Modulatory Effects of Antidepressant Classes on the Innate and Adaptive Immune System in Depression

Abstract

Current reviews exploring for unique immune-modulatory profiles of antidepressant classes are limited by focusing mainly on cytokine modulation only and neglecting other aspects of the innate and adaptive immune system. These reviews also do not include recent comparative clinical trials, immune-genetic studies and therapeutics with unique neurotransmitter profiles (e. g., agomelatine). This systematic review extends the established literature by comprehensively reviewing the effects of antidepressants classes on both the innate and adaptive immune system. Antidepressants appear, in general, to reduce pro-inflammatory factor levels, particularly C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6. We caution against conclusions as to which antidepressant possesses the greater anti-inflammatory effect, given the methodological heterogeneity among studies and the small number of comparative studies. The effects of antidepressant classes on adaptive immune factors are complex and poorly understood, and few studies have been conducted. Methodological heterogeneity is high among these studies (e. g., length of study, cohort characteristics, dosage used and immune marker analysis). We recommend larger, comparative studies – in clinical and pre-clinical populations.

Key words

antidepressant - immune - innate - adaptive - inflammatory

• References

• 1 Murray CJ, Vos T, Lozano R et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 380. 2197-2223
• 2 Holtzheimer PE, Meeks TW, Kelley ME et al. A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression. Int J Geriatr Psych 2008; 23: 625-631
• 3 Licinio J. Translational Psychiatry: leading the transition from the cesspool of devastation to a place where the grass is really greener. Transl Psychiatry 2011; 1: e1
• 4 Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354: 1231-1242
• 5 Rush AJ, Trivedi MH, Wisniewski SR 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: 1905-1917
• 6 Rush AJ, Trivedi MH, Wisniewski SR et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354: 1231-1242
• 7 Muller N, Hofschuster E, Ackenheil M et al. Investigations of the cellular immunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuropsychopharmacol Biol Psychiatry 1993; 17: 713-730
• 8 Dowlati Y, Herrmann N, Swardfager W et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446-457
• 9 Haapakoski R, Mathieu J, Ebmeier KP et al. Cumulative meta-analysis of interleukins 6 and 1beta, tumour necrosis factor alpha and C-reactive protein in patients with major depressive disorder. Brain Behav Immun 2015; 49: 206-215
• 10 Dantzer R, O’Connor JC, Freund GG et al. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46-56
• 11 Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732-741
• 12 McAfoose J, Baune BT. Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 2009; 33: 355-366
• 13 Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 2012; 37: 1397-1416
• 14 Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacology 2012; 37: 137-162
• 15 Eyre H, Baune BT. Neuroplastic changes in depression: A role for the immune system. Psychoneuroendocrinology 2012;
• 16 Moylan S, Maes M, Wray NR et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 2012;
• 17 Leonard B, Maes M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012; 36: 764-785
• 18 Setiawan E, Wilson AA, Mizrahi R et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA psychiatry 2015; 72: 268-275
• 19 Eyre HA, Stuart MJ, Baune BT. A phase-specific neuroimmune model of clinical depression. Prog Neuropsychopharmacol Biol Psychiatry 2014; 54: 265-274
• 20 Peng L, Verkhratsky A, Gu L et al. Targeting astrocytes in major depression. Expert Rev Neurother 2015; 15: 1299-1306
• 21 Hannestad J, Dellagioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 2011; 36: 2452-2459
• 22 Uher R, Tansey KE, Dew T et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry 2014;
• 23 Martino M, Rocchi G, Escelsior A et al. Immunomodulation mechanism of antidepressants: interactions between serotonin/norepinephrine balance and Th1/Th2 bBalance. Curr Neuropharmacol 2012; 10: 97-123
• 24 Ransohoff RM, Brown MA. Innate immunity in the central nervous system. J Clin Invest 2012; 122: 1164-1171
