2018
Dose-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
2013
Effects of memantine on event-related potential, oscillations, and complexity in individuals with and without family histories of alcoholism.
Narayanan B, Stevens MC, Jiantonio RE, Krystal JH, Pearlson GD. Effects of memantine on event-related potential, oscillations, and complexity in individuals with and without family histories of alcoholism. Journal Of Studies On Alcohol And Drugs 2013, 74: 245-57. PMID: 23384372, PMCID: PMC3568163, DOI: 10.15288/jsad.2013.74.245.Peer-Reviewed Original ResearchConceptsNMDA receptor functionFHN subjectsFamily historyReceptor functionFHP individualsAlpha activityN-methyl-D-aspartate receptor functionNMDA receptor antagonist memantineEffects of memantineAuditory oddball discrimination taskPositive family historyFamily history-negative subjectsEvent-related potentialsAlcoholism family historyCortical information processingOddball discrimination taskFHN individualsMemantine administrationAcute effectsDrug interactionsP3b amplitudeFHP subjectsMemantineSeparate occasionsTheta activity
2012
Glycine 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 functionSymptomsNMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia
Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 16720-16725. PMID: 23012427, PMCID: PMC3478611, DOI: 10.1073/pnas.1208494109.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlgorithmsBrainCognitionDouble-Blind MethodExcitatory Amino Acid AntagonistsFemaleHumansInfusions, IntravenousKetamineMagnetic Resonance ImagingMaleMemoryModels, NeurologicalPattern Recognition, VisualPsychomotor PerformanceReceptors, N-Methyl-D-AspartateSchizophreniaSynaptic TransmissionYoung AdultConceptsNeural systemsLarge-scale brain systemsTask-dependent activationN-methyl-D-aspartate receptorsRealistic computational modelingSevere neuropsychiatric illnessNMDA glutamate receptor antagonistGlutamate receptor antagonistsBrain systemsNMDA receptor functionTask performanceMultiple interacting regionsCognitionCortical disinhibitionGlutamatergic neurotransmissionReceptor antagonistCortical computationGlutamate's roleReciprocal relationshipNeuropsychiatric illnessLocal circuitsReceptor functionSchizophreniaPresent findingsComputational modelingImpaired Visual Cortical Plasticity in Schizophrenia
Çavuş I, Reinhart RM, Roach BJ, Gueorguieva R, Teyler TJ, Clapp WC, Ford JM, Krystal JH, Mathalon DH. Impaired Visual Cortical Plasticity in Schizophrenia. Biological Psychiatry 2012, 71: 512-520. PMID: 22364738, PMCID: PMC3292767, DOI: 10.1016/j.biopsych.2012.01.013.Peer-Reviewed Original ResearchConceptsHigh-frequency stimulationVisual cortical plasticityCortical plasticityVisual steady-state responseN-methyl-D-aspartate receptor functionHealthy control subjectsLong-term potentiation paradigmLong-term potentiationForm of neuroplasticityRepetitive visual stimulationSustained potentiationControl subjectsVEP assessmentSchizophrenia patientsStandard visual stimuliInfrequent target stimuliCore pathophysiologyReceptor functionPotentiationSchizophreniaVisual stimulationComponent scoresStimulationVisual stimuliBaselineMemantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism
Jamadar S, DeVito EE, Jiantonio RE, Meda SA, Stevens MC, Potenza MN, Krystal JH, Pearlson GD. Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism. Psychopharmacology 2012, 222: 129-140. PMID: 22311382, PMCID: PMC3674025, DOI: 10.1007/s00213-011-2628-2.Peer-Reviewed Original ResearchConceptsNMDA receptor antagonistFamily historyFHN subjectsReceptor antagonistFHP subjectsN-methyl-D-aspartate receptor functionReceptor functionIdentical-appearing placeboEffects of memantineFMRI activityNMDA receptor functionCorrect rejectsSingle doseMemantineGo/No-Go taskSeparate daysTemporal regionsCingulate activation
2011
Intravenous Ethanol Infusion Decreases Human Cortical γ-Aminobutyric Acid and N-Acetylaspartate as Measured with Proton Magnetic Resonance Spectroscopy at 4 Tesla
