The electroencephalography protocol for the Accelerating Medicines Partnership® Schizophrenia Program: Reliability and stability of measures

Daniel H Mathalon^{1

2}, Spero Nicholas^{3

4}, Brian J Roach^{3

4}, Tashrif Billah⁵, Suzie Lavoie^{6

7}, Thomas Whitford^{6

8}, Holly K Hamilton^{9

10}, Lauren Addamo^{6

7}, Andrey Anohkin¹¹, Tristan Bekinschtein¹², Aysenil Belger^{13

14}, Kate Buccilli^{6

7}, John Cahill¹⁵, Ricardo E Carrión^{16

17}, Stefano Damiani¹⁸, Ilvana Dzafic^{6

7}, Bjørn H Ebdrup^{19

20}, Igor Izyurov²¹, Johanna Jarcho²², Raoul Jenni²³, Anna Jo²⁴, Sarah Kerins²⁵, Clarice Lee^{6

7}, Elizabeth A Martin²⁶, Rocio Mayol-Troncoso^{27

28}, Margaret A Niznikiewicz^{29

30}, Muhammad Parvaz^{31

32}, Oliver Pogarell³³, Julio Prieto-Montalvo³⁴, Rachel Rabin^{35

36}, David R Roalf³⁷, Jack Rogers^{38

39}, Dean F Salisbury⁴⁰, Riaz Shaik³¹, Stewart Shankman⁴¹, Michael C Stevens^{15

42}, Yi Nam Suen⁴³, Nicole C Swann⁴⁴, Xiaochen Tang⁴⁵, Judy L Thompson⁴⁶, Ivy Tso⁴⁷, Julian Wenzel⁴⁸, Juan Helen Zhou^{49

50}, Jean Addington⁵¹, Luis Alameda^{52

53}, Celso Arango³⁴, Nicholas J K Breitborde⁴⁷, Matthew R Broome^{38

54}, Kristin S Cadenhead⁵⁵, Monica E Calkins³⁷, Rolando I Castillo-Passi^{27

56}, Eric Yu Hai Chen⁵⁷, Jimmy Choi⁴², Philippe Conus⁵², Cheryl M Corcoran³¹, Barbara A Cornblatt^{16

17}, Covadonga M Diaz-Caneja³⁴, Lauren M Ellman²², Paolo Fusar-Poli^{18

53}, Pablo A Gaspar²⁷, Carla Gerber^{58

59}, Louise Birkedal Glenthøj^{60

61}, Leslie E Horton⁴⁰, Christy Lai Ming Hui⁵⁷, Joseph Kambeitz⁴⁸, Lana Kambeitz-Ilankovic^{33

48}, Matcheri S Keshavan⁶², Minah Kim^{63

64}, Sung-Wan Kim^{24

65}, Nikolaos Koutsouleris^{33

53}, Jun Soo Kwon⁶⁶, Kerstin Langbein²¹, Daniel Mamah⁶⁷, Vijay A Mittal⁶⁸, Merete Nordentoft^{20

60}, Godfrey D Pearlson^{15

69}, Jesus Perez^{70

71}, Diana O Perkins¹³, Albert R Powers^{15

72}, Fred W Sabb⁵⁸, Jason Schiffman²⁶, Jai L Shah^{36

73}, Steven M Silverstein⁴⁶, Stefan Smesny²¹, William S Stone⁶², Gregory P Strauss⁷⁴, Rachel Upthegrove^{38

75}, Swapna K Verma^{76

77}, Jijun Wang⁴⁵, Daniel H Wolf³⁷, Tianhong Zhang⁴⁵, Sylvain Bouix⁷⁸, Ofer Pasternak^{5

79}, Kang-Ik K Cho⁵, Michael J Coleman⁵, Dominic Dwyer^{6

7}, Angela Nunez^{15

72}, Zailyn Tamayo¹⁵, Stephen J Wood^{6

7}, Rene S Kahn³¹, John M Kane^{16

17}, Patrick D McGorry^{6

7}, Carrie E Bearden^{26

80}, Barnaby Nelson^{6

7}, Scott W Woods^{15

72}, Martha E Shenton^{5

79

81}; Accelerating Medicines Partnership® Schizophrenia Program; Gregory A Light^{55

