Exploring the role of TNF-α, TGF-β, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis.
Bipolar disorder
Continuum
IL-6
Schizophrenia
TGF-β
TNF-α
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
04 Oct 2024
04 Oct 2024
Historique:
received:
20
06
2024
accepted:
23
09
2024
medline:
5
10
2024
pubmed:
5
10
2024
entrez:
4
10
2024
Statut:
epublish
Résumé
Psychotic and mood disorders are discussed as part of the same continuum. The potential role of immune dysregulation in defining their clinical presentations, however, remains unclear. Differences in TNF-α, IL-6 and TGF-β levels were investigated in 143 patients with schizophrenia (SCH = 63) and bipolar disorder (BD = 80), in remission. Cytokines were evaluated against the dimensional assessment of psychosis and affective symptoms using the schizo-bipolar scale, together with the severity of the same symptom domains measured by the brief psychiatric rating scale (BPRS). Lower TGF-β was associated with more lifetime episodes, family risk for psychosis, and more severe mood and psychotic symptoms in all patients. BPRS Affect symptoms domain correlated with lower TGF-β levels in BD, and higher TGF-β levels in SCH patients. Using moderated mediation analysis, TGF-β was a relevant predictor only in the setting of non-categorical symptom distribution, with familial risk for psychosis confirmed as a significant moderator. Severity of BPRS Affect symptoms domain was an independent predictor of inclination towards the psychosis spectrum. The underlying immune dysregulation may be shared by the disorders, rather than a unique characteristic of each, having significant implications for our understanding of the continuum vs. categorical approach to psychosis and mood disorders.
Identifiants
pubmed: 39367011
doi: 10.1038/s41598-024-73937-0
pii: 10.1038/s41598-024-73937-0
doi:
Substances chimiques
Transforming Growth Factor beta
0
Interleukin-6
0
Tumor Necrosis Factor-alpha
0
IL6 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23117Informations de copyright
© 2024. The Author(s).
Références
Morrissette, D. & Stahl, S. Affective symptoms in schizophrenia. Drug Discov. Today Therap. Strateg.8, 3–9 (2011).
doi: 10.1016/j.ddstr.2011.10.005
Fountoulakis, K. N. et al. Mood symptoms in stabilized patients with schizophrenia: A bipolar type with predominant psychotic features? Psychiatr. Danub.29, 148–154 (2017).
pubmed: 28636572
doi: 10.24869/psyd.2017.148
Sorella, S. et al. Testing the expanded continuum hypothesis of schizophrenia and bipolar disorder. Neural and psychological evidence for shared and distinct mechanisms. Neuroimage Clin.23, 101854 (2019).
doi: 10.24869/psyd.2017.148
Keshavan, M. S. et al. A dimensional approach to the psychosis spectrum between bipolar disorder and schizophrenia: The schizo-bipolar scale. Schizophr. Res.133, 250–254 (2011).
pubmed: 21996268
pmcid: 3381911
doi: 10.1016/j.schres.2011.09.005
Lesh, T. A. et al. Cytokine alterations in first-episode schizophrenia and bipolar disorder: Relationships to brain structure and symptoms. J. Neuroinflamm.15, 165 (2018).
doi: 10.1186/s12974-018-1197-2
Momtazmanesh, S., Zare-Shahabadi, A. & Rezaei, N. Cytokine alterations in schizophrenia: An updated review. Front. Psychiatry10, 892 (2019).
pubmed: 31908647
pmcid: 6915198
doi: 10.3389/fpsyt.2019.00892
Zhang, Y. et al. Peripheral cytokine levels across psychiatric disorders: A systematic review and network meta-analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiatry125, 110740 (2023).
doi: 10.1016/j.pnpbp.2023.110740
Barbosa, I. G., Bauer, M. E., Machado-Vieira, R. & Teixeira, A. L. Cytokines in bipolar disorder: Paving the way for neuroprogression. Neural Plast.2014, 360481 (2014).
pubmed: 25313338
pmcid: 4172873
doi: 10.1155/2014/360481
Muneer, A. Bipolar disorder: Role of inflammation and the development of disease biomarkers. Psychiatry Investig.13, 18–33 (2016).
pubmed: 26766943
doi: 10.4306/pi.2016.13.1.18
Borovcanin, M. et al. 2030—Can TGF-β be a valuable marker for psychosis? Eur. Psychiatry28, 1 (2013).
