The Impact of Immunological Factors on Depression Treatment – Relation Between Antidepressants and Immunomodulation Agents

  • Jovana Vojvodic Clinic for Psychiatric Disorders “Dr. Laza Lazarevic”, Belgrade, Serbia
  • Goran Mihajlovic Faculty of Medical Sciences, Department of Psychiatry, University of Kragujevac, Kragujevac, Serbia
  • Petar Vojvodic Clinic for Psychiatric Disorders “Dr. Laza Lazarevic”, Belgrade, Serbia
  • Dusan Radomirovic Faculty of Medicine, University of Nis, Serbia
  • Aleksandra Vojvodic Department of Dermatology and Venereology, Military Medical Academy, Belgrade, Serbia
  • Tatjana Vlaskovic-Jovicevic Clinic for Psychiatric Disorders “Dr. Laza Lazarevic”, Belgrade, Serbia
  • Zorica Peric-Hajzler Military Medical Academy, Belgrade, Serbia
  • Dusica Matovic Military Medical Academy, Belgrade, Serbia
  • Sanja Dimitrijevic Department of Gynecology, Military Medical Academy, Belgrade, Serbia
  • Goran Sijan Clinic for Plastic Surgery and Burns, Military Medical Academy, Belgrade, Serbia
  • Maria Grazia Roccia Department of Nuclear Physics, Sub-nuclear and Radiation, G. Marconi University, Rome, Italy
  • Massimo Fioranelli Department of Nuclear Physics, sub-nuclear and radiation, G. Marconi University, Rome, Italy
  • Torello Lotti University of Rome G. Marconi, Rome, Italia
Keywords: depression, inflammation, antidepressants, cytokines


It is determined that 30% of patients with depression are resistant to antidepressant medication. The increased concentration of inflammation factors, such as C-reactive protein, and pro-inflammatory cytokines, have been detected in serum in these patients. It is necessary to establish new therapeutic possibilities and protocols that are created to overcome the difficulties caused by increased concentration of inflammatory biomarkers in depressive patients. The Selective Serotonin Reuptake Inhibitors (SSRIs) are considered to be the most powerful antidepressants, increasing the level of serotonin in endogenous depression, as well as in that caused by immunological mechanisms. It is believed that agents that influence cytokines, immunological signal pathways and cytokine syntheses, like the inhibitors of cyclooxygenase enzyme and other non-steroidal anti-inflammatory drugs (NSAIDs), are very important in the potential treatment of residual symptoms of depression. Treatment with cytokine antagonists is one of the potential adjuvant therapies, along with antidepressants. Signal pathways blockers, such as the inhibitors of cyclooxygenase and other NSAIDs, are in the phase of research, in terms of their antidepressant effects. Also, it has been shown that the inhibition of indolamin-2,3 deoxygenase (IDO) and kynurenine (KYN) signal pathways in the synthesis of neurotransmitters, by application of IDO antagonists, are leading to suppression of pro-inflammatory cytokine effects. Antidepressants may have anti-inflammatory effects, depending on dose and type, and they achieve this effect through the decrease of pro-inflammatory cytokine production and increase of anti-inflammatory cytokines. Also, antidepressants modulate the humoral and cellular immune system. This work aims to summarise certain neurobiological and neuroimmunological specificities that have been observed in patients with depression, antidepressants and immunomodulation agents. The understanding of complex and heterogenic pathophysiology of depression through the prism of the altered immune system, is of major importance, in terms of better optimisation of pharmacotherapy, and options for a personalised approach in depressive disorder treatment.


