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BMC Medicine
Published in: BMC Medicine 1/2016

Open Access 01-12-2016 | Opinion

Immuno-psychiatry: an agenda for clinical practice and innovative research

Authors: Marion Leboyer, Michael Berk, Robert H. Yolken, Ryad Tamouza, David Kupfer, Laurent Groc

Published in: BMC Medicine | Issue 1/2016

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Abstract

Background

The diagnostic scheme for psychiatric disorders is currently based purely on descriptive nomenclature given that biomarkers subtypes and clearly defined causal mechanisms are lacking for the vast majority of disorders. The emerging field of “immuno-psychiatry” has the potential to widen the exploration of a mechanism-based nosology, possibly leading to the discovery of more effective personalised treatment strategies.

Discussion

Disturbances in immuno-inflammatory and related systems have been implicated in the aetiology, pathophysiology, phenomenology and comorbidity of several psychiatric disorders, including major mood disorders and schizophrenia. A fundamental challenge in their clinical management is to identify bio-signatures that might indicate risk, state, trait, prognosis or theragnosis. Here, we provide the rationale for a clinical and research agenda to refine future clinical practice and conceptual views, and to delineate pathways toward innovative treatment discovery.

Conclusion

The development of bio-signatures will allow clinicians to tailor interventions to the abovementioned biomarker subtypes – a major translational goal for research in this field.
Literature
1.
Berk M, Nierenberg AA. Three paths to drug discovery in psychiatry. Am J Psychiatry. 2015;172(5):412–4.CrossRefPubMed
2.
Berk M, Williams LJ, Jacka FN, O'Neil A, Pasco JA, Moylan S, Allen NB, Stuart AL, Hayley AC, Byrne ML, et al. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013;11:200.CrossRefPubMedPubMedCentral
3.
Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R, Jones PB. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. Lancet Psychiatry. 2015;2(3):258–70.CrossRefPubMedPubMedCentral
4.
Modabbernia A, Taslimi S, Brietzke E, Ashrafi M. Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry. 2013;74(1):15–25.CrossRefPubMed
5.
Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011;70(7):663–71.CrossRefPubMedPubMedCentral
6.
7.
Danese A, Pariante CM, Caspi A, Taylor A, Poulton R. Childhood maltreatment predicts adult inflammation in a life-course study. Proc Natl Acad Sci U S A. 2007;104(4):1319–24.CrossRefPubMedPubMedCentral
8.
Copeland WE, Wolke D, Lereya ST, Shanahan L, Worthman C, Costello EJ. Childhood bullying involvement predicts low-grade systemic inflammation into adulthood. Proc Natl Acad Sci U S A. 2014;111(21):7570–5.CrossRefPubMedPubMedCentral
9.
Rosenblat JD, McIntyre RS. Are medical comorbid conditions of bipolar disorder due to immune dysfunction? Acta Psychiatr Scand. 2015;132(3):180–91.CrossRefPubMed
10.
Niculescu AB, Levey D, Le-Niculescu H, Niculescu E, Kurian SM, Salomon D. Psychiatric blood biomarkers: avoiding jumping to premature negative or positive conclusions. Mol Psychiatry. 2015;20(3):286–8.CrossRefPubMedPubMedCentral
11.
McGorry P, Keshavan M, Goldstone S, Amminger P, Allott K, Berk M, Lavoie S, Pantelis C, Yung A, Wood S, et al. Biomarkers and clinical staging in psychiatry. World Psychiatry. 2014;13(3):211–23.CrossRefPubMedPubMedCentral
12.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9(1):46–56.CrossRefPubMedPubMedCentral
13.
14.
Benros ME, Waltoft BL, Nordentoft M, Ostergaard SD, Eaton WW, Krogh J, Mortensen PB. Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiat. 2013;70(8):812–20.CrossRef
15.
Chen SW, Zhong XS, Jiang LN, Zheng XY, Xiong YQ, Ma SJ, Qiu M, Huo ST, Ge J, Chen Q. Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: a systematic review and meta-analysis. Behav Brain Res. 2016;296:61–9.CrossRefPubMed