doi: 10.1016/S0924-9338(13)76960-8
Doğanavşargil Baysal, Ö. et al. Levels of TNF alpha, soluble TNF receptors (sTNF-R1, sTNF-R2) in bipolar disorder. Noro Psikiyatr. Ars.57, 136–140 (2019).
pubmed: 32550780
pmcid: 7285647
Luo, Y., He, H., Zhang, J., Ou, Y. & Fan, N. Changes in serum TNF-α, IL-18, and IL-6 concentrations in patients with chronic schizophrenia at admission and at discharge. Compr. Psychiatry90, 82–87 (2019).
pubmed: 30782515
doi: 10.1016/j.comppsych.2019.01.003
Goldsmith, D. R., Rapaport, M. H. & Miller, B. J. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatry21, 1696–1709 (2016).
pubmed: 26903267
pmcid: 6056174
doi: 10.1038/mp.2016.3
Li, H. et al. IL-23 and TGF-β1 levels as potential predictive biomarkers in treatment of bipolar I disorder with acute manic episode. J. Affect. Disord.174, 361–366 (2015).
pubmed: 25545602
doi: 10.1016/j.jad.2014.12.033
Kim, Y.-K. et al. T-helper types 1, 2, and 3 cytokine interactions in symptomatic manic patients. Psychiatry Res.129, 267–272 (2004).
pubmed: 15661320
doi: 10.1016/j.psychres.2004.08.005
Goldsmith, D. R. et al. TNF-α and IL-6 are associated with the deficit syndrome and negative symptoms in patients with chronic schizophrenia. Schizophr. Res.199, 281–284 (2018).
pubmed: 29499967
pmcid: 6111000
doi: 10.1016/j.schres.2018.02.048
Wu, X. et al. Are serum levels of inflammatory markers associated with the severity of symptoms of bipolar disorder? Front. Psychiatry13, 1063479 (2023).
pubmed: 36741577
pmcid: 9894870
doi: 10.3389/fpsyt.2022.1063479
Boiko, A. S., Mednova, I. A., Kornetova, E. G., Bokhan, N. A. & Ivanova, S. A. Serum growth factors in schizophrenia patients. CIMB45, 3291–3301 (2023).
pubmed: 37185739
pmcid: 10136551
doi: 10.3390/cimb45040215
Chourbaji, S. et al. IL-6 knockout mice exhibit resistance to stress-induced development of depression-like behaviors. Neurobiol. Dis.23, 587–594 (2006).
pubmed: 16843000
doi: 10.1016/j.nbd.2006.05.001
Valvassori, S. S. et al. Depressive-like behavior accompanies neuroinflammation in an animal model of bipolar disorder symptoms induced by ouabain. Pharmacol. Biochem. Behav.219, 173434 (2022).
pubmed: 35901967
doi: 10.1016/j.pbb.2022.173434
Behrens, M. M., Ali, S. S. & Dugan, L. L. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J. Neurosci.28, 13957–13966 (2008).
pubmed: 19091984
pmcid: 2752712
doi: 10.1523/JNEUROSCI.4457-08.2008
Lin, C. et al. Relationship between TNF-α levels and psychiatric symptoms in first-episode drug-naïve patients with schizophrenia before and after risperidone treatment and in chronic patients. BMC Psychiatry21, 561 (2021).
pubmed: 34763685
pmcid: 8588730
doi: 10.1186/s12888-021-03569-5
Nayem, J. et al. Altered serum TNF-α and MCP-4 levels are associated with the pathophysiology of major depressive disorder: A case-control study results. PLoS ONE18, e0294288 (2023).
pubmed: 37967104
pmcid: 10651034
doi: 10.1371/journal.pone.0294288
Dobolyi, A., Vincze, C., Pál, G. & Lovas, G. The neuroprotective functions of transforming growth factor beta proteins. Int. J. Mol. Sci.13, 8219–8258 (2012).
pubmed: 22942700
pmcid: 3430231
doi: 10.3390/ijms13078219
Ben-Azu, B. et al. Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia. Int. Immunopharmacol.70, 338–353 (2019).
pubmed: 30852289
doi: 10.1016/j.intimp.2019.02.052
Kim, Y.-K. et al. Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry28, 1129–1134 (2004).
doi: 10.1016/j.pnpbp.2004.05.047
Kim, Y.-K. et al. Cytokine changes and tryptophan metabolites in medication-naïve and medication-free schizophrenic patients. Neuropsychobiology59, 123–129 (2009).