82}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. daniel.mathalon@ucsf.edu.
² Mental Health Service, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA. daniel.mathalon@ucsf.edu.
³ Mental Health Service, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA.
⁴ Northern California Institute for Research and Education, San Francisco, CA, USA.
⁵ Department of Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Orygen, Parkville, VIC, Australia.
⁷ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁸ School of Psychology, University of New South Wales (UNSW), Kensington, NSW, Australia.
⁹ Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹⁰ University of Minnesota, Minneapolis, MN, USA.
¹¹ Washington University School of Medicine, St. Louis, MO, USA.
¹² Consciousness and Cognition Lab, Department of Psychology, University of Cambridge, Cambridge, UK.
¹³ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ UNC Intellectual and Developmental Disabilities Research Center, Carrboro, NC, USA.
¹⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
¹⁷ Institute of Behavioral Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
¹⁸ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁹ Centre for Neuropsychiatric Schizophrenia Research, CNSR Mental Health Centre, Glostrup, Denmark.
²⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²¹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
²² Department of Psychology & Neuroscience, Temple University, Philadelphia, PA, USA.
²³ Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland.
²⁴ Department of Psychiatry, Chonnam National University Medical School, Gwangju, Korea.
²⁵ Early Psychosis Detection and Clinical Intervention (EPIC) lab, Department of Psychosis Studies, King's College, London, UK.
²⁶ Department of Psychological Science, University of California, Irvine, CA, USA.
²⁷ Department of Psychiatry, IMHAY, University of Chile, Santiago, Chile.
²⁸ Facultad de Psicología, Universidad Alberto Hurtado, Santiago, Chile.
²⁹ Harvard Medical School, Boston, MA, USA.
³⁰ Boston VA Research Institute, Boston, MA, USA.
³¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Munich, Germany.
³⁴ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Instituto de Salud Carlos III, School of Medicine, Universidad Complutense, Madrid, Spain.
³⁵ PEPP-Montreal, Douglas Research Centre, Montreal, QC, Canada.
³⁶ Department of Psychiatry, McGill University, Montreal, QC, Canada.
³⁷ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁸ Institute for Mental Health, University of Birmingham, Birmingham, UK.
³⁹ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, UK.
⁴⁰ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴¹ Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
⁴² Olin Neuropsychiatry Research Center, Hartford HealthCare Behavioral Health Network, Hartford, CT, USA.
⁴³ School of Nursing, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁴⁴ Department of Human Physiology, University of Oregon, Eugene, OR, USA.
⁴⁵ Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴⁶ Departments of Psychiatry and Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
⁴⁷ Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁴⁸ Department of Psychiatry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁴⁹ Centre for Sleep and Cognition, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵⁰ Centre for Translational MR Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵¹ Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
⁵² General Psychiatry Service, Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne), Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁵³ Department of Psychosis Studies, King's College, London, UK.
⁵⁴ Early Intervention for Psychosis Services, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
⁵⁵ Department of Psychiatry, University of California, San Diego, CA, USA.
⁵⁶ Department of Neurology and Psychiatry, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
⁵⁷ Department of Psychiatry, School of Clinical Medicine, LKF Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁵⁸ Prevention Science Institute, University of Oregon, Eugene, OR, USA.
⁵⁹ Oregon Research Institute, Springfield, OR, USA.
⁶⁰ Copenhagen Research Centre for Mental Health, Mental Health Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁶¹ Department of Psychology, University of Copenhagen, Copenhagen, Denmark.
⁶² Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁶³ Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea.
⁶⁴ Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea.
⁶⁵ Mindlink, Gwangju Bukgu Mental Health Center, Gwangju, Korea.
⁶⁶ Department of Psychiatry, Hanyang University Hospital, Seoul, South Korea.
⁶⁷ Department of Psychiatry, Washington University Medical School, St. Louis, MO, USA.
⁶⁸ Department of Psychology, Northwestern University, Evanston, IL, USA.
⁶⁹ Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, CT, USA.
⁷⁰ CAMEO, Early Intervention in Psychosis Service, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
⁷¹ Institute of Biomedical Research (IBSAL), Department of Medicine, Universidad de Salamanca, Salamanca, Spain.
⁷² Connecticut Mental Health Center, New Haven, CT, USA.
⁷³ Douglas Research Centre, Montreal, QC, Canada.
⁷⁴ Department of Psychology, University of Georgia, Athens, GA, USA.
⁷⁵ Department of Psychiatry, University of Oxford, Oxford, UK.
⁷⁶ Institute of Mental Health, Singapore, Singapore.
⁷⁷ Duke-NUS Medical School, Singapore, Singapore.
⁷⁸ Department of Software Engineering and Information Technology, École de technologie supérieure, Montreal, QC, Canada.
⁷⁹ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸⁰ Departments of Psychiatry and Biobehavioral Sciences & Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁸¹ Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
⁸² Veterans Affairs San Diego Health Care System, San Diego, CA, USA.

