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Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects?

Molecular Psychiatry (2024)Cite this article

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Abstract

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30–40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine’s mechanism of action in mood disorders; while many studies have focused on ketamine’s role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system’s abilities to modulate glutamatergic transmission, and our current understanding of ketamine’s anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine’s mechanism of action. This review will summarize ketamine’s anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.

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Fig. 1: Proposed immunoregulatory mechanisms of ketamine’s antidepressant actions.

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References

  1. World Health Organization. Suicide worldwide in 2019: global health estimates. Geneva: WHO; 2021.

  2. McGrath T, Baskerville R, Rogero M, Castell L. Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases. Nutrients. 2022;14:917. https://doi.org/10.3390/nu14050917. Published 2022 Feb 22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Mulinari S. Monoamine theories of depression: historical impact on biomedical research. J Hist Neurosci. 2012;21:366–92. https://doi.org/10.1080/0964704X.2011.623917.

    Article  PubMed  Google Scholar 

  4. Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17. https://doi.org/10.1176/ajp.2006.163.11.1905.

    Article  PubMed  Google Scholar 

  5. Rush AJ, Warden D, Wisniewski SR, Fava M, Trivedi MH, Gaynes BN. et al. STAR*D: revising conventional wisdom. CNS Drugs. 2009;23:627–47. https://doi.org/10.2165/00023210-200923080-00001.

    Article  PubMed  Google Scholar 

  6. Saveanu R, Etkin A, Duchemin AM, Goldstein-Piekarski A, Gyurak A, Debattista C. The international Study to Predict Optimized Treatment in Depression (iSPOT-D): outcomes from the acute phase of antidepressant treatment. J Psychiatr Res. 2015;61:1–12. https://doi.org/10.1016/j.jpsychires.2014.12.018.

    Article  PubMed  Google Scholar 

  7. Gaynes BN. Identifying difficult-to-treat depression: differential diagnosis, subtypes, and comorbidities. J Clin Psychiatry. 2009;70:10–15. https://doi.org/10.4088/JCP.8133su1c.02.

    Article  PubMed  Google Scholar 

  8. Sforzini L, Worrell C, Kose M, Anderson IM, Aouizerate B, Arolt V. et al. A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials. Mol Psychiatry. 2022;27:1286–99. https://doi.org/10.1038/s41380-021-01381-x.

    Article  CAS  PubMed  Google Scholar 

  9. McIntyre RS, Rosenblat JD, Nemeroff CB, Sanacora G, Murrough JW, Berk M. et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am J Psychiatry. 2021;178:383–99. https://doi.org/10.1176/appi.ajp.2020.20081251.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Phillips JL, Norris S, Talbot J, Birmingham M, Hatchard T, Ortiz A. et al. Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial. Am J Psychiatry. 2019;176:401–9. https://doi.org/10.1176/appi.ajp.2018.18070834.

    Article  PubMed  Google Scholar 

  11. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ. et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety. 2014;31:335–43. https://doi.org/10.1002/da.22253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Feder A, Parides MK, Murrough JW, Perez A, Morgan JE, Saxena S. et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71:681–8. https://doi.org/10.1001/jamapsychiatry.2014.62.

    Article  CAS  PubMed  Google Scholar 

  13. Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signaling in depression: progress and prospects. Nat Rev Drug Discov. 2017;16:472–86. https://doi.org/10.1038/nrd.2017.16.

    Article  CAS  PubMed  Google Scholar 

  14. Freudenberg F, Celikel T, Reif A. The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity. Neurosci Biobehav Rev. 2015;52:193–206. https://doi.org/10.1016/j.neubiorev.2015.03.005.

    Article  CAS  PubMed  Google Scholar 

  15. Yang Y, Song Y, Zhang X, Zhao W, Ma T, Liu Y. et al. Ketamine relieves depression-like behaviors induced by chronic postsurgical pain in rats through anti-inflammatory, anti-oxidant effects and regulating BDNF expression. Psychopharmacology (Berl). 2020;237:1657–69. https://doi.org/10.1007/s00213-020-05490-3.