pubmed: 19390223
doi: 10.1159/000213565
Güven, G. et al. Peripheral expression of IL-6, TNF-α and TGF-β1 in Alzheimer’s disease patients. Turk. J. Immunol.12, 28–34 (2024).
doi: 10.4274/tji.galenos.2024.76598
Lambert, M., Karow, A., Leucht, S., Schimmelmann, B. G. & Naber, D. Remission in schizophrenia: Validity, frequency, predictors, and patients’ perspective 5 years later. Dial. Clin. Neurosci.12, 393–407 (2010).
doi: 10.31887/DCNS.2010.12.3/mlambert
Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry23, 56–62 (1960).
pubmed: 14399272
pmcid: 495331
doi: 10.1136/jnnp.23.1.56
Young, R. C., Biggs, J. T., Ziegler, V. E. & Meyer, D. A. A rating scale for mania: Reliability, validity and sensitivity. Br. J. Psychiatry133, 429–435 (1978).
pubmed: 728692
doi: 10.1192/bjp.133.5.429
Shafer, A. Meta-analysis of the brief psychiatric rating scale factor structure. Psychol. Assess.17, 324–335 (2005).
pubmed: 16262458
doi: 10.1037/1040-3590.17.3.324
Sakinyte, K. & Holmberg, C. Psychometric and clinical evaluation of schizophrenia remission criteria in outpatients with psychotic disorders. BMC Psychiatry23, 207 (2023).
pubmed: 36978160
pmcid: 10052840
doi: 10.1186/s12888-023-04701-3
Durgam, S. et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: A phase II trial. Bipolar Disord.17, 63–75 (2015).
pubmed: 25056368
doi: 10.1111/bdi.12238
Tohen, M. et al. The International Society for Bipolar Disorders (ISBD) task force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord.11, 453–473 (2009).
pubmed: 19624385
doi: 10.1111/j.1399-5618.2009.00726.x
Potkin, S. G. et al. The neurobiology of treatment-resistant schizophrenia: Paths to antipsychotic resistance and a roadmap for future research. NPJ Schizophr.6, 1 (2020).
pubmed: 31911624
pmcid: 6946650
doi: 10.1038/s41537-019-0090-z
Fountoulakis, K. N. et al. The CINP guidelines on the definition and evidence-based interventions for treatment-resistant bipolar disorder. Int. J. Neuropsychopharmacol.23, 230–256 (2020).
pubmed: 31802122
doi: 10.1093/ijnp/pyz064
Witkowska, A. M. & Borawska, M. H. Soluble intercellular adhesion molecule-1 (sICAM-1): An overview. Eur. Cytokine Netw.15, 91–98 (2004).
pubmed: 15319166
Hall, R. C. Global assessment of functioning. A modified scale. Psychosomatics36, 267–275 (1995).
pubmed: 7638314
doi: 10.1016/S0033-3182(95)71666-8
Sheehan, D. V. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry59(Suppl 20), 22–33 (1998).
pubmed: 9881538
The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines (World Health Organization, 1992).
Fico, G. et al. Duration of untreated illness and bipolar disorder: Time for a new definition? Results from a cross-sectional study. J. Affect. Disord.294, 513–520 (2021).
pubmed: 34330047
doi: 10.1016/j.jad.2021.07.062
Howes, O. D. et al. The clinical significance of duration of untreated psychosis: An umbrella review and random-effects meta-analysis. World Psychiatry20, 75–95 (2021).
pubmed: 33432766
pmcid: 7801839
doi: 10.1002/wps.20822
Jurisic, V. Multiomic analysis of cytokines in immuno-oncology. Expert Rev. Proteom.17, 663–674 (2020).
doi: 10.1080/14789450.2020.1845654
Hayes, A. F. Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach (Guilford Publications, 2017).
