Cited by 501Tryptophan and brain disordersSchizophrenia research and treatmentNeuroinflammation and Neurodegeneration Mechanisms

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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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Background
Depressive and Negative Symptoms in the Early and Established Stages of Schizophrenia: Integrating Structural Brain Alterations, Cognitive Performance, and Plasma Interleukin 6 Levels
Zuelli, F. M. D. G. C., Donohoe, G. J., Griffiths, S. L., Del‐Ben, C. M., Watson, A., Burke, T., Lalousis, P. A., McKernan, D. P., Morris, D. W., Kelly, J. F., et al. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100429 · Cited by 5
Self-citation
Common Issues Among Asthma, Epilepsy, and Schizophrenia: From Inflammation to Ca2+/cAMP Signalling
Bergantin, L. B. (2020) · Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry · doi:10.2174/1871523019999201110192029 · Cited by 5
Rethinking Immunity and Cognition in Clinical High Risk for Psychosis
Griffiths, S. L., Upthegrove, R., Zuelli, F. M. D. G. C., & Deakin, J. F. W. (2022) · Current topics in behavioral neurosciences · doi:10.1007/7854_2022_399 · Cited by 5
Self-citation
The immune-stress/endocrine-redox-metabolic nature of psychosis’ etiopathology; focus on the intersystemic pathways interactions
Karanikas, E. (2022) · Neuroscience Letters · doi:10.1016/j.neulet.2022.137011 · Cited by 5
Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors
Wang, C., Wang, Z., Li, M., Li, C., Yu, H., Zhou, D.-S., & Chen, Z. (2017) · InTech eBooks · doi:10.5772/intechopen.69154 · Cited by 6
Association between prenatal maternal infection and disordered eating behaviours in adolescence: a UK population-based prospective birth cohort study
Solmi, F., Stavola, B. L. D., Khandaker, G. M., Bulik, C. M., Dalman, C., & Lewis, G. (2019) · Psychological Medicine · doi:10.1017/s0033291719000795 · Cited by 5
“Depression and psychosis are associated with dysregulated immunological profiles and, particularly, with increased inflammatory marker levels in peripheral blood (Upthegrove et al., 2014; Goldsmith et al., 2016).”
Background
Plasma linoelaidyl carnitine levels positively correlated with symptom improvement in olanzapine-treated first-episode drug-naïve schizophrenia
Wang, X., Xiu, M., Wang, K., Su, X., Li, X., & Wu, F. (2022) · Metabolomics · doi:10.1007/s11306-022-01909-4 · Cited by 5
Central insulin dysregulation in antipsychotic-naïve first-episode psychosis: In silico exploration of gene expression signatures
Lee, J., Xue, X., Au, E., McIntyre, W. B., Asgariroozbehani, R., Tseng, G. C., Papoulias, M., Panganiban, K. J., Agarwal, S. M., McCullumsmith, R. E., et al. (2023) · Psychiatry Research · doi:10.1016/j.psychres.2023.115636 · Cited by 5
Prenatal exposure and fetal programming of schizophrenia
Okechukwu, C. E. (2019) · Nigerian Journal of Experimental and Clinical Biosciences · doi:10.4103/njecp.njecp_12_19 · Cited by 5
Microdosing Psychedelics to Restore Synaptic Density in Schizophrenia
Sapienza, J., Spangaro, M., Comai, S., Sabé, M., Torre, J. T. L., Buonarroti, M., Cavallaro, R., & Bosia, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26188949 · Cited by 5
Prevalence and 3-year incidence of physical illnesses after schizophrenia diagnosis: Comparison with general population
Chen, Y., Chen, P., Pan, C., Chen, P., Su, S., Tsai, S., Chen, C.-C., & Kuo, C. (2024) · Schizophrenia Research · doi:10.1016/j.schres.2024.01.009 · Cited by 4
Eosinophils and Cognitive Impairment in Schizophrenia: A New Perspective
Obeagu, E. I., & Bluth, M. H. (2024) · Journal of Blood Medicine · doi:10.2147/jbm.s451988 · Cited by 4
“63,64 By considering the eosinophil profile of individuals with schizophrenia, personalized treatment plans can be developed.”