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Author Biography

Torello Lotti, University of Rome G. Marconi, Rome, Italia

Prof. Lotti is Full Professor of the Dermatology and Venereology at University of Studies Guglielmo Marconi, Rome, Italy. He is Honorary Professor of Dermatology - China Medical University Shenyang (2011), Lecturer at the New York Academy of Sciences "Howard Fox Memorial Lecture" (14 March 2012 - New York, NY – USA), and Chair, Executive Scientific Committee Vitiligo Research Foundation, New York , NY , USA. He is President of the World Health Academy, Dermatology since 2013. He has been Full Professor of the Dermatology and Venereology Division at University of Florence School of Medicine, Florence, Italy, from 2006 to 2010. He is Visiting Professor in six International Universities worldwide, and Key Note Lecturer in several international dermatology Societies. His activities in serving Dermatology have been numerous: President of the Italian Society of Dermatology and Venereology (SIDeMaST , 2009-2010) and President of the International Society of Dermatology ( ISD, 2009-2010), President of the European Society for Cosmetic and Aesthetic Dermatology (2003-2004), Editor in Chief of the Journal of the European Academy of Dermatology and Venereology (1992-2002) , Editor "Therapeutic Hotline"- Dermatologic Therapy (2007-)and served as Editor in Chief of the Giornale Italiano di Dermatologia in the period of presidency of the Societa' Italiana di Dermatologia (2009-2010). He has been President of numerous international congresses and is currently Editor in Chief of the Giornale Italiano di Dermatologia e Venereologia ( 2010-2020 ). He is Ordinary Member of the main Scientific Societies worldwide (EADV, SIDEV , ESDR , ISD, AAD, SID) and Honorary Member of several Scientific Societies of the Dermatology field. Moreover, he is a Scientific reviewer of ten sectorial journals, among which are the British Journal of Dermatology, Journal of Investigative Dermatology, Journal of the American Academy of Dermatology , Dermatologic Therapy. He has authored 1054 scientific publications (393 peer reviewed articles, 288 books chapters e 365 abstracts). For more information, see


Müller N. Immunological aspects of the treatment of depression and schizophrenia. Dialogues in Clinical Neuroscience. 2017; 19(1):55-63.

Felger JC, Lotrich FE. Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience. 2013; 246:199-229.

M Schmidt F, C Kirkby K, Lichtblau N. Inflammation and immune regulation as potential drug targets in antidepressant treatment. Current neuropharmacology. 2016; 14(7):674-87.

Vogelzangs N, Duivis HE, Beekman AT, Kluft C, Neuteboom J, Hoogendijk W, Smit JH, de Jonge P, Penninx BW. Association of depressive disorders, depression characteristics and antidepressant medication with inflammation. Translational psychiatry. 2012; 2(2):e79.

Müller N. The role of anti-inflammatory treatment in psychiatric disorders. Psychiatria Danubina. 2013; 25(3):292-298.

Hughes MM, Connor TJ, Harkin A. Stress-related immune markers in depression: implications for treatment. International Journal of Neuropsychopharmacology. 2016; 19(6):1-19.

Jeon SW, Kim YK. Neuroinflammation and cytokine abnormality in major depression: cause or consequence in that illness? World journal of psychiatry. 2016; 6(3):283-293.

Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacology & therapeutics. 2011; 130(2):226-38.

Leboyer M, Berk M, Yolken RH, Tamouza R, Kupfer D, Groc L. Immuno-psychiatry: an agenda for clinical practice and innovative research. BMC medicine. 2016; 14(1):173.

Gibney SM, Drexhage HA. Evidence for a dysregulated immune system in the etiology of psychiatric disorders. Journal of Neuroimmune Pharmacology. 2013; 8(4):900-20.

Ma K, Zhang H, Baloch Z. Pathogenetic and therapeutic applications of tumor necrosis factor-α (TNF-α) in major depressive disorder: a systematic review. International journal of molecular sciences. 2016; 17(5):733.

Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA psychiatry. 2013; 70(1):31-41.

Zhou AJ, Lee Y, Salvadore G, Hsu B, Fonseka TM, Kennedy SH, McIntyre RS. Sirukumab: a potential treatment for mood disorders? Advances in therapy. 2017; 34(1):78-90.

Köhler O, Petersen L, Mors O, Gasse C. Inflammation and depression: combined use of selective serotonin reuptake inhibitors and NSAIDs or paracetamol and psychiatric outcomes. Brain and behavior. 2015; 5(8):e00338.

