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Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis

Upthegrove, Rachel, Manzanares-Teson, Nuria, Barnes, Nicholas M.·2014·Schizophrenia Research

DOI 10.1016/j.schres.2014.03.005

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Abstract

This systematic review sets out to give a comprehensive overview of the cytokine profile at the onset of psychosis un-confounded by medication. We aim to provide insight into the early pathophysiological process of psychosis and areas for future research of potential biomarkers able to chart the extent of illness or effectiveness of treatment. Following PRISMA guidelines, a systematic primary search identified 4638 citations, 4651 studies were retrieved and screened, and 23 studies met the inclusion criteria (published in English before June 2013, patients with neuroleptic naive first episode psychosis, and assessed circulating cytokines). These reported 570 patients, 683 healthy control subjects, and 20 cytokine/cytokine receptors. Papers that contained sufficient stratified data were included in a random-effects pooled effect size meta-analysis. Highly significant effect sizes were found for elevated IL-1β, sIL-2r, IL-6, and TNF-α. Non-significant effect size estimates were obtained for IL-2, IL-4, and IFN-γ. Thus, we found significant elevation in pro-inflammatory cytokine levels in the serum of patients with medication-naive first episode psychosis. This adds to the evidence of a pro-inflammatory immune deregulation in schizophrenia and suggests these cytokines should be the focus for further research in biomarkers of progress and extent of illness. Future studies should focus on the medication-naive group at the early stages of illness with numbers large enough to allow for the control of other potential confounding factors.