PMID: 40480970
PMCID: PMC12144291
DOI: 10.1038/s41537-025-00622-0

The electroencephalography protocol for the Accelerating Medicines Partnership® Schizophrenia Program: Reliability and stability of measures

Daniel H Mathalon et al. Schizophrenia (Heidelb). 2025.

. 2025 Jun 6;11(1):85.

doi: 10.1038/s41537-025-00622-0.

Authors

Affiliations

¹ Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA. daniel.mathalon@ucsf.edu.
² Mental Health Service, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA. daniel.mathalon@ucsf.edu.
³ Mental Health Service, Veterans Affairs San Francisco Health Care System, San Francisco, CA, USA.
⁴ Northern California Institute for Research and Education, San Francisco, CA, USA.
⁵ Department of Psychiatry, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Orygen, Parkville, VIC, Australia.
⁷ Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.
⁸ School of Psychology, University of New South Wales (UNSW), Kensington, NSW, Australia.
⁹ Department of Psychiatry and Behavioral Sciences and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.
¹⁰ University of Minnesota, Minneapolis, MN, USA.
¹¹ Washington University School of Medicine, St. Louis, MO, USA.
¹² Consciousness and Cognition Lab, Department of Psychology, University of Cambridge, Cambridge, UK.
¹³ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ UNC Intellectual and Developmental Disabilities Research Center, Carrboro, NC, USA.
¹⁵ Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
¹⁶ Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
¹⁷ Institute of Behavioral Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
¹⁸ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁹ Centre for Neuropsychiatric Schizophrenia Research, CNSR Mental Health Centre, Glostrup, Denmark.
²⁰ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
²¹ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
²² Department of Psychology & Neuroscience, Temple University, Philadelphia, PA, USA.
²³ Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital and University of Lausanne (CHUV-UNIL), Lausanne, Switzerland.
²⁴ Department of Psychiatry, Chonnam National University Medical School, Gwangju, Korea.
²⁵ Early Psychosis Detection and Clinical Intervention (EPIC) lab, Department of Psychosis Studies, King's College, London, UK.
²⁶ Department of Psychological Science, University of California, Irvine, CA, USA.
²⁷ Department of Psychiatry, IMHAY, University of Chile, Santiago, Chile.
²⁸ Facultad de Psicología, Universidad Alberto Hurtado, Santiago, Chile.
²⁹ Harvard Medical School, Boston, MA, USA.
³⁰ Boston VA Research Institute, Boston, MA, USA.
³¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Munich, Germany.
³⁴ Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Instituto de Salud Carlos III, School of Medicine, Universidad Complutense, Madrid, Spain.
³⁵ PEPP-Montreal, Douglas Research Centre, Montreal, QC, Canada.
³⁶ Department of Psychiatry, McGill University, Montreal, QC, Canada.
³⁷ Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁸ Institute for Mental Health, University of Birmingham, Birmingham, UK.
³⁹ Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, UK.
⁴⁰ Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁴¹ Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, USA.
⁴² Olin Neuropsychiatry Research Center, Hartford HealthCare Behavioral Health Network, Hartford, CT, USA.
⁴³ School of Nursing, LKS Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁴⁴ Department of Human Physiology, University of Oregon, Eugene, OR, USA.
⁴⁵ Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴⁶ Departments of Psychiatry and Neuroscience, University of Rochester Medical Center, Rochester, NY, USA.
⁴⁷ Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁴⁸ Department of Psychiatry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁴⁹ Centre for Sleep and Cognition, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵⁰ Centre for Translational MR Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁵¹ Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
⁵² General Psychiatry Service, Treatment and Early Intervention in Psychosis Program (TIPP-Lausanne), Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
⁵³ Department of Psychosis Studies, King's College, London, UK.
⁵⁴ Early Intervention for Psychosis Services, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
⁵⁵ Department of Psychiatry, University of California, San Diego, CA, USA.
⁵⁶ Department of Neurology and Psychiatry, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile.
⁵⁷ Department of Psychiatry, School of Clinical Medicine, LKF Faculty of Medicine, University of Hong Kong, Hong Kong, China.
⁵⁸ Prevention Science Institute, University of Oregon, Eugene, OR, USA.
⁵⁹ Oregon Research Institute, Springfield, OR, USA.
⁶⁰ Copenhagen Research Centre for Mental Health, Mental Health Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁶¹ Department of Psychology, University of Copenhagen, Copenhagen, Denmark.
⁶² Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁶³ Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea.
⁶⁴ Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea.
⁶⁵ Mindlink, Gwangju Bukgu Mental Health Center, Gwangju, Korea.
⁶⁶ Department of Psychiatry, Hanyang University Hospital, Seoul, South Korea.
⁶⁷ Department of Psychiatry, Washington University Medical School, St. Louis, MO, USA.
⁶⁸ Department of Psychology, Northwestern University, Evanston, IL, USA.
⁶⁹ Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, CT, USA.
⁷⁰ CAMEO, Early Intervention in Psychosis Service, Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
⁷¹ Institute of Biomedical Research (IBSAL), Department of Medicine, Universidad de Salamanca, Salamanca, Spain.
⁷² Connecticut Mental Health Center, New Haven, CT, USA.
⁷³ Douglas Research Centre, Montreal, QC, Canada.
⁷⁴ Department of Psychology, University of Georgia, Athens, GA, USA.
⁷⁵ Department of Psychiatry, University of Oxford, Oxford, UK.
⁷⁶ Institute of Mental Health, Singapore, Singapore.
⁷⁷ Duke-NUS Medical School, Singapore, Singapore.
⁷⁸ Department of Software Engineering and Information Technology, École de technologie supérieure, Montreal, QC, Canada.
⁷⁹ Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁸⁰ Departments of Psychiatry and Biobehavioral Sciences & Psychology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
⁸¹ Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.
⁸² Veterans Affairs San Diego Health Care System, San Diego, CA, USA.

