2022
Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder
Smart K, Worhunsky PD, Scheinost D, Angarita GA, Esterlis I, Carson RE, Krystal JH, O'Malley SS, Cosgrove KP, Hillmer AT. Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder. Alcohol Clinical And Experimental Research 2022, 46: 770-782. PMID: 35342968, PMCID: PMC9117461, DOI: 10.1111/acer.14816.Peer-Reviewed Original ResearchConceptsMetabotropic glutamate 5 receptorsDefault mode networkFunctional magnetic resonance imagingReceptor availabilityPositron emission tomographyAUD groupFunctional connectivityReceptor positron emission tomographyResting-state functional magnetic resonance imagingNetwork-level functional connectivityBrain connectivityWeeks of abstinenceGlobal functional connectivityAlcohol use disorderMagnetic resonance imagingFMRI outcomesHealthy controlsSupervised abstinencePET resultsUse disordersSynaptic plasticityResonance imagingBrain regionsEmission tomographyOrbitofrontal cortex
2020
Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence
Hillmer AT, Angarita GA, Esterlis I, Anderson JM, Nabulsi N, Lim K, Ropchan J, Carson RE, Krystal JH, Malley S, Cosgrove KP. Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence. Neuropsychopharmacology 2020, 46: 380-385. PMID: 32919411, PMCID: PMC7852514, DOI: 10.1038/s41386-020-00856-9.Peer-Reviewed Original ResearchMeSH KeywordsAlcohol AbstinenceBrainGlutamic AcidHumansPositron-Emission TomographyPyridinesReceptor, Metabotropic Glutamate 5ConceptsMetabotropic glutamate 5 receptorsSmoking statusAlcohol abstinenceEarly abstinenceMGlu5 receptor negative allosteric modulatorReceptor negative allosteric modulatorChronic alcohol useCortical brain regionsAlcohol use disorderEmission Tomography ImagingPositron emission tomography (PET) imagingNegative allosteric modulatorsDSM-5 criteriaCue-induced reinstatementHealthy controlsPreclinical literatureGlutamate systemPreclinical modelsHuman evidenceReceptor drugsPET scansUse disordersHuman studiesReceptor availabilityStudy durationImaging the glutamate synapse
Krystal JH. Imaging the glutamate synapse. Nature Medicine 2020, 26: 165-167. PMID: 32015559, DOI: 10.1038/s41591-020-0760-4.Peer-Reviewed Original Research
2019
Measuring the effects of ketamine on mGluR5 using [18F]FPEB and PET
Holmes SE, Gallezot JD, Davis MT, DellaGioia N, Matuskey D, Nabulsi N, Krystal JH, Javitch JA, DeLorenzo C, Carson RE, Esterlis I. Measuring the effects of ketamine on mGluR5 using [18F]FPEB and PET. Cerebrovascular And Brain Metabolism Reviews 2019, 40: 2254-2264. PMID: 31744389, PMCID: PMC7585925, DOI: 10.1177/0271678x19886316.Peer-Reviewed Original ResearchConceptsEffects of ketamineKetamine infusionGlutamate transmissionMetabotropic glutamate receptor 5Ketamine-induced effectsKetamine-induced changesGlutamate receptor 5Promising treatment targetDrug challenge studiesTwo-tissue compartment modelMGluR5 radioligandBlood pressureMGluR5 availabilityBaseline scanOutcome measuresHealthy subjectsHeart ratePsychiatric disordersReceptor 5Modulatory effectsMGluR5Treatment targetsChallenge studiesArterial input functionChallenge paradigmAltered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments
Duman RS, Sanacora G, Krystal JH. Altered Connectivity in Depression: GABA and Glutamate Neurotransmitter Deficits and Reversal by Novel Treatments. Neuron 2019, 102: 75-90. PMID: 30946828, PMCID: PMC6450409, DOI: 10.1016/j.neuron.2019.03.013.Peer-Reviewed Original ResearchConceptsAltered connectivityDepressed patientsExcitatory glutamate neuronsMajor neuronal typesRapid-acting agentsAtrophy of neuronsTreatment of depressionLimbic brain regionsChronic stress exposureStress-related disordersBrain imaging studiesImportant sex differencesNeurotransmitter deficitsGABA interneuronsImmunologic mechanismsGlutamate neuronsCurrent antidepressantsExcitotoxic effectsNeurochemical deficitsGlutamate dysfunctionPathophysiological mechanismsGABA systemInflammatory cytokinesAdrenal glucocorticoidsHippocampal region
2018
The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?
Abdallah CG, Sanacora G, Duman RS, Krystal JH. The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology & Therapeutics 2018, 190: 148-158. PMID: 29803629, PMCID: PMC6165688, DOI: 10.1016/j.pharmthera.2018.05.010.Peer-Reviewed Original ResearchConceptsRapid-acting antidepressantsNeurobiology of depressionMechanism of actionChronic stress pathologyRole of glutamateAntidepressant effectsEfficacy findingsGlutamate activationBiomarker findingsNeurobiology of stressVivo pharmacodynamicsCurrent perspective paperKetamineChronic stressReproducible biomarkersBehavioral effectsGlutamate inhibitionDepressionStress pathologyAntidepressantsNeurobiologyInhibitionActivationPharmacodynamicsPharmacokineticsUtility 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
Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence
Holmes SE, Girgenti MJ, Davis MT, Pietrzak RH, DellaGioia N, Nabulsi N, Matuskey D, Southwick S, Duman RS, Carson RE, Krystal JH, Esterlis I, Friedman M, Kowall N, Brady C, McKee A, Stein T, Huber B, Kaloupek D, Alvarez V, Benedek D, Ursano R, Williamson D, Cruz D, Young K, Duman R, Krystal J, Mash D, Hardegree M, Serlin G. Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 8390-8395. PMID: 28716937, PMCID: PMC5547601, DOI: 10.1073/pnas.1701749114.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderMGluR5 availabilityPositron emission tomographyGlutamate systemMetabotropic glutamate receptor 5Treatment of PTSDHuman posttraumatic stress disorderGlutamate receptor 5Mechanism-based treatmentsExpression of FKBP5Promising treatment targetHuman postmortem tissueTargeted pharmacological treatmentStress psychopathologyPharmacological treatmentExpression of proteinsReceptor 5MGluR5Treatment targetsPostmortem tissueEmission tomographyStress disorderPostmortem samplesPromising targetDisordersKetamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression
Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, Yang J, Pittenger C, Sanacora G, Krystal JH, Parsey RV, Carson RE, DeLorenzo C. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C]ABP688 and PET imaging study in depression. Molecular Psychiatry 2017, 23: 824-832. PMID: 28397841, PMCID: PMC5636649, DOI: 10.1038/mp.2017.58.Peer-Reviewed Original ResearchConceptsMajor depressive disorderMGluR5 availabilityPositron emission tomographyKetamine administrationControl groupAspartate glutamate receptor antagonistIntravenous ketamine administrationKetamine-induced reductionMetabotropic glutamatergic receptorsRapid antidepressant effectsGlutamate receptor antagonistsKetamine-induced changesEffects of ketaminePET imaging studiesMechanism of actionGlutamate surgeAntidepressant effectsAntidepressant efficacyAntidepressant responseGlutamatergic receptorsControl subjectsReceptor antagonistHealthy controlsDepressive disorderSustained decreaseNMDA Glutamate Receptor Antagonism and the Heritable Risk for Alcoholism: New Insights from a Study of Nitrous Oxide
Krystal JH, Petrakis IL, O’Malley S, Krishnan-Sarin S, Pearlson G, