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
2020
Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia
Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, Driesen N, Ranganathan M, D’Souza D, Taylor M, Krystal JH, Howes OD. Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia. JAMA Network Open 2020, 3: e204693. PMID: 32437573, PMCID: PMC7243091, DOI: 10.1001/jamanetworkopen.2020.4693.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScalePlacebo conditionPositive symptomsNegative symptomsHealthy participantsMean differenceKetamine administrationPANSS scoresHealthy volunteersPsychotomimetic symptomsTherapeutic useAcute ketamine administrationAcute ketamine challengePlacebo-controlled studyEffect sizeMagnitude of symptomsStudy-level dataPsychiatric Rating ScaleMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsAssociation of ketamineNegative Syndrome ScaleSignificant increaseAcute administrationBolus doses
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 oscillations
2013
Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans
Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular Psychiatry 2013, 18: 1199-1204. PMID: 23337947, PMCID: PMC3646075, DOI: 10.1038/mp.2012.194.Peer-Reviewed Original ResearchConceptsFunctional connectivityNegative symptomsGamma-aminobutyric acid (GABA) neuronsNMDA receptor antagonist ketamineAspartate glutamate receptor antagonistContinuous ketamine infusionGlutamate receptor antagonistsNMDA-R antagonistsCortical functional connectivityNMDA-R antagonist ketamineSchizophrenia-like symptomsHealthy human subjectsNegative Syndrome ScaleBrain functional connectivityPrimary samplesRegion-specific mannerFunctional magnetic resonanceKetamine infusionReceptor antagonistPathological increaseSyndrome ScaleSymptomsPreclinical researchKetamineBrain oscillations
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 functionSymptoms
2006
Enhanced Sensitivity to the Euphoric Effects of Alcohol in Schizophrenia
D'Souza DC, Gil RB, Madonick S, Perry EB, Forselius-Bielen K, Braley G, Donahue L, Tellioglu T, Zimolo Z, Gueorguieva R, Krystal JH. Enhanced Sensitivity to the Euphoric Effects of Alcohol in Schizophrenia. Neuropsychopharmacology 2006, 31: 2767-2775. PMID: 16985503, DOI: 10.1038/sj.npp.1301207.Peer-Reviewed Original ResearchConceptsEffects of alcoholHealthy subjectsBlood alcohol levelsPositive psychotic symptomsSmall transient increaseSelf-medication hypothesisPerceptual alterationsAlcohol administrationMotor functionAlcohol dosesElevated riskPsychotic symptomsLifetime exposureSchizophrenia patientsSchizophrenia symptomsEuphoric effectsNegative symptomsAlcohol levelsAlcohol useStimulatory effectSubjective effectsTransient increaseSchizophreniaStimulatory responseAlcohol responsesThe 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 behaviorDosesGreater vulnerability to the amnestic effects of ketamine in males
Morgan CJ, Perry EB, Cho HS, Krystal JH, D’Souza D. Greater vulnerability to the amnestic effects of ketamine in males. Psychopharmacology 2006, 187: 405-414. PMID: 16896964, DOI: 10.1007/s00213-006-0409-0.Peer-Reviewed Original ResearchConceptsAmnestic effectsProcessing of wordsGeneral cognitive functioningGreater performance decrementsGreater subjective senseGender differencesObjectivesThe current studyGreater vulnerabilityCognitive measuresCognitive differencesCognitive functioningPerceptual alterationsPerformance decrementsNMDA-R functionAttention dataMemory impairmentSubjective senseNegative symptomsCurrent studyFunctioningHVLTKetamine studiesAnxietyMemoryKetamine administration
2005
Comparative 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 ResearchAbsence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine
Cho HS, D’Souza D, Gueorguieva R, Perry EB, Madonick S, Karper LP, Abi-Dargham A, Belger A, Abi-Saab W, Lipschitz D, Bennet A, Seibyl JP, Krystal JH. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology 2005, 179: 136-143. PMID: 15682309, DOI: 10.1007/s00213-004-2066-5.Peer-Reviewed Original ResearchConceptsHealthy human subjectsBehavioral sensitizationReceptor antagonistN-methyl-D-aspartate (NMDA) glutamate receptor antagonistBehavioral effectsHuman subjectsGlutamate receptor antagonistsNMDA receptor antagonistConclusionsThe current dataEvidence of sensitizationRetrospective studyKetamine administrationOutcome measuresNegative symptomsObjectivesThe purposePrevious exposureFirst exposureKetamineSensitizationAntagonistExposurePerceptual alterationsCurrent dataSeparate studiesSubjects
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
2002
Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms
Abi-Saab W, Seibyl JP, D'Souza C, Karper LP, Gueorgueva R, Abi-Dargham A, Wong ML, Rajhans S, Erdos JP, Heninger GR, Charney DS, Krystal JH. Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms. Psychopharmacology 2002, 162: 55-62. PMID: 12107618, DOI: 10.1007/s00213-002-1057-7.Peer-Reviewed Original ResearchConceptsReceptor antagonismSchizophrenic patientsNeuroleptic-free schizophrenic patientsBrief Psychiatric Rating ScaleDouble-blind conditionsPsychiatric Rating ScaleTest dayRitanserin pretreatmentIntravenous infusionReceptor modulationAntipsychotic activityMale inpatientsReceptor stimulationPlasma prolactinCortisol levelsSchizoaffective disorderSchizophrenia symptomsPositive symptomsNegative symptomsRandomized orderPatientsRating ScaleBehavioral activationSymptomsRitanserin