    Article  CAS  PubMed  Google Scholar 

  16. Williams NR, Heifets BD, Blasey C, Sudheimer K, Pannu J, Pankow H. et al. Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. Am J Psychiatry. 2018;175:1205–15. https://doi.org/10.1176/appi.ajp.2018.18020138.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zanos P, Thompson SM, Duman RS, Zarate CAJr, Gould TD. Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS Drugs. 2018;32:197–227. https://doi.org/10.1007/s40263-018-0492-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kadriu B, Greenwald M, Henter ID, Gilbert JR, Kraus C, Park LT. et al. Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. Int J Neuropsychopharmacol. 2021;24:8–21. https://doi.org/10.1093/ijnp/pyaa087.

    Article  CAS  PubMed  Google Scholar 

  19. Greeson JM, Gettes DR, Spitsin S, Dubé B, Benton TD, Lynch KG. et al. The Selective Serotonin Reuptake Inhibitor Citalopram Decreases Human Immunodeficiency Virus Receptor and Coreceptor Expression in Immune Cells. Biol psychiatry. 2016;80:33–39. https://doi.org/10.1016/j.biopsych.2015.11.003.

    Article  CAS  PubMed  Google Scholar 

  20. Hannestad J, DellaGioia N, Ortiz N, Pittman B, Bhagwagar Z. Citalopram reduces endotoxin-induced fatigue. Brain, Behav, Immun. 2011;25:256–9. https://doi.org/10.1016/j.bbi.2010.10.013.

    Article  CAS  PubMed  Google Scholar 

  21. Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R. et al. Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacol : Off Publ Am Coll Neuropsychopharmacol. 1999;20:370–9. https://doi.org/10.1016/S0893-133X(98)00088-8.

    Article  CAS  Google Scholar 

  22. Obuchowicz E, Bielecka AM, Paul-Samojedny M, Pudełko A, Kowalski J. Imipramine and fluoxetine inhibit LPS-induced activation and affect morphology of microglial cells in the rat glial culture. Pharmacol Rep.: PR. 2014;66:34–43. https://doi.org/10.1016/j.pharep.2013.08.002.

    Article  CAS  PubMed  Google Scholar 

  23. Zhou S, Ye D, Xia H, Xu H, Tang W, Tang Q. et al. Sertraline inhibits stress-induced tumor growth through regulating CD8 + T cell-mediated anti-tumor immunity. Anti-cancer drugs. 2022;33:935–42. https://doi.org/10.1097/CAD.0000000000001383.

    Article  CAS  PubMed  Google Scholar 

  24. Irwin MR, & Slavich GM Psychoneuroimmunology. In J. T. Cacioppo, L. G. Tassinary, & G. G. Berntson (Eds.), Handbook of psychophysiology (4th ed., pp. 377–98). New York, NY: Cambridge University Press (2017).

  25. Smith RS. The macrophage theory of depression [published correction appears in Med Hypotheses 1991 Oct;36(2):178]. Med Hypotheses. 1991;35:298–306. https://doi.org/10.1016/0306-9877(91)90272-z.

    Article  CAS  PubMed  Google Scholar 

  26. Ur E, White PD, Grossman A. Hypothesis: cytokines may be activated to cause depressive illness and chronic fatigue syndrome. Eur Arch Psychiatry Clin Neurosci. 1992;241:317–22. https://doi.org/10.1007/BF02195983.

    Article  CAS  PubMed  Google Scholar 

  27. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35. https://doi.org/10.1007/s00401-009-0619-8.

    Article  PubMed  Google Scholar 

  28. Graeber MB, Li W, Rodriguez ML. Role of microglia in CNS inflammation. FEBS Lett. 2011;585:3798–3805. https://doi.org/10.1016/j.febslet.2011.08.033.

    Article  CAS  PubMed  Google Scholar 

  29. Medina A, Watson SJ, Bunney W,Jr, Myers RM, Schatzberg A, Barchas J. et al. Evidence for alterations of the glial syncytial function in major depressive disorder. J Psychiatr Res. 2016;72:15–21. https://doi.org/10.1016/j.jpsychires.2015.10.010.

    Article  PubMed  Google Scholar 

  30. Ma X, Yang S, Zhang Z, Liu L, Shi W, Yang S. et al. Rapid and sustained restoration of astrocytic functions by ketamine in depression model mice. Biochem Biophys Res Commun. 2022;616:89–94. https://doi.org/10.1016/j.bbrc.2022.03.068.