Background
Psychiatric Disorders and Inflammation
Dantzer, R. (2017) · Wiley-VCH eBooks · doi:10.1002/9783527692156.ch29 · Cited by 4
Serum Interleukin-1β and tumor necrosis factor–α in first-episode drug-naive and chronic schizophrenia patients: Associated with cognitive deficits
Zhang, L., Liu, F., Zheng, H., Wu, R., & Zhao, J. (2021) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2021.102605 · Cited by 4
Higher lymphocyte count associated with larger hippocampal volume and fewer depressive symptoms in drug–na ïve first-episode psychosis
Toll, A., Blanco‐Hinojo, L., Bergé, D., Martín-Subero, M., Casanovas, F., El-Abidi, K., Pérez, V., & Mané, A. (2023) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2023.01.002 · Cited by 5
Neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-α (TNF-α) levels in patients with schizophrenia
Çakıl, A. G., Kaya, H., Nural, A. S., Çakmak, I. B., Okay, İ. T., & Göka, E. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06346-2 · Cited by 4
“Proinflammatory interleukin (IL)6, TNF-α, IL-1B, and interferon-γ (IFN-γ) are increased in both first-episode psychosis patients who did not receive any antipsychotic treatment and those within psychotic exacerbations, whereas anti-inflammatory cytokine IL-10 levels are decreased among them (Miller et al. 2011; Uptheg…”
Background
Phenotypic Resemblance to Neuropsychiatric Disorder and Altered mRNA Profiles in Cortex and Hippocampus Underlying IL15Rα Knockout
He, Y., Yu, Y., Li, Y., Duan, W., Sun, Z., Yang, J., Kastin, A. J., Pan, W., Zhang, Y., & Wang, K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.582279 · Cited by 4
Pioneering Changes in Psychiatry: Biomarkers, Psychedelics, and AI
Kargbo, R. B. (2023) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.3c00333 · Cited by 4
Evaluation of IL-1β, IL-6, and inflammatory markers during exacerbation and after antipsychotic treatment in drug-free schizophrenia patients
Kalyoncu, S., Aytaç, H. M., & Güçlü, O. (2025) · International Journal of Psychiatry in Clinical Practice · doi:10.1080/13651501.2025.2560349 · Cited by 3
“…(Giulian et al., 1988). studies, including several meta-analyses, have found elevated il-1ß levels in drug-naïve, first-episode psychosis patients (upthegrove et al., 2014); in both adults and children using atypical antipsychotics (Di Nicola et al., 2013; Falcone et al., 2015; lesh et al.,…”
Molecular Signatures of Schizophrenia and Insights into Potential Biological Convergence
Saada, M., & Stern, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199830 · Cited by 3
“For example, synaptic signaling alterations have been associated with cognitive impairment [13], whereas immune dysregulation and mitochondrial dysfunction have been linked to negative symptoms in some cohorts [58,63–65].”
Inflammatory markers (IL-6 and CRP) in childhood and their association with brain structure and psychotic experiences in adulthood
Merritt, K., Palmer, E. R., Laguna, P. A. L., Sethi, A., Rogers, J. C., Evans, C. J., Reichenberg, A., Khandaker, G. M., Upthegrove, R., Lewis, G., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2025.106247 · Cited by 3
“Meta-analyses report elevated levels of peripheral inflammatory markers in individuals with psychotic disorders, particularly interleukin-6 (IL-6) and C-reactive protein (CRP) (Upthegrove et al., 2014; Pillinger et al., 2019; Misiak et al., 2021).”
