2024
CONNEX, a Phase III Randomized Trial Program Assessing Efficacy and Safety of Iclepertin in Schizophrenia: Recruitment and Baseline Characteristics
Blahova Z, Ikezawa S, Falkai P, Krystal J, Rangan T. CONNEX, a Phase III Randomized Trial Program Assessing Efficacy and Safety of Iclepertin in Schizophrenia: Recruitment and Baseline Characteristics. BJPsych Open 2024, 10: s72-s73. DOI: 10.1192/bjo.2024.230.Peer-Reviewed Original ResearchVirtual Reality Functional Capacity Assessment ToolComposite T-scoreSchizophrenia Cognition Rating ScaleSchizophrenia Consensus Cognitive BatteryCognitive impairmentGlycine transporter-1 inhibitorStable antipsychotic treatmentN-methyl-d-aspartate receptor signallingConsensus Cognitive BatteryCognitive remediation therapyIncrease synaptic levelsCognition Rating ScaleT-scoreDuration of illnessCo-agonist glycineAntipsychotic treatmentAntipsychotic medicationSchizophrenia treatmentCognitive batteryRemediation therapyCognitive symptomsTreatment researchSchizophreniaImprove cognitionPlacebo-controlled parallel-group trialIllusory generalizability of clinical prediction models
Chekroud A, Hawrilenko M, Loho H, Bondar J, Gueorguieva R, Hasan A, Kambeitz J, Corlett P, Koutsouleris N, Krumholz H, Krystal J, Paulus M. Illusory generalizability of clinical prediction models. Science 2024, 383: 164-167. PMID: 38207039, DOI: 10.1126/science.adg8538.Peer-Reviewed Original Research
2023
Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia
Surti T, Ranganathan M, Johannesen J, Gueorguieva R, Deaso E, Kenney J, Krystal J, D'Souza D. Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia. Schizophrenia Research 2023, 256: 36-43. PMID: 37141764, PMCID: PMC10257994, DOI: 10.1016/j.schres.2023.04.010.Peer-Reviewed Original ResearchConceptsGlycine transporter 1Cytochrome P450 2D6 extensive metabolizersGlyT1 inhibitorsWeeks of washoutWeeks of CTMedication adherenceReceptor hypofunctionImpaired neuroplasticityPharmacodynamic variabilityNMDAR functionExtensive metabolizersTreatment periodPsychotic symptomsStable outpatientsCognitive impairmentGlyT1 occupancyTransporter 1CTNeuroplasticityCognitive training strategiesSchizophreniaComputerized CTCognitive performanceAugmentation studiesGreater improvement511. Common and Distinct Effects of Incentives on Spatial Working Memory in Schizophrenia and Obsessive-Compulsive Disorder
Sarantopoulos C, Shin D, Schleifer C, Moujaes F, Adkinson B, Ji J, Kolabaric A, Flynn M, Santamauro N, Krystal J, Murray J, Repovs G, Martin W, Pittenger C, Anticevic A, Cho Y. 511. Common and Distinct Effects of Incentives on Spatial Working Memory in Schizophrenia and Obsessive-Compulsive Disorder. Biological Psychiatry 2023, 93: s300-s301. DOI: 10.1016/j.biopsych.2023.02.751.Peer-Reviewed Original ResearchEfficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme
Reuteman-Fowler C, Blahova Z, Ikezawa S, Marder S, Falkai P, Krystal J. Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme. Neuroscience Applied 2023, 2: 102592. DOI: 10.1016/j.nsa.2023.102592.Peer-Reviewed Original Research
2022
Efficacy and safety of BI 425809 in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme
Wunderlich G, Blahova Z, Hake S, Ikezawa S, Marder S, Falkai P, Krystal J. Efficacy and safety of BI 425809 in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme. Neuroscience Applied 2022, 1: 100342. DOI: 10.1016/j.nsa.2022.100342.Peer-Reviewed Original Research
2021
Potential Schizophrenia Medications Point to New Disease Model
Krystal J. Potential Schizophrenia Medications Point to New Disease Model. Psychiatric News 2021, 56 DOI: 10.1176/appi.pn.2021.11.37.Peer-Reviewed Original ResearchDopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia
Abi-Dargham A, Javitch JA, Slifstein M, Anticevic A, Calkins ME, Cho YT, Fonteneau C, Gil R, Girgis R, Gur RE, Gur RC, Grinband J, Kantrowitz J, Kohler C, Krystal J, Murray J, Ranganathan M, Santamauro N, Van Snellenberg J, Tamayo Z, Wolf D, D’Souza D, Srihari V, Gueorguieva R, Patel P, Forselius-Bielen K, Lu J, Butler A, Fram G, Afriyie-Agyemang Y, Selloni A, Cadavid L, Gomez-Luna S, Gupta A, Radhakrishnan R, Rashid A, Aker R, Abrahim P, Nia A, Surti T, Kegeles L, Carlson M, Goldberg T, Gangwisch J, Benedict E, Govil P, Brazis S, Mayer M, de la Garrigue N, Fallon N, Baumvoll T, Abeykoon S, Perlman G, Bobchin K, Elliott M, Schmidt L, Rush S, Port A, Heffernan Z, Laney N, Kantor J, Hohing T, Gray D, Lieberman J. Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia. Schizophrenia Bulletin 2021, 48: 199-210. PMID: 34423843, PMCID: PMC8781338, DOI: 10.1093/schbul/sbab095.Peer-Reviewed Original ResearchConceptsCortical dopamine neurotransmissionPositive allosteric modulationImportant therapeutic targetPF-06412562Dopaminergic receptorsD1R stimulationDA levelsTolerable dosesLevel of stimulationDopamine neurotransmissionReceptor stimulationTherapeutic targetPartial agonistCognitive deficitsBiased agonismFull agonismTarget engagementAllosteric modulationNew drugsStimulationPoor bioavailabilitySchizophreniaOptimal stimulationDrugsExpression levels
2020
Dopamine and glutamate in schizophrenia: biology, symptoms and treatment
McCutcheon RA, Krystal JH, Howes OD. Dopamine and glutamate in schizophrenia: biology, symptoms and treatment. World Psychiatry 2020, 19: 15-33. PMID: 31922684, PMCID: PMC6953551, DOI: 10.1002/wps.20693.Peer-Reviewed Original ResearchDopamine systemAberrant dopamine signallingStriatal dopamine synthesisNovel pharmacological therapiesPathophysiology of schizophreniaEnvironmental risk factorsPharmacological therapyGlutamatergic dysfunctionDopaminergic functionRisk factorsGlutamate systemDopamine synthesisGenetic risk variantsPreclinical studiesPsychotic symptomsDopamine functionNew treatmentsNeural circuitsDopamine signalingNeuronal signalingSchizophreniaConsistent findingRisk variantsSymptomsGlutamate
2019
Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits
Ji JL, Diehl C, Schleifer C, Tamminga CA, Keshavan MS, Sweeney JA, Clementz BA, Hill SK, Pearlson G, Yang G, Creatura G, Krystal JH, Repovs G, Murray J, Winkler A, Anticevic A. Schizophrenia Exhibits Bi-directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits. Cerebral Cortex 2019, 29: 4463-4487. PMID: 31157363, PMCID: PMC6917525, DOI: 10.1093/cercor/bhy306.Peer-Reviewed Original ResearchConceptsBrain-wide alterationsResting-state functional magnetic resonanceSensory-motor cortexFunctional magnetic resonanceNeural dysconnectivityPolysynaptic connectionsCortico-striatoFunctional disturbancesChronic patientsAssociation cortexFocal disruptionNeural effectsCerebellar circuitsPatientsDysconnectivityStriatal componentsSchizophreniaCortexSpecific alterationsHallmark featureCognitive performanceAlterationsFunctional pathwaysQuestion accountsMagnetic resonanceS159. NMDA Receptor Antagonism Effects on Delayed Spatial Working Memory and Distraction in Comparison With Schizophrenia
Moujaes F, Preller K, Vollenweider F, Schleifer C, Ji J, Adkinson B, Kolobaric A, Flynn M, Fineberg S, Krystal J, Repovs G, Santamauro N, Morgan P, Savic A, Cho Y, Murray J, Anticevic A. S159. NMDA Receptor Antagonism Effects on Delayed Spatial Working Memory and Distraction in Comparison With Schizophrenia. Biological Psychiatry 2019, 85: s358. DOI: 10.1016/j.biopsych.2019.03.910.Peer-Reviewed Original ResearchA multicenter study of ketamine effects on functional connectivity: Large scale network relationships, hubs and symptom mechanisms
