2018
Utility 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
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
2003
Clinical Studies Implementing Glutamate Neurotransmission in Mood Disorders
SANACORA G, ROTHMAN DL, MASON G, KRYSTAL JH. Clinical Studies Implementing Glutamate Neurotransmission in Mood Disorders. Annals Of The New York Academy Of Sciences 2003, 1003: 292-308. PMID: 14684453, DOI: 10.1196/annals.1300.018.Peer-Reviewed Original ResearchNMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 2003, 169: 215-233. PMID: 12955285, DOI: 10.1007/s00213-003-1582-z.Peer-Reviewed Original ResearchConceptsTreatment of schizophreniaReceptor antagonistN-methyl-D-aspartate (NMDA) glutamate receptor antagonistPharmacotherapy of schizophreniaGlutamate receptor antagonistsReceptor antagonist effectsNMDA receptor antagonistNMDA receptor antagonist effectsNMDA receptor contributionTranslational Neuroscience ApproachGlutamatergic activityGlutamatergic functionNew medicationsClinical studiesReceptor contributionTherapeutic implicationsMedication developmentCortical connectivityAntagonist effectsAntagonist responseNew treatment insightsSchizophreniaModel psychosisTreatment insightsAntagonist
1999
Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists
Krystal J, Belger A, D'Souza D, Anand A, Charney D, Aghajanian G, Moghaddam B. Therapeutic Implications of the Hyperglutamatergic Effects of NMDA Antagonists. Neuropsychopharmacology 1999, 21: s143-s157. DOI: 10.1016/s0893-133x(99)00102-5.Peer-Reviewed Original ResearchHealthy human subjectsNMDA antagonist effectsNMDA antagonistsClinical studiesMetabotropic glutamate receptor agonistN-methyl-D-aspartate (NMDA) subtypeD2 receptor blockadeGlutamate receptor agonistsD2 receptor stimulationDopamine 2 receptorNovel pharmacologic strategiesEffects of ketaminePathophysiology of schizophreniaCourse of schizophreniaNovel pharmacotherapeutic strategiesHuman subjectsHyperglutamatergic stateSerotonin 2AGlutamate neuronsGlutamate releaseCerebral cortexPharmacologic strategiesCurrent antipsychoticsPharmacotherapeutic strategiesSubanesthetic dosesGlutamate 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
1996
Noradrenergic mechanisms in stress and anxiety: II. Clinical studies
Bremner J, Krystal J, Southwick S, Charney D. Noradrenergic mechanisms in stress and anxiety: II. Clinical studies. Synapse 1996, 23: 39-51. PMID: 8723134, DOI: 10.1002/(sici)1098-2396(199605)23:1<39::aid-syn5>3.0.co;2-i.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderBlood pressureNoradrenergic functionHeart rateNoradrenergic systemClinical studiesAdrenergic receptorsPanic disorderAnxiety disordersGrowth hormone responseMeasurement of norepinephrineNorepinephrine responseNoradrenergic mechanismsBaseline norepinephrineNoradrenergic responsivenessPharmacological challengeCatecholaminergic functionHormone responseTraumatic remindersPatientsAcute stressorStress disorderNorepinephrineBaseline measuresConsistent finding
1995
Effects of the benzodiazepine antagonist flumazenil in PTSD
Randall P, Bremner J, Krystal J, Nagy L, Heninger G, Nicolaou A, Charney D. Effects of the benzodiazepine antagonist flumazenil in PTSD. Biological Psychiatry 1995, 38: 319-324. PMID: 7495926, DOI: 10.1016/0006-3223(94)00306-n.Peer-Reviewed Original ResearchConceptsVisual analogue rating scaleAdministration of flumazenilAnxiety symptomsCrossover study designBenzodiazepine antagonist flumazenilGABAA receptor complexBenzodiazepine/GABAA receptor complexPanic disorder patientsAnalogue rating scalesFlumazenil administrationPTSD Symptom ScaleIntravenous infusionAntagonist flumazenilGABAA antagonistHealthy controlsClinical studiesDisorder patientsSymptom ScaleFlumazenilPanic disorderPanic attacksVietnam combat veteransStudy designRating ScalePTSD symptomsYohimbine facilitated acoustic startle in combat veterans with post-traumatic stress disorder
Morgan CA, Grillon C, Southwick SM, Nagy LM, Davis M, Krystal JH, Charney DS. Yohimbine facilitated acoustic startle in combat veterans with post-traumatic stress disorder. Psychopharmacology 1995, 117: 466-471. PMID: 7604149, DOI: 10.1007/bf02246220.Peer-Reviewed Original ResearchConceptsAcoustic startle reflexRandomized double-blind placebo-controlled designCombat controlsDouble-blind placebo-controlled designAlpha-2 receptor antagonistEffects of yohimbinePlacebo-controlled designHealthy human controlsCombat veteransPost-traumatic stress disorderSevere stress resultsHealthy combat controlsInstantaneous rise timeSaline placeboCardiovascular effectsExcitatory effectsNeuronal reactivityNoradrenergic functionReceptor antagonistClinical studiesAcoustic startleYohimbinePTSD patientsPTSD subjectsNeurochemical basis
1990
Clinical studies of 5-HT function using I.V. l-Tryptophan
Price L, Charney D, Delgado P, Goodman W, Krystal J, Woods S, Heninger G. Clinical studies of 5-HT function using I.V. l-Tryptophan. Progress In Neuro-Psychopharmacology And Biological Psychiatry 1990, 14: 459-472. PMID: 2236580, DOI: 10.1016/0278-5846(90)90002-x.Peer-Reviewed Original ResearchConceptsPRL responseClinical studiesDrug actionAntidepressant drug actionLong-term treatmentSuch clinical studiesThymoleptic drugsTime-dependent fashionPlasma TrpObsessive-compulsive disorderSerum prolactinElectrophysiological findingsDepressed patientsHealthy controlsAntidepressant drugsTherapeutic effectPreclinical studiesReceptor sensitivityPanic disorderChallenge agentNeuropsychiatric diseasesNeuropsychopharmacological studiesClinical levelCompulsive disorderL-Trp