    Article  CAS  PubMed  Google Scholar 

  31. Fenn AM, Gensel JC, Huang Y, Popovich PG, Lifshitz J, Godbout JP. Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol psychiatry. 2014;76:575–84. https://doi.org/10.1016/j.biopsych.2013.10.014.

    Article  CAS  PubMed  Google Scholar 

  32. Chao CC, Hu S, Molitor TW, Shaskan EG, Peterson PK. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol (Baltim, Md: 1950). 1992;149:2736–41.

    Article  CAS  Google Scholar 

  33. Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med. 2006;38:333–47. https://doi.org/10.1038/emm.2006.40.

    Article  CAS  PubMed  Google Scholar 

  34. Chang Y, Lee JJ, Hsieh CY, Hsiao G, Chou DS, Sheu JR. Inhibitory effects of ketamine on lipopolysaccharide-induced microglial activation. Mediators Inflamm. 2009;2009:705379. https://doi.org/10.1155/2009/705379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu M, Zhao L, Wang Y, Guo Q, An Q, Geng J. et al. Ketamine Regulates the Autophagy Flux and Polarization of Microglia through the HMGB1-RAGE Axis and Exerts Antidepressant Effects in Mice. J Neuropathol Exp Neurol. 2022;81:931–42. https://doi.org/10.1093/jnen/nlac035.

    Article  CAS  PubMed  Google Scholar 

  36. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B. et al. NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacol : Off Publ Am Coll Neuropsychopharmacol. 2013;38:1609–16. https://doi.org/10.1038/npp.2013.71.

    Article  CAS  Google Scholar 

  37. Zhang K, Yang C, Chang L, Sakamoto A, Suzuki T, Fujita Y, et al. Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1. Transl Psychiatry. 2020;10:32. https://doi.org/10.1038/s41398-020-0733-x. PMID: 32066676; PMCID: PMC7026089.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hasselmann H, Gamradt S, Taenzer A, Nowacki J, Zain R, Patas K, et al. Pro-inflammatory Monocyte Phenotype and Cell- Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder. Front Immunol. 2018;9:2693. https://doi.org/10.3389/fimmu.2018.02693. Published 2018 Nov 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lynall ME, Turner L, Bhatti J, Cavanagh J, de Boer P, Mondelli V. et al. Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression. Biol Psychiatry. 2020;88:185–96. https://doi.org/10.1016/j.biopsych.2019.11.017.

    Article  CAS  PubMed  Google Scholar 

  40. Setiawan E, Attwells S, Wilson AA, Mizrahi R, Rusjan PM, Miller L. et al. Association of translocator protein total distribution volume with duration of untreated major depressive disorder: a cross-sectional study. Lancet Psychiatry. 2018;5:339–47. https://doi.org/10.1016/S2215-0366(18)30048-8.

    Article  PubMed  Google Scholar 

  41. Schmidt H, Ebeling D, Bauer H, Bach A, Bohrer H, Gebhard MM. et al. Ketamine attenuates endotoxin-induced leukocyte adherence in rat mesenteric venules. Crit Care Med. 1995;23:2008–14. https://doi.org/10.1097/00003246-199512000-00009.

    Article  CAS  PubMed  Google Scholar 

  42. Hofbauer R, Moser D, Hammerschmidt V, Kapiotis S, Frass M. Ketamine significantly reduces the migration of leukocytes through endothelial cell monolayers. Crit Care Med. 1998;26:1545–9. https://doi.org/10.1097/00003246-199809000-00022.

    Article  CAS  PubMed  Google Scholar 

  43. Medina-Rodriguez EM, Lowell JA, Worthen RJ, Syed SA, Beurel E. Involvement of Innate and Adaptive Immune Systems Alterations in the Pathophysiology and Treatment of Depression. Front Neurosci. 2018;12:547https://doi.org/10.3389/fnins.2018.00547.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65:732–41. https://doi.org/10.1016/j.biopsych.2008.11.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK. et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57. https://doi.org/10.1016/j.biopsych.2009.09.033.

    Article  CAS  PubMed  Google Scholar 

  46. Yang JJ, Wang N, Yang C, Shi JY, Yu HY, Hashimoto K. Serum interleukin-6 is a predictive biomarker for ketamine’s antidepressant effect in treatment-resistant patients with major depression. Biol Psychiatry. 2015;77:e19–e20.