McNamara RK, Lotrich FE. Elevated immune-inflammatory signaling in mood disorders: a new therapeutic target? Expert review of neurotherapeutics. 2012; 12(9):1143-61.

Maciel IS, Silva RB, Morrone FB, Calixto JB, Campos MM. Synergistic effects of celecoxib and bupropion in a model of chronic inflammation-related depression in mice. PLoS One. 2013; 8(9):e77227.

Hochstrasser T, Ehrlich D, Sperner-Unterweger B, Humpel C. Antidepressants and Anti-Inflammatory Drugs Differentially Reduce the Release of NGF and BDNF from Rat Platelets. Pharmacopsychiatry. 2013; 46(1):29-34.

Bhatt S, Shukla P, Raval J, Goswami S. Role of aspirin and dexamethasone against experimentally induced depression in rats. Basic & clinical pharmacology & toxicology. 2016; 119(1):10-8.

Andrade C. Antidepressant augmentation with anti-inflammatory agents. The Journal of clinical psychiatry. 2014; 75(9):975-7.

Hung YY, Huang KW, Kang HY, Huang GY, Huang TL. Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. Psychopharmacology. 2016; 233(9):1707-14.

Hung YY, Lin CC, Kang HY, Huang TL. TNFAIP3, a negative regulator of the TLR signaling pathway, is a potential predictive biomarker of response to antidepressant treatment in major depressive disorder. Brain, behavior, and immunity. 2017; 59:265-72.

Strawbridge R, Young AH, Cleare AJ. Biomarkers for depression: recent insights, current challenges and future prospects. Neuropsychiatric disease and treatment. 2017; 13:1245-1262.

Almeida OP, Flicker L, Yeap BB, Alfonso H, Mccaul K, Hankey GJ. Aspirin decreases the risk of depression in older men with high plasma homocysteine. Translational psychiatry. 2012; 2(8):e151.

Laugeray A, Launay JM, Callebert J, Mutlu O, Guillemin GJ, Belzung C, Barone PR. Chronic treatment with the IDO1 inhibitor 1-Methyl-D-Tryptophan minimizes the behavioural and biochemical abnormalities induced by unpredictable chronic mild stress in mice-comparison with fluoxetine. PLOS one. 2016; 11(11):e0164337.

Choi GY, Kim HB, Hwang ES, Lee S, Kim MJ, Choi JY, Lee SO, Kim SS, Park JH. Curcumin alters neural plasticity and viability of intact hippocampal circuits and attenuates behavioral despair and COX-2 expression in chronically stressed rats. Mediators of inflammation. 2017; 2017.

Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in immunology. 2006; 27(1):24-31.

Greeson JM, Gettes DR, Spitsin S, Dubé B, Benton TD, Lynch KG, Douglas SD, Evans DL. The Selective Serotonin Reuptake Inhibitor Citalopram Decreases HIV Receptor and Coreceptor Expression in Immune Cells. Biological psychiatry. 2016; 80(1):33-39.

Eyre HA, Lavretsky H, Kartika J, Qassim A, Baune BT. Modulatory effects of antidepressant classes on the innate and adaptive immune system in depression. Pharmacopsychiatry. 2016; 26(03):85-96.

Horowitz MA, Wertz J, Zhu D, Cattaneo A, Musaelyan K, Nikkheslat N, Thuret S, Pariante CM, Zunszain PA. Antidepressant compounds can be both pro-and anti-inflammatory in human hippocampal cells. International Journal of Neuropsychopharmacology. 2015; 18(3):pyu076.

How to Cite
Vojvodic J, Mihajlovic G, Vojvodic P, Radomirovic D, Vojvodic A, Vlaskovic-Jovicevic T, Peric-Hajzler Z, Matovic D, Dimitrijevic S, Sijan G, Roccia MG, Fioranelli M, Lotti T. The Impact of Immunological Factors on Depression Treatment – Relation Between Antidepressants and Immunomodulation Agents. Open Access Maced J Med Sci [Internet]. 2019Sep.12 [cited 2020Oct.23];7(18):3064-9. Available from:

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