Fleming LM, Javitt DC, Carter CS, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman J, Krystal JH, Corlett PR. A multicenter study of ketamine effects on functional connectivity: Large scale network relationships, hubs and symptom mechanisms. NeuroImage Clinical 2019, 22: 101739. PMID: 30852397, PMCID: PMC6411494, DOI: 10.1016/j.nicl.2019.101739.Peer-Reviewed Original ResearchConceptsDorsolateral prefrontal cortexN-methyl-D-aspartate (NMDA) glutamate receptor antagonistFunctional connectivityKetamine-induced alterationsGlutamate receptor antagonistsAltered brain functionState functional connectivityRsfMRI connectivityRisk patientsMulticenter studyKetamine effectsReceptor antagonistDLPFC connectivityMimic symptomsHealthy individualsKetamine usePositive symptomsCertain biomarkersBrain functionPrefrontal cortexPatientsConnectivity signaturesSeed-based measuresSchizophreniaKetamineAltered functional connectivity and low-frequency signal fluctuations in early psychosis and genetic high risk
Tang Y, Zhou Q, Chang M, Chekroud A, Gueorguieva R, Jiang X, Zhou Y, He G, Rowland M, Wang D, Fu S, Yin Z, Leng H, Wei S, Xu K, Wang F, Krystal JH, Driesen NR. Altered functional connectivity and low-frequency signal fluctuations in early psychosis and genetic high risk. Schizophrenia Research 2019, 210: 172-179. PMID: 30685394, DOI: 10.1016/j.schres.2018.12.041.Peer-Reviewed Original ResearchConceptsFunctional connectivityHigh-risk individualsAltered functional connectivityHealthy comparison subjectsGenetic high riskGenetic high-risk individualsLow-frequency signal fluctuationsFunctional magnetic resonanceALFF abnormalitiesALFF measuresFunctional connectivity measuresBasal gangliaFirst episodeHigh riskEarly psychosisComparison subjectsSchizophrenia diathesisSchizophrenia vulnerabilityFESzGenetic riskLow-frequency fluctuationsIllnessSchizophreniaVoxel connectivityGHR
2018
2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE
Krystal J. 2. MICROCIRCUITS, MACROCIRCUITS, AND CORTICOL DYSFUNCTION IN SCHIZOPHRENIA: A COMPUTATIONAL AND TRANSLATIONAL NEUROSCIENCE PERSPECTIVE. Schizophrenia Bulletin 2018, 44: s1-s1. PMCID: PMC5887654, DOI: 10.1093/schbul/sby014.001.Peer-Reviewed Original ResearchNMDA glutamate receptorsNMDA receptor antagonistCortical functional connectivityPathophysiology of schizophreniaReceptor antagonistTranslational neuroscience perspectiveGlutamate receptorsHealthy humansAnimal modelsSchizophrenia patientsMemory impairmentNeuropsychiatric disordersSynaptic signalingFunctional connectivityNovel therapeuticsSchizophreniaDisordersPresentationPatientsPathophysiologyDysfunctionKetamineAntagonistSymptomsAbnormalitiesDose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
D’Souza D, Carson RE, Driesen N, Johannesen J, Ranganathan M, Krystal JH, Ahn K, Bielen K, Carbuto M, Deaso E, D’Souza D, Ranganathan M, Naganawa M, Ranganathan M, D’Souza D, Nabulsi N, Zheng M, Lin S, Huang Y, Carson R, Driesen N, Ahn K, Morgan P, Suckow R, He G, McCarthy G, Krystal J, Johannesen J, Kenney J, Gelernter J, Gueorguieva R, Pittman B. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biological Psychiatry 2018, 84: 413-421. PMID: 29499855, PMCID: PMC6068006, DOI: 10.1016/j.biopsych.2017.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAdultAzabicyclo CompoundsBrainCognitive DysfunctionDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycine Plasma Membrane Transport ProteinsHumansImidazolesKetamineLong-Term PotentiationMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedPositron-Emission TomographySchizophreniaYoung AdultConceptsHealthy control subjectsLong-term potentiationSchizophrenia patientsControl subjectsCognitive impairmentClinical trialsGlyT1 occupancyN-methyl-D-aspartate receptor functionGlycine transporter-1 inhibitorKetamine-induced disruptionKetamine-induced effectsFunctional magnetic resonance imagingMagnetic resonance imagingPositron emission tomographyMemory-related activationF-MKSubstudy 1Schizophrenia subjectsResonance imagingReceptor functionCortical regionsEmission tomographyTarget engagementPotentiationSchizophrenia
2017
Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders
Foss-Feig JH, Adkinson BD, Ji JL, Yang G, Srihari VH, McPartland JC, Krystal JH, Murray JD, Anticevic A. Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders. Biological Psychiatry 2017, 81: 848-861. PMID: 28434615, PMCID: PMC5436134, DOI: 10.1016/j.biopsych.2017.03.005.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderSpectrum disorderFunctional magnetic resonance imagingRecent theoretical accountsEarly course schizophreniaNeurodevelopmental disordersPharmacological challenge studiesNeural correlatesNeuroscience literatureTheoretical accountsNeural circuitryTheoretical neuroscienceNoninvasive neuroimagingBehavioral dysfunctionFuture researchNeuropsychiatric conditionsComputational modelSchizophreniaProton magnetic resonance spectroscopyDisordersInhibition imbalanceMagnetic resonance imagingDistinct modalitiesPoint of convergenceInhibition balanceComputational Psychiatry and the Challenge of Schizophrenia
Krystal JH, Murray JD, Chekroud AM, Corlett PR, Yang G, Wang XJ, Anticevic A. Computational Psychiatry and the Challenge of Schizophrenia. Schizophrenia Bulletin 2017, 43: 473-475. PMID: 28338845, PMCID: PMC5464204, DOI: 10.1093/schbul/sbx025.Peer-Reviewed Original ResearchConceptsComputational psychiatryReinforcement learning theoryNeural circuit modelMachine learningComplex datasetsFormal modelLarge datasetsLearning theorySchizophrenia researchDatasetSchizophreniaFormal theoryEnormous challengesPsychiatryDisordersLearningChallengesTheoryDifficultiesModelReadersApplicationsResearchPathImpaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective
Krystal JH, Anticevic A, Yang GJ, Dragoi G, Driesen NR, Wang XJ, Murray JD. Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective. Biological Psychiatry 2017, 81: 874-885. PMID: 28434616, PMCID: PMC5407407, DOI: 10.1016/j.biopsych.2017.01.004.Peer-Reviewed Original ResearchConceptsNeural activityNeural ensemblesComputational neuroscience perspectiveHigher cognitive functionsNeuroscience perspectiveDevelopmental perspectiveDevelopmental correlatesCognitive functionNegative functional consequencesCortical networksComputational neuroscienceNeural codeCortical activityCognitive impairmentNeural dysfunctionAspartate glutamate receptor antagonistTemporal tuningSpatial tuningGlutamate receptor antagonistsPathophysiology of schizophreniaNeural network functionSchizophreniaPsychiatric disordersBalance of excitationInput-output curves
2016
The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models
Khlestova E, Johnson JW, Krystal JH, Lisman J. The Role of GluN2C-Containing NMDA Receptors in Ketamine's Psychotogenic Action and in Schizophrenia Models. Journal Of Neuroscience 2016, 36: 11151-11157. PMID: 27807157, PMCID: PMC5148234, DOI: 10.1523/jneurosci.1203-16.2016.Peer-Reviewed Original ResearchConceptsNMDAR antagonistsNMDA receptor hypofunction hypothesisDifferent NMDAR subtypesHealthy human subjectsSymptoms of schizophreniaPsychotogenic effectsNMDA receptorsNMDAR subtypesSchizophrenia modelKetamine's abilityNegative symptomsKetamineMultiple subtypesPsychotic statesPreferential involvementSchizophreniaAntagonistGluN2CSubtypesReceptorsEEG powerHuman subjectsNMDARSymptomsΔ oscillationsAltered Global Signal Topography in Schizophrenia
Yang GJ, Murray JD, Glasser M, Pearlson GD, Krystal JH, Schleifer C, Repovs G, Anticevic A. Altered Global Signal Topography in Schizophrenia. Cerebral Cortex 2016, 27: 5156-5169. PMID: 27702810, PMCID: PMC6075538, DOI: 10.1093/cercor/bhw297.Peer-Reviewed Original ResearchConceptsSCZ patientsGS topographyHealthy subjectsResting-state functional magnetic resonance imagingBlood oxygen level-dependent (BOLD) signalDevelopment of pharmacotherapiesGlobal signal topographyHealthy comparison subjectsFunctional magnetic resonance imagingLevel-dependent signalMagnetic resonance imagingAnti-correlated relationshipExtensive abnormalitiesComparison subjectsAssociation cortexNeural information flowResonance imagingNeuropsychiatric diseasesSensory areasPatientsSchizophreniaSensory regionsProfound alterationsSignal topographyAlterations