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In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study
Holmes, S. E., Hinz, R., Drake, R., Gregory, C. J., Conen, S., Matthews, J. C., Anton‐Rodriguez, J., Gerhard, A., & Talbot, P. S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.180 · Cited by 97
Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment
Reale, M., Costantini, E., & Greig, N. H. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.536257 · Cited by 111
The Promise of Biological Markers for Treatment Response in First-Episode Psychosis: A Systematic Review
Fond, G. B., d’Albis, M.-A., Jamain, S., Tamouza, R., Arango, C., Fleischhacker, W. W., Glenthoj, B. Y., Leweke, F. M., Lewis, S. W., McGuire, P. K., et al. (2015) · Schizophrenia Bulletin · doi:10.1093/schbul/sbv002 · Cited by 99
Molecular substrates of schizophrenia: homeostatic signaling to connectivity
Landek‐Salgado, M. A., Faust, T. E., & Sawa, A. (2015) · Molecular Psychiatry · doi:10.1038/mp.2015.141 · Cited by 95
Is it time for immunopsychiatry in psychotic disorders?
Leboyer, M., Oliveira, J., Tamouza, R., & Groc, L. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4266-1 · Cited by 98
Clinical studies of neuroinflammatory mechanisms in schizophrenia
Watkins, C. C., & Andrews, S. R. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.07.018 · Cited by 101
Applications of blood-based protein biomarker strategies in the study of psychiatric disorders
Chan, M. K., Gottschalk, M. G., Haenisch, F., Tomasik, J., Ruland, T., Rahmoune, H., Guest, P. C., & Bahn, S. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2014.08.002 · Cited by 98
“A subsequent systematic review of 23 studies involving 570 antipsychotic-naı̈ve first-episode schizophrenia patients and 683 healthy control subjects by Upthegrove et al. (2014) indicated a robust elevation of IL-1b, sIL-2r, IL-6, and TNF-a levels at the onset of schizophrenia.”
Serum kynurenic acid is reduced in affective psychosis
Wurfel, B. E., Drevets, W. C., Bliss, S. A., McMillin, J. R., Suzuki, H., Ford, B. N., Morris, H. M., Teague, T. K., Dantzer, R., & Savitz, J. B. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.88 · Cited by 91
Greater extracellular free-water in first-episode psychosis predicts better neurocognitive functioning
Lyall, A. E., Pasternak, O., Robinson, D. G., Newell, D., Trampush, J. W., Gallego, J. A., D, M. F. M., Malhotra, A. K., Karlsgodt, K. H., Kubicki, M. R., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.43 · Cited by 93
“” Moreover, a recent genome-wide analysis implicated immune-related pathways as a principal risk factor in schizophrenia (28) and studies of FEP patients report greater pro-inflammatory cytokines and cytokine receptors (16,34,35).”
Background
Constructing the Immune Signature of Schizophrenia for Clinical Use and Research; An Integrative Review Translating Descriptives Into Diagnostics
Kroken, R. A., Sommer, I. E., Steen, V. M., Dieset, I., & Johnsen, E. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00753 · Cited by 95
“However, as a general Th1/Th2 imbalance is not found the interpretation of the findings in terms of underlying immune disturbances is not clear (1).”
Background
Is It Possible to Predict the Future in First-Episode Psychosis?
Suvisaari, J., Mantere, O., Keinänen, J., Mäntylä, T. J. S., Rikandi, E., Lindgren, M., Kieseppä, T., & Raij, T. T. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00580 · Cited by 96
The potential shared role of inflammation in insulin resistance and schizophrenia: A bidirectional two-sample mendelian randomization study
Perry, B. I., Burgess, S., Jones, H. J., Zammit, S., Upthegrove, R., Mason, A. M., Day, F. R., Langenberg, C., Wareham, N. J., Jones, P. B., et al. (2021) · PLoS Medicine · doi:10.1371/journal.pmed.1003455 · Cited by 91
“Higher levels of circulating inflammatory markers have been associated with both psychosis and cardiometabolic disorders, both cross-sectionally and longitudinally [18– 20].”
BackgroundSelf-citation
The pro‐cognitive mechanisms of physical exercise in people with schizophrenia
Firth, J., Cotter, J., Carney, R., & Yung, A. R. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13772 · Cited by 79
“This is consistent with the findings that the early stages of schizophrenia are associated with more inflammation, compared with chronic illness (Miller et al., 2011; Upthegrove et al., 2014).”
Impaired regulatory T cell control of astroglial overdrive and microglial pruning in schizophrenia
Zuelli, F. M. D. G. C., & Deakin, J. F. W. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.004 · Cited by 90
Tryptophan Metabolism and White Matter Integrity in Schizophrenia