  47. Kiraly DD, Horn SR, Van Dam NT, Costi S, Schwartz J, Kim-Schulze S, et al. Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl Psychiatry. 2017;7:e1065. https://doi.org/10.1038/tp.2017.31. Published 2017 Mar 21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang N, Yu HY, Shen XF, Gao ZQ, Yang C, Yang JJ. et al. The rapid antidepressant effect of ketamine in rats is associated with down-regulation of pro-inflammatory cytokines in the hippocampus. Ups J Med Sci. 2015;120:241–8. https://doi.org/10.3109/03009734.2015.1060281.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg. 2012;115:934–43. https://doi.org/10.1213/ANE.0b013e3182662e30.

    Article  CAS  PubMed  Google Scholar 

  50. Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ. et al. Low-dose ketamine affects immune responses in humans during the early postoperative period. Br J Anaesth. 2007;99:522–7. https://doi.org/10.1093/bja/aem218.

    Article  CAS  PubMed  Google Scholar 

  51. Roussabrov E, Davies JM, Bessler H, Greemberg L, Roytblat L, Yardeni IZ, et al. Effect of Ketamine on Inflammatory and Immune Responses After Short- Duration Surgery in Obese Patients. Open Anaesth J. 2008;2:40–5.

    Article  CAS  Google Scholar 

  52. Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y, Shigematsu A. Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg. 1999;89:665–9. https://doi.org/10.1097/00000539-199909000-00024.

    Article  CAS  PubMed  Google Scholar 

  53. Taniguchi T, Kanakura H, Takemoto Y, Kidani Y, Yamamoto K. Effects of ketamine and propofol on the ratio of interleukin-6 to interleukin-10 during endotoxemia in rats. Tohoku J Exp Med. 2003;200:85–92. https://doi.org/10.1620/tjem.200.85.

    Article  CAS  PubMed  Google Scholar 

  54. Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM. et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study. Psychiatry Res. 2018;269:207–11. https://doi.org/10.1016/j.psychres.2018.08.078.

    Article  CAS  PubMed  Google Scholar 

  55. Park M, Newman LE, Gold PW, Luckenbaugh DA, Yuan P, Machado-Vieira R. et al. Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression. J Psychiatr Res. 2017;84:113–8. https://doi.org/10.1016/j.jpsychires.2016.09.025.

    Article  PubMed  Google Scholar 

  56. Maes M, Mihaylova I, Ruyter MD, Kubera M, Bosmans E. The immune effects of TRYCATs (tryptophan catabolites along the IDO pathway): relevance for depression - and other conditions characterized by tryptophan depletion induced by inflammation. Neuro Endocrinol Lett. 2007;28:826–31. DecPMID: 18063923.

    CAS  PubMed  Google Scholar 

  57. Moffett JR, Namboodiri MA. Tryptophan and the immune response. Immunol Cell Biol. 2003;81:247–65. https://doi.org/10.1046/j.1440-1711.2003.t01-1-01177.x. AugPMID: 12848846.

    Article  CAS  PubMed  Google Scholar 

  58. Kopra E, Mondelli V, Pariante C, Nikkheslat N. Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review. J Psychopharmacol. 2021;35:934–45. https://doi.org/10.1177/02698811211026426. Epub 2021 Jun 26PMID: 34180293; PMCID: PMC8358579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Machado-Vieira R, Gold PW, Luckenbaugh DA, Ballard ED, Richards EM, Henter ID. et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry. 2017;22:127–33. https://doi.org/10.1038/mp.2016.36.

    Article  CAS  PubMed  Google Scholar 

  60. Medeiros GC, Gould TD, Prueitt WL, Nanavati J, Grunebaum MF, Farber NB, et al. Blood-based biomarkers of antidepressant response to ketamine and esketamine: A systematic review and meta-analysis. Mol Psychiatry. 2022;27:3658–69. https://doi.org/10.1038/s41380-022-01652-1. SepEpub 2022 Jun 27. PMID: 35760879; PMCID: PMC9933928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wium-Andersen MK, Orsted DD, Nordestgaard BG. Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study. Biol Psychiatry. 2014;76:249–57. https://doi.org/10.1016/j.biopsych.2013.10.009.

    Article  CAS  PubMed  Google Scholar 

  62. Moriarity DP, Horn SR, Kautz MM, Haslbeck JMB, Alloy LB. How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses. Brain Behav Immun. 2021;91:393–403. https://doi.org/10.1016/j.bbi.2020.10.020.

    Article  CAS  PubMed  Google Scholar 

  63. Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T. et al. Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry. 2016;21:1351–7. https://doi.org/10.1038/mp.2015.206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aderem A. Role of Toll-like receptors in inflammatory response in macrophages. Crit Care Med. 2001;29:S16–S18. https://doi.org/10.1097/00003246-200107001-00008.

    Article  CAS  PubMed  Google Scholar 

  65. Chang Y, Chen TL, Sheu JR, Chen RM. Suppressive effects of ketamine on macrophage functions. Toxicol Appl Pharm. 2005;204:27–35. https://doi.org/10.1016/j.taap.2004.08.011.

    Article  CAS  Google Scholar 

  66. Schmidt FM, Lichtblau N, Minkwitz J, Chittka T, Thormann J, Kirkby KC. et al. Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity. J Psychiatr Res. 2014;55:29–34. https://doi.org/10.1016/j.jpsychires.2014.04.021.

    Article  PubMed  Google Scholar 

  67. Zhan Y, Zhou Y, Zheng W, Liu W, Wang C, Lan X. et al. Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder. Transl Psychiatry. 2020;10:246https://doi.org/10.1038/s41398-020-00933-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nowak W, Grendas LN, Sanmarco LM, Estecho IG, Arena AR, Eberhardt N. et al. Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces anti-inflammatory M2 macrophages by NMDAR and mTOR. EBioMedicine. 2019;50:290–305. https://doi.org/10.1016/j.ebiom.2019.10.063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang J, Sundrud MS, Skepner J, Yamagata T. Targeting Th17 cells in autoimmune diseases. Trends Pharm Sci. 2014;35:493–500. https://doi.org/10.1016/j.tips.2014.07.006.

    Article  CAS  PubMed  Google Scholar 

  70. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 cells. Annu Rev Immunol. 2009;27:485–517. https://doi.org/10.1146/annurev.immunol.021908. 132710.

    Article  CAS  PubMed  Google Scholar 

  71. Chen Y, Jiang T, Chen P, Ouyang J, Xu G, Zeng Z. et al. Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res. 2011;188:224–30. https://doi.org/10.1016/j.psychres.2010.10.029.

    Article  CAS  PubMed  Google Scholar 

  72. Davami MH, Baharlou R, Ahmadi Vasmehjani A, Ghanizadeh A, Keshtkar M, Dezhkam I. et al. Elevated IL-17 and TGF-β serum levels: a positive correlation between T-helper 17 cell-related pro-inflammatory responses with major depressive disorder. Basic Clin Neurosci. 2016;7:137–42. https://doi.org/10.15412/J.BCN.03070207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cui M, Dai W, Kong J, Chen H. Th17 Cells in Depression: Are They Crucial for the Antidepressant Effect of Ketamine? Front Pharmacol. 2021;12:649144. https://doi.org/10.3389/fphar.2021.649144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee JE, Lee JM, Park YJ, Kim BS, Jeon YT, Chung Y. Inhibition of autoimmune Th17 cell responses by pain killer ketamine. Oncotarget. 2017;8:89475–85. Published 2017 May 31. https://doi.org/10.18632/oncotarget.18324.

  75. Griffiths CEM, Fava M, Miller AH, Russell J, Ball SG, Xu W. et al. Impact of Ixekizumab Treatment on Depressive Symptoms and Systemic Inflammation in Patients with Moderate-to-Severe Psoriasis: An Integrated Analysis of Three Phase 3 Clinical Studies. Psychother Psychosom. 2017;86:260–7. https://doi.org/10.1159/000479163.

    Article  PubMed  Google Scholar 

  76. Weigand MA, Schmidt H, Zhao Q, Plaschke K, Martin E, Bardenheuer HJ. Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg. 2000;90:206–12. https://doi.org/10.1097/00000539-200001000-00041.

    Article  CAS  PubMed  Google Scholar 

  77. Welters ID, Hafer G, Menzebach A, Mühling J, Neuhäuser C, Browning P. et al. Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines. Anesth Analg. 2010;110:934–41.

