Bipolar disorder (BD) is a psychiatric condition associated with elevated frequency of clinical comorbidities and cognitive impairment. The neurobiology of BD is not completely understood. Recent evidence has implicated immune dysfunction in its physiopathology. Here, we review several data supporting the presence of immunological dysfunction in BD: (i) increased frequency of autoimmune diseases; (ii) distinct immune cell profile; (iii) release of/altered cytokines by stimulated mononuclear cells; (iv) elevated levels of circulating immune markers, and (v) inflammatory changes in the central nervous system. We also discuss the interplay between immunological dysfunction and neuroprogression in BD.

Keywords:
Mania, Depression, Aspirin, Interleukin, Lymphocytes, Mood disorder
1.
Fajutrao L, Locklear J, Priaulx J, Heyes A: A systematic review of the evidence of the burden of bipolar disorder in Europe. Clin Pract Epidemiol Ment Health 2009;23:1-8.
2.
Berk M, Kapczinski F, Andreazza AC, Dean OM, Giorlando F, Maes M, Yücel M, Gama CS, Dodd S, Dean B, Magalhães PV, Amminger P, McGorry P, Malhi GS: Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35:804-817.
3.
Eaton WW, Pedersen MG, Nielsen PR, Mortensen PB: Autoimmune diseases, bipolar disorder, and non-affective psychosis. Bipolar Disord 2010;12:638-646.
4.
Bachen EA, Chesney MA, Criswell LA: Prevalence of mood and anxiety disorders in women with systemic lupus erythematosus. Arthritis Rheum 2009;61:822-829.
5.
Edwards LJ, Constantinescu CS: A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Mult Scler 2004;10:575-581.
6.
Kupka RW, Nolen WA, Post RM, McElroy SL, Altshuler LL, Denicoff KD, Frye MA, Keck PE Jr, Leverich GS, Rush AJ, Suppes T, Pollio C, Drexhage HA: High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure. Biol Psychiatry 2002;51:305-311.
7.
Hillegers MH, Reichart CG, Wals M, Verhulst FC, Ormel J, Nolen WA, Drexhage HA: Signs of a higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents. Eur Neuropsychopharmacol 2007;17:394-399.
8.
Darko DF, Rose J, Gillin JC, Golshan S, Baird SM: Neutrophilia and lymphopenia in major mood disorders. Psychiatry Res 1988;25:243-251.
9.
Abeer, El-Sayed A, Ramy HA: Immunological changes in patients with mania: changes in cell mediated immunity in a sample from Egyptian patients. Egypt J Immunol 2006;13:79-85.
10.
do Prado CH, Rizzo LB, Wieck A, Lopes RP, Teixeira AL, Grassi-Oliveira R, Bauer ME: Reduced regulatory T cells are associated with higher levels of Th1/TH17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology 2013;38:667-676.
11.
Drexhage RC, Hoogenboezem TH, Versnel MA, Berghout A, Nolen WA, Drexhage HA: The activation of monocyte and T cell networks in patients with bipolar disorder. Brain Behav Immun 2011;25:1206-1213.
12.
Knijff EM, Breunis MN, van Geest MC, Kupka RW, Ruwhof C, de Wit HJ, Nolen WA, Drexhage HA: A relative resistance of T cells to dexamethasone in bipolar disorder. Bipolar Disord 2006;8:740-750.
13.
Kim YK, Jung HG, Myint AM, Kim H, Park SH: Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder. J Affect Disord 2007;104:91-95.
14.
Liu HC, Yang YY, Chou YM, Chen KP, Shen WW, Leu SJ: Immunologic variables in acute mania of bipolar disorder. J Neuroimmunol 2004;150:116-122.
15.
Boufidou F, Nikolaou C, Alevizos B, Liappas IA, Christodoulou GN: Cytokine production in bipolar affective disorder patients under lithium treatment. J Affect Disord 2004;82:309-313.
16.
Knijff EM, Breunis MN, Kupka RW, de Wit HJ, Ruwhof C, Akkerhuis GW, Nolen WA, Drexhage HA: An imbalance in the production of IL-1β and IL-6 by monocytes of bipolar patients: restoration by lithium treatment. Bipolar Disord 2007;9:743-753.
17.
McAdams C, Leonard BE: Neutrophil and monocyte phagocytosis in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 1993;17:971-984.
18.
Padmos RC, Hillegers MH, Knijff EM, Vonk R, Bouvy A, Staal FJ, de Ridder D, Kupka RW, Nolen WA, Drexhage HA: A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. Arch Gen Psychiatry 2008;65:395-407.
19.
Modabbernia A, Taslimi S, Brietzke E, Ashrafi M: Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 2013;74:15-25.
20.
Munkholm K, Braüner JV, Kessing LV, Vinberg M: Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 2013;47:1119-1133.
21.
Barbosa IG, Rocha NP, de Miranda AS, Magalhães PV, Huguet RB, de Souza LP, Kapczinski F, Teixeira AL: Increased levels of adipokines in bipolar disorder. J Psychiatr Res 2012;46:389-393.
