Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity

Abbott, 2006, Astrocyte-endothelial interactions at the blood-brain barrier, Nat Rev Neurosci., 7, 41, 10.1038/nrn1824 Berger, 2017, Ventricular volumes across stages of schizophrenia and other psychoses, Aust N Z J Psychiatry., 51, 1041, 10.1177/0004867417715914 Boerrigter, 2017, Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder, J Neuroinflammation., 14, 10.1186/s12974-017-0962-y Borovcanin, 2017, Interleukin-6 in schizophrenia—is there a therapeutic relevance?, Front. Psychiatry, 8, 10.3389/fpsyt.2017.00221 Brown, 2022, Maternal immune activation with high molecular weight poly(I:C) in Wistar rats leads to elevated immune cell chemoattractants, J. Neuroimmunol., 364, 10.1016/j.jneuroim.2022.577813 Bulzacka, 2016, Chronic peripheral inflammation is associated with cognitive impairment in schizophrenia: results from the multicentric FACE-SZ dataset, Schizophr Bull., 42, 1290, 10.1093/schbul/sbw029 Castle, 2006, The diagnostic interview for psychoses (DIP): development, reliability and applications, Psychol Med., 36, 69, 10.1017/S0033291705005969 Chopra, 2021, Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: a longitudinal, randomised, triple-blind placebo-controlled mri study, Neuropsychopharmacol., 46, 1494, 10.1038/s41386-021-00980-0 Comer, 2020, The inflamed brain in schizophrenia: the convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation, Front. Cell. Neurosci., 14, 274, 10.3389/fncel.2020.00274 Cropley, 2014, Using longitudinal imaging to map the ‘relapse signature’ of schizophrenia and other psychoses, Epidemiol Psychiatr Sci., 23, 219, 10.1017/S2045796014000341 Deakin, 2018, The benefit of minocycline on negative symptoms of schizophrenia in patients with recent-onset psychosis (BeneMin): a randomised, double-blind, placebo-controlled trial, Lancet Psychiatry, 5, 885, 10.1016/S2215-0366(18)30345-6 Dickerson, 2019, Schizophrenia is associated with an aberrant immune response to epstein-barr virus, Schizophr. Bull., 45, 1112, 10.1093/schbul/sby164 Felger, 2016, Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression, Mol Psychiatry., 21, 1358, 10.1038/mp.2015.168 Fillman, 2013, Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia, Mol. Psychiatry., 18, 206, 10.1038/mp.2012.110 Fillman, 2016, Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca’s area volume, Mol Psychiatry., 21, 1090, 10.1038/mp.2015.90 Fond, 2020, The role of inflammation in the treatment of schizophrenia, Front Psychiatry., 11, 160, 10.3389/fpsyt.2020.00160 Fornito, 2009, Anatomical abnormalities of the anterior cingulate cortex in schizophrenia: bridging the gap between neuroimaging and neuropathology, Schizophr. Bull., 35, 973, 10.1093/schbul/sbn025 Furlan, 2019, Natural killer cells protect white matter integrity in bipolar disorder, Brain Behav Immun., 81, 410, 10.1016/j.bbi.2019.06.037 Garver, 2000, Brain and ventricle instability during psychotic episodes of the schizophrenias, Schizophr Res., 44, 11, 10.1016/S0920-9964(00)00015-3 Grace, 2012, Dopamine system dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia, Neuropharmacology, 62, 1342, 10.1016/j.neuropharm.2011.05.011 Hoang, 2022, Inflammatory subtypes in antipsychotic-naïve first-episode schizophrenia are associated with altered brain morphology and topological organization, Brain Behav Immun., 100, 297, 10.1016/j.bbi.2021.11.019 Huang, 2015, Statistical significance of clustering using soft thresholding, J Comput Graph Stat., 24, 975, 10.1080/10618600.2014.948179 Hubert, 1985, Comparing partitions, J. Classif., 2, 193, 10.1007/BF01908075 Jablensky, 2000, Psychotic disorders in urban areas: an overview of the study on low prevalence disorders, Aust N Z J Psychiatry., 34, 221, 10.1080/j.1440-1614.2000.00728.x Jacomb, 2018, C-reactive protein: higher during acute psychotic episodes and related to cortical thickness in schizophrenia and healthy controls, Front Immunol., 9, 10.3389/fimmu.2018.02230 Johnsen, 2016, The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis, BMC Psychiatry, 16, 10.1186/s12888-016-0769-x Kay, 1987, The positive and negative syndrome scale (PANSS) for schizophrenia, Schizophr Bull., 13, 261, 10.1093/schbul/13.2.261 Khandaker, 2015, Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment, Lancet Psychiatry, 2, 258, 10.1016/S2215-0366(14)00122-9 2011, 2667 Laskaris, 2021, Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder, Brain Behav Immun., 95, 299, 10.1016/j.bbi.2021.04.002 Lesh, 2018, Cytokine alterations in first-episode schizophrenia and bipolar disorder: relationships to brain structure and symptoms, J. Neuroinflammation, 15, 10.1186/s12974-018-1197-2 Li, 2019, Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder, Neuropsychopharmacol., 44, 1552, 10.1038/s41386-019-0346-3 Lizano, 