  78. Liu FL, Chen TL, Chen RM. Mechanisms of ketamine-induced immunosuppression. Acta Anaesthesiol Taiwan. 2012;50:172–7. https://doi.org/10.1016/j.aat.2012.12.001.

    Article  PubMed  Google Scholar 

  79. Zhang F, Hillhouse TM, Anderson PM, Koppenhaver PO, Kegen TN, Manicka SG. et al. Opioid receptor system contributes to the acute and sustained antidepressant-like effects, but not the hyperactivity motor effects of ketamine in mice. Pharm Biochem Behav. 2021;208:173228. https://doi.org/10.1016/j.pbb.2021.173228.

    Article  CAS  Google Scholar 

  80. Johnston JN, Kadriu B, Kraus C, Henter ID, Zarate CA Jr. Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacology. 2024;49:23–40.

  81. Richardson B, MacPherson A, Bambico F. Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments. Brain Behav Immun Health. 2022;26:100554.

  82. Sukhram SD, Yilmaz G, Gu J. Antidepressant Effect of Ketamine on Inflammation-Mediated Cytokine Dysregulation in Adults with Treatment-Resistant Depression: Rapid Systematic Review. Oxid Med Cell Longev. 2022;2022:1061274.

  83. Nikkheslat N. Targeting inflammation in depression: Ketamine as an anti-inflammatory antidepressant in psychiatric emergency. Brain Behav Immun Health. 2021;18:100383.

  84. Bohlson SS, Tenner AJ. Complement in the Brain: Contributions to Neuroprotection, Neuronal Plasticity, and Neuroinflammation. Annu Rev Immunol. 2023;41:431–52.

    Article  CAS  PubMed  Google Scholar 

  85. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343:227–35.

    Article  CAS  PubMed  Google Scholar 

  86. Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N. et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78. https://doi.org/10.1016/j.cell.2007.10.036.

    Article  CAS  PubMed  Google Scholar 

  87. Crider A, Feng T, Pandya CD, Davis T, Nair A, Ahmed AO. et al. Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior. Brain Behav Immun. 2018;70:246–56. https://doi.org/10.1016/j.bbi.2018.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Kohl J. et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122:3473–81. https://doi.org/10.1182/blood-2013-05-502229.

    Article  CAS  PubMed  Google Scholar 

  89. Lappin DF, Whaley K. Modulation of complement gene expression by glucocorticoids. Biochem J. 1991;280:117–23. https://doi.org/10.1042/bj2800117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Volanakis JE. Transcriptional regulation of complement genes. Annu Rev Immunol. 1995;13:277–305. https://doi.org/10.1146/annurev.iy.13.040195.001425.

    Article  CAS  PubMed  Google Scholar 

  91. Shavva VS, Mogilenko DA, Dizhe EB, Oleinikova GN, Perevozchikov AP, Orlov SV. Hepatic nuclear factor 4α positively regulates complement C3 expression and does not interfere with TNFα-mediated stimulation of C3 expression in HepG2 cells. Gene. 2013;524:187–92. https://doi.org/10.1016/j.gene.2013.04.036.

    Article  CAS  PubMed  Google Scholar 

  92. Shinjyo N, Ståhlberg A, Dragunow M, Pekny M, Pekna M. Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells. 2009;27:2824–32. https://doi.org/10.1002/stem.225.

    Article  CAS  PubMed  Google Scholar 

  93. Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW. et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron. 2015;85:101–15.

  94. Pillai A. Chronic stress and complement system in depression. Braz J Psychiatry. 2022;44:366–7.

  95. Reginia A, Kucharska-Mazur J, Jabłoński M, Budkowska M, Dolegowska B, Sagan L, et al. Assessment of Complement Cascade Components in Patients With Bipolar Disorder. Front Psychiatry. 2018;9:614. https://doi.org/10.3389/fpsyt.2018.00614.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Yang J, Li R, Shi Y, Jiang S, Liu J. Is serum complement C1q related to major depressive disorder. Indian J Psychiatry. 2020;62:659–63. https://doi.org/10.4103/psychiatry.IndianJPsychiatry_394_19.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Song C, Dinan T, Leonard BE. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord. 1994;30:283–8. https://doi.org/10.1016/0165-327(94)90135-x.

