Abstract
Treatment resistant (TR) psychosis is considered to be a significant cause of disability and functional impairment. Numerous efforts have been made to identify the clinical predictors of TR. However, the exploration of molecular and biological markers is still at an early stage. To understand the TR condition and identify potential molecular and biological markers, we analyzed demographic information, clinical data, structural brain imaging data, and molecular brain imaging data in 7 Tesla magnetic resonance spectroscopy from a first episode psychosis cohort that includes 136 patients. Age, gender, race, smoking status, duration of illness, and antipsychotic dosages were controlled in the analyses. We found that TR patients had a younger age at onset, more hospitalizations, more severe negative symptoms, a reduction in the volumes of the hippocampus (HP) and superior frontal gyrus (SFG), and a reduction in glutathione (GSH) levels in the anterior cingulate cortex (ACC), when compared to non-TR patients. The combination of multiple markers provided a better classification between TR and non-TR patients compared to any individual marker. Our study shows that ACC-GSH, HP and SFG volumes, and age at onset, could potentially be biomarkers for TR diagnosis, while hospitalization and negative symptoms could be used to evaluate the progression of the disease. Multimodal cohorts are essential in obtaining a comprehensive understanding of brain disorders.
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References
Secher RG, Hjorthøj CR, Austin SF, Thorup A, Jeppesen P, Mors O, et al. Ten-year follow-up of the OPUS specialized early intervention trial for patients with a first episode of psychosis. Schizophr Bull. 2015;41:617–26.
Nucifora FC, Woznica E, Lee BJ, Cascella N, Sawa A. Treatment resistant schizophrenia: Clinical, biological, and therapeutic perspectives. Neurobiol Dis. 2018;131:104257.
Wimberley T, Støvring H, Sørensen HJ, Horsdal HT, MacCabe JH, Gasse C. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry. 2016;3:358–66.
Lally J, Ajnakina O, Di Forti M, Trotta A, Demjaha A, Kolliakou A, et al. Two distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses. Psychol Med. 2016;46:3231–40.
Nucifora FC, Mihaljevic M, Lee BJ, Sawa A. Clozapine as a model for antipsychotic development. Neurotherapeutics 2017;14:750–61.
Legge SE, Hamshere ML, Ripke S, Pardinas AF, Goldstein JI, Rees E, et al. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. Mol Psychiatry. 2018;23:162–3.
Kinon BJ. The group of treatment resistant schizophrenias. Heterogeneity in Treatment Resistant Schizophrenia (TRS). Front Psychiatry. 2018;9:757.
Shah P, Iwata Y, Plitman E, Brown EE, Caravaggio F, Kim J, et al. The impact of delay in clozapine initiation on treatment outcomes in patients with treatment-resistant schizophrenia: a systematic review. Psychiatry Res. 2018;268:114–22.
Kayo M, Tassell I, Hiroce V, Menezes A, Elkis H. Does lack of improvement in the first two weeks predict treatment resistance in recent-onset psychosis? Clin (Sao Paulo) 2012;67:1479–82.
Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJM, Birnbaum ML, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) working group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174:216–29.
Demjaha A, Lappin JM, Stahl D, Patel MX, MacCabe JH, Howes OD, et al. Antipsychotic treatment resistance in first-episode psychosis: prevalence, subtypes and predictors. Psychol Med. 2017;47:1981–9.
Fusar-Poli P, Rutigliano G, Stahl D, Davies C, Bonoldi I, Reilly T, et al. Development and validation of a clinically based risk calculator for the transdiagnostic prediction of psychosis. JAMA Psychiatry. 2017;74:493–500.
Kanahara N, Yamanaka H, Suzuki T, Takase M, Iyo M. First-episode psychosis in treatment-resistant schizophrenia: a cross-sectional study of a long-term follow-up cohort. BMC Psychiatry. 2018;18:274.
Kowalec K, Lu Y, Sariaslan A, Song J, Ploner A, Dalman C, et al. Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish national register and genomic study. Mol Psychiatry. 2019:1–9. https://doi.org/10.1038/s41380-019-0575-1.
Frydecka D, Beszłej JA, Gościmski P, Kiejna A, Misiak B. Profiling cognitive impairment in treatment-resistant schizophrenia patients. Psychiatry Res. 2016;235:133–8.
