Abstract
Identifying biomarkers in schizophrenia during the first episode without the confounding effects of treatment has been challenging. Leveraging these biomarkers to establish diagnosis and make individualized predictions of future treatment responses to antipsychotics would be of great value, but there has been limited progress. In this study, by using machine learning algorithms and the functional connections of the superior temporal cortex, we successfully identified the first-episode drug-naive (FEDN) schizophrenia patients (accuracy 78.6%) and predict their responses to antipsychotic treatment (accuracy 82.5%) at an individual level. The functional connections (FC) were derived using the mutual information and the correlations, between the blood-oxygen-level dependent signals of the superior temporal cortex and other cortical regions acquired with the resting-state functional magnetic resonance imaging. We also found that the mutual information and correlation FC was informative in identifying individual FEDN schizophrenia and prediction of treatment response, respectively. The methods and findings in this paper could provide a critical step toward individualized identification and treatment response prediction in first-episode drug-naive schizophrenia, which could complement other biomarkers in the development of precision medicine approaches for this severe mental disorder.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Subject-specific whole-brain parcellations of nodes and boundaries are modulated differently under 10 Hz rTMS
Scientific Reports Open Access 03 August 2023
-
Machine learning methods to predict outcomes of pharmacological treatment in psychosis
Translational Psychiatry Open Access 02 March 2023
-
Machine Learning and Non-Affective Psychosis: Identification, Differential Diagnosis, and Treatment
Current Psychiatry Reports Open Access 18 November 2022
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout

References
Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382:1575–86.
Fraguas D, Diaz-Caneja CM, Pina-Camacho L, Janssen J, Arango C. Progressive brain changes in children and adolescents with early-onset psychosis: a meta-analysis of longitudinal MRI studies. Schizophr Res. 2016;173:132–9.
Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2012;18:595–606.
Berk M, Conus P, Lucas N, Hallam K, Malhi GS, Dodd S, et al. Setting the stage: from prodrome to treatment resistance in bipolar disorder. Bipolar Disord. 2007;9:671–8.
Passos IC, Mwangi B, Vieta E, Berk M, Kapczinski F. Areas of controversy in neuroprogression in bipolar disorder. Acta Psychiatr Scand. 2016;134:91–103.
Cao B, Passos IC, Mwangi B, Amaral-Silva H, Tannous J, Wu M-J, et al. Hippocampal subfield volumes in mood disorders. Mol Psychiatry. 2017;22:1352–1358.
Ho NF, Iglesias JE, Sum MY, Kuswanto CN, Sitoh YY, De Souza J, et al. Progression from selective to general involvement of hippocampal subfields in schizophrenia. Mol Psychiatry. 2017 Jan; 22(1): 142–152
Vita A, De Peri L, Deste G, Sacchetti E. Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies. Transl Psychiatry. 2012;2:e190.
Cloutier M, Sanon Aigbogun M, Guerin A, Nitulescu R, Ramanakumar AV, Kamat SA, et al. The economic burden of schizophrenia in the United States in 2013. J Clin Psychiatry. 2016;2012:764–71.
Schnack HG, Nieuwenhuis M, van Haren NEM, Abramovic L, Scheewe TW, Brouwer RM, et al. Can structural MRI aid in clinical classification? A machine learning study in two independent samples of patients with schizophrenia, bipolar disorder and healthy subjects. Neuroimage. 2014;84:299–306.
Kambeitz J, Cabral C, Sacchet MD, Gotlib IH, Zahn R, Serpa MH, et al. Detecting neuroimaging biomarkers for depression: a meta-analysis of multivariate pattern recognition studies. Biol Psychiatry. 2016;40:1742–51.
Fusar-Poli P, Smieskova R, Kempton MJ, Ho BC, Andreasen NC, Borgwardt S. Progressive brain changes in schizophrenia related to antipsychotic treatment? A meta-analysis of longitudinal MRI studies. Neurosci Biobehav Rev. 2013;37:1680–91.
Baglivo V, Cao B, Mwangi B, Bellani M, Perlini C, Lasalvia A, et al. Hippocampal subfield volumes in patients with first-episode psychosis. Schizophrenia Bulletin. 2017;44:3, 6 April 552–559.
Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Schizophr Bull. 1999;25:721–9.
Johnsen E, Jørgensen HA. Effectiveness of second generation antipsychotics: a systematic review of randomized trials. BMC Psychiatry. 2008;8:31
Komossa K, Rummel-Kluge C, Schwarz S, Schmid F, Hunger H, Kissling W, et al. Risperidone versus other atypical antipsychotics for schizophrenia. In: Cochrane Database of Systematic Reviews. 2011 https://doi.org/10.1002/14651858.CD006626.pub2.