    Article  CAS  PubMed  Google Scholar 

  98. Lamers F, Bot M, Jansen R, Chan MK, Cooper JD, Bahn S. et al. Serum proteomic profiles of depressive subtypes. Transl Psychiatry. 2016;6:e851https://doi.org/10.1038/tp.2016.115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Pillai A, Bruno D, Nierenberg J, Pandya C, Feng T, Reichert C. et al. Complement component 3 levels in the cerebrospinal fluid of cognitively intact elderly individuals with major depressive disorder. Biomark Neuropsychiatry. 2019;1:100007https://doi.org/10.1016/j.bionps.2019.100007.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Park C, Rosenblat JD, Brietzke E, Pan Z, Lee Y, Cao B. et al. Stress, epigenetics and depression: A systematic review. Neurosci Biobehav Rev. 2019;102:139–52. https://doi.org/10.1016/j.neubiorev.2019.04.010.

    Article  CAS  PubMed  Google Scholar 

  101. Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996;29:23–6. https://doi.org/10.1055/s-2007-979537.

    Article  CAS  PubMed  Google Scholar 

  102. Duman RS, Shinohara R, Fogaça MV, Hare B. Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry. 2019;24:1816–32. https://doi.org/10.1038/s41380-019-0400-x.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Miller OH, Moran JT, Hall BJ. Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: Direct inhibition and disinhibition. Neuropharmacology. 2016;100:17–26. https://doi.org/10.1016/j.neuropharm.2015.07.028.

    Article  CAS  PubMed  Google Scholar 

  104. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S. et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018;554:317–22. https://doi.org/10.1038/nature25509.

    Article  CAS  PubMed  Google Scholar 

  105. Lin S, Huang L, Luo ZC, Li X, Jin SY, Du ZJ. et al. The ATP Level in the Medial Prefrontal Cortex Regulates Depressive-like Behavior via the Medial Prefrontal Cortex-Lateral Habenula Pathway. Biol Psychiatry. 2022;92:179–92. https://doi.org/10.1016/j.biopsych.2022.02.014.

    Article  CAS  PubMed  Google Scholar 

  106. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS. et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4. https://doi.org/10.1016/s0006-3223(99)00230-9.

    Article  CAS  PubMed  Google Scholar 

  107. Borbély É, Simon M, Fuchs E, Wiborg O, Czéh B, Helyes Z. Novel drug developmental strategies for treatment-resistant depression. Br J Pharm. 2022;179:1146–86. https://doi.org/10.1111/bph.15753.

    Article  CAS  Google Scholar 

  108. van Beek J, Nicole O, Ali C, Ischenko A, MacKenzie ET, Buisson A. et al. Complement anaphylatoxin C3a is selectively protective against NMDA-induced neuronal cell death. Neuroreport. 2001;12:289–93. https://doi.org/10.1097/00001756-200102120-00022.

    Article  PubMed  Google Scholar 

  109. Osaka H, Mukherjee P, Aisen PS, Pasinetti GM. Complement-derived anaphylatoxin C5a protects against glutamate-mediated neurotoxicity. J Cell Biochem. 1999;73:303–11.

    Article  CAS  PubMed  Google Scholar 

  110. Mukherjee P, Thomas S, Pasinetti GM. Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo. J Neuroinflamm. 2008;5:5. https://doi.org/10.1186/1742-2094-5-5. Published 2008 Jan 29.

    Article  CAS  Google Scholar 

  111. Li N, Lee B, Liu R-J, Banasr M, Dwyer JM, Iwata M. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. https://doi.org/10.1126/science.1190287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H. et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61. https://doi.org/10.1016/j.biopsych.2010.12.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M. et al. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology. 2020;45:990–7. https://doi.org/10.1038/s41386-020-0644-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Liszewski MK, Kolev M, Le Friec G, Leung M, Bertram PG, Fara AF. et al. Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation. Immunity. 2013;39:1143–57. https://doi.org/10.1016/j.immuni.2013.10.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kolev M, Kemper C. Keeping It All Going-Complement Meets Metabolism. Front Immunol. 2017;8:1. https://doi.org/10.3389/fimmu.2017.00001. Published 2017 Jan 18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zeigerer A, Bogorad RL, Sharma K, Gilleron J, Seifert S, Sales S. et al. Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep. 2015;11:884–92. https://doi.org/10.1016/j.celrep.2015.04.018.