16.
Atladottir HO, Thorsen P, Ostergaard L, Schendel DE, Lemcke S, Abdallah M, Parner ET. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J Autism Dev Disord. 2010;40(12):1423–30.CrossRefPubMed
17.
Bergink V, Gibney SM, Drexhage HA. Autoimmunity, inflammation, and psychosis: a search for peripheral markers. Biol Psychiatry. 2014;75(4):324–31.CrossRefPubMed
18.
Brown AS, Sourander A, Hinkka-Yli-Salomaki S, McKeague IW, Sundvall J, Surcel HM. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19(2):259–64.CrossRefPubMed
19.
Vuillermot S, Joodmardi E, Perlmann T, Ogren SO, Feldon J, Meyer U. Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments. J Neurosci. 2012;32(2):436–51.CrossRefPubMed
20.
Ripke S, O'Dushlaine C, Chambert K, Moran JL, Kahler AK, Akterin S, Bergen SE, Collins AL, Crowley JJ, Fromer M, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat Genet. 2013;45(10):1150–9.CrossRefPubMedPubMedCentral
21.
Oliveira J, Busson M, Etain B, Jamain S, Hamdani N, Boukouaci W, Amokrane K, Bennabi M, Le Guen E, Dargel AA, et al. Polymorphism of Toll-like receptor 4 gene in bipolar disorder. J Affect Disord. 2014;152-154:395–402.CrossRefPubMed
22.
Kazma R, Mefford JA, Cheng I, Plummer SJ, Levin AM, Rybicki BA, Casey G, Witte JS. Association of the innate immunity and inflammation pathway with advanced prostate cancer risk. PLoS One. 2012;7(12):e51680.CrossRefPubMedPubMedCentral
23.
Voineagu I, Eapen V. Converging pathways in autism spectrum disorders: interplay between synaptic dysfunction and immune responses. Front Hum Neurosci. 2013;7:738.CrossRefPubMedPubMedCentral
24.
Pocklington AJ, Rees E, Walters JT, Han J, Kavanagh DH, Chambert KD, Holmans P, Moran JL, McCarroll SA, Kirov G, et al. Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia. Neuron. 2015;86(5):1203–14.CrossRefPubMedPubMedCentral
25.
O'Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM, Cryan JF, Dinan TG. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65(3):263–7.CrossRefPubMed
26.
Coelho R, Viola TW, Walss-Bass C, Brietzke E, Grassi-Oliveira R. Childhood maltreatment and inflammatory markers: a systematic review. Acta Psychiatr Scand. 2014;129(3):180–92.CrossRefPubMed
27.
Etain B, Aas M, Andreassen OA, Lorentzen S, Dieset I, Gard S, Kahn JP, Bellivier F, Leboyer M, Melle I, et al. Childhood trauma is associated with severe clinical characteristics of bipolar disorders. J Clin Psychiatry. 2013;74(10):991–8.CrossRefPubMed
28.
Sun H, Damez-Werno DM, Scobie KN, Shao NY, Dias C, Rabkin J, Koo JW, Korb E, Bagot RC, Ahn FH, et al. ACF chromatin-remodeling complex mediates stress-induced depressive-like behavior. Nat Med. 2015;21(10):1146–53.CrossRefPubMedPubMedCentral
29.
Davis J, Moylan S, Harvey BH, Maes M, Berk M. Neuroprogression in schizophrenia: Pathways underpinning clinical staging and therapeutic corollaries. Aust N Z J Psychiatry. 2014;48(6):512–29.CrossRefPubMed
30.
Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA receptor trafficking in synaptic plasticity and memory. Nat Rev Neurosci. 2010;11(10):675–81.CrossRefPubMed
31.
Krugers HJ, Joels M. Long-lasting consequences of early life stress on brain structure, emotion and cognition. Curr Top Behav Neurosci. 2014;18:81–92.CrossRefPubMed
32.
Felger JC, Haroon E, Miller AH. Risk and resilience: animal models shed light on the pivotal role of inflammation in individual differences in stress-induced depression. Biol Psychiatry. 2015;78(1):7–9.CrossRefPubMedPubMedCentral
33.
Jerrell JM, McIntyre RS, Tripathi A. A cohort study of the prevalence and impact of comorbid medical conditions in pediatric bipolar disorder. J Clin Psychiatry. 2010;71(11):1518–25.CrossRefPubMed
34.