Self-citation
The Influence of Gut Microbiota in Psychosis
Murray, N., Ghomi, R. H., Nemani, K., & O’Connor, K. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-99971-7.00018-7 · Cited by 3
Adiponectin, resistin, interleukin-4 and TGF-β2 levels in treatment resistant schizophrenia patients
Karampas, A., Leontaritis, G., Markozannes, G., Asimakopoulos, A., Archimandriti, D. T., Spyrou, P., Georgiou, G. K., Plakoutsis, M., Kotsis, K. T., Voulgari, P. V., et al. (2024) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2024.111221 · Cited by 3
Molecular signatures and emerging therapeutic targets in schizophrenia: A biomarker-centric perspective in psychiatric disorders
Hakami, M. A. (2025) · Schizophrenia Research · doi:10.1016/j.schres.2025.05.026 · Cited by 3
The effect of electroconvulsive therapy on hematologic inflammatory markers in schizophrenia in association with type of antipsychotic medication
Önen, S., & Taymur, İ. (2020) · The European Research Journal · doi:10.18621/eurj.586551 · Cited by 3
“to previous serum concentrations after remission of symptoms with antipsychotic treatment [36, 46].”
Background
The specific phenotype of depression in recent onset schizophrenia spectrum disorders: A symptom profile and network comparison to recent onset major depressive disorder without psychotic features
Herniman, S. E., Wood, S. J., Cotton, S., Allott, K., Davey, C. G., Berk, M., Phillips, L., Liemburg, E. J., Castelein, S., Veling, W., et al. (2021) · Schizophrenia Research · doi:10.1016/j.schres.2021.11.048 · Cited by 3
“These immunological disturbances might also contribute to SSD (Khandaker et al., 2015; Upthegrove et al., 2014), and metabolic disturbances are common in SSD, at least due to anti-psychotic medication side-effects (Reynolds and Kirk, 2010; Tschoner et al.”
Background
Systemic Inflammatory Biomarkers in DSM-5–Defined Disorders and COVID-19: Evidence From Published Meta-analyses
Duong, A., Jeong, H., Sabbagh, D. E. S. E., & Andreazza, A. C. (2022) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2022.01.006 · Cited by 3
The immunopsychiatry of early-onset psychosis
Wedervang‐Resell, K., & Szabó, A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-89832-4.00013-5 · Cited by 3
Differential expression of haptoglobin in individuals at clinical high risk of psychosis and its association with global functioning and clinical symptoms
Healy, C., Byrne, J. F., Susai, S. R., Föcking, M., Mongan, D., Kodosaki, E., Heurich, M., Cagney, G., Wynne, K. J., Bearden, C. E., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.12.018 · Cited by 3
“Several studies have noted peripheral inflammatory dysregulation in individuals with both chronic and recent onset schizophrenia (Dickerson et al. (2016)), those with first episode psychosis (FEP) (Fraguas et al. (2019)) and those with FEP who were medication-naive (Upthegrove et al., 2014).”
Background
The Neuroimmune System in Psychiatric Disorders
Hassan, Y., ESTEVES, S. C., Leyrer‐Jackson, J. M., & Thomas, M. P. (2024) · Springer eBooks · doi:10.1007/978-3-031-68237-7_56 · Cited by 2
The Gordian knot of the immune-redox systems’ interactions in psychosis
Karanikas, E. (2023) · International Clinical Psychopharmacology · doi:10.1097/yic.0000000000000481 · Cited by 3
Association Study of Tumor Necrosis Factor Receptor 1 (TNFR1) Gene Polymorphisms with Schizophrenia in the Polish Population
Suchanek-Raif, R., Kucia, K. A., Kowalczyk, M., Raif, P., Paul-Samojedny, M., Fila-Daniłow, A., & Kowalski, J. (2017) · Mediators of Inflammation · doi:10.1155/2017/6016023 · Cited by 3
“An elevated level of TNF-α has been found in patients with schizophrenia [6].”
