2021
Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial
Patel KT, Stevens MC, Dunlap A, Gallagher A, O’Malley S, DeMartini K, Potenza MN, Krystal JH, Pearlson GD. Effects of the Fyn kinase inhibitor saracatinib on ventral striatal activity during performance of an fMRI monetary incentive delay task in individuals family history positive or negative for alcohol use disorder. A pilot randomised trial. Neuropsychopharmacology 2021, 47: 840-846. PMID: 34475522, PMCID: PMC8882177, DOI: 10.1038/s41386-021-01157-5.Peer-Reviewed Original ResearchConceptsProtein tyrosine kinasesSrc regulationSrc familyProtein kinaseTyrosine kinaseFyn kinaseSrc inhibitorSrc/FynDependent pathwayKinaseNMDAR upregulationNMDAR functionNMDA receptorsRegulationSaracatinibGluN2B subunitGlutamate receptorsFynInhibitorsReceptorsSubunitsN-methyl-D-aspartate (NMDA) glutamate receptorsPrevious evidence
2019
Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo–control study
Chen MH, Cheng CM, Gueorguieva R, Lin WC, Li CT, Hong CJ, Tu PC, Bai YM, Tsai SJ, Krystal JH, Su TP. Maintenance of antidepressant and antisuicidal effects by D-cycloserine among patients with treatment-resistant depression who responded to low-dose ketamine infusion: a double-blind randomized placebo–control study. Neuropsychopharmacology 2019, 44: 2112-2118. PMID: 31421635, PMCID: PMC6898334, DOI: 10.1038/s41386-019-0480-y.Peer-Reviewed Original ResearchConceptsTreatment-resistant depressionAntisuicidal effectsPlacebo groupKetamine infusionDCS groupD-cycloserineDouble-blind randomized placebo-controlled studyN-methyl-D-aspartate (NMDA) glutamate receptorsHamilton Depression Rating Scale scoresLow-dose ketamine infusionRandomized placebo-controlled studyDepression Rating Scale scoresHAMD item 3Single subanesthetic doseInitial clinical responsePlacebo-controlled studyRating Scale scoresClinical responseDose titrationSubanesthetic doseAugmentation treatmentGlutamate receptorsMixed model analysisSuicidal riskScale score
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 therapeuticsSchizophreniaDisordersPresentationPatientsPathophysiologyDysfunctionKetamineAntagonistSymptomsAbnormalities
2014
N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia
Anticevic A, Corlett PR, Cole MW, Savic A, Gancsos M, Tang Y, Repovs G, Murray JD, Driesen NR, Morgan PT, Xu K, Wang F, Krystal JH. N-Methyl-D-Aspartate Receptor Antagonist Effects on Prefrontal Cortical Connectivity Better Model Early Than Chronic Schizophrenia. Biological Psychiatry 2014, 77: 569-580. PMID: 25281999, DOI: 10.1016/j.biopsych.2014.07.022.Peer-Reviewed Original ResearchConceptsHealthy volunteersFunctional connectivityKetamine effectsChronic schizophreniaIllness progressionChronic illnessHigh riskRecent pharmacologic studiesReceptor antagonist effectsAspartate glutamate receptorsStages of schizophreniaCourse of schizophreniaGlutamate dysfunctionPharmacologic modelsPrefrontal cortex functionIllness stageNMDAR antagonistsFunctional dysconnectivityGlutamate receptorsPharmacologic studiesHealthy subjectsSchizophrenia onsetFunctional alterationsDevelopment of therapeuticsAntagonist effects
2013
Glutamatergic targets for new alcohol medications
Holmes A, Spanagel R, Krystal JH. Glutamatergic targets for new alcohol medications. Psychopharmacology 2013, 229: 539-554. PMID: 23995381, PMCID: PMC3811052, DOI: 10.1007/s00213-013-3226-2.Peer-Reviewed Original ResearchConceptsGlutamate systemGlycineB siteAlcohol-related behaviorsNMDA receptorsAlcohol abuseAlcohol consumptionN-methyl-D-aspartate receptorsChronic alcohol exposureElevated extracellular glutamatePathophysiology of alcoholismAMPA receptor subunitsAlcohol use disorderNovel pharmacotherapeutic approachesEffects of alcoholAlcohol medicationsBlocking NMDAHyperglutamatergic stateMetabotropic receptorsPharmacotherapeutic approachesAlcohol exposureExcess glutamateExtracellular glutamateGlutamate receptorsPreclinical studiesKainate receptorsDeep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence
Xie P, Kranzler HR, Krystal JH, Farrer LA, Zhao H, Gelernter J. Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addiction Biology 2013, 19: 955-964. PMID: 23855403, PMCID: PMC3815683, DOI: 10.1111/adb.12072.Peer-Reviewed Original ResearchConceptsOpioid dependenceSubstance dependenceRare variantsN-methyl-D-aspartate (NMDA) glutamate receptorsCo-occurring alcohol dependenceHealthy control subjectsControl subjectsNMDA systemOpioid abuseGlutamate receptorsSchizophrenia risk genesSD riskAlcohol dependenceSignificant associationCocaine dependenceAdditional subjectsOD riskRisk genesDISC1African AmericansFirst demonstrationCommon variantsRiskSubjectsMinor allele frequency
2012
Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder
Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C. Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder. Biological Psychiatry 2012, 72: 964-970. PMID: 22784486, PMCID: PMC3667652, DOI: 10.1016/j.biopsych.2012.05.028.Peer-Reviewed Original ResearchConceptsObsessive-compulsive disorderKetamine infusionDepression symptomsLow-dose ketamine infusionTreatment-refractory obsessive-compulsive disorderOCD symptomsPathogenesis of OCDIncomplete symptom reliefTreatment-Refractory ObsessiveOpen-label trialRapid antidepressant effectsAspartate glutamate receptorsEffects of ketaminePotent noncompetitive antagonistGlutamate abnormalitiesAntidepressant effectsAntidepressant responseSymptom reliefKetamine effectsComorbid depressionAcute effectsGlutamate receptorsDepressive symptomsNoncompetitive antagonistInfusion
2010
Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists
Krystal JH, Mathew SJ, D’Souza D, Garakani A, Gunduz-Bruce H, Charney DS. Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists. CNS Drugs 2010, 24: 669-693. PMID: 20658799, DOI: 10.2165/11533230-000000000-00000.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPreliminary clinical trialsPositive allosteric modulatorsPsychiatric disordersClinical trialsAnimal modelsAllosteric modulatorsGroup II mGluR agonistGroup IMetabotropic glutamate receptor agonistAnxiety disordersPotential psychiatric applicationsGlutamate receptor agonistsMetabotropic glutamate receptorsTreatment of schizophreniaRole of glutamateForm of depressionMGluR agonistAntidepressant propertiesMGluR5 agonistReceptor agonistGlutamate receptorsMood disordersArea of schizophreniaPromising agentAgonists
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 receptorsThe NMDA receptor as a therapeutic target in major depressive disorder.
Pittenger C, Sanacora G, Krystal JH. The NMDA receptor as a therapeutic target in major depressive disorder. CNS & Neurological Disorders - Drug Targets 2007, 6: 101-15. PMID: 17430148, DOI: 10.2174/187152707780363267.Peer-Reviewed Original ResearchConceptsMajor depressive disorderNMDA receptorsDepressive disorderNovel antidepressant medicationsCognitive side effectsPotential of drugsAntidepressant medicationAntidepressant propertiesSuch medicationsGlutamatergic neurotransmissionGlutamate receptorsPreclinical studiesPsychotomimetic propertiesSide effectsTherapeutic targetAnimal modelsUseful agentNeurotransmissionReceptorsLines of evidenceMedicationsDisordersDrugsCurrent knowledgeDepressionEffect 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 dayAntiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam
Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, Gueorguieva R, Petrakis IL, Zvartau EE, Krystal JH. Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam. Alcohol Clinical And Experimental Research 2007, 31: 604-611. PMID: 17374039, DOI: 10.1111/j.1530-0277.2007.00344.x.Peer-Reviewed Original ResearchConceptsAlcohol withdrawal symptomsWithdrawal symptomsActive medicationAlcohol withdrawalGlutamatergic activationEthanol detoxificationAspartate glutamate receptor antagonistGlutamate release inhibitorGlutamate receptor antagonistsMale alcohol-dependent inpatientsAdditional diazepamDiazepam administrationClinical evidenceStandard pharmacotherapyReceptor antagonistAlcohol-dependent inpatientsRelease inhibitorEthanol dependenceAlcohol abstinenceGlutamate receptorsReceptor inhibitorsWithdrawal severityPlaceboMedicationsNew treatments
2006
Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism
Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC. Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism. Neuropsychopharmacology 2006, 31: 1793-1800. PMID: 16395307, DOI: 10.1038/sj.npp.1300994.Peer-Reviewed Original ResearchConceptsNMDA glutamate receptorsNMDA receptor antagonismKetamine doseReceptor antagonismGlutamate receptorsKetamine effectsProtective effectPlacebo-controlled human laboratory studyOpiate receptor antagonismEfficacy of naltrexoneDose-related fashionNMDA receptor antagonist effectsReceptor antagonist effectsTotal PANSS scoreHuman laboratory studiesPharmacotherapy of alcoholismTreatment of alcoholismHealthy human subjectsHigher ketamine doseNegative Syndrome ScaleLower ketamine doseSignificant behavioral effectsSubanesthetic dosePANSS scoresEthanol drink
2003
N-methyl-d-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability
Krystal JH, Petrakis IL, Mason G, Trevisan L, D'Souza DC. N-methyl-d-aspartate glutamate receptors and alcoholism: reward, dependence, treatment, and vulnerability. Pharmacology & Therapeutics 2003, 99: 79-94. PMID: 12804700, DOI: 10.1016/s0163-7258(03)00054-8.Peer-Reviewed Original ResearchConceptsGlutamatergic systemEthanol abuseGlutamate receptorsN-methyl-D-aspartate (NMDA) subtypePrimary excitatory neurotransmitterAspartate glutamate receptorsAction of ethanolEthanol withdrawalGlutamatergic agentsGlutamatergic functionExcitatory neurotransmitterTranslational neuroscience perspectiveGlutamate systemEthanol intoxicationBehavioral effectsEthanol contributeAlcoholismBrainReceptorsTreatmentAbuseN-methylSubtypesNeurotransmittersIntoxicationAltered 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
2000
IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans
D’Souza D, Gil R, Cassello K, Morrissey K, Abi-Saab D, White J, Sturwold R, Bennett A, Karper L, Zuzarte E, Charney D, Krystal J. IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans. Biological Psychiatry 2000, 47: 450-462. PMID: 10704956, DOI: 10.1016/s0006-3223(99)00133-x.Peer-Reviewed Original ResearchMeSH KeywordsAcoustic StimulationAdministration, OralAdultAmino AcidsAntimetabolitesBiological AvailabilityCycloserineDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycineHumansInjections, IntravenousMaleMiddle AgedNeuropsychological TestsPsychiatric Status Rating ScalesReceptors, GlycineReceptors, N-Methyl-D-AspartateReflex, StartleSerineConceptsAcoustic startle responseN-methyl-D-aspartate (NMDA) glutamate receptorsD-cycloserineStartle responseCentral nervous system effectsTest dayCSF glycine levelsOral D-cycloserineCSF amino acidsNervous system effectsDouble-blind conditionsCognitive test performanceD-cycloserine effectsHealthy human subjectsCentral bioavailabilityIntravenous glycineLumbar punctureSecond test dayGlycine administrationModulates neurotransmissionGlycine levelsGlutamate receptorsCoagonist siteCerebrospinal fluidHealthy humans
1999
Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation.
Chambers RA, Bremner JD, Moghaddam B, Southwick SM, Charney DS, Krystal JH. Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation. Seminars In Clinical Neuropsychiatry 1999, 4: 274-81. PMID: 10553033, DOI: 10.153/scnp00400274.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderGlutamate releaseNMDA antagonistsStress disorderN-methyl-D-aspartate (NMDA) subtypeDevelopment of PTSDDissociative symptomsStress exposureRecent preclinical dataTraumatic stress exposureHyperglutamatergic stateNeuroprotective potentialPreclinical dataNeural toxicityClinical studiesGlutamate receptorsTraumatized individualsPerceptual effectsPerceptual alterationsNeural plasticityAntagonistBrain functionSymptomsInfluence behaviorDrugsNMDA Agonists and Antagonists as Probes of Glutamatergic Dysfunction and Pharmacotherapies in Neuropsychiatric Disorders
Krystal J, D'Souza C, Petrakis I, Belger A, Berman R, Charney D, AbiSaab W, Madonick S. NMDA Agonists and Antagonists as Probes of Glutamatergic Dysfunction and Pharmacotherapies in Neuropsychiatric Disorders. Harvard Review Of Psychiatry 1999, 7: 125-143. PMID: 10483932, DOI: 10.3109/hrp.7.3.125.Peer-Reviewed Original ResearchConceptsN-methyl-D-aspartate (NMDA) subclassChronic pain syndromePain syndromeGlutamatergic dysfunctionNMDA agonistClinical studiesMajor depressionNMDA antagonistsGlutamate receptorsCoagonist siteParkinson's diseaseHuman psychopharmacological studiesPartial agonistAlzheimer's diseaseNeuropsychiatric conditionsNeuropsychiatric disordersDiseasePsychopharmacological studiesAnxiety disordersHuntington's diseaseAgonistsAntagonistTherapeutic hypothesesDisordersAddiction disorders