:0 and Cer18:0 decreased upon treatment, whereas sphingosine and S1P levels increased.

Conclusions

Psychosomatic – psychotherapeutic treatment was associated with a reduction in specific ceramide ratios and an increase in sphingosine and S1P levels potentially resulting from increased activity of sphingolipid metabolizing enzymes. Stress-induced mental disorders might be associated with disturbed sphingolipid levels that seem to be balanced during psychosomatic treatment. This study offers a further piece of evidence that the sphingolipid metabolism could be involved in the pathophysiology of stress-induced disorders, and its analysis could be helpful for treatment monitoring.
Literature
1.
Cohen S, Janicki-Deverts D, Miller GE (2007) Psychological stress and disease. JAMA 298(14):1685–1687PubMedCrossRef
2.
Lupien SJ et al (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10(6):434–445PubMedCrossRef
3.
McEwen BS (1998) Stress, adaptation, and disease. Allostasis and allostatic load. Ann N Y Acad Sci 840:33–44PubMedCrossRef
4.
Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21(1):55–89PubMed
5.
Langgartner D, Lowry CA, Reber SO (2018) Old friends, immunoregulation, and stress resilience. Pflugers Arch
6.
Hannun YA, Obeid LM (2018) Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19(3):175–191PubMedCrossRef
7.
Goni FM, Alonso A (2002) Sphingomyelinases: enzymology and membrane activity. FEBS Lett 531(1):38–46PubMedCrossRef
8.
9.
Ishibashi Y et al (2007) A novel endoglycoceramidase hydrolyzes oligogalactosylceramides to produce galactooligosaccharides and ceramides. J Biol Chem 282(15):11386–11396PubMedCrossRef
10.
Okino N et al (2003) The reverse activity of human acid ceramidase. J Biol Chem 278(32):29948–29953PubMedCrossRef
11.
Oliveira TG et al (2016) The impact of chronic stress on the rat brain lipidome. Mol Psychiatry 21(1):80–88PubMedCrossRef
12.
Reichel M et al (2018) Chronic psychosocial stress in mice is associated with increased acid Sphingomyelinase activity in liver and serum and with hepatic C16:0-Ceramide accumulation. Front Psychiatry 9:496PubMedPubMedCentralCrossRef
13.
Schumacher F et al (2022) Stress induces major depressive disorder by a neutral Sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma. J Mol Med (Berl) 100(10):1493–1508PubMedCrossRef
14.
Kornhuber J et al (2005) High activity of acid Sphingomyelinase in major depression. J Neural Transm 112(11):1583–1590PubMedCrossRef
15.
16.
Brunkhorst-Kanaan N et al (2019) Targeted lipidomics reveal derangement of ceramides in major depression and bipolar disorder. Metabolism 95:65–76PubMedCrossRef
17.
Schumacher F et al (2022) Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice. J Biol Chem 298(8):102185PubMedPubMedCentralCrossRef
18.
19.
Liu X et al (2016) Plasma lipidomics reveals potential lipid markers of major depressive disorder. Anal Bioanal Chem 408(23):6497–6507PubMedCrossRef
20.
Moaddel R et al (2018) Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. Psychopharmacology 235(10):3017–3030PubMedPubMedCentralCrossRef
21.
Demirkan A et al (2013) Plasma phosphatidylcholine and sphingomyelin concentrations are associated with depression and anxiety symptoms in a Dutch family-based lipidomics study. J Psychiatr Res 47(3):357–362PubMedCrossRef
22.
Hammad SM et al (2012) Altered blood sphingolipidomics and elevated plasma inflammatory cytokines in combat veterans with Post-Traumatic stress disorder. Neurobiol Lipids 10:2PubMed
23.
Konjevod M et al (2022) Plasma lipidomics in subjects with combat posttraumatic stress disorder. Free Radic Biol Med 189:169–177PubMedCrossRef
24.
Dong MX et al (2021) Metabolomics profiling reveals altered lipid metabolism and identifies a panel of lipid metabolites as biomarkers for Parkinson’s disease related anxiety disorder. Neurosci Lett 745:135626PubMedCrossRef
25.
Zoicas I et al (2020) Ceramides affect alcohol consumption and depressive-like and anxiety-like behavior in a brain region- and ceramide species-specific way in male mice. Addict Biol 25(6):e12847PubMedCrossRef
26.
Zoicas I et al (2023) Development of comorbid depression after social fear conditioning in mice and its effects on brain sphingolipid metabolism. Cells, 12(10)
27.
Yang J et al (2020) Revision to psychopharmacology mRNA and MicroRNA profiles are associated with stress susceptibility and resilience induced by psychological stress in the prefrontal cortex. Psychopharmacology 237(10):3067–3093PubMedCrossRef
28.
Ginkel C et al (2012) Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelin-associated glycoprotein in oligodendrocytes. J Biol Chem 287(50):41888–41902PubMedPubMedCentralCrossRef
29.
Shan B et al (2020) Gut microbiome-derived lactate promotes to anxiety-like behaviors through GPR81 receptor-mediated lipid metabolism pathway. Psychoneuroendocrinology 117:104699PubMedCrossRef
30.
Rhein C et al (2021) mRNA expression of SMPD1 encoding acid Sphingomyelinase decreases upon antidepressant treatment. Int J Mol Sci, 22(11)
31.