PMID: 40480970
PMCID: PMC12144291
DOI: 10.1038/s41537-025-00622-0

Abstract

Individuals at clinical high risk for psychosis (CHR) have variable clinical outcomes and low conversion rates, limiting development of novel and personalized treatments. Moreover, given risks of antipsychotic drugs, safer effective medications for CHR individuals are needed. The Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ) Program was launched to address this need. Based on past CHR and schizophrenia studies, AMP SCZ assessed electroencephalography (EEG)-based event-related potential (ERP), event-related oscillation (ERO), and resting EEG power spectral density (PSD) measures, including mismatch negativity (MMN), auditory and visual P300 to target (P3b) and novel (P3a) stimuli, 40-Hz auditory steady state response, and resting EEG PSD for traditional frequency bands (eyes open/closed). Here, in an interim analysis of AMP SCZ EEG measures, we assess test-retest reliability and stability over sessions (baseline, month-2 follow-up) in CHR (n = 654) and community control (CON; n = 87) participants. Reliability was calculated as Generalizability (G)-coefficients, and changes over session were assessed with paired t-tests. G-coefficients were generally good to excellent in both groups (CHR: mean = 0.72, range = 0.49-0.85; CON: mean = 0.71, range = 0.44-0.89). Measure magnitudes significantly (p < 0.001) decreased over session (MMN, auditory and visual target P3b, visual novel P3a, 40-Hz ASSR) and/or over runs within sessions (MMN, auditory/visual novel P3a and target P3b), consistent with habituation effects. Despite these small systematic habituation effects, test-retest reliabilities of the AMP SCZ EEG-based measures are sufficiently strong to support their use in CHR studies as potential predictors of clinical outcomes, markers of illness progression, and/or target engagement or secondary outcome measures in controlled clinical trials.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: B.H.E. is part of the Advisory Board of Boehringer Ingelheim, Lundbeck Pharma A/S; and has received lecture fees from Boehringer Ingelheim, Otsuka Pharma Scandinavia AB, and Lundbeck Pharma A/S; C.A. has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Menarini, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda; C.D.C. has received grant support from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation and honoraria or travel support from Angelini, Janssen, and Viatris; C.M.C. is an Associate Editor of Nature: Schizophrenia; D.D. has received honorary funds for one educational seminar for CSL Sequiris; D.O.P. has been a consultant to Alkermes; E.Y.H.C. has received speaker fees at non-promotional educational events; GAL has been a consultant for Bristol Myers Squibb, Cerevel, Johnson & Johnson, Neurocrine, NeuroSig, and Sosei-Heptares; J.K. has received speaking or consulting fees from Janssen, Boehringer Ingelheim, ROVI and Lundbeck; J.M.K. is a consultant to or receives honoraria and/or travel support and/or speakers fees from Alkermes, Allergan, Boehringer-Ingelheim, Cerevel, Dainippon Sumitomo, H. Lundbeck, HealthRhythms, HLS Therapeutics, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, Karuna Therapeutics/Bristol Myers Squibb, LB Pharmaceuticals, Mapi, Maplight, Merck, Minerva, Neurocrine, Newron, Novartis, NW PharmaTech, Otsuka, Roche, Saladax, Sunovion, and Teva; and is on Advisory Boards for Alkermes, Boehringer-Ingelheim, Cerevel, Click Therapeutics, Karuna/BMS, Lundbeck, Merck, Newron, Novartis, Otsuka, Sumitomo, Teva, and Terran; and has received grant support from Lundbeck, Janssen, Otsuka, and Sunovion; and has shareholder interest in Cerevel (public/stock), HealthRhythms (private/stock options), Karuna/BMS (public), LB Pharmaceuticals (private/stock options), North Shore Therapeutics (private/stock), and Vanguard Research Group (private/40% owner); P.F.P. has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Proxymm Science, Otsuka, outside the current study; R.S.K. has been a consultant to Alkermes and Boehringer-Ingelheim; R.U. has received speaker fees at non-promotional educational event: Otsuka: Consultancy for Viatris and Springer Healthcare. Honorary General Secretary British Association for Psychopharmacology (unpaid); S.W.W. has received speaking fees from the American Psychiatric Association and from Medscape Features. He has been granted US patent No. 8492418 B2 for a method of treating prodromal schizophrenia with glycine agonists. He owns stock in NW PharmaTech; and Z.T. has been a consultant for Manifest Technologies. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

**Fig. 1. Intervals between baseline and month-2 EEG sessions by group.**
Frequency distributions of inter-session intervals, in days, between baseline and month-2 EEG sessions, as well as central tendency indicators, are plotted for the full sample (i.e., quality control rating ≥ 2) of community controls (CON) on the left and clinical high risk participants (CHR;) on the right. Mean (orange), median (green), and modal (blue) inter-session intervals (in days) are indicated with colored vertical lines and are presented in the top right corner of each plot. Distributions were skewed to the right, indicating that a minority of participants had longer inter-session intervals. QC quality control.

Fig. 2. Grand average event-related potential waveforms and event-related oscillation time-frequency maps, scalp topographies, and baseline to month-2 test-retest reliability maps for each task by group.
For each event-related potential (ERP; (A)-Auditory Target P3b, (B)-Auditory Novel P3a, (C)-Visual Target P3b, (D)-Visual Novel P3a, (E)-Mismatch Negativity) or 40-Hz auditory steady state response (ASSR) event-related oscillation (ERO; (F)- Inter-trial Coherence; (G)-Evoked Power; (H)-Total Power) measure, grand average waveforms or time-frequency heat maps, averaged over baseline and month-2 follow-up, from the single scalp electrode (ERP) or fronto-central 6-electrode cluster (ERO) where the measure was most prominent, are shown in row 1. In each case (**A-H**), community control (CON) results are shown on the left, and clinical high risk (CHR) results are shown on the right. For ERP components (A–E): Row 1 shows grand average ERP waveforms for single stimulus types, as well as difference waves between stimulus types. Light gray vertical bars are centered on the ERP component’s peak and indicate the window over which values were averaged to measure the component’s amplitude. Row 2 shows the scalp topography maps for these ERP component amplitudes, averaged over baseline and month-2 assessments. Row 3 shows baseline and month-2 overlays of the grand average ERP difference waves, averaged over the cluster of electrodes where the component is most prominent (e.g., CPz/Pz-6 auditory target P300 represents average of 6 electrodes centered on CPz and Pz, shown also with white circles around included electrodes in G-coefficient topography maps in row 4). For ERO measures from the 40-Hz ASSR paradigm (F–H): Row 1 shows time-frequency heat maps for inter-trial coherence (F), evoked power (G), and total power (F). Row 2 shows scalp topography maps for these ERO measures averaged over the 100–500 ms time window and 38–42 Hz frequency band. Row 3 shows baseline and month-2 overlays of the ERO measure's waveform extracted for the 38–42 Hz frequency band. For all ERP and ERO measures (A–H): Row 4 shows scalp topography maps of the test-retest Generalizability (G)-coefficients, and white circles around the electrodes indicate the electrodes included in the average measure. Row 5 shows scatterplots of these average measures for month-2 vs. baseline.

**Fig. 3. Auditory and visual oddball task performance and target reaction times for baseline and month-2 by group.**
Performance error rates and median target reaction time distributions at baseline and month-2 follow-up are presented for the auditory oddball task (AOD) on the left and the visual oddball task(VOD) on the right. For each task, community controls (CON) are shown on the left, and clinical high risk participants (CHR) are shown on the right. The distributions of false alarm (FA) rates are shown for standard stimuli (row 1) and for novel non-target stimuli (row 2), and the distributions of miss rates for target stimuli are shown in row 3. Overall, these distributions indicate low false alarm and miss rates, as indicated by the median values shown in the right upper corner of the plots. Row 4 shows the distributions of median target reaction times in milleseconds (ms), and their mean values are presented in the right upper corner of the plots. Row 5 shows the month-2 vs. baseline scatterplots of median target reaction times (RT), corresponding to the G-coefficients presented in Table 3.

**Fig. 4. Resting EEG power spectral densities, scalp topographies, and baseline to month-2 test-retest reliability maps by group.**
Power spectral density (PSD) plots of resting electroencephalography (EEG) for eyes open (green line) and eyes closed (black line) conditions, averaged over baseline and month-2 follow-up, are presented in row 1 for community controls (CON) on the left and clinical high risk (CHR) participants on the right for conventional EEG frequency bands Delta (A), Theta (B), Alpha (C), Beta (D), and Gamma (E). PSD values are plotted on a log scale. Gray vertical bars indicate the definition of each frequency band. Rows 2 and 3 show the scalp topography maps of PSD for each frequency band (A−E) during eyes open and closed conditions, averaged over baseline and month-2 follow-up assessments. White circles indicate the electrodes where the PSD was most prominent. PSD plots averaged over the white circled electrodes in the topography maps are overlaid for baseline and month-2 for eyes open (rows 4) and eyes closed (row 5) conditions. Scalp topography maps of test-retest G-coefficients for PSD values at each frequency band (A−E) are shown for eyes open (row 6) and eyes closed (row 7) conditions. White circles indicate electrodes over which PSDs were averaged, and scatterplots of month-2 vs. baseline PSD values, corresponding to the G-coefficients presented in Table 3, are presented for eyes open condition in row 8 and for eyes closed condition in row 9. For these scatterplots, PSD values are plotted on a log scale.

**Fig. 5. ERP component amplitudes by task run and EEG session.**
ERP component mean amplitudes and standard error bars are presented by run for baseline and month-2 sessions for mismatch negativity (MMN; N = 546; top row), visual oddball (VOD) novel P3a and target P3b (N = 546; middle row), and auditory oddball (AOD) novel P3a and target P3b (N = 582; bottom row) using clusters of 6 electrodes centered on midline electrodes indicated in each plot (e.g., Fz/FCz-6 cluster comprises mean of electrodes Fz, F1, F2, FCz, FC1, FC2). QC = Quality Control. Included data were for sessions where all runs were completed and where the QC rating for both sessions was ≥ 3.

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References

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The electroencephalography protocol for the Accelerating Medicines Partnership® Schizophrenia Program: Reliability and stability of measures

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The electroencephalography protocol for the Accelerating Medicines Partnership® Schizophrenia Program: Reliability and stability of measures

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