Zhou, X., Tian, B. & Han, H.-B. Serum interleukin-6 in schizophrenia: A system review and meta-analysis. Cytokine141, 155441 (2021).
pubmed: 33529887
doi: 10.1016/j.cyto.2021.155441
Luo, Y., He, H., Zhang, M., Huang, X. & Fan, N. Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients. Psychiatry Res.244, 19–23 (2016).
pubmed: 27455146
doi: 10.1016/j.psychres.2016.07.027
Chen, P. et al. Association of serum interleukin-6 with negative symptoms in stable early-onset schizophrenia. World J. Psychiatry14, 794–803 (2024).
pubmed: 38984340
pmcid: 11230098
doi: 10.5498/wjp.v14.i6.794
Al-Hakeim, H. K., Al-Rammahi, D. A. & Al-Dujaili, A. H. IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J. Affect. Disord.182, 106–114 (2015).
pubmed: 25985379
doi: 10.1016/j.jad.2015.04.044
Kunz, M. et al. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: Differences in pro- and anti-inflammatory balance. Braz. J. Psychiatry33, 268–274 (2011).
pubmed: 21971780
Su, L. et al. Comparison of olfactory function, cognitive function and serum tumor necrosis factor-α between bipolar and schizophrenic patients in the remission stage. BMC Psychiatry23, 811 (2023).
pubmed: 37936082
pmcid: 10631022
doi: 10.1186/s12888-023-05330-6
Lv, M. H. et al. Decreased serum TNF-alpha levels in chronic schizophrenia patients on long-term antipsychotics: Correlation with psychopathology and cognition. Psychopharmacology (Berl.)232, 165–172 (2015).
pubmed: 24958229
doi: 10.1007/s00213-014-3650-y
Ouyang, L. et al. IL-17 and TNF-β: Predictive biomarkers for transition to psychosis in ultra-high risk individuals. Front. Psychiatry13, 1072380 (2022).
pubmed: 36590607
pmcid: 9800867
doi: 10.3389/fpsyt.2022.1072380
Ergün, S. et al. The relationship between psychopathology and cognitive functions with cytokines in clinically stable patients with schizophrenia. Psychiatry Clin. Psychopharmacol.28, 66–72 (2018).
doi: 10.1080/24750573.2017.1380920
Kapelski, P. et al. Association study of functional polymorphisms in interleukins and interleukin receptors genes: IL1A, IL1B, IL1RN, IL6, IL6R, IL10, IL10RA and TGFB1 in schizophrenia in Polish population. Schizophr. Res.169, 1–9 (2015).
pubmed: 26481614
doi: 10.1016/j.schres.2015.10.008
Kartalci, S., Karabulut, A. B., Erbay, L. G. & Acar, C. Effects of electroconvulsive therapy on some inflammatory factors in patients with treatment-resistant schizophrenia. J. ECT32, 174–179 (2016).
pubmed: 26886746
doi: 10.1097/YCT.0000000000000303
Miller, B. J., Buckley, P., Seabolt, W., Mellor, A. & Kirkpatrick, B. Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects. Biol. Psychiatry70, 663–671 (2011).
pubmed: 21641581
pmcid: 4071300
doi: 10.1016/j.biopsych.2011.04.013
Meyer, U., Schwarz, M. J. & Müller, N. Inflammatory processes in schizophrenia: A promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacol. Ther.132, 96–110 (2011).
pubmed: 21704074
doi: 10.1016/j.pharmthera.2011.06.003
Gur, R. E. et al. Flat affect in schizophrenia: Relation to emotion processing and neurocognitive measures. Schizophr. Bull.32, 279–287 (2006).
pubmed: 16452608
pmcid: 2632232
doi: 10.1093/schbul/sbj041
So, S.H.-W. et al. Moment-to-moment affective dynamics in schizophrenia and bipolar disorder. Eur. Psychiatry66, e67 (2023).
pubmed: 37544924
pmcid: 10594258
doi: 10.1192/j.eurpsy.2023.2438
Henry, C. et al. Affective lability and affect intensity as core dimensions of bipolar disorders during euthymic period. Psychiatry Res.159, 1–6 (2008).
pubmed: 18295902
doi: 10.1016/j.psychres.2005.11.016
Schirmbeck, F. et al. Impact of comorbid affective disorders on longitudinal clinical outcomes in individuals at ultra-high risk for psychosis. Schizophrenia Bull.48, 100–110 (2022).
doi: 10.1093/schbul/sbab088
Myint, A.-M., Leonard, B. E., Steinbusch, H. W. M. & Kim, Y.-K. Th1, Th2, and Th3 cytokine alterations in major depression. J. Affect. Disord.88, 167–173 (2005).
pubmed: 16126278
doi: 10.1016/j.jad.2005.07.008
Musil, R. et al. Elevated macrophage migration inhibitory factor and decreased transforming growth factor-beta levels in major depression—No influence of celecoxib treatment. J. Affect. Disord.134, 217–225 (2011).