Wang C, Shi W, Huang C, Zhu J, Huang W, Chen G. The efficacy, acceptability, and safety of five atypical antipsychotics in patients with first-episode drug-naïve schizophrenia: a randomized comparative trial. Ann Gen Psychiatry. 2017;16:47 https://doi.org/10.1186/s12991-017-0170-2
Emsley R, Rabinowitz J, Medori R. Time course for antipsychotic treatment response in first-episode schizophrenia. Am J Psychiatry. 2006;163:743–5.
Rattehalli RD, Zhao S, Li BG, Jayaram MB, Xia J, Sampson S Risperidone versus placebo for schizophrenia. Cochrane Database Syst. Rev. 2016; 2016. https://doi.org/10.1002/14651858.CD006918.pub3.
Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179–94.
Jovicich J, Czanner S, Greve D, Haley E, Van Der Kouwe A, Gollub R, et al. Reliability in multi-site structural MRI studies: effects of gradient non-linearity correction on phantom and human data. Neuroimage. 2006;30:436–43.
Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, et al. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002;33:341–55.
Desikan RS, Ségonne F, Fischl B, Quinn BT, Dickerson BC, Blacker D, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage. 2006;31:968–80.
Zhou D, Thompson WK, Siegle G. MATLAB toolbox for functional connectivity. Neuroimage. 2009;47:1590–607.
Salvador R, Suckling J, Schwarzbauer C, Bullmore E. Undirected graphs of frequency-dependent functional connectivity in whole brain networks. Philos Trans R Soc B Biol Sci. 2005;360:937–46.
Nichols T, Hayasaka S. Controlling the familywise error rate in functional neuroimaging: a comparative review. Stat Methods Med Res. 2003;12:419–46.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 1995;57:289–300.
Pedregosa F, Varoquaux G Scikit-learn: Machine learning in Python. 2011 https://doi.org/10.1007/s13398-014-0173-7.2.
Cao B, Luo Q, Fu Y, Du L, Qiu T, Yang X, et al. Predicting individual responses to the electroconvulsive therapy with hippocampal subfield volumes in major depression disorder. Sci Rep. 2018;8:5434.
Cortes C, Vapnik V. Support-vector networks. Machine Learning. 1995;20(3):273–297.
Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale Rating Criteria. 1999.
Arbabshirani MR, Kiehl KA, Pearlson GD, Calhoun VD. Classification of schizophrenia patients based on resting-state functional network connectivity. Front Neurosci. 2013;7:1–16.
Davatzikos C, Shen D, Gur RCRE, Wu X, Liu D, Fan Y, et al. Whole-brain morphometric study of schizophrenia revealing a spatially complex set of focal abnormalities. Arch Gen Psychiatry. 2005;62:1218–27.
Sun D, van Erp TGM, Thompson PM, Bearden CE, Daley M, Kushan L, et al. Elucidating a magnetic resonance imaging-based neuroanatomic biomarker for psychosis: classification analysis using probabilistic brain atlas and machine learning algorithms. Biol Psychiatry. 2009;66:1055–60.
Gheiratmand M, Rish I, Cecchi GA, Brown MRG, Greiner R, Polosecki PI, et al. Learning stable and predictive network-based patterns of schizophrenia and its clinical symptoms. npj Schizophr. 2017;3:22.
Borgwardt S, Koutsouleris N, Aston J, Studerus E, Smieskova R, Riecher-Rössler A, et al. Distinguishing prodromal from first-episode psychosis using neuroanatomical single-subject pattern recognition. Schizophr Bull. 2013;39:1105–14.
Liu Y, Teverovskiy L, Carmichael O, Kikinis R, Shenton M, Carter CS, et al. Discriminative MR image feature analysis for automatic schizophrenia and Alzheimer’s disease classification. In: MICCAI. Medical Image Computing and Computer-Assisted Intervention – MICCAI 2004, 393–401.
Mourao-Miranda J, Reinders AATS, Rocha-Rego V, Lappin J, Rondina J, Morgan C, et al. Individualized prediction of illness course at the first psychotic episode: a support vector machine MRI study. Psychol Med. 2012;42:1037–47.
Rathi Y, Malcolm J, Michailovich O, Goldstein J, Seidman L, McCarley RW, et al. Biomarkers for identifying first-episode schizophrenia patients using diffusion weighted imaging. Med image Comput Comput Interv Part 1 2010: 657–65.
Schwarz D, Kasparek T. Brain morphometry of MR images for automated classification of first-episode schizophrenia. Inf Fusion. 2014;19:97–102.
Pettersson-Yeo W, Benetti S, Marquand AF, Dell’acqua F, Williams SCR, Allen P, et al. Using genetic, cognitive and multi-modal neuroimaging data to identify ultra-high-risk and first-episode psychosis at the individual level. Psychol Med. 2013;43:2547–62.
Ramyead A, Studerus E, Kometer M, Uttinger M, Gschwandtner U, Fuhr P, et al. Prediction of psychosis using neural oscillations and machine learning in neuroleptic-naive at-risk patients. World J Biol Psychiatry. 2015;2975:1–11.