Godin O, Etain B, Henry C, Bougerol T, Courtet P, Mayliss L, Passerieux C, Azorin JM, Kahn JP, Gard S, et al. Metabolic syndrome in a French cohort of patients with bipolar disorder: results from the FACE-BD cohort. J Clin Psychiatry. 2014;75(10):1078–85. quiz 1085.CrossRefPubMed
35.
Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiat. 2014;71(10):1121–8.CrossRef
36.
Ellenbogen MA, Santo JB, Linnen AM, Walker CD, Hodgins S. High cortisol levels in the offspring of parents with bipolar disorder during two weeks of daily sampling. Bipolar Disord. 2010;12(1):77–86.CrossRefPubMed
37.
Pasco JA, Jacka FN, Williams LJ, Henry MJ, Nicholson GC, Kotowicz MA, Berk M. Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study. J Affect Disord. 2008;107(1-3):221–5.CrossRefPubMed
38.
Coury DL, Ashwood P, Fasano A, Fuchs G, Geraghty M, Kaul A, Mawe G, Patterson P, Jones NE. Gastrointestinal conditions in children with autism spectrum disorder: developing a research agenda. Pediatrics. 2012;130 Suppl 2:S160–8.CrossRefPubMed
39.
40.
Kantrowitz J, Javitt DC. Glutamatergic transmission in schizophrenia: from basic research to clinical practice. Curr Opin Psychiatry. 2012;25(2):96–102.PubMedPubMedCentral
41.
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091–8.CrossRefPubMedPubMedCentral
42.
Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, Parsons TD, Lynch DR, Dalmau J, Balice-Gordon RJ. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):5866–75.CrossRefPubMedPubMedCentral
43.
Mikasova L, De Rossi P, Bouchet D, Georges F, Rogemond V, Didelot A, Meissirel C, Honnorat J, Groc L. Disrupted surface cross-talk between NMDA and Ephrin-B2 receptors in anti-NMDA encephalitis. Brain. 2012;135(Pt 5):1606–21.CrossRefPubMed
44.
Planaguma J, Leypoldt F, Mannara F, Gutierrez-Cuesta J, Martin-Garcia E, Aguilar E, Titulaer MJ, Petit-Pedrol M, Jain A, Balice-Gordon R, et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain. 2015;138(Pt 1):94–109.CrossRefPubMed
45.
Coutinho E, Harrison P, Vincent A. Do neuronal autoantibodies cause psychosis? A neuroimmunological perspective. Biol Psychiatry. 2014;75(4):269–75.CrossRefPubMed
46.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2010;10(1):63–74.CrossRef
47.
48.
Marquard J, Otter S, Welters A, Stirban A, Fischer A, Eglinger J, Herebian D, Kletke O, Klemen MS, Stozer A, et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med. 2015;21(4):363–72.CrossRefPubMed
49.
Sharp CD, Fowler M, Jackson TH, Houghton J, Warren A, Nanda A, Chandler I, Cappell B, Long A, Minagar A, et al. Human neuroepithelial cells express NMDA receptors. BMC Neurosci. 2003;4:28.CrossRefPubMedPubMedCentral
50.
Reijerkerk A, Kooij G, van der Pol SM, Leyen T, Lakeman K, van Het Hof B, Vivien D, de Vries HE. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. J Neurochem. 2010;113(2):447–53.CrossRefPubMed
51.
Ganor Y, Besser M, Ben-Zakay N, Unger T, Levite M. Human T cells express a functional ionotropic glutamate receptor GluR3, and glutamate by itself triggers integrin-mediated adhesion to laminin and fibronectin and chemotactic migration. J Immunol. 2003;170(8):4362–72.CrossRefPubMed
52.
Bozic M, Valdivielso JM. The potential of targeting NMDA receptors outside the CNS. Expert Opin Ther Targets. 2015;19(3):399–413.CrossRefPubMed
53.
Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 2012;11(3):191–200.CrossRefPubMed
54.
Baumeister D, Ciufolini S, Mondelli V. Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment? Psychopharmacology (Berl). 2016;233(9):1575–89.CrossRef
55.
Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull. 2007;33(3):729–36.CrossRefPubMed
56.
Sutterland AL, Fond G, Kuin A, Koeter MW, Lutter R, van Gool T, Yolken R, Szoke A, Leboyer M, de Haan L. Beyond the association. Toxoplasma gondii in schizophrenia, bipolar disorder, and addiction: systematic review and meta-analysis. Acta Psychiatr Scand. 2015;132(3):161–79.CrossRefPubMed