Background
Proteomics for diagnostic and therapeutic blood biomarker discovery in schizophrenia and other psychotic disorders
Cotter, D., Sabherwal, S., & Schubert, K. O. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813176-3.00025-0 · Cited by 3
The influence of modifiable cardiovascular risk factors on cognition, functioning, and inflammatory markers in first-episode psychosis: Results from a 2-year follow-up study
Pujol, N., Bergé, D., Mané, A., Bioque, M., Mezquida, G., Amoretti, S., Baeza, I., González-Pinto, A., Lobo, A., Cuesta, M. J., et al. (2022) · Psychiatry Research · doi:10.1016/j.psychres.2022.114760 · Cited by 3
Bioenergetic markers in cerebrospinal fluid in first-episode psychosis: Are they predictors of early antipsychotic response and 1-year outcomes?
Giné-Servén, E., Boix-Quintana, E., Ballesteros, A., Daví-Loscos, E., Guanyabens, N., Casado, V., Martínez-Ramírez, M., Crespo‐Facorro, B., Cuesta, M. J., & Labad, J. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111336 · Cited by 2
Is There a Link Between Type 2 Diabetes Mellitus and Negative Symptoms in Schizophrenia? A Scoping Review
Bitter, I., Czobor, P., & Tombor, L. (2025) · Brain Sciences · doi:10.3390/brainsci15050499 · Cited by 2
“Peripheral levels of Interleukin-1 β (IL-1 β ), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α ) are elevated during first-episode psychosis and psychotic relapses in schizophrenia [54,55], as well as in the pathogenesis [56] and complications of type 2 diabetes [57,58].”
The Role of Inflammatory Processes in the Etiopathogenesis of Schizophrenia
Rudkowski, K., Samochowiec, J., Kucharska–Mazur, J., & Mazur, A. (2023) · Archives of Psychiatry and Psychotherapy · doi:10.12740/app/163306 · Cited by 2
Differential inflammatory profiles in carriers of reciprocal 22q11.2 copy number variants
O’Hora, K., Amir, C., Chiem, E., Schleifer, C. H., Grigoryan, V., Kushan, L., Chiang, J. J., Cole, S. W., Irwin, M. R., & Bearden, C. E. (2024) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2024.107135 · Cited by 2
“…et al., 2002; Reale et al., 2011; Wu et al., 2019; Xiu et al., 2019; Zhang et al., 2016, 2002), first episode psychosis (Di Nicola et al., 2013; Upthegrove et al., 2014), and clinical high risk for psychosis (Park and Miller, 2020) suggest a link between psychosis and pro-inflammatory…”
Background
Identification of Factors to Predict Transition to Schizophrenia in Subjects with Ultra-high Risk for Psychosis: A Protocol for a Multicenter, Longitudinal Study of Sleep Parameters and Cytokine Levels
Yamada, Y., Mishima, K., Ohnishi, T., Suzuki, M., Nemoto, T., Mizuno, M., Kishimoto, T., Tomita, H., Ozone, M., Kitamura, S., et al. (2024) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.24.1239 · Cited by 3
“Although little information is available on altered concentrations of cytokines in the blood in people with the UHR [25], the knowledge about those in patients with first-episode psychosis (FEP) has been accumulated [22-24, 27-32 27-32, 34, 35 ].”
Cognitive and Psychomotor Processing Speed in Medication‐Naïve Individuals With First‐Episode of Psychosis: The Role of Peripheral Inflammatory Markers
Yorca‐Ruiz, Á., Martínez-Asensi, C., Herrero, R. M., Díaz‐Pons, A., de la Foz, V. O., Cacho, L. M. F., Alcantara, A. C., Crespo‐Facorro, B., & Ayesa‐Arriola, R. (2025) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.70006 · Cited by 2
“These processes may contribute to altered connectivity and cognitive processing [67, 68], potentially affecting biological mechanisms underlying PS/PMS deficits [69].”
Low-dose methotrexate as a potential treatment for schizophrenia via astrocytic and neuroimmune modulation
Lima, T. U., Zuelli, F. M. D. G. C., de Souza, A. P., Colodete, D. A. E., da Silva, N. R., Verza, F. A., Deakin, J. F. W., Del-Bel, E. A., Louzada‐Júnior, P., Del‐Ben, C. M., et al. (2025) · Schizophrenia Research · doi:10.1016/j.schres.2025.07.022 · Cited by 2

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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