Chiappelli, J., Postolache, T. T., Kochunov, P., Rowland, L. M., Wijtenburg, S. A., Shukla, D. K., Tagamets, M. A., Du, X. M., Savransky, A., Lowry, C. A., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.66 · Cited by 84
“One of the possibilities explaining the link between tryptophan level and FA may in part be related to evidence of chronic inflammation in schizophrenia (Miller et al, 2011; Upthegrove et al, 2014).”
Background
Mechanisms Underlying the Comorbidity of Schizophrenia and Type 2 Diabetes Mellitus
Mizuki, Y., Sakamoto, S., Okahisa, Y., Yada, Y., Hashimoto, N., Takaki, M., & Yamada, N. (2020) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyaa097 · Cited by 84
C-Reactive Protein/Albumin and Neutrophil/Albumin Ratios as Novel Inflammatory Markers in Patients with Schizophrenia
Balcioglu, Y. H., & Kirlioglu, S. S. (2020) · Psychiatry Investigation · doi:10.30773/pi.2020.0185 · Cited by 80
Long-term pathological consequences of prenatal infection: beyond brain disorders
Labouesse, M. A., Langhans, W., & Meyer, U. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00087.2015 · Cited by 80
The Emerging Immunogenetic Architecture of Schizophrenia
Pouget, J. G. (2018) · Schizophrenia Bulletin · doi:10.1093/schbul/sby038 · Cited by 77
Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis
Patlola, S. R., Donohoe, G. J., & McKernan, D. P. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.01.042 · Cited by 75
A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue
Hoseth, E. Z., Ueland, T., Dieset, I., Birnbaum, R., Shin, J. H., Kleinman, J. E., Hyde, T. M., Mørch, R. H., Hope, S., Lekva, T., et al. (2016) · Schizophrenia Bulletin · doi:10.1093/schbul/sbw183 · Cited by 76
Meta-analysis of cytokine and C-reactive protein levels in high-risk psychosis
Park, S., & Miller, B. J. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.03.012 · Cited by 75
Association of baseline inflammatory markers and the development of negative symptoms in individuals at clinical high risk for psychosis
Goldsmith, D. R., Haroon, E., Miller, A. H., Addington, J., Bearden, C. E., Cadenhead, K., Cannon, T. D., Cornblatt, B. A., Mathalon, D. H., McGlashan, T. H., et al. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.11.315 · Cited by 74
“, 2009), alterations in inflammatory markers (Goldsmith et al., 2016; Miller et al., 2011; Potvin et al., 2008; Upthegrove et al., 2014), and recent data implicating the innate immune system and complement system in disordered synaptic pruning (Sekar et al.”
Background
Stratification and prediction of remission in first-episode psychosis patients: the OPTiMiSE cohort study
Martinuzzi, E., Barbosa, S., Daoudlarian, D., Ali, W. B. H., Gilet, C., Fillatre, L., Khalfallah, O., Troudet, R., Jamain, S., Fond, G. B., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-018-0366-5 · Cited by 74
Interaction of BDNF with cytokines in chronic schizophrenia
Zhang, X. Y., Tan, Y., Chen, D., Tan, S., Yang, F., Wu, H. E., Zunta‐Soares, G. B., Huang, X., Kosten, T. R., & Soares, J. C. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.09.014 · Cited by 73
“, 2012) in the serum of patients with medication-naïve first episode psychosis (Upthegrove et al., 2014).”
Influential
The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis
Johnsen, E., Fathian, F., Kroken, R. A., Steen, V. M., Jørgensen, H. A., Gjestad, R., & Løberg, E. (2016) · BMC Psychiatry · doi:10.1186/s12888-016-0769-x · Cited by 72
Thyroid hormones in persons with schizophrenia: A systematic review and meta-analysis
Misiak, B., Stańczykiewicz, B., Wiśniewski, M., Bartoli, F., Carrà, G., Cavaleri, D., Samochowiec, J., Jarosz, K., Rosińćzuk, J., & Frydecka, D. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2021.110402 · Cited by 71
Changes in serum TNF-α, IL-18, and IL-6 concentrations in patients with chronic schizophrenia at admission and at discharge
Luo, Y., He, H., Zhang, J., Ou, Y., & Fan, N. (2019) · Comprehensive Psychiatry · doi:10.1016/j.comppsych.2019.01.003 · Cited by 70
Neuroinflammation in psychiatric disorders: An introductory primer
Dunn, G. A., Loftis, J. M., & Sullivan, E. L. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172981 · Cited by 73
Evaluating the Hypothesis That Schizophrenia Is an Inflammatory Disorder
Miller, B. J., & Goldsmith, D. R. (2020) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.20200015 · Cited by 73
The value of interleukin 6 as a peripheral diagnostic marker in schizophrenia
Chase, K. A., Cone, J. J., Rosen, C., & Sharma, R. P. (2016) · BMC Psychiatry · doi:10.1186/s12888-016-0866-x · Cited by 69
Neuroinflammatory and cognitive consequences of combined radiation and immunotherapy in a novel preclinical model
McGinnis, G. J., Friedman, D. J., Young, K. H., Torres, E. R. S., Thomas, C. R., Gough, M. J., & Raber, J. (2016) · Oncotarget · doi:10.18632/oncotarget.13551 · Cited by 75
“IL-2, a hallmark of proinflammatory polarization [92], demonstrated a robust tumor x treatment interaction.”
Background
Blood-Based Protein Changes in Childhood Are Associated With Increased Risk for Later Psychotic Disorder: Evidence From a Nested Case–Control Study of the ALSPAC Longitudinal Birth Cohort
English, J. A., Lopez, L. M., O’Gorman, A., Föcking, M., Hryniewiecka, M., Scaife, C., Sabherwal, S., Wynne, K. J., Dicker, P., Rutten, B. P. F., et al. (2017) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx075 · Cited by 70
A loss of mature microglial markers without immune activation in schizophrenia
Snijders, G. J. L., van Zuiden, W., Sneeboer, M. A. M., van Berlekom, A. B., van der Geest, A. T., Schnieder, T. P., MacIntyre, D. J., Hol, E. M., Kahn, R. S., & de Witte, L. D. (2021) · Glia · doi:10.1002/glia.23962 · Cited by 70
Inflammatory biomarkers in schizophrenia: Implications for heterogeneity and neurobiology
Miller, B. J., & Goldsmith, D. R. (2019) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2019.100006 · Cited by 72
Oxidative stress in drug naïve first episode psychosis and antioxidant effects of risperidone
Noto, C. D. S., Ota, V., Gadelha, A., Noto, M. N., Barbosa, D. S., Bonifácio, K. L., Nunes, S. O. V., Cordeiro, Q., Belangero, S. I., Bressan, R. A., et al. (2015) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2015.07.003 · Cited by 67
“Previous studies have consistently reportedmajor imbalances in immuno-inflammatory, oxidative and nitrosative stress pathways even at early stages of schizophrenia (Anderson et al., 2013; Miller et al., 2011; Upthegrove et al., 2014).”
Result
Investigating the neuroimmunogenic architecture of schizophrenia
Birnbaum, R., Jaffe, A. E., Chen, Q., Shin, J. H., BrainSeq Consortium, Schubert, C. R., O'Donnell, P., Quan, J., Wendland, J. R., Xi, H. S., et al. (2018) · Molecular Psychiatry · doi:10.1038/mp.2017.89 · Cited by 67
Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor
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Persistent psychotic symptoms following COVID-19 infection
Lim, S. T., Janaway, B., Costello, H., Trip, A., & Price, G. W. (2020) · BJPsych Open · doi:10.1192/bjo.2020.76 · Cited by 66
Effects of depression on the cytokine profile in drug naïve first-episode psychosis
Noto, C. D. S., Ota, V., Santoro, M. L., Ortiz, B. B., Rizzo, L. B., Higuchi, C. H., Cordeiro, Q., Belangero, S. I., Bressan, R. A., Gadelha, A., et al. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.01.026 · Cited by 65
“Upthegrove et al. (2014) recently published a meta-analysis examining patients with drug naïve first episode psychosis (FEP).”
Background
Antipsychotic treatment reduces psychotic symptoms and markers of low-grade inflammation in first episode psychosis patients, but increases their body mass index.
Haring, L., Koido, K., Vasar, V., Leping, V., Zilmer, K., Zilmer, M., & Vasar, E. (2015) · Schizophrenia Research · doi:10.1016/j.schres.2015.08.027 · Cited by 63
“Nevertheless, there is considerable evidence to suggest that low-grade inflammation already occurs during the early stages of schizophrenia manifestation (Miller et al., 2011; De Witte et al., 2014; Upthegrove et al., 2014).”
Background
Inflammatory, cardio-metabolic and diabetic profiling of chronic schizophrenia
Balõtšev, R., Koido, K., Vasar, V., Janno, S., Kriisa, K., Mahlapuu, R., Ljubajev, U., Parksepp, M., Veiksaar, P., Volke, V., et al. (2017) · European psychiatry · doi:10.1016/j.eurpsy.2016.05.010 · Cited by 63

Authors: Upthegrove, R., Manzanares-Teson, N., & Barnes, N. M.
Affiliations: Birmingham and Solihull Mental Health NHS Foundation Trust (GB)
University of Birmingham (GB)
Corresponding author: Upthegrove, Rachel
ORCID: Upthegrove, Rachel
Barnes, Nicholas M.
Venue: Schizophrenia Research
Publisher: Elsevier BV
Published: 2014-05
Volume: 155
Issue: 1-3
Pages: 101-108
ISSN: 0920-9964 (ISSN-L)
DOI: 10.1016/j.schres.2014.03.005
OpenAlex: W1969833165
Cited by: 501
References: 57
Citations by year: 2026: 29 · 2025: 38 · 2024: 34 · 2023: 46 · 2022: 41 · 2021: 51 · 2020: 42 · 2019: 48 · 2018: 52 · 2017: 47 · 2016: 37 · 2015: 28 · 2014: 7
FWCI: 3.13
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Schizophrenia Research (publishedVersion)
PubMed (publishedVersion)
University of Birmingham Research Portal (University of Birmingham) (publishedVersion)
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: first-episode psychosis, cytokines
MeSH terms: Humans, Psychotic Disorders, Antipsychotic Agents, Cytokines, Databases, Factual

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Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis

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