2023
Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms
Krystal J, Kavalali E, Monteggia L. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology 2023, 49: 41-50. PMID: 37488280, PMCID: PMC10700627, DOI: 10.1038/s41386-023-01629-w.Peer-Reviewed Original ResearchConceptsMood disordersEffective treatmentN-methyl-D-aspartate receptorsGlutamatergic N-methyl-D-aspartate receptorRapid antidepressant effectsTreatment-resistant depressionKey clinical aspectsRapid antidepressant actionsNovel effective treatmentsSynaptic signaling mechanismsMore effective treatmentsSynaptic plasticity mechanismsOpen channel blockerAntidepressant actionAntidepressant effectsKetamine effectsChannel blockersClinical aspectsClinical practiceNew treatmentsNeuropsychiatric disordersCircuit mechanismsDisordersTreatmentKetamine
2022
Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia
Abram SV, Roach BJ, Fryer SL, Calhoun VD, Preda A, van Erp TGM, Bustillo JR, Lim KO, Loewy RL, Stuart BK, Krystal JH, Ford JM, Mathalon DH. Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia. Molecular Psychiatry 2022, 27: 2448-2456. PMID: 35422467, PMCID: PMC9135621, DOI: 10.1038/s41380-022-01502-0.Peer-Reviewed Original ResearchConceptsThalamic dysconnectivityHealthy controlsDysconnectivity patternsIllness courseHealthy volunteersN-methyl-D-aspartate (NMDA) receptor hypofunctionResting-state functional magnetic resonance imaging studyHallucination severityEarly illness schizophreniaExcess glutamate releaseGlutamate release inhibitorNMDAR antagonist ketaminePlacebo-controlled studyMagnetic resonance imaging studySub-anesthetic dosesSchizophrenia-like symptomsResonance imaging studyFunctional magnetic resonance imaging studyKetamine infusionGlutamate releaseNMDAR hypofunctionReceptor hypofunctionKetamine effectsThalamic connectivityRelease inhibitor
2021
The effect of ketamine on psychopathology and implications for understanding schizophrenia and its therapeutic use: a meta-analysis
Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, Driesen N, Ranganathan M, D'Souza D, Taylor M, Krystal J, Howes O. The effect of ketamine on psychopathology and implications for understanding schizophrenia and its therapeutic use: a meta-analysis. BJPsych Open 2021, 7: s237-s237. PMCID: PMC8771247, DOI: 10.1192/bjo.2021.634.Peer-Reviewed Original ResearchBrief Psychiatric Rating ScaleEffects of ketaminePlacebo conditionPositive symptomsKetamine administrationKetamine effectsHealthy participantsHealthy volunteersNegative symptomsTherapeutic useAcute ketamine administrationAcute ketamine challengeMagnitude of symptomsStudy-level dataSub-group analysisPsychiatric Rating ScaleSchizophrenia-like symptomatologySchizophrenia-like symptomsMean change scoresNegative Syndrome ScalePositive psychotic symptomsSignificant increaseEffect sizeBolus dosesKetamine challenge
2019
A 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 measuresSchizophreniaKetamine
2018
The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects
Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GMI, Purohit P, de Graaf RA, Esterlis I, Juchem C, Pittman BP, Krystal JH, Rothman DL, Sanacora G, Mason GF. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology 2018, 43: 2154-2160. PMID: 29977074, PMCID: PMC6098048, DOI: 10.1038/s41386-018-0136-3.Peer-Reviewed Original ResearchConceptsGlutamate-glutamine cyclingGlutamate neurotransmissionAntidepressant effectsKetamine effectsRodent studiesN-methyl-D-aspartate receptor antagonistRapid antidepressant effectsClinician-Administered Dissociative States ScaleEffects of ketamineGlutamine enrichmentKetamine infusionGlutamate releaseKetamine administrationSubanesthetic dosesPsychotomimetic effectsReceptor antagonistNormal salineSchizophrenia pathophysiologyFrontal cortexMRS scansDepressed subjectsKetamineNeurotransmissionPrefrontal cortexPilot studyUtility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial
Javitt DC, Carter CS, Krystal JH, Kantrowitz JT, Girgis RR, Kegeles LS, Ragland JD, Maddock RJ, Lesh TA, Tanase C, Corlett PR, Rothman DL, Mason G, Qiu M, Robinson J, Potter WZ, Carlson M, Wall MM, Choo TH, Grinband J, Lieberman JA. Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial. JAMA Psychiatry 2018, 75: 11-19. PMID: 29167877, PMCID: PMC5833531, DOI: 10.1001/jamapsychiatry.2017.3572.Peer-Reviewed Original ResearchConceptsTarget engagement biomarkerKetamine infusionClinical trialsClinical studiesEarly-stage clinical studiesEarly phase clinical studiesTarget engagementFunctional target engagementRecent pivotal trialsFMRI responsesBlood oxygen level-dependent (BOLD) responseUtility of imagingProton magnetic resonance spectroscopySufficient effect sizeLevel-dependent responsesPlacebo infusionPivotal trialsPreclinical evidenceEngagement biomarkersKetamine effectsMean ageBrain glutamateHealthy volunteersMAIN OUTCOMEPsychiatric history