Kornhuber J et al (2010) Functional inhibitors of acid Sphingomyelinase (FIASMAs): a novel Pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem 26(1):9–20PubMedCrossRef
32.
Mühle C et al (2019) Secretory acid Sphingomyelinase in the serum of medicated patients predicts the prospective course of depression. J Clin Med, 8(6)
33.
Elojeimy S et al (2006) New insights on the use of Desipramine as an inhibitor for acid ceramidase. FEBS Lett 580(19):4751–4756PubMedCrossRef
34.
Löwe B et al (2002) Gesundheitsfragebogen für Patienten (PHQ-D). Manual und Testunterlagen. 2. Auflage (PRIMEMD Patient Health Questionnaire (PHQ) — German version. Manual and materials (2nd ed).
35.
Kobel F, Morawa E, Erim Y (2020) Effectiveness of inpatient psychotherapy for patients with and without migratory background: do they benefit equally?? Front Psychiatry 11:542PubMedPubMedCentralCrossRef
36.
Philipps A et al (2019) Effectiveness of a multimodal, day clinic Group-Based treatment program for Trauma-Related disorders: differential therapy outcome for complex PTSD vs. Non-Complex Trauma-Related disorders. Front Psychiatry 10:800PubMedPubMedCentralCrossRef
37.
Mühle C, Kornhuber J (2017) Assay to measure Sphingomyelinase and ceramidase activities efficiently and safely. J Chromatogr A 1481:137–144PubMedCrossRef
38.
Muhle C, Kornhuber J (2023) Characterization of a neutral Sphingomyelinase activity in human serum and plasma. Int J Mol Sci, 24(3)
39.
40.
Naser E et al (2020) Characterization of the small molecule ARC39, a direct and specific inhibitor of acid Sphingomyelinase in vitro. J Lipid Res 61(6):896–910PubMedPubMedCentralCrossRef
41.
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc B 57:289–300CrossRef
42.
43.
Beumer W et al (2012) The immune theory of psychiatric diseases: a key role for activated microglia and Circulating monocytes. J Leukoc Biol 92(5):959–975PubMedCrossRef
44.
Sommershof A et al (2009) Substantial reduction of Naive and regulatory T cells following traumatic stress. Brain Behav Immun 23(8):1117–1124PubMedCrossRef
45.
Li Y et al (2010) Altered expression of CD4(+)CD25(+) regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J Affect Disord 124(1–2):68–75PubMedCrossRef
46.
Simon MS et al (2023) Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection. Brain Behav Immun Health 29:100608PubMedPubMedCentralCrossRef
47.
48.
Himmerich H et al (2010) Regulatory T cells increased while IL-1beta decreased during antidepressant therapy. J Psychiatr Res 44(15):1052–1057PubMedCrossRef
49.
Obermanns J et al (2021) Analysis of cytokine levels, T regulatory cells and serotonin content in patients with depression. Eur J Neurosci 53(10):3476–3489PubMedCrossRef
50.
Aoki M et al (2016) Sphingosine-1-Phosphate signaling in immune cells and inflammation: roles and therapeutic potential. Mediators Inflamm 2016:p8606878
51.
Velazquez FN et al (2021) Bioactive sphingolipids: advancements and contributions from the laboratory of dr. Lina M. Obeid. Cell Signal 79:109875PubMedCrossRef
52.
Corbett BF et al (2019) Sphingosine-1-phosphate receptor 3 in the medial prefrontal cortex promotes stress resilience by reducing inflammatory processes. Nat Commun 10(1):3146PubMedPubMedCentralCrossRef
53.
Maharaj A et al (2022) Insights from Long-term Follow-up of a Girl with adrenal insufficiency and Sphingosine-1-Phosphate lyase deficiency. J Endocr Soc 6(5):bvac020PubMedPubMedCentralCrossRef
54.
55.
Urs AN, Dammer E, Sewer MB (2006) Sphingosine regulates the transcription of CYP17 by binding to steroidogenic factor-1. Endocrinology 147(11):5249–5258PubMedCrossRef
56.
Rabano M et al (2003) Sphingosine-1-phosphate stimulates cortisol secretion. FEBS Lett 535(1–3):101–105PubMedCrossRef
57.
Ozbay T, Merrill AH Jr., Sewer MB (2004) ACTH regulates steroidogenic gene expression and cortisol biosynthesis in the human adrenal cortex via sphingolipid metabolism. Endocr Res 30(4):787–794PubMedCrossRef
Metadata
Title
Psychosomatic - psychotherapeutic treatment of stress-related disorders impacts the sphingolipid metabolism towards increased sphingosine and sphingosine-1-phosphate levels
Authors
Franziska Werner
Fabian Schumacher
Christiane Mühle
Werner Adler
Caterina Schug
Eva Schäflein
Eva Morawa
Burkhard Kleuser
Johannes Kornhuber
Yesim Erim
Cosima Rhein
Publication date
05-03-2025
Publisher
Springer Berlin Heidelberg
Published in
European Archives of Psychiatry and Clinical Neuroscience
Print ISSN: 0940-1334
Electronic ISSN: 1433-8491
DOI
https://doi.org/10.1007/s00406-025-01985-2