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 trial
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 improvementEfficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program
Wunderlich G, Blahova Z, Hake S, Ikezawa S, Marder S, Falkai P, Krystal J. Efficacy and Safety of Iclepertin (BI 425809) in Patients With Schizophrenia: CONNEX, A Phase III Randomized Controlled Trial Program. CNS Spectrums 2023, 28: 229-229. DOI: 10.1017/s1092852923001530.Peer-Reviewed Original ResearchCognitive impairmentEfficacy endpointVirtual Reality Functional Capacity Assessment ToolCognitive symptomsPlacebo-controlled parallel-group trialKey secondary efficacy endpointsN-methyl-D-aspartate receptorsSafety extension studyPrimary efficacy endpointSecondary efficacy endpointsParallel-group trialPhase II trialPoor functional outcomeComposite T-scoreMulti-center studyPhase III programRole of glutamateLong-term safetyScale total scoreDemonstration of efficacyGlycine transporter 1Industry-sponsored studiesCapacity assessment toolII trialTolerability dataEfficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme
Falkai P, Reuteman-Fowler C, Blahova Z, Ikezawa S, Marder S, Krystal J. Efficacy and safety of iclepertin (BI 425809) in patients with schizophrenia: CONNEX, a Phase III randomised controlled trial programme. European Psychiatry 2023, 66: s637-s637. PMCID: PMC10661489, DOI: 10.1192/j.eurpsy.2023.1325.Peer-Reviewed Original ResearchCognitive impairmentEfficacy endpointVirtual Reality Functional Capacity Assessment ToolCognitive symptomsJazz PharmaceuticalsPlacebo-controlled parallel-group trialBoehringer IngelheimKey secondary efficacy endpointsN-methyl-D-aspartate receptorsSafety extension studyPrimary efficacy endpointSecondary efficacy endpointsParallel-group trialPhase II trialPoor functional outcomeComposite T-scorePhase III programRole of glutamateLong-term safetyScale total scoreGrant/research supportDemonstration of efficacyGlycine transporter 1Industry-sponsored studiesCapacity assessment tool
2022
Long-term safety of ketamine and esketamine in treatment of depression
Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opinion On Drug Safety 2022, 21: 777-787. PMID: 35416105, DOI: 10.1080/14740338.2022.2066651.Peer-Reviewed Original ResearchConceptsLong-term safetyClinical trialsRacemic ketamineLong-term safety effectsRapid-acting antidepressant effectsLower urinary tract symptomsKetamine/esketamineTreatment-resistant depressionUrinary tract symptomsCommon side effectsTreatment of depressionLong-term impairmentElevated heart ratePhase three clinical trialsTract symptomsAntidepressant effectsBlood pressureIncreased riskBladder pathologyEsketamineHeart ratePsychiatric disordersSide effectsCognitive impairmentHigh doses
2018
Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia
Cheng WJ, Chen CH, Chen CK, Huang MC, Pietrzak RH, Krystal JH, Xu K. Similar psychotic and cognitive profile between ketamine dependence with persistent psychosis and schizophrenia. Schizophrenia Research 2018, 199: 313-318. PMID: 29510925, DOI: 10.1016/j.schres.2018.02.049.Peer-Reviewed Original ResearchConceptsSZ patientsCognitive impairmentCognitive functionSocial-emotional cognitionCogstate Brief BatteryPsychomotor processing speedTreatment-seeking patientsSpatial problemsSymptom profilesSevere symptom profileVerbal memoryCognitive profileKetamine-dependent patientsVisual learningBrief batteryProcessing speedNegative Syndrome ScaleBiology of psychosisKetamine usersCognitive dysfunctionPersistent psychosisMemorySubscale scoresKetamine abuseMinority of usersDose-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
Impaired 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
2014
Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia.