22.
Barbosa IG, Huguet RB, Mendonça VA, Sousa LP, Neves FS, Bauer ME, Teixeira AL: Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2011;261:139-143.
23.
Hope S, Dieset I, Agartz I, Steen NE, Ueland T, Melle I, Aukrust P, Andreassen OA: Affective symptoms are associated with markers of inflammation and immune activation in bipolar disorders but not in schizophrenia. J Psychiatr Res 2011;45:1608-1616.
24.
Barbosa IG, Rocha NP, Bauer ME, de Miranda AS, Huguet RB, Reis HJ, Zunszain PA, Horowitz MA, Pariante CM, Teixeira AL: Chemokines in bipolar disorder: trait or state? Eur Arch Psychiatry Clin Neurosci 2013;263:159-165.
25.
Machado-Vieira R, Andreazza AC, Viale CI, Zanatto V, Cereser V Jr, da Silva Vargas R, Kapczinski F, Portela LV, Souza DO, Salvador M, Gentil V: Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects. Neurosci Lett 2007;421:33-36.
26.
Tsai SY, Chung KH, Wu JY, Kuo CJ, Lee HC, Huang SH: Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder. J Affect Disord 2012;136:110-116.
27.
Barbosa IG, Pessoa Rocha N, Huebra L, Oliveira C, Nobre V, Teixeira AL: Not all inflammatory biomarkers are elevated in bipolar disorder: evidence for procalcitonin. Biol Psychiatry 2013;74:e29-e30.
28.
Kapczinski F, Dal-Pizzol F, Teixeira AL, Magalhaes PV, Kauer-Sant'Anna M, Klamt F, Pasquali MA, Quevedo J, Gama CS, Post R: A systemic toxicity index developed to assess peripheral changes in mood episodes. Mol Psychiatry 2010;15:784-786.
29.
Söderlund J, Olsson SK, Samuelsson M, Walther-Jallow L, Johansson C, Erhardt S, Landén M, Engberg G: Elevation of cerebrospinal fluid interleukin-1β in bipolar disorder. J Psychiatry Neurosci 2011;36:114-118.
30.
Rao JS, Harry GJ, Rapoport SI, Kim HW: Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients. Mol Psychiatry 2010;15:384-392.
31.
Bezchlibnyk YB, Wang JF, McQueen GM, Young LT: Gene expression differences in bipolar disorder revealed by cDNA array analysis of post-mortem frontal cortex. J Neurochem 2001;79:826-834.
32.
Dean B, Gibbons AS, Tawadros N, Brooks L, Everall IP, Scarr E: Different changes in cortical tumor necrosis factor-α-related pathways in schizophrenia and mood disorders. Mol Psychiatry 2013;18:767-773.
33.
Eyre H, Baune BT: Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 2012;37:1397-1416.
34.
Khairova RA, Machado-Vieira R, Du J, Manji HK: A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J Neuropsychopharmacol 2009;12:561-578.
35.
Cacci E, Claasen JH, Kokaia Z: Microglia-derived tumor necrosis factor-α exaggerates death of newborn hippocampal progenitor cells in vitro. J Neurosci Res 2005;80:789-797.
36.
Kupferschmidt DA, Zakzanis KK: Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature. Psychiatry Res 2011;193:71-79.
37.
Brooks JO 3rd, Wang PW, Bonner JC, Rosen AC, Hoblyn JC, Hill SJ, Ketter TA: Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder. J Psychiatr Res 2009;43:181-188.
38.
Barbosa IG, Rocha NP, Huguet RB, Ferreira RA, Salgado JV, Carvalho LA, Pariante CM, Teixeira AL: Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J Affect Disord 2012;137:151-155.
39.
Jones KA, Thomsen C: The role of the innate immune system in psychiatric disorders. Mol Cell Neurosci 2013;53:52-62.
40.
Wieck A, Grassi-Oliveira R, Prado CH, Rizzo LB, Oliveira AS, Kommers-Molina J, Viola TW, Teixeira AL, Bauer ME: Differential neuroendocrine and immune responses to acute psychosocial stress in women with type 1 bipolar disorder. Brain Behav Immun 2013;34:47-55.
41.
Nery FG, Monkul ES, Hatch JP, Fonseca M, Zunta-Soares GB, Frey BN, Bowden CL, Soares JC: Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 2008;23:87-94.
42.
Berk M, Dean O, Drexhage H, McNeil JJ, Moylan S, Oneil A, Davey CG, Sanna L, Maes M: Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med 2013;11:74.
43.
Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, Drevets W: Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2×2 clinical trial. BMJ Open 2012;2:e000643.
44.
Austin M, Tan YC: Mania associated with infliximab. Aust NZ J Psychiatry 2012;46:684-685.
45.
Elisa B, Beny L: Induction of manic switch by the tumour necrosis factor-alpha antagonist infliximab. Psychiatry Clin Neurosci 2010;64:442-443.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.