2017
Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression
Su TP, Chen MH, Li CT, Lin WC, Hong CJ, Gueorguieva R, Tu PC, Bai YM, Cheng CM, Krystal JH. Dose-Related Effects of Adjunctive Ketamine in Taiwanese Patients with Treatment-Resistant Depression. Neuropsychopharmacology 2017, 42: 2482-2492. PMID: 28492279, PMCID: PMC5686503, DOI: 10.1038/npp.2017.94.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntidepressive AgentsAsian PeopleBlood PressureBrain-Derived Neurotrophic FactorDepressive Disorder, MajorDepressive Disorder, Treatment-ResistantDose-Response Relationship, DrugDouble-Blind MethodFemaleHeart RateHumansKetamineMaleMiddle AgedPolymorphism, GeneticPsychiatric Status Rating ScalesTaiwanTreatment OutcomeConceptsTreatment-resistant depressionHamilton Depression Rating ScaleAntidepressant effectsKetamine effectsBDNF genotypeBrain-derived neurotrophic factor (BDNF) genotypeChinese populationDose-related efficacyPlacebo-controlled trialSignificant dose-related effectsDepression Rating ScaleNeurotrophic factor genotypeDose-related effectsSingle ketamine infusionMost patientsKetamine infusionTaiwanese patientsAdjunctive ketamineResponder analysisBDNF geneS-ketamineKetamine levelsPatientsMet alleleRating Scale
2015
Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe
Stone J, Kotoula V, Dietrich C, De Simoni S, Krystal JH, Mehta MA. Perceptual distortions and delusional thinking following ketamine administration are related to increased pharmacological MRI signal changes in the parietal lobe. Journal Of Psychopharmacology 2015, 29: 1025-1028. PMID: 26152321, DOI: 10.1177/0269881115592337.Peer-Reviewed Original ResearchConceptsPerceptual distortionBOLD responsePsychotomimetic States InventoryFunctional MRI acquisitionKetamine-induced effectsPerceptual alterationsDelusional thinkingBrain activityDelusional interpretationDelusional thoughtsCognitive symptomsBOLD increasesParietal cortexHealthy participantsParietal lobeStates InventorySubjective changesParacentral lobuleKetamine administrationSubcortical increasesKetamine effectsHealthy humansSignal changesMRI signal changesKetamine infusion
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
Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions
Corlett PR, Cambridge V, Gardner JM, Piggot JS, Turner DC, Everitt JC, Arana FS, Morgan HL, Milton AL, Lee JL, Aitken MR, Dickinson A, Everitt BJ, Absalom AR, Adapa R, Subramanian N, Taylor JR, Krystal JH, Fletcher PC. Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions. PLOS ONE 2013, 8: e65088. PMID: 23776445, PMCID: PMC3680467, DOI: 10.1371/journal.pone.0065088.Peer-Reviewed Original ResearchConceptsMemory strengthMemory reconsolidationIndividual brain responsesError-dependent learningPsychotogenic effectsSubsequent memoryFear memoryBizarre beliefsBrain responsesDelusional beliefsPrediction errorImpact of ketamineIndividual vulnerabilityBrain signalsSubject studyReconsolidationIndependent samplesLearning procedureMemoryKetamine effectsDelusionsBeliefsPlacebo administrationPsychosisNMDA receptor antagonist
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 antagonistInfusionKetamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology
Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ, Krystal JH, Nutt D, Barker GJ. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Molecular Psychiatry 2012, 17: 664-665. PMID: 22212598, PMCID: PMC3883303, DOI: 10.1038/mp.2011.171.Peer-Reviewed Original Research
2011
Glutamatergic Modulation of Auditory Information Processing in the Human Brain
Gunduz-Bruce H, Reinhart RM, Roach BJ, Gueorguieva R, Oliver S, D'Souza DC, Ford JM, Krystal JH, Mathalon DH. Glutamatergic Modulation of Auditory Information Processing in the Human Brain. Biological Psychiatry 2011, 71: 969-977. PMID: 22036036, PMCID: PMC3290754, DOI: 10.1016/j.biopsych.2011.09.031.Peer-Reviewed Original ResearchConceptsN-acetylcysteineAuditory mismatch negativityReceptor antagonistN-methyl-D-aspartate receptor antagonistAspartate glutamate receptor antagonistOral N-acetylcysteinePlacebo-controlled studyGlutamate receptor antagonistsEffects of ketamineInfusion of salineMismatch negativityTest dayMMN amplitudeCystine-glutamate exchangerAuditory information processingP300 event-related potentialGlutamatergic modulationCognitive enhancing agentsEvent-related potentialsKetamine effectsHealthy volunteersHealthy humansSchizophrenia patientsPositive symptomsKetamine