Boggs DL, Carlson J, Cortes-Briones J, Krystal JH, D'Souza DC. Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. Current Pharmaceutical Design 2014, 20: 5077-92. PMID: 24345265, PMCID: PMC4442779, DOI: 10.2174/1381612819666131216121019.Peer-Reviewed Original ResearchConceptsCognitive impairmentStandardized cognitive test batteryCognitive test batteryInformation processing impairmentsNicotinic medicationsProcessing impairmentsCore deficitAttentional deficitsTest batteryCognitive deficitsProximal measuresBrain functionCognitionSchizophreniaDeficitsImpairmentNumber of medicationsNicotinic acetylcholine receptorsCertain symptomsConsistent improvementClinical evidenceTreatment strategiesClinical studiesNicotinic receptorsClinical utility
2012
Linking Microcircuit Dysfunction to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical Working Memory Model
Murray JD, Anticevic A, Gancsos M, Ichinose M, Corlett PR, Krystal JH, Wang XJ. Linking Microcircuit Dysfunction to Cognitive Impairment: Effects of Disinhibition Associated with Schizophrenia in a Cortical Working Memory Model. Cerebral Cortex 2012, 24: 859-872. PMID: 23203979, PMCID: PMC3948492, DOI: 10.1093/cercor/bhs370.Peer-Reviewed Original ResearchConceptsWorking memoryNeural levelSpatial WM taskWorking Memory ModelSpatial working memoryPersistent activity patternsWM representationsWM taskWM maintenanceBrain mechanismsWM deficitsMicrocircuit dysfunctionPrefrontal cortexCognitive deficitsBehavioral dataMemory modelBehavioral variabilityWM deteriorationCognitive impairmentCortical disinhibitionExcitation-inhibition balanceMain model predictionsDisinhibitionBehavioral deficitsDeficitsGlycine treatment of the risk syndrome for psychosis: Report of two pilot studies
Woods SW, Walsh BC, Hawkins KA, Miller TJ, Saksa JR, D'Souza DC, Pearlson GD, Javitt DC, McGlashan TH, Krystal JH. Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies. European Neuropsychopharmacology 2012, 23: 931-940. PMID: 23089076, PMCID: PMC4028140, DOI: 10.1016/j.euroneuro.2012.09.008.Peer-Reviewed Original ResearchConceptsPilot studyRisk syndromeSyndrome patientsNegative symptomsShort-term pilot studyEffect sizeAdjunctive antipsychotic medicationOpen-label studyPatients meeting criteriaNMDA receptor functionDurability of effectPsychosis risk symptomsGlycine site agonistsGroup effect sizesWeeks of evaluationAntipsychotic medicationSyndrome subjectsPromising effect sizesTreatment needsLarge effect sizesMeeting criteriaCognitive impairmentReduced symptomsReceptor functionSymptoms
2008
Impairment of Working Memory Maintenance and Response in Schizophrenia: Functional Magnetic Resonance Imaging Evidence
Driesen NR, Leung HC, Calhoun VD, Constable RT, Gueorguieva R, Hoffman R, Skudlarski P, Goldman-Rakic PS, Krystal JH. Impairment of Working Memory Maintenance and Response in Schizophrenia: Functional Magnetic Resonance Imaging Evidence. Biological Psychiatry 2008, 64: 1026-1034. PMID: 18823880, PMCID: PMC2650279, DOI: 10.1016/j.biopsych.2008.07.029.Peer-Reviewed Original ResearchConceptsMemory taskPrefrontal activityMemory maintenanceBrain activationFunctional Magnetic Resonance Imaging EvidenceWorking Memory MaintenanceCognitive impairmentHealthy comparison participantsPrefrontal cortical activityFunctional magnetic resonanceMemory loadComparison participantsTask accuracyDistinct neurobiologyCortical activityHealthy participantsBasic research insightsImaging EvidenceMemoryCortical deficitsCortical functionPoor performanceTaskSchizophreniaResponse phaseIdentifying Cognitive Mechanisms Targeted for Treatment Development in Schizophrenia: An Overview of the First Meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative
Carter CS, Barch DM, Buchanan RW, Bullmore E, Krystal JH, Cohen J, Geyer M, Green M, Nuechterlein KH, Robbins T, Silverstein S, Smith EE, Strauss M, Wykes T, Heinssen R. Identifying Cognitive Mechanisms Targeted for Treatment Development in Schizophrenia: An Overview of the First Meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biological Psychiatry 2008, 64: 4-10. PMID: 18466880, PMCID: PMC2577821, DOI: 10.1016/j.biopsych.2008.03.020.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntipsychotic AgentsBiomedical ResearchBrainCognition DisordersCooperative BehaviorDrug IndustryHumansNational Institute of Mental Health (U.S.)Neuropsychological TestsResearch Support as TopicSchizophreniaSchizophrenic PsychologyUnited StatesUnited States Food and Drug AdministrationConceptsCognitive Neuroscience Treatment ResearchSchizophrenia (MATRICS) initiativeTreatment researchCognitive neuroscience fieldCNTRICS initiativeCognitive mechanismsCognitive constructsTreatment developmentNeuroscience fieldCognitive impairmentCognitionBasic animalSchizophreniaResearchFirst meetingImpairmentConstructsParadigmTranslational researchTranslation effortsNovel treatmentsOrganization
2005
Functional Neuroimaging and Electrophysiology Biomarkers for Clinical Trials for Cognition in Schizophrenia
Cho RY, Ford JM, Krystal JH, Laruelle M, Cuthbert B, Carter CS. Functional Neuroimaging and Electrophysiology Biomarkers for Clinical Trials for Cognition in Schizophrenia. Schizophrenia Bulletin 2005, 31: 865-869. PMID: 16166611, DOI: 10.1093/schbul/sbi050.Peer-Reviewed Original ResearchConceptsFunctional neuroimagingCognitive impairmentCognitive processesNeurobiological indicesTest-retest reliabilityCognitive functionTreatment researchDiscrepant findingsCognitionMental healthAdditional basic researchSchizophreniaNeuroimagingNovel pharmacotherapeuticsImpairmentParadigmResearchParticipantsBasic researchNIMHMatricFindingsRelative advantagesTrialsPerspectiveComparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine: Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function
Krystal JH, Perry EB, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, MacDougall L, Abi-Saab W, D’Souza D. Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine: Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function. JAMA Psychiatry 2005, 62: 985-995. PMID: 16143730, DOI: 10.1001/archpsyc.62.9.985.Peer-Reviewed Original Research
2003
Preliminary evidence of hippocampal dysfunction in adolescent MDMA (“ecstasy”) users: possible relationship to neurotoxic effects
Jacobsen LK, Mencl WE, Pugh KR, Skudlarski P, Krystal JH. Preliminary evidence of hippocampal dysfunction in adolescent MDMA (“ecstasy”) users: possible relationship to neurotoxic effects. Psychopharmacology 2003, 173: 383-390. PMID: 14647960, DOI: 10.1007/s00213-003-1679-4.Peer-Reviewed Original ResearchConceptsFunctional magnetic resonance imagingMDMA usersCognitive deficitsMDMA useBrain functionDivided attentionMemory taskMemory loadResultsMDMA usersLeft hippocampusHippocampal dysfunctionSubstance useCognitive impairmentAdolescencePreliminary evidenceReaction timeDevelopmental impactPilot sampleDeficitsMDMAMagnetic resonance imagingIQAttentionMemoryHippocampus
2001
A neurobiological basis for substance abuse comorbidity in schizophrenia
Chambers R, Krystal J, Self D. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biological Psychiatry 2001, 50: 71-83. PMID: 11526998, PMCID: PMC2913410, DOI: 10.1016/s0006-3223(01)01134-9.Peer-Reviewed Original ResearchConceptsDrug rewardLong-term substance abuseMedication side effectsPrior drug exposureSubstance abuse comorbidityNeuropathology of schizophreniaPrimary disease symptomsAddictive behaviorsDrug-seeking behaviorHippocampal dysfunctionDrug exposureFrontal cortexNucleus accumbensHippocampal formationSchizophrenic patientsSide effectsCognitive impairmentNegative symptomsSubstance abuseAltered integrationNeural circuitrySymptomsSchizophreniaMotivational changesComorbidities
1998
Complications of alcohol withdrawal: pathophysiological insights.
Trevisan LA, Boutros N, Petrakis IL, Krystal JH. Complications of alcohol withdrawal: pathophysiological insights. Alcohol Research 1998, 22: 61-6. PMID: 15706735, PMCID: PMC6761825.Peer-Reviewed Original ResearchConceptsAcute alcohol withdrawalAlcohol withdrawalLong-term sobrietyDelirium tremensAcute withdrawalMental confusionSignificant illnessPathophysiological insightsDisease processPsychiatric problemsCognitive impairmentComplicationsHeavy drinkingMemory disordersWithdrawalDeliriumMedicationsRelapseTremensPatientsSeizuresIllnessImpairmentSeverityHallucinations