• 25 Martino G, Pluchino S, Bonfanti L et al. Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol Rev 2011; 91: 1281-1304
• 26 Stuart MJ, Baune BT. Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: a systematic review of biomarker studies. Neurosci Biobehav Rev 2014; 42: 93-115
• 27 Filiano AJ, Gadani SP, Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res 2014;
• 28 Moher D, Altman DG, Liberati A et al. PRISMA statement. Epidemiology 2011; 22: 128 author reply 128
• 29 Janssen DG, Caniato RN, Verster JC et al. A psychoneuroimmunological review on cytokines involved in antidepressant treatment response. Hum Psychopharmacol 2010; 25: 201-215
• 30 Tsao CW, Lin YS, Chen CC et al. Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 899-905
• 31 O’Brien SM, Scott LV, Dinan TG. Antidepressant therapy and C-reactive protein levels. Br J Psychiatry 2006; 188: 449-452
• 32 Leo R, Di Lorenzo G, Tesauro M et al. Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy. J Clin Psychiatry 2006; 67: 1760-1766
• 33 Basterzi AD, Aydemir C, Kisa C et al. IL-6 levels decrease with SSRI treatment in patients with major depression. Hum Psychopharmacol 2005; 20: 473-476
• 34 Tuglu C, Kara SH, Caliyurt O et al. Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder. Psychopharmacology 2003; 170: 429-433
• 35 Sluzewska A, Rybakowski JK, Laciak M et al. Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann N Y Acad Sci 1995; 762: 474-476
• 36 Hernandez ME, Mendieta D, Martinez-Fong D et al. Variations in circulating cytokine levels during 52 week course of treatment with SSRI for major depressive disorder. Eur Neuropsychopharmacol 2008; 18: 917-924
• 37 Eller T, Vasar V, Shlik J et al. Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 445-450
• 38 Sutcigil L, Oktenli C, Musabak U et al. Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy. Clin Dev Immunol 2007; 2007: 76396
• 39 Mamdani F, Berlim MT, Beaulieu MM et al. Gene expression biomarkers of response to citalopram treatment in major depressive disorder. Transl Psychiatry 2011; 1: e13
• 40 Mamdani F, Berlim MT, Beaulieu MM et al. Pharmacogenomic predictors of citalopram treatment outcome in major depressive disorder. World J Biol Psychiatry 2014; 15: 135-144
• 41 Honda K, Yanai H, Negishi H et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 2005; 434: 772-777
• 42 Paun A, Pitha PM.. The IRF family, revisited. Biochimie 2007; 89: 744-753
• 43 Lu R, Au WC, Yeow WS et al. Regulation of the promoter activity of interferon regulatory factor-7 gene. Activation by interferon and silencing by hypermethylation. J Biol Chem 2000; 275: 31805-31812
• 44 Wicks SJ, Grocott T, Haros K et al. Reversible ubiquitination regulates the Smad/TGF-beta signalling pathway. Biochem Soc Trans 2006; 34: 761-763
• 45 Myint AM, Leonard BE, Steinbusch HW et al. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 2005; 88: 167-173
• 46 Carlin AF, Uchiyama S, Chang YC et al. Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood 2009; 113: 3333-3336
• 47 Chen GY, Tang J, Zheng P et al. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 2009; 323: 1722-1725
• 48 Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci 2010; 30: 3482-3488
• 49 Frank MG, Hendricks SE, Johnson DR et al. Antidepressants augment natural killer cell activity: in vivo and in vitro. Neuropsychobiology 1999; 39: 18-24
• 50 Kook AI, Mizruchin A, Odnopozov N et al. Depression and immunity: the biochemical interrelationship between the central nervous system and the immune system. Biol Psychiatry 1995; 37: 817-819
• 51 Hernandez ME, Martinez-Fong D, Perez-Tapia M et al. Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. Eur Neuropsychopharmacol 2010; 20: 88-95
• 52 Frank MG, Hendricks SE, Burke WJ et al. Clinical response augments NK cell activity independent of treatment modality: a randomized double-blind placebo controlled antidepressant trial. Psychol Med 2004; 34: 491-498
• 53 Gladkevich A, Kauffman HF, Korf J. Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 559-576
• 54 Ravindran AV, Griffiths J, Merali Z et al. Lymphocyte subsets associated with major depression and dysthymia: modification by antidepressant treatment. Psychosom Med 1995; 57: 555-563