pubmed: 21684012
doi: 10.1016/j.jad.2011.05.047
Kapelski, P. et al. Family association study of transforming growth factor Beta1 gene polymorphisms in schizophrenia. Psychiatr. Pol.50, 761–770 (2016).
pubmed: 27847927
doi: 10.12740/PP/61273
Maes, M. & Carvalho, A. F. The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol. Neurobiol.55, 8885–8903 (2018).
pubmed: 29611101
doi: 10.1007/s12035-018-1016-x
Zhong, H. et al. Neonatal inflammation via persistent TGF-β1 downregulation decreases GABAAR expression in basolateral amygdala leading to the imbalance of the local excitation-inhibition circuits and anxiety-like phenotype in adult mice. Neurobiol. Dis.169, 105745 (2022).
pubmed: 35513229
doi: 10.1016/j.nbd.2022.105745
Sun, M. et al. Canonical TGF-β signaling is required for the balance of excitatory/inhibitory transmission within the hippocampus and prepulse inhibition of acoustic startle. J. Neurosci.30, 6025–6035 (2010).
pubmed: 20427661
pmcid: 6632596
doi: 10.1523/JNEUROSCI.0789-10.2010
Kalkman, H. O. Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia. Pharmacol. Therap.121, 115–122 (2009).
doi: 10.1016/j.pharmthera.2008.11.002
Krieglstein, K., Suter-Crazzolara, C., Fischer, W. H. & Unsicker, K. TGF-beta superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J14, 736–742 (1995).
pubmed: 7882977
pmcid: 398139
doi: 10.1002/j.1460-2075.1995.tb07052.x
Mathieu, P., Piantanida, A. P. & Pitossi, F. Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation17, 200–201 (2010).
pubmed: 20134202
doi: 10.1159/000258723
Chleilat, E. et al. TGF-β signaling regulates development of midbrain dopaminergic and hindbrain serotonergic neuron subgroups. Neuroscience381, 124–137 (2018).
pubmed: 29689292
doi: 10.1016/j.neuroscience.2018.04.019
Fillman, S. G., Sinclair, D., Fung, S. J., Webster, M. J. & Shannon Weickert, C. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl. Psychiatry4, e365 (2014).
pubmed: 24569695
pmcid: 3944638
doi: 10.1038/tp.2014.8
Jovanovic, A. M. et al. Childhood maltreatment correlates with higher concentration of transforming growth factor beta (TGF-β) in adult patients with major depressive disorder. Psychiatry Res.301, 113987 (2021).
pubmed: 34023675
doi: 10.1016/j.psychres.2021.113987
Zwicker, A. et al. Basic symptoms in offspring of parents with mood and psychotic disorders. BJPsych Open5, e54 (2019).
pubmed: 31530297
pmcid: 6582212
doi: 10.1192/bjo.2019.40
Kirli, U. et al. Psychotic experiences and mood episodes predict each other bidirectionally: A 6-year follow-up study in a community-based population. Soc. Psychiatry Psychiatr. Epidemiol.54, 331–341 (2019).
pubmed: 30671600
doi: 10.1007/s00127-018-1641-8
Trotta, A. et al. Familial risk and childhood adversity interplay in the onset of psychosis. BJPsych Open1, 6–13 (2015).
pubmed: 27703716
pmcid: 4995579
doi: 10.1192/bjpo.bp.115.000158
Boks, M. P. M., Leask, S., Vermunt, J. K. & Kahn, R. S. The structure of psychosis revisited: The role of mood symptoms. Schizophr. Res.93, 178–185 (2007).
pubmed: 17383856
doi: 10.1016/j.schres.2007.02.017
Qiu, A. et al. Canonical TGF-β signaling regulates the relationship between prenatal maternal depression and amygdala development in early life. Transl. Psychiatry11, 170 (2021).
pubmed: 33723212
pmcid: 7961018
doi: 10.1038/s41398-021-01292-z
Cowan, H. R., Mittal, V. A., Allen, D. N., Gold, J. M. & Strauss, G. P. Heterogeneity of emotional experience in schizophrenia: Trait affect profiles predict clinical presentation and functional outcome. J. Abnorm. Psychol.129, 760–767 (2020).
pubmed: 32584084
pmcid: 7541640
doi: 10.1037/abn0000554
Deng, Z. et al. TGF-β signaling in health, disease, and therapeutics. Signal Transduct. Target Ther.9, 61 (2024).
pubmed: 38514615
pmcid: 10958066
doi: 10.1038/s41392-024-01764-w