57.
Fond G, Boyer L, Gaman A, Laouamri H, Attiba D, Richard JR, Delavest M, Houenou J, Le Corvoisier P, Charron D, et al. Treatment with anti-toxoplasmic activity (TATA) for toxoplasma positive patients with bipolar disorders or schizophrenia: a cross-sectional study. J Psychiatr Res. 2015;63:58–64.CrossRefPubMed
58.
Dean OM, Maes M, Ashton M, Berk L, Kanchanatawan B, Sughondhabirom A, Tangwongchai S, Ng C, Dowling N, Malhi GS, et al. Protocol and rationale-the efficacy of minocycline as an adjunctive treatment for major depressive disorder: a double blind, randomised, placebo controlled trial. Clin Psychopharmacol Neurosci. 2014;12(3):180–8.CrossRefPubMedPubMedCentral
59.
Sommer IE, de Witte L, Begemann M, Kahn RS. Nonsteroidal anti-inflammatory drugs in schizophrenia: ready for practice or a good start? A meta-analysis. J Clin Psychiatry. 2012;73(4):414–9.CrossRefPubMed
60.
Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010;71(5):520–7.CrossRefPubMed
61.
Na KS, Lee KJ, Lee JS, Cho YS, Jung HY. Efficacy of adjunctive celecoxib treatment for patients with major depressive disorder: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2014;48:79–85.CrossRefPubMed
62.
Iyengar RL, Gandhi S, Aneja A, Thorpe K, Razzouk L, Greenberg J, Mosovich S, Farkouh ME. NSAIDs are associated with lower depression scores in patients with osteoarthritis. Am J Med. 2013;126(11):1017. e11–8.CrossRefPubMed
63.
Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kohlmann K, Hewitt K, Moss K, Allwang C, Schapkaitz I, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2014;75(6):628–36.CrossRefPubMed
64.
Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481–6.CrossRefPubMedPubMedCentral
65.
Chang EI, Zarate MA, Rabaglino MB, Richards EM, Arndt TJ, Keller-Wood M, Wood CE. Ketamine decreases inflammatory and immune pathways after transient hypoxia in late gestation fetal cerebral cortex. Physiol Rep. 2016;4:e12741.CrossRefPubMedPubMedCentral
66.
Cattaneo A, Gennarelli M, Uher R, Breen G, Farmer A, Aitchison KJ, Craig IW, Anacker C, Zunsztain PA, McGuffin P, et al. Candidate genes expression profile associated with antidepressants response in the GENDEP study: differentiating between baseline ‘predictors’ and longitudinal ‘targets’. Neuropsychopharmacology. 2013;38(3):377–85.CrossRefPubMed
67.
Mondelli V, Ciufolini S, Belvederi Murri M, Bonaccorso S, Di Forti M, Giordano A, Marques TR, Zunszain PA, Morgan C, Murray RM, et al. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr Bull. 2015;41(5):1162–70.CrossRefPubMedPubMedCentral
68.
Girgis RR, Kumar SS, Brown AS. The cytokine model of schizophrenia: emerging therapeutic strategies. Biol Psychiatry. 2014;75(4):292–9.CrossRefPubMed
69.
Perron H, Hamdani N, Faucard R, Lajnef M, Jamain S, Daban-Huard C, Sarrazin S, LeGuen E, Houenou J, Delavest M, et al. Molecular characteristics of human endogenous retrovirus type-W in schizophrenia and bipolar disorder. Transl Psychiatry. 2012;2:e201.CrossRefPubMedPubMedCentral
70.
Curtin F, Lang AB, Perron H, Laumonier M, Vidal V, Porchet HC, Hartung HP. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin Ther. 2012;34(12):2268–78.CrossRefPubMed
71.
72.
Abazyan B, Nomura J, Kannan G, Ishizuka K, Tamashiro KL, Nucifora F, Pogorelov V, Ladenheim B, Yang C, Krasnova IN, et al. Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology. Biol Psychiatry. 2010;68(12):1172–81.CrossRefPubMedPubMedCentral
Metadata
Title
Immuno-psychiatry: an agenda for clinical practice and innovative research
Authors
Marion Leboyer
Michael Berk
Robert H. Yolken
Ryad Tamouza
David Kupfer
Laurent Groc
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2016
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-016-0712-5

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