2007
Psychiatric safety of ketamine in psychopharmacology research
Perry EB, Cramer JA, Cho HS, Petrakis IL, Karper LP, Genovese A, O’Donnell E, Krystal JH, D’Souza D. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology 2007, 192: 253-260. PMID: 17458544, DOI: 10.1007/s00213-007-0706-2.Peer-Reviewed Original ResearchConceptsSubanesthetic dosesHealthy human subjectsKetamine administrationClinical research programHuman subjectsTest sessionsPsychotic spectrum disordersPsychiatric safetyResidual sequelaePlacebo infusionIntravenous infusionKetamine effectsPsychopharmacology studiesResultsFour hundredAdverse reactionsObjectiveTo reportHealthy subjectsStudy participationClinical investigationHealthy humansSide effectsKetamineInfusionDosesAdministration
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
2001
Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists
Krupitsky E, Burakov A, Romanova T, Grinenko N, Grinenko A, Fletcher J, Petrakis I, Krystal J. Attenuation of Ketamine Effects by Nimodipine Pretreatment in Recovering Ethanol Dependent Men: Psychopharmacologic Implications of the Interaction of NMDA and L-Type Calcium Channel Antagonists. Neuropsychopharmacology 2001, 25: 936-947. PMID: 11750186, DOI: 10.1016/s0893-133x(01)00346-3.Peer-Reviewed Original ResearchConceptsVoltage-sensitive calcium channelsL-type voltage-sensitive calcium channelsKetamine effectsStimulant effectsCalcium channelsDouble-blind placebo-controlled studyN-methyl-D-aspartate (NMDA) glutamate receptorsL-type calcium channel antagonistL-type VSCC antagonistBehavioral effectsTransient behavioral effectsPlacebo-controlled studyCalcium channel antagonistsImproved memory functionInteraction of NMDAAspects of schizophreniaNimodipine pretreatmentVSCC antagonistsVerbal fluency impairmentPatient groupKetamine responseChannel antagonistsNMDA antagonistsNMDA receptorsEthanol intoxication
2000
Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine: Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists
Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH. Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine: Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists. JAMA Psychiatry 2000, 57: 270-276. PMID: 10711913, DOI: 10.1001/archpsyc.57.3.270.Peer-Reviewed Original ResearchMeSH KeywordsAdultAffectBrief Psychiatric Rating ScaleCognition DisordersDouble-Blind MethodExcitatory Amino Acid AntagonistsFemaleGlutamatesHumansKetamineLamotrigineMaleMental DisordersPerceptual DisordersPlacebosPsychiatric Status Rating ScalesReceptors, N-Methyl-D-AspartateSchizophreniaSchizophrenic PsychologyTriazinesVerbal LearningConceptsN-methyl-D-aspartate receptor antagonistNMDA receptor dysfunctionReceptor antagonistNeuropsychiatric effectsGlutamate releaseReceptor dysfunctionSymptom subscalesPlacebo 2 hoursClinician-Administered Dissociative States ScaleAdministration of lamotrigineAdministration of ketamineDouble-blind conditionsNMDA receptor antagonistMood-elevating effectsPositive symptom subscaleBrief Psychiatric RatingNovel therapeutic agentsNegative symptom subscaleHopkins Verbal Learning TestVerbal Learning TestKetamine effectsPsychiatric illnessHealthy subjectsPathophysiologic processesPreclinical studiesDissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions
Krystal J, Bennett A, Abi-Saab D, Belger A, Karper L, D’Souza D, Lipschitz D, Abi-Dargham A, Charney D. Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biological Psychiatry 2000, 47: 137-143. PMID: 10664830, PMCID: PMC10060085, DOI: 10.1016/s0006-3223(99)00097-9.Peer-Reviewed Original ResearchConceptsExecutive cognitive functionSecond test dayPerseverative errorsWCST performanceCognitive functionTest daySecond studyExecutive componentTask repetitionAltered perceptionWCSTNMDA antagonist ketamineNegative symptomsFrontal cortexRule acquisitionTest changesFirst studySingle repetitionKetamine effectsRepetitionTotal errorDistractibilityReceptor contributionNMDA receptor contributionRecallAttenuation of ketamine effects in healthy humans by lamotrigine, a drug that reduces glutamate release
Anand A, Berman R, Charney D, Krystal J. Attenuation of ketamine effects in healthy humans by lamotrigine, a drug that reduces glutamate release. Schizophrenia Research 2000, 41: 33. DOI: 10.1016/s0920-9964(00)90372-4.Peer-Reviewed Original Research