, Volume 20, Issue 3, pp 169–176 | Cite as

Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients

  • Daniela L. Krause
  • Michael Riedel
  • Norbert Müller
  • Elif Weidinger
  • Markus J. Schwarz
  • Aye-Mu Myint
Inflammation in acute and chronic neurological and psychiatric diseases



Immune activation induces a pro-inflammatory state, which enhances the tryptophan degradation into kynurenine (KYN). The involvement of kynurenines has been shown in patients with major depression. Here, the effects of anti-inflammatory medication and antidepressants on cytokines and tryptophan metabolite changes in blood culture with immune challenge [bacterial mimetic lipopolysaccharide (LPS)] were investigated.

Materials and methods

A total of 21 depressed patients and 38 matched controls were recruited. Whole blood cultures were stimulated with LPS and drugs were added (celecoxib, venlafaxine, reboxetine, imipramine and fluoxetine). Cytokines and kynurenines were analysed.


After stimulation with LPS, the interferon-γ and interleukin (IL)-10 secretions were significantly higher in controls than in patients (p = 0.045, p = 0.032), respectively. Adding imipramine and celecoxib abolished the significance for IL-10. Challenge with LPS induced the kynurenine pathway in each group. Regarding the ratio KYNA/KYN, which indicated how much of KYN formed is further catabolised into the neuroprotective arm, the controls’ blood cultures showed a significantly higher ratio (p = 0.045).


Stimulation with LPS induced increased production of pro-inflammatory and anti-inflammatory cytokines in both groups, but higher responses in controls. This lower production of cytokine responses in depressed patients indicates that their immune cells are in a refractory phase, induced by a pre-existing pro-inflammatory state. For kynurenines, the whole metabolism was enhanced by LPS; however, an imbalance to neuroprotective metabolites was observed just in control blood. A drug effect could only be shown for imipramine and celecoxib, which were beneficial in terms of re-balancing the immune function but not in re-balancing neuroactive metabolites.


Depression Kynurenines Antidepressants Celecoxib LPS Psychoimmunology 



The study carried out mentioned in this manuscript was funded by the Commission of European Communities 7th Framework Programme Collaborative Project “MOODINFLAME” (Grant No. 22963).