Palaniyappan L, Marques TR, Taylor H, Handley R, Mondelli V, Bonaccorso S, et al. Cortical folding defects as markers of poor treatment response in first-episode psychosis. JAMA Psychiatry. 2013;70:1031–40.
Mondelli V, Ciufolini S, Belvederi Murri M, Bonaccorso S, Di Forti M, Giordano A, et al. Cortisol and inflammatory biomarkers predict poor treatment response in first episode psychosis. Schizophr Bull. 2015;41:1162–70.
Egerton A, Broberg BV, Van Haren N, Merritt K, Barker GJ, Lythgoe DJ, et al. Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE). Mol Psychiatry. 2018;23:2145–55.
Egerton A, Brugger S, Raffin M, Barker GJ, Lythgoe DJ, McGuire PK, et al. Anterior cingulate glutamate levels related to clinical status following treatment in first-episode schizophrenia. Neuropsychopharmacology 2012;37:2515–21.
Demjaha A, Egerton A, Murray RM, Kapur S, Howes OD, Stone JM, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014;75:e11–13.
Jauhar S, Veronese M, Nour MM, Rogdaki M, Hathway P, Turkheimer FE, et al. Determinants of treatment response in first-episode psychosis: an 18F-DOPA PET study. Mol Psychiatry. 2019;24:1502–12.
Kim E, Howes OD, Veronese M, Beck K, Seo S, Park JW, et al. Presynaptic dopamine capacity in patients with treatment-resistant schizophrenia taking clozapine: an [18F]DOPA PET Study. Neuropsychopharmacology 2017;42:941–50.
Howes OD, Bose SK, Turkheimer F, Valli I, Egerton A, Valmaggia LR, et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am J Psychiatry. 2011;168:1311–7.
Dempster K, Jeon P, MacKinley M, Williamson P, Théberge J, Palaniyappan L. Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate. Mol Psychiatry. 2020;25:1640–50.
Kochunov P, Huang J, Chen S, Li Y, Tan S, Fan F, et al. White matter in schizophrenia treatment resistance. Am J Psychiatry. 2019;176:829–38.
Blessing EM, Murty VP, Zeng B, Wang J, Davachi L, Goff DC. Anterior hippocampal-cortical functional connectivity distinguishes antipsychotic naïve first-episode psychosis patients from controls and may predict response to second-generation antipsychotic treatment. Schizophr Bull. 2019;46:680–9.
Wang AM, Pradhan S, Coughlin JM, Trivedi A, DuBois SL, Crawford JL, et al. Assessing brain metabolism with 7-T proton magnetic resonance spectroscopy in patients with first-episode psychosis. JAMA Psychiatry. 2019;76:314–23.
Kamath V, Lasutschinkow P, Ishizuka K, Sawa A. Olfactory functioning in first-episode psychosis. Schizophr Bull. 2018;44:672–80.
Faria AV, Crawford J, Ye C, Hsu J, Kenkare A, Schretlen D, et al. Relationship between neuropsychological behavior and brain white matter in first-episode psychosis. Schizophr Res. 2019;208:49–54.
Posporelis S, Coughlin JM, Marsman A, Pradhan S, Tanaka T, Wang H, et al. Decoupling of brain temperature and glutamate in recent onset of schizophrenia: a 7T proton magnetic resonance spectroscopy study. Biol Psychiatry Cogn Neurosci Neuroimaging. 2018;3:248–54.
Kamath V, Crawford J, DuBois S, Nucifora FC, Nestadt G, Sawa A, et al. Contributions of olfactory and neuropsychological assessment to the diagnosis of first-episode schizophrenia. Neuropsychology 2019;33:203–11.
Good KP, Tibbo P, Milliken H, Whitehorn D, Alexiadis M, Robertson N, et al. An investigation of a possible relationship between olfactory identification deficits at first episode and four-year outcomes in patients with psychosis. Schizophr Res 2010;124:60–5.
Kästner A, Malzahn D, Begemann M, Hilmes C, Bickeböller H, Ehrenreich H. Odor naming and interpretation performance in 881 schizophrenia subjects: association with clinical parameters. BMC Psychiatry. 2013;13:218.
Deakin B, Suckling J, Barnes TRE, Byrne K, Chaudhry IB, Dazzan P, et al. 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. 2018;5:885–94.