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
2000
Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT
Laruelle M, Abi-Dargham A, van Dyck C, Gil R, D’Souza D, Krystal J, Seibyl J, Baldwin R, Innis R. Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [123I]β-CIT. Biological Psychiatry 2000, 47: 371-379. PMID: 10704949, DOI: 10.1016/s0006-3223(99)00257-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAge FactorsBrain StemCarrier ProteinsCase-Control StudiesCocaineDopamineDopamine Plasma Membrane Transport ProteinsFemaleHumansIodine RadioisotopesMaleMembrane GlycoproteinsMembrane Transport ProteinsMiddle AgedNeostriatumNerve Tissue ProteinsSchizophreniaSerotoninSerotonin Plasma Membrane Transport ProteinsTomography, Emission-Computed, Single-PhotonConceptsAmphetamine-induced dopamine releaseStriatal dopamine transporterDopamine transporterControl subjectsDAT densityDopamine releaseNegative symptomsStriatal DAT densityDuration of illnessDopamine nerve terminalsHealthy control subjectsSerotonin transporter densityCohort of subjectsRelative deficitSingle photon emissionNeurodegenerative processesPostmortem studiesNerve terminalsSerotonin functionTrend-level associationReceptor radiotracerPatientsDopamine functionLower striatalTransporter densityDissociation 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 contributionRecall
1998
Naltrexone Augmentation of Neuroleptics in Schizophrenia
Sernyak M, Glazer W, Heninger G, Charney D, Woods S, Petrakis I, Krystal J, Price L. Naltrexone Augmentation of Neuroleptics in Schizophrenia. Journal Of Clinical Psychopharmacology 1998, 18: 248-251.. PMID: 9617985, DOI: 10.1097/00004714-199806000-00011.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScaleTotal BPRS scoreBPRS scoresNegative symptomsAddition of naltrexoneBPRS subscale scoresOngoing neuroleptic treatmentSingle-blind basisPlacebo-controlled trialSingle-blind fashionSubscale scoresBPRS total scorePsychiatric Rating ScaleDSM-III criteriaSubsequent treatmentRepeated-measures analysisNaltrexone augmentationNeuroleptic medicinesNeuroleptic regimenTransient exacerbationPlacebo armNeuroleptic treatmentClinical benefitRepeated-measures ANOVANaltrexoneInteractive effects of subanesthetic ketamine and subhypnotic lorazepam in humans
Krystal J, Karper L, Bennett A, D’Souza D, Abi-Dargham A, Morrissey K, Abi-Saab D, Bremner J, Bowers Jr. M, Suckow R, Stetson P, Heninger G, Charney D. Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans. Psychopharmacology 1998, 135: 213-229. PMID: 9498724, DOI: 10.1007/s002130050503.Peer-Reviewed Original ResearchConceptsWisconsin Card Sorting TestClinician-Administered Dissociative States ScalePerceptual alterationsAmnestic effectsInteractive effectsCard Sorting TestBrief Psychiatric Rating ScaleAttention impairmentSorting TestPerceptual effectsProverb interpretationEmotional distressDissociative effectsCortical impairmentNegative symptomsState scaleBehavioral effectsTest dayPsychiatric Rating ScaleLorazepam 2ImpairmentRating ScaleSubanesthetic ketamineHealthy humansPlacebo 2
1997
The role of serotonin in the pathophysiology and treatment of schizophrenia
Abi-Dargham A, Laruelle M, Aghajanian GK, Charney D, Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. Journal Of Neuropsychiatry 1997, 9: 1-17. PMID: 9017523, DOI: 10.1176/jnp.9.1.1.Peer-Reviewed Original ResearchConceptsRole of serotoninBeneficial effectsSubcortical dopamine activityCerebrospinal fluid studiesCortex of patientsTreatment of schizophreniaBrain tissue analysisSerotonergic hypofunctionDopaminergic antagonistsPharmacological challengeDopamine activityNegative symptomsFluid studiesSchizophreniaPathophysiologySerotoninIllnessTissue analysisTreatmentMore researchAntagonismCompelling evidenceHypofunctionPatientsAntagonist
1994
Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS. Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans: Psychotomimetic, Perceptual, Cognitive, and Neuroendocrine Responses. JAMA Psychiatry 1994, 51: 199-214. PMID: 8122957, DOI: 10.1001/archpsyc.1994.03950030035004.Peer-Reviewed Original ResearchMeSH KeywordsAdultBlood PressureCognitionDissociative DisordersDose-Response Relationship, DrugDouble-Blind MethodFemaleFrontal LobeHomovanillic AcidHumansHydrocortisoneKetamineMaleMethoxyhydroxyphenylglycolNeuropsychological TestsPerceptionProlactinPsychiatric Status Rating ScalesPsychoses, Substance-InducedPulseReceptors, N-Methyl-D-AspartateSchizophreniaSchizophrenic PsychologyConceptsWisconsin Card Sorting TestCard Sorting TestMini-Mental State ExaminationSorting TestNegative symptomsTests of vigilanceVerbal fluency taskDissociative statesState ExaminationFrontal cortical dysfunctionPsychosis Proneness ScalesClinician-Administered Dissociative States ScaleWord recallImmediate recallVerbal fluencyFluency taskVigilance taskCognitive deficitsCognitive functionRecallState scaleBrief Psychiatric Rating ScaleCortical dysfunctionTest dayPsychiatric Rating Scale