Chua SE, Cheung C, Cheung V, Tsang JTK, Chen EYH, Wong JCH, et al. Cerebral grey, white matter and csf in never-medicated, first-episode schizophrenia. Schizophr Res. 2007;89:12–21.
Pietersen CY, Mauney Sa, Kim SS, Passeri E, Lim MP, Rooney RJ, et al. Molecular profiles of parvalbumin-immunoreactive neurons in the superior temporal cortex in schizophrenia. J Neurogenet. 2014;28:1–16.
Mueller TM, Yates SD, Haroutunian V, Meador-Woodruff JH. Altered fucosyltransferase expression in the superior temporal gyrus of elderly patients with schizophrenia. Schizophr Res. 2017;182:66–73.
Steiner J, Brisch R, Schiltz K, Dobrowolny H, Mawrin C, Krzyzanowska M, et al. GABAergic system impairment in the hippocampus and superior temporal gyrus of patients with paranoid schizophrenia: a post-mortem study. Schizophr Res. 2016;177:10–17.
Guo W, Xiao C, Liu G, Wooderson SC, Zhang Z, Zhang J, et al. Decreased resting-state interhemispheric coordination in first-episode, drug-naive paranoid schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2014;48:14–19.
McKinney B, Ding Y, Lewis DA, Sweet RA. DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia. Transl Psychiatry. 2017;7:e1032.
Lui S, Deng W, Huang X, Jiang L, Ma X, Chen H, et al. Association of cerebral deficits with clinical symptoms in antipsychotic-naive first-episode schizophrenia: An optimized voxel-based morphometry and resting state functional connectivity study. Am J Psychiatry. 2009;166:196–205.
Straube B, Green A, Sass K, Kircher T. Superior temporal sulcus disconnectivity during processing of metaphoric gestures in Schizophrenia. Schizophr Bull. 2014;40:936–44.
Shah C, Zhang W, Xiao Y, Yao L, Zhao Y, Gao X, et al. Common pattern of gray-matter abnormalities in drug-naive and medicated first-episode schizophrenia: a multimodal meta-analysis. Psychol Med. 2017;47:401–13.
Barta PE, Pearlson GD, Powers RE, Richards SS, Tune LE. Auditory hallucinations and smaller superior temporal gyrus volume in schizophrenia. Am J Psychiatry. 1990;147:604–12.
Friston KJ. The disconnection hypothesis. Schizophrenia Research 1998;30:115–25.
Sarpal DK, Robinson DG, Lencz T, Argyelan M, Ikuta T, Karlsgodt K, et al. Antipsychotic treatment and functional connectivity of the striatum in first-episode schizophrenia. JAMA Psychiatry. 2015;72:5–13.
Sarpal DK, Argyelan M, Robinson DG, Szeszko PR, Karlsgodt KH, John M, et al. Baseline striatal functional connectivity as a predictor of response to antipsychotic drug treatment. Am J Psychiatry. 2016;173:69–77.
Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull. 2015;114:169–79.
Acknowledgements
Supported in part by the NARSAD Young Investigator Grant of the Brain & Behavior Research Foundation (B.C.), the Michael E. Debakey VA Medical Center and the Beth K. and Stuart C. Yudofsky Division of Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine in Houston, TX (R.Y.C.), and NIMH grant R01 085667, the Dunn Research Foundation and the Pat Rutherford, Jr. Endowed Chair in Psychiatry (J.C.S.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
B.C., R.Y.C., D.C., M.X., L.W., and X.Y.Z. reported no biomedical financial interests or potential conflicts of interest. J.C.S. has received grants/research support from Forrest, BMS, J&J, Merck, Stanley Medical Research Institute, NIH and has been a speaker for Pfizer and Abbott.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Cao, B., Cho, R.Y., Chen, D. et al. Treatment response prediction and individualized identification of first-episode drug-naïve schizophrenia using brain functional connectivity. Mol Psychiatry 25, 906–913 (2020). https://doi.org/10.1038/s41380-018-0106-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41380-018-0106-5
Keywords
- support vector machines
- SVM
This article is cited by
-
Machine learning methods to predict outcomes of pharmacological treatment in psychosis
Translational Psychiatry (2023)
-
Subject-specific whole-brain parcellations of nodes and boundaries are modulated differently under 10 Hz rTMS
Scientific Reports (2023)
-
Frontal lobe fALFF measured from resting-state fMRI as a prognostic biomarker in first-episode psychosis
Neuropsychopharmacology (2022)
-
Machine Learning and Non-Affective Psychosis: Identification, Differential Diagnosis, and Treatment
Current Psychiatry Reports (2022)
-
Abnormal within- and cross-networks functional connectivity in different outcomes of herpes zoster patients
Brain Imaging and Behavior (2022)