Gomez R, Behar KL, Watzl J, Weinzimer SA, Gulanski B, Sanacora G, Koretski J, Guidone E, Jiang L, Petrakis IL, Pittman B, Krystal JH, Mason GF. Intravenous Ethanol Infusion Decreases Human Cortical γ-Aminobutyric Acid and N-Acetylaspartate as Measured with Proton Magnetic Resonance Spectroscopy at 4 Tesla. Biological Psychiatry 2011, 71: 239-246. PMID: 21855054, PMCID: PMC3227760, DOI: 10.1016/j.biopsych.2011.06.026.Peer-Reviewed Original ResearchConceptsIntravenous ethanol infusionProton magnetic resonance spectroscopyEthanol infusionNAA levelsN-acetylaspartateCortical γ-aminobutyric acidAcute pharmacologic effectsLevels of GABAHealthy social drinkersBreath alcohol levelsN-acetylaspartyl-glutamateCortical GABAEthanol modulatesFirst infusionΓ-aminobutyric acidGABA levelsPharmacologic effectsBrain ethanolOccipital GABAInfusionAlcohol levelsMagnetic resonance spectroscopyReceptor functionBreath ethanolHuman cortex
2010
Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence
Krystal JH, Petrakis IL, Limoncelli D, Nappi SK, Trevisan L, Pittman B, D'Souza DC. Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence. Neuropsychopharmacology 2010, 36: 701-710. PMID: 21124304, PMCID: PMC3055693, DOI: 10.1038/npp.2010.203.Peer-Reviewed Original ResearchConceptsNMDA receptor functionAlcohol-dependent patientsHuman alcohol dependenceAntagonist-like effectsReceptor functionReceptor antagonistDCS effectsD-cycloserineAlcohol-like effectsAlcohol dependenceNMDA glutamate receptor functionN-methyl-D-aspartate (NMDA) glutamate receptor antagonistStandard alcohol drinksGlutamate receptor antagonistsChronic alcohol consumptionDouble-blind conditionsNMDA receptor antagonistAlcohol-dependent menGlutamate receptor functionAlcohol-dependent animalsPlasma levelsGlycine administrationGlycine levelsNMDA receptorsCoagonist site
2008
Ethanol-like effects of thiopental and ketamine in healthy humans
Dickerson D, Pittman B, Ralevski E, Perrino A, Limoncelli D, Edgecombe J, Acampora G, Krystal J, Petrakis I. Ethanol-like effects of thiopental and ketamine in healthy humans. Journal Of Psychopharmacology 2008, 24: 203-211. PMID: 19028835, PMCID: PMC4484757, DOI: 10.1177/0269881108098612.Peer-Reviewed Original ResearchConceptsEthanol-like effectsEthanol-related effectsNMDA receptor antagonistBlock NMDA receptorsNMDA receptor antagonismSeparate test daysGamma-aminobutyric acidReceptor antagonismSubanesthetic dosesReceptor antagonistNMDA receptorsFamily historyEthanol intoxicationHealthy humansPharmacological agentsEthanol effectsKetamineReceptor activityReceptor functionLarger studyBehavioral effectsThiopentalIntoxicationSubjective intoxicationTest dayA Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy
Norberg MM, Krystal JH, Tolin DF. A Meta-Analysis of D-Cycloserine and the Facilitation of Fear Extinction and Exposure Therapy. Biological Psychiatry 2008, 63: 1118-1126. PMID: 18313643, DOI: 10.1016/j.biopsych.2008.01.012.Peer-Reviewed Original ResearchConceptsExposure therapyFear extinctionD-cycloserineNMDA receptor functionPartial N-methyl-d-aspartate (NMDA) receptor agonistEffects of DCSExposure-based therapyExposure-based treatmentsFear memory consolidationReceptor functionN-methyl-D-aspartate receptor agonistMemory consolidationDCS doseTranslational researchExposure procedureTherapy literatureEnglish-language journal articlesReceptor agonistQuantitative reviewTrial designMeta-AnalysisTherapyStudy authorsTypes of subjectsEffective agent
2007
Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors
Trevisan L, Petrakis IL, Pittman B, Gueorguieva R, D’Souza D, Perry E, Limoncelli D, Krystal JH. Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors. Alcohol Clinical And Experimental Research 2007, 32: 36-42. PMID: 18028532, DOI: 10.1111/j.1530-0277.2007.00543.x.Peer-Reviewed Original ResearchConceptsCo-agonist siteHealthy human subjectsEthanol administrationD-cycloserineHigh-dose d-cycloserineAlcohol levelsReceptor functionPlacebo 4 hoursDouble-blind conditionsNMDA receptor functionNMDA glutamate receptorsMild sedative effectDoses of ethanolGlutamate receptor functionBreath alcohol levelsHuman subjectsVerbal fluencyGlycineB siteGroups of subjectsEthanol antagonismCombination of ethanolSedative effectsNMDA receptorsClinical significanceGlutamate receptorsEffect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients
Krupitsky EM, Neznanova O, Masalov D, Burakov AM, Didenko T, Romanova T, Tsoy M, Bespalov A, Slavina TY, Grinenko AA, Petrakis IL, Pittman B, Gueorguieva R, Zvartau EE, Krystal JH. Effect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients. American Journal Of Psychiatry 2007, 164: 519-523. PMID: 17329479, DOI: 10.1176/ajp.2007.164.3.519.Peer-Reviewed Original ResearchConceptsNMDA receptor antagonist memantineAlcohol cue-induced cravingEffects of memantineAspartic acid (NMDA) glutamate receptorsDose-related fashionDouble-blind conditionsNMDA receptor functionNMDA receptor antagonistAlcohol-dependent patientsAlcohol cuesCue-induced alcoholTreatment of alcoholismCue-induced cravingEthanol-like effectsReceptor antagonistAlcohol-dependent inpatientsGlutamate receptorsMemantineAlcohol cravingMotivational disturbancesRandomized orderReceptor functionBehavioral effectsSubjective effectsTest day
2006
Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects
Neumeister A, Carson R, Henry S, Planeta-Wilson B, Binneman B, Maguire RP, Luckenbaugh DA, D'Souza C, Krystal JH, Frost JJ. Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects. Journal Of Clinical Psychopharmacology 2006, 26: 595-599. PMID: 17110816, DOI: 10.1097/01.jcp.0000245558.14284.aa.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntipsychotic AgentsBehaviorBrainBrain MappingCluster AnalysisCross-Over StudiesDouble-Blind MethodFemaleFluorodeoxyglucose F18GlycineHumansInfusions, IntravenousMagnetic Resonance ImagingMaleNeuropsychological TestsPositron-Emission TomographyRadiopharmaceuticalsReference ValuesSerineConceptsN-methyl-D-aspartate receptor functionReceptor functionRegional cerebral metabolic rateAdministration of glycineCerebral metabolic effectsMagnetic resonance imaging studyPositron emission tomography studyHealthy control subjectsNMDA receptor functionCerebral metabolic rateEmission tomography studiesTest dayHealthy human subjectsResonance imaging studySignificant reductionPositron emission tomographyDorsolateral prefrontal cortexIntravenous glycinePlacebo infusionCerebral metabolismPatient populationControl subjectsGlycine administrationGlycine infusionIntravenous administrationThe vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia
Krystal JH, D’Souza D, Gallinat J, Driesen N, Abi-Dargham A, Petrakis I, Heinz A, Pearlson G. The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia. Neurotoxicity Research 2006, 10: 235-252. PMID: 17197373, DOI: 10.1007/bf03033360.Peer-Reviewed Original ResearchConceptsSubstance abuse riskSubstance abuseSubstance abuse disordersAbuse riskSubstances of abuseNicotinic cholinergicPatient groupDopaminergic inputAbused substancesAbuse disordersSchizophrenic patientsDysphoric effectsAbuse liabilityHigh dosesLow dosesNegative symptomsReceptor functionAltered responseSchizophreniaSchizophrenic individualsRiskReward processingSubjective distressImpulsive behaviorDoses
2005
Cortical γ-Aminobutyric Acid Type A–Benzodiazepine Receptors in Recovery From Alcohol Dependence: Relationship to Features of Alcohol Dependence and Cigarette Smoking
Staley JK, Gottschalk C, Petrakis IL, Gueorguieva R, O’Malley S, Baldwin R, Jatlow P, Verhoeff NP, Perry E, Weinzimmer D, Frohlich E, Ruff E, van Dyck CH, Seibyl JP, Innis RB, Krystal JH. Cortical γ-Aminobutyric Acid Type A–Benzodiazepine Receptors in Recovery From Alcohol Dependence: Relationship to Features of Alcohol Dependence and Cigarette Smoking. JAMA Psychiatry 2005, 62: 877-888. PMID: 16061765, DOI: 10.1001/archpsyc.62.8.877.Peer-Reviewed Original ResearchConceptsWeeks of abstinenceIomazenil single-photon emissionSingle photon emissionDays of sobrietyAlcohol dependenceIomazenil uptakeTomographic scanBenzodiazepine receptorsVoxel-based statistical parametric mappingReceptor adaptationDistribution volumeReceptor functionGamma-aminobutyric acid type ABenzodiazepine receptor levelsIodine I 123Reduced receptor functionHuman alcohol dependenceLast alcoholic drinkHealthy comparison groupStatistical parametric mappingAlcohol withdrawalClinical featuresSmoking statusCigarette smokingAcute withdrawalImpact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo
Bressan RA, Erlandsson K, Stone JM, Mulligan RS, Krystal JH, Ell PJ, Pilowsky LS. Impact of Schizophrenia and Chronic Antipsychotic Treatment on [123I]CNS-1261 Binding to N-Methyl-D-Aspartate Receptors In Vivo. Biological Psychiatry 2005, 58: 41-46. PMID: 15992521, DOI: 10.1016/j.biopsych.2005.03.016.Peer-Reviewed Original ResearchConceptsHealthy control subjectsTypical antipsychoticsControl subjectsN-methyl-D-aspartate receptor functionN-methyl-D-aspartate receptorsAntipsychotic drug discoveryChronic antipsychotic treatmentDrug-free patientsImpact of schizophreniaNMDA receptor activityHealthy normal volunteersClozapine treatmentAntipsychotic treatmentGlutamatergic systemPatient groupAntipsychotic drugsNonsignificant reductionNMDA receptorsNormal volunteersSchizophrenia patientsControl groupReceptor activityBrain regionsReceptor functionTomography radiotracer
2004
Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects
Krystal JH, Abi-Saab W, Perry E, D’Souza D, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 2004, 179: 303-309. PMID: 15309376, DOI: 10.1007/s00213-004-1982-8.Peer-Reviewed Original ResearchConceptsGroup II metabotropic glutamate receptor agonistMetabotropic glutamate receptor agonistHealthy human subjectsNMDA glutamate receptor antagonistGlutamate receptor agonistsGlutamate receptor antagonistsTest dayCognitive effectsPerceptual changesKetamine infusionReceptor antagonistReceptor agonistDysphoric moodMemory impairmentBehavioral consequencesSignificant dose-related improvementGroup II mGluR agonistReceptor functionHuman subjectsMemoryNegative symptomsDose-related improvementNMDA receptor functionPreliminary evidenceDisruptive effectsThe Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis
D'Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH. The Psychotomimetic Effects of Intravenous Delta-9-Tetrahydrocannabinol in Healthy Individuals: Implications for Psychosis. Neuropsychopharmacology 2004, 29: 1558-1572. PMID: 15173844, DOI: 10.1038/sj.npp.1300496.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnxietyArousalAttentionBehaviorCognitionDose-Response Relationship, DrugDouble-Blind MethodDronabinolFemaleHallucinogensHemodynamicsHumansHydrocortisoneInjections, IntravenousMaleMemory, Short-TermMental RecallPanicProlactinPsychiatric Status Rating ScalesPsychometricsPsychoses, Substance-InducedSpeechVerbal LearningConceptsCannabinoid receptor functionWord recallRecognition recallVerbal fluencyCognitive deficitsProspective safety dataNegative symptomsAbuse disordersHealthy individualsCounterbalanced studyMonths poststudyRecallPsychotomimetic effectsPsychotic disordersReceptor functionPsychosisEndogenous psychosesIndividualsDistractibilityFluencyTransient symptomsDisordersEndocrine effectsSafety dataAnxiety
2003
Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients
Krystal JH, Petrakis IL, Limoncelli D, Webb E, Gueorgueva R, D'Souza DC, Boutros NN, Trevisan L, Charney DS. Altered NMDA Glutamate Receptor Antagonist Response in Recovering Ethanol-Dependent Patients. Neuropsychopharmacology 2003, 28: 2020-2028. PMID: 12888778, DOI: 10.1038/sj.npp.1300252.Peer-Reviewed Original ResearchConceptsEthanol-dependent patientsNMDA receptor antagonistReceptor antagonistEthanol dependenceN-methyl-D-aspartate (NMDA) glutamate receptorsDouble-blind studySelective NMDA receptor antagonistNMDA receptor functionAlcohol-dependent patientsHealthy comparison subjectsTreatment of alcoholismHealthy comparison groupExecutive cognitive functionKetamine infusionKetamine 0.5NMDA receptorsGlutamate receptorsComparison subjectsPatientsAmnestic effectsRandomized orderReceptor functionCognitive functionAntagonist responseAntagonist
2002
Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments
Krystal JH, Sanacora G, Blumberg H, Anand A, Charney DS, Marek G, Epperson CN, Goddard A, Mason GF. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Molecular Psychiatry 2002, 7: s71-s80. PMID: 11986998, DOI: 10.1038/sj.mp.4001021.Peer-Reviewed Original ResearchConceptsCortical GABA levelsMood-stabilizing treatmentMood disordersGABA levelsΓ-amino-butyric acid (GABA) systemMood-stabilizing agentsGlutamate receptor functionDevelopment of medicationsGABA deficitAvailable antidepressantsGABAergic modulationAntimanic effectsGlutamatergic activityClinical evidenceNovel antidepressantsGABA systemAntidepressant drugsNew agentsReceptor functionAvailable evidenceReceptor targetsAntidepressantsDisordersGlutamateTreatment