    Article  CAS  PubMed  Google Scholar 

  117. Kaur G, Tan LX, Rathnasamy G, La Cunza N, Germer CJ, Toops KA. et al. Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration. Proc Natl Acad Sci USA. 2018;115:9014–9. https://doi.org/10.1073/pnas.1805039115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain [published correction appears in Nat Rev Neurosci. 2009 Oct;10(10):759]. Nat Rev Neurosci. 2009;10:647–58. https://doi.org/10.1038/nrn2699.

    Article  CAS  PubMed  Google Scholar 

  119. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P. et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7. https://doi.org/10.1038/nm.2886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. McEwen BS, Eiland L, Hunter RG, Miller MM. Stress and anxiety: structural plasticity and epigenetic regulation as a consequence of stress. Neuropharmacology. 2012;62:3–12. https://doi.org/10.1016/j.neuropharm.2011.07.014.

    Article  CAS  PubMed  Google Scholar 

  121. Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett. 2015;601:20–9.

  122. Nordman JC, Bartsch CJ, Li Z. Opposing effects of NMDA receptor antagonists on early life stress-induced aggression in mice. Aggress Behav. 2022;48:365–73. https://doi.org/10.1002/ab.22022

    Article  PubMed  PubMed Central  Google Scholar 

  123. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705. https://doi.org/10.1016/j.neuron.2012.03.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pavlovski D, Thundyil J, Monk PN, Wetsel RA, Taylor SM, Woodruff TM. Generation of complement component C5a by ischemic neurons promotes neuronal apoptosis. FASEB J.2012;26:3680–90. https://doi.org/10.1096/fj.11-202382.

    Article  CAS  PubMed  Google Scholar 

  125. Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–89. https://doi.org/10.1146/annurev-neuro-061010-113810.

    Article  CAS  PubMed  Google Scholar 

  126. Sellgren CM, Gracias J, Watmuff B, Biag JD, Thanos JM, Whittredge PB. et al. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci. 2019;22:374–85. https://doi.org/10.1038/s41593-018-0334-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83. https://doi.org/10.1038/nature16549.

  128. Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K. et al. Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron. 2018;100:1322–36.e7. https://doi.org/10.1016/j.neuron.2018.10.014.

    Article  CAS  PubMed  Google Scholar 

  129. Wei Y, Xiao L, Fan W, Zou J, Yang H, Liu B. et al. Astrocyte Activation, but not Microglia, Is Associated with the Experimental Mouse Model of Schizophrenia Induced by Chronic Ketamine. J Mol Neurosci. 2022;72:1902–15.

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Acknowledgements

The authors acknowledge funding support from US National Institutes of Health/ National Institute of Mental Health (NIMH) grants (MH120876, MH121959, and MH128771), and from the Merit Review Award (BX004758) from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development to AP. AP also acknowledges funding support from the Louis A. Faillace Endowed Chair in Psychiatry. Funding for this work was also provided in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857) to CAZ. The views expressed do not necessarily reflect the views of the NIH, the Department of Health and Human Services, the Department of Veterans Affairs, or the United States Government. The authors thank NIH intramural program 7SE research unit and staff for their support, and Ms. Ioline Henter (NIMH) for her invaluable editorial assistance.

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  1. Pathophysiology of Neuropsychiatric Disorders Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA

    Brandi Quintanilla & Anilkumar Pillai

  2. Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Carlos A. Zarate Jr

  3. Research and Development, Charlie Norwood VA Medical Center, Augusta, GA, USA

    Anilkumar Pillai

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BQ prepared the initial manuscript draft. AP and CAZ edited the manuscript. All authors had an opportunity to review and provide input on the final manuscript.

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Correspondence to Anilkumar Pillai.

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Competing interests

AP received research funding support from Acadia Pharmaceuticals. Dr. Zarate is a full-time U.S government employee. He is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2 R,6 R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2 R,6 R)-hydroxynorketamine and (2 S,6 S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorder. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. Dr. Quintanilla has no conflict of interest to disclose, financial or otherwise.

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Quintanilla, B., Zarate, C.A. & Pillai, A. Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects?. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02507-7

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