• 55 Rothermundt M, Arolt V, Fenker J et al. Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 2001; 251: 90-97
• 56 Iken K, Chheng S, Fargin A et al. Serotonin upregulates mitogen-stimulated B lymphocyte proliferation through 5-HT1A receptors. Cell Immunol 1995; 163: 1-9
• 57 Piletz JE, Halaris A, Iqbal O et al. Pro-inflammatory biomakers in depression: treatment with venlafaxine. World J Biol Psychiatry 2009; 10: 313-323
• 58 Li Z, Qi D, Chen J et al. Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-alpha) in the Chinese patients with major depressive disorder: a prospective longitudinal study. Psychoneuroendocrinology 2013; 38: 107-114
• 59 Fornaro M, Rocchi G, Escelsior A et al. Might different cytokine trends in depressed patients receiving duloxetine indicate differential biological backgrounds. J Affect Disord 2013; 145: 300-307
• 60 Kalman J, Palotas A, Juhasz A et al. Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression – evolution of antidepressants and the role of the “neuro-immune” system. Neurochem Res 2005; 30: 1429-1438
• 61 Lanquillon S, Krieg JC, Bening-Abu-Shach U et al. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22: 370-379
• 62 Weizman R, Laor N, Podliszewski E et al. Cytokine production in major depressed patients before and after clomipramine treatment. Biol Psychiatry 1994; 35: 42-47
• 63 Schleifer SJ, Keller SE, Bartlett JA. Depression and immunity: clinical factors and therapeutic course. Psychiatry Res 1999; 85: 63-69
• 64 Narita K, Murata T, Takahashi T et al. Plasma levels of adiponectin and tumor necrosis factor-alpha in patients with remitted major depression receiving long-term maintenance antidepressant therapy. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1159-1162
• 65 Cattaneo A, Gennarelli M, Uher R et al. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology 2013; 38: 377-385
• 66 Chang HH, Lee IH, Gean PW et al. Treatment response and cognitive impairment in major depression: association with C-reactive protein. Brain Behav Immun 2012; 26: 90-95
• 67 Yoshimura R, Hori H, Ikenouchi-Sugita A et al. Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRI-refractory depression. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 722-726
• 68 Basterzi AD, Yazici K, Buturak V et al. Effects of venlafaxine and fluoxetine on lymphocyte subsets in patients with major depressive disorder: a flow cytometric analysis. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 70-75
• 69 Maxeiner HG, Rojewski MT, Schmitt A et al. Flow cytometric analysis of T cell subsets in paired samples of cerebrospinal fluid and peripheral blood from patients with neurological and psychiatric disorders. Brain Behav Immun 2009; 23: 134-142
• 70 Tynan RJ, Weidenhofer J, Hinwood M et al. A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 2012; 26: 469-479
• 71 Tedeschini E, Levkovitz Y, Iovieno N et al. Efficacy of antidepressants for late-life depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry 2011; 72: 1660-1668
• 72 Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol Psychiatry 2013; 18: 963-974
• 73 Otte C. Incomplete remission in depression: role of psychiatric and somatic comorbidity. Dialogues Clin Neurosci 2008; 10: 453-460
• 74 Baune BT, Stuart M, Gilmour A et al. The relationship between subtypes of depression and cardiovascular disease: a systematic review of biological models. Transl Psychiatry 2012; 2: e92
• 75 Stuart MJ, Baune BT. Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine co-morbidity. Neurosci Biobehav Rev 2012; 36: 658-676
• 76 Himmerich H, Bartsch S, Hamer H et al. Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro. J Psychiatr Res 2013; 47: 1751-1759
• 77 Ramirez K, Niraula A, Sheridan JF. GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and behavioral alterations. Brain Behav Immun 2016; 51: 154-168
• 78 Martinez JM, Garakani A, Yehuda R et al. Proinflammatory and “resiliency” proteins in the CSF of patients with major depression. Depress Anxiety 2012; 29: 32-38
• 79 Molteni R, Macchi F, Zecchillo C et al. Modulation of the inflammatory response in rats chronically treated with the antidepressant agomelatine. Eur Neuropsychopharmacol 2013; 23: 1645-1655
• 80 Baganz NL, Blakely RD. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 2013; 4: 48-63