2019, Association of choroid plexus enlargement with cognitive, inflammatory, and structural phenotypes across the psychosis spectrum, Am J Psychiatry., 176, 564, 10.1176/appi.ajp.2019.18070825 Lizano, 2021, Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis, Mol Psychiatry., 26, 3430, 10.1038/s41380-020-00914-0 Loughland, 2010, Australian schizophrenia research bank: a database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia, Aust N Z J Psychiatry., 44, 1029 Marcinowicz, 2021, A meta-Analysis of the influence of antipsychotics on cytokines levels in first episode psychosis, J Clin Med., 10, 2488, 10.3390/jcm10112488 Metcalf, 2017, Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study, Brain Behav Immun., 59, 253, 10.1016/j.bbi.2016.09.008 Miller, 2011, Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects, Biol Psychiatry., 70, 663, 10.1016/j.biopsych.2011.04.013 Miller, 2014, C-reactive protein levels in schizophrenia: a review and meta-analysis, Clin Schizophr Relat Psychoses., 7, 223, 10.3371/CSRP.MICU.020813 Misiak, 2018, Cytokines and C-reactive protein alterations with respect to cognitive impairment in schizophrenia and bipolar disorder: a systematic review, Schizophr. Res., 192, 16, 10.1016/j.schres.2017.04.015 Mokhtari, 2016, The Major histocompatibility complex (MHC) in schizophrenia: a review, J Clin Cell Immunol., 7, 479, 10.4172/2155-9899.1000479 North, 2021, Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions, Eur Arch Psychiatry Clin Neurosci., 271, 595, 10.1007/s00406-021-01237-z Noto, 2015, High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance, World J. Biol. Psychiatry, 16, 422, 10.3109/15622975.2015.1062552 Perkins, 2015, Towards a psychosis risk blood diagnostic for persons experiencing high-risk symptoms: preliminary results from the NAPLS project, Schizophr. Bull., 41, 419, 10.1093/schbul/sbu099 Perry, 2021, Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study, Brain Behav. Immun., 97, 176, 10.1016/j.bbi.2021.07.009 Pillinger, 2019, A meta-analysis of immune parameters, variability, and assessment of modal distribution in psychosis and test of the immune subgroup hypothesis, Schizophr. Bull., 45, 1120, 10.1093/schbul/sby160 Purves-Tyson TD, Robinson K, Brown AM, et al. Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia. Frontiers in Immunology. 2020;11. Accessed February 16, 2022. https://www.frontiersin.org/article/10.3389/fimmu.2020.02002. Randolph, 1998, The repeatable battery for the assessment of neuropsychological status (RBANS): preliminary clinical validity, J. Clin. Exp. Neuropsychol., 20, 310, 10.1076/jcen.20.3.310.823 Sekar, 2016, Schizophrenia risk from complex variation of complement component 4, Nature, 530, 177, 10.1038/nature16549 Tamouza, 2021, Identification of inflammatory subgroups of schizophrenia and bipolar disorder patients with HERV-W ENV antigenemia by unsupervised cluster analysis, Transl Psychiatry., 11 Tarantino, 2021, Natural killer cells in first-episode psychosis: an innate immune signature?, Mol Psychiatry., 26, 5297, 10.1038/s41380-020-01008-7 Upthegrove, 2014, Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis, Schizophr. Res., 155, 101, 10.1016/j.schres.2014.03.005 Van Rheenen, 2018, Widespread volumetric reductions in schizophrenia and schizoaffective patients displaying compromised cognitive abilities, Schizophr Bull., 44, 560, 10.1093/schbul/sbx109 Varol, 2017, HYDRA: revealing heterogeneity of imaging and genetic patterns through a multiple max-margin discriminative analysis framework, Neuroimage, 145, 346, 10.1016/j.neuroimage.2016.02.041 Velakoulis, 1999, Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study, Arch. Gen. Psychiatry, 56, 133, 10.1001/archpsyc.56.2.133 Velakoulis, 2006, Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals, Arch Gen Psychiatry., 63, 139, 10.1001/archpsyc.63.2.139 Vetlugina, 2016, Adjunctive use of interferon γ inducer for treatment of patients with schizophrenia, Acta Neuropsychiatr., 28, 149, 10.1017/neu.2015.60 Warre-Cornish, 2020, Interferon-γ signaling in human iPSC–derived neurons recapitulates neurodevelopmental disorder phenotypes, Sci Adv., 6, 10.1126/sciadv.aay9506 Watson, 2023, Cognitive function in early-phase schizophrenia-spectrum disorder: IQ subtypes, brain volume and immune markers, Psychol. Med., 53, 2842, 10.1017/S0033291721004815 Williams, 2022, Inflammation and brain structure in schizophrenia and other neuropsychiatric disorders: a mendelian randomization study, JAMA Psychiat., 79, 498, 10.1001/jamapsychiatry.2022.0407 Wu, 2019, Association of peripheral cytokine levels with cerebral structural abnormalities in schizophrenia, Brain Res., 1724, 10.1016/j.brainres.2019.146463 Zhang, 2016, Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation, Transl. Psychiatry., 6, e982, 10.1038/tp.2016.238