  1. Basterzi AD, Aydemir C, Kisa C, Aksaray S, Tuzer V, Yazici K, Goka E (2005) IL-6 levels decrease with SSRI treatment in patients with major depression. Hum Psychopharmacol 20:473–476PubMedCrossRefGoogle Scholar
  2. Bender DA, McCreanor GM (1985) Kynurenine hydroxylase: a potential rate-limiting enzyme in tryptophan metabolism. Biochem Soc Trans 13:441–443PubMedGoogle Scholar
  3. Chiarugi A, Calvani M, Meli E, Traggiai E, Moroni F (2001) Synthesis and release of neurotoxic kynurenine metabolites by human monocyte-derived macrophages. J Neuroimmunol 120:190–198PubMedCrossRefGoogle Scholar
  4. Dantzer R (2006) Cytokine, sickness behavior, and depression. Neurol Clin 24:441–460PubMedCrossRefGoogle Scholar
  5. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457PubMedCrossRefGoogle Scholar
  6. Heyes MP, Saito K, Major EO, Milstien S, Markey SP, Vickers JH (1993) A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from l-tryptophan by 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate. Brain 116(Pt 6):1425–1450PubMedGoogle Scholar
  7. Himmerich H, Fulda S, Sheldrick AJ, Plumakers B, Rink L (2010) IFN-gamma reduction by tricyclic antidepressants. Int J Psychiatry Med 40:413–424PubMedCrossRefGoogle Scholar
  8. Kim JP, Choi DW (1987) Quinolinate neurotoxicity in cortical cell culture. Neuroscience 23:423–432PubMedCrossRefGoogle Scholar
  9. Kubera M, Basta-Kaim A, Budziszewska B, Rogoz Z, Skuza G, Leskiewicz M, Tetich M, Jaworska-Feil L, Maes M, Lason W (2006) Effect of amantadine and imipramine on immunological parameters of rats subjected to a forced swimming test. Int J Neuropsychopharmacol 9:297–305PubMedCrossRefGoogle Scholar
  10. Kubera M, Maes M, Budziszewska B, Basta-Kaim A, Leskiewicz M, Grygier B, Rogoz Z, Lason W (2009) Inhibitory effects of amantadine on the production of pro-inflammatory cytokines by stimulated in vitro human blood. Pharmacol Rep 61:1105–1112PubMedGoogle Scholar
  11. Maes M (1999) Major depression and activation of the inflammatory response system. Adv Exp Med Biol 461:25–46PubMedCrossRefGoogle Scholar
  12. Mellor AL, Munn DH (1999) Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol Today 20:469–473PubMedCrossRefGoogle Scholar
  13. Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B, Spellmann I, Hetzel G, Maino K, Kleindienst N, Moller HJ, Arolt V, Riedel M (2006) The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11:680–684PubMedCrossRefGoogle Scholar
  14. Myint AM, Kim YK (2003) Cytokine–serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 61:519–525PubMedCrossRefGoogle Scholar
  15. Myint AM, Leonard BE, Steinbusch HW, Kim YK (2005) Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 88:167–173PubMedCrossRefGoogle Scholar
  16. Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H, Leonard B (2007a) Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Disord 98:143–151PubMedCrossRefGoogle Scholar
  17. Myint AM, Steinbusch HW, Goeghegan L, Luchtman D, Kim YK, Leonard BE (2007b) Effect of the COX-2 inhibitor celecoxib on behavioural and immune changes in an olfactory bulbectomised rat model of depression. Neuroimmunomodulation 14:65–71PubMedCrossRefGoogle Scholar
  18. Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372PubMedGoogle Scholar
  19. Nishino S, Ueno R, Ohishi K, Sakai T, Hayaishi O (1989) Salivary prostaglandin concentrations: possible state indicators for major depression. Am J Psychiatry 146:365–368PubMedGoogle Scholar
  20. Perkins MN, Stone TW (1982) An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 247:184–187PubMedCrossRefGoogle Scholar
  21. Raison CL, Dantzer R, Kelley KW, Lawson MA, Woolwine BJ, Vogt G, Spivey JR, Saito K, Miller AH (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry 15:393–403PubMedCrossRefGoogle Scholar
  22. Rivest S, Lacroix S, Vallieres L, Nadeau S, Zhang J, Laflamme N (2000) How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 223:22–38PubMedCrossRefGoogle Scholar
  23. Runeson BS, Rich CL (1994) Diagnostic and statistical manual of mental disorders, 3rd edn. (DSM-III), adaptive functioning in young Swedish suicides. Ann Clin Psychiatry 6:181–183PubMedCrossRefGoogle Scholar
  24. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer Zu Schwabedissen L, Bogerts B, Myint AM (2011) Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 8:94PubMedCrossRefGoogle Scholar
  25. Tsao CW, Lin YS, Chen CC, Bai CH, Wu SR (2006) Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 30:899–905PubMedCrossRefGoogle Scholar
  26. Yasui H, Takai K, Yoshida R, Hayaishi O (1986) Interferon enhances tryptophan metabolism by inducing pulmonary indoleamine 2, 3-dioxygenase: its possible occurrence in cancer patients. Proc Natl Acad Sci USA 83:6622–6626PubMedCrossRefGoogle Scholar
  27. Zwilling D, Huang SY, Sathyasaikumar KV, Notarangelo FM, Guidetti P, Wu HQ, Lee J, Truong J, Andrews-Zwilling Y, Hsieh EW, Louie JY, Wu T, Scearce-Levie K, Patrick C, Adame A, Giorgini F, Moussaoui S, Laue G, Rassoulpour A, Flik G, Huang Y, Muchowski JM, Masliah E, Schwarcz R, Muchowski PJ (2011) Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145:863–874PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Daniela L. Krause
    • 1
  • Michael Riedel
    • 1
    • 2
  • Norbert Müller
    • 1
  • Elif Weidinger
    • 1
  • Markus J. Schwarz
    • 1
  • Aye-Mu Myint
    • 1
  1. 1.Department of PsychiatryLudwig-Maximilians University MunichMunichGermany
  2. 2.Psychiatry, Vinzenz von Paul HospitalRottweilGermany

Personalised recommendations