Koshiyama D, Kirihara K, Tada M, Nagai T, Fujioka M, Ichikawa E, et al. Electrophysiological evidence for abnormal glutamate-GABA association following psychosis onset. Transl Psychiatry. 2018;8:1–10.
Lesh TA, Maddock RJ, Howell A, Wang H, Tanase C, Daniel Ragland J, et al. Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis. Mol Psychiatry. 2021;26:761–71.
Kim S, Shin SH, Santangelo B, Veronese M, Kang SK, Lee JS, et al. Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis. Mol Psychiatry. 2020. https://doi.org/10.1038/s41380-020-00879-0.
Galderisi S, Davidson M, Kahn RS, Mucci A, Boter H, Gheorghe MD, et al. Correlates of cognitive impairment in first episode schizophrenia: the EUFEST study. Schizophr Res. 2009;115:104–14.
Wilson RS, Yung AR, Morrison AP. Comorbidity rates of depression and anxiety in first episode psychosis: a systematic review and meta-analysis. Schizophr Res. 2020;216:322–9.
Andreasen NC, Flaum M, Arndt S, Alliger R, Swayze VW. Positive and negative symptoms: assessment and validity. In: Marneros A, Andreasen NC, Tsuang MT, editors. Negative Versus Positive Schizophrenia, Berlin, Heidelberg: Springer Berlin Heidelberg; 1991. p. 28–51.
Testa SM, Winicki JM, Pearlson GD, Gordon B, Schretlen DJ. Accounting for estimated IQ in neuropsychological test performance with regression-based techniques. J Int Neuropsychol Soc. 2009;15:1012–22.
Schretlen DJ, Vannorsdall TD, Winicki JM, Mushtaq Y, Hikida T, Sawa A, et al. Neuroanatomic and cognitive abnormalities related to herpes simplex virus type 1 in schizophrenia. Schizophr Res. 2010;118:224–31.
Schretlen DJ, Cascella NG, Meyer SM, Kingery LR, Testa SM, Munro CA, et al. Neuropsychological functioning in bipolar disorder and schizophrenia. Biol Psychiatry. 2007;62:179–86.
Reid MA, Salibi N, White DM, Gawne TJ, Denney TS, Lahti AC. 7T proton magnetic resonance spectroscopy of the anterior cingulate cortex in first-episode schizophrenia. Schizophr Bull. 2019;45:180–9.
Mori S, Wu D, Ceritoglu C, Li Y, Kolasny A, Vaillant MA, et al. MRICloud: delivering high-throughput MRI neuroinformatics as cloud-based software as a service. Comput Sci Eng. 2016;18:21–35.
Tang X, Oishi K, Faria AV, Hillis AE, Albert MS, Mori S, et al. Bayesian Parameter Estimation and Segmentation in the Multi-Atlas Random Orbit Model. PLoS One. 2013. https://doi.org/10.1371/journal.pone.0065591.
Oishi K, Faria A, Jiang H, Li X, Akhter K, Zhang J, et al. Atlas-based whole brain white matter analysis using large deformation diffeomorphic metric mapping: application to normal elderly and Alzheimer’s disease participants. Neuroimage 2009;46:486–99.
Leucht S, Samara M, Heres S, Davis JM. Dose equivalents for antipsychotic drugs: the DDD method. Schizophr Bull. 2016;42:S90–94. Suppl 1.
Haijma SV, Van Haren N, Cahn W, Koolschijn PCMP, Hulshoff Pol HE, Kahn RS. Brain volumes in schizophrenia: a meta-analysis in over 18000 subjects. Schizophr Bull. 2013;39:1129–38.
van Erp TGM, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, et al. Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium. Mol Psychiatry. 2016;21:547–53.
Cahn W, Hulshoff Pol HE, Lems EB, van Haren NE, Schnack HG, van der Linden JA, et al. Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Arch Gen Psychiatry. 2002;59:1002–10.
Wang M, Barker PB, Cascella N, Coughlin JM, Nestadt G, Nucifora FC, et al. Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study. BioRxiv. 2020. https://doi.org/10.1101/2020.08.25.267419.
Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1–56.
Camm JA, Lüscher TF, Serruys PW. The ESC textbook of cardiovascular medicine. 6th ed. Oxford: Oxford University Press; 2009.
Thompson PM, Jahanshad N, Ching CRK, Salminen LE, Thomopoulos SI, Bright J, et al. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries. Transl Psychiatry. 2020;10:1–28.
Immonen J, Jääskeläinen E, Korpela H, Miettunen J. Age at onset and the outcomes of schizophrenia: a systematic review and meta‐analysis. Early Inter Psychiatry. 2017;11:453–60.
Bozzatello P, Bellino S, Rocca P Predictive factors of treatment resistance in first episode of psychosis: a systematic review. Front Psychiatry. 2019. https://doi.org/10.3389/fpsyt.2019.00067.
Briend F, Nelson EA, Maximo O, Armstrong WP, Kraguljac NV, Lahti AC. Hippocampal glutamate and hippocampus subfield volumes in antipsychotic-naive first episode psychosis subjects and relationships to duration of untreated psychosis. Transl Psychiatry. 2020;10:1–11.
Lieberman JA, Girgis RR, Brucato G, Moore H, Provenzano F, Kegeles L, et al. Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry. 2018;23:1764–72.
Zhang Y, Catts VS, Sheedy D, McCrossin T, Kril JJ, Shannon, et al. Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Transl Psychiatry. 2016;6:e982.
Fusar-Poli P, Crossley N, Woolley J, Carletti F, Perez-Iglesias R, Broome M, et al. White matter alterations related to P300 abnormalities in individuals at high risk for psychosis: an MRI-EEG study. J Psychiatry Neurosci. 2011;36:239–48.
Sedlak TW, Paul BD, Parker GM, Hester LD, Snowman AM, Taniguchi Y, et al. The glutathione cycle shapes synaptic glutamate activity. Proc Natl Acad Sci USA. 2019;116:2701–6.
Landek-Salgado MA, Faust TE, Sawa A. Molecular substrates of schizophrenia: homeostatic signaling to connectivity. Mol Psychiatry. 2016;21:10–28.
Maren S, Phan KL, Liberzon I. The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci. 2013;14:417–28.
Ravishankar M, Morris A, Burgess A, Khatib D, Stanley JA, Diwadkar VA. Cortical-hippocampal functional connectivity during covert consolidation sub-serves associative learning: evidence for an active ‘rest’ state. Brain Cogn. 2019;131:45–55.
Cascella NG, Fieldstone SC, Rao VA, Pearlson GD, Sawa A, Schretlen DJ. Gray-matter abnormalities in deficit schizophrenia. Schizophr Res. 2010;120:63–70.
Acknowledgements
This study is supported by the National Institutes of Mental Health Grants MH-092443 (to AS), MH-094268 (to AS), MH-105660 (to AS), and MH-107730 (to AS); foundation grants from Stanley (to AS), RUSK/S-R (to AS), and a NARSAD young investigator award from Brain and Behavior Research Foundation (to AS, KY). The original recruitment of study participants was partly funded by the Mitsubishi Tanabe Pharma Corporation. The authors thank Drs. Brian Caffo for kindly contributing to scientific discussions and feedback related to this work. The authors appreciate Ms. Yukiko Lema for research management and manuscript organization, and thank Dr. Melissa A Landek-Salgado for critical reading of the manuscript.
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The current research was designed by AS. The analytic pipeline was designed by KY. The data were analyzed by KY, LL, ZN, AN, MS, and PDC. Data analysis and interpretation regarding clinical scales were assisted by NC and MM. Data analysis and interpretation regarding smell test were assisted by VK. Data analysis and interpretation regarding 7 T MRS data were assisted by MW and PB. Data analysis and interpretation regarding brain volume data were assisted by AF. Study participants were recruited and/or interviewed by NC, FCN, JMC, GN, TWS, AK (Kenkare), and AK (Kelly). The manuscript was drafted by KY, LL, and AS. All authors contributed to the discussion of the results and have approved the final manuscript to be published.
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The authors declare no competing interests. As noted in the acknowledgement section, the original recruitment of study participants was partly funded by Mitsubishi Tanabe Pharma Corporation. However, this company is not involved in this specific study.
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Yang, K., Longo, L., Narita, Z. et al. A multimodal study of a first episode psychosis cohort: potential markers of antipsychotic treatment resistance. Mol Psychiatry 27, 1184–1191 (2022). https://doi.org/10.1038/s41380-021-01331-7
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DOI: https://doi.org/10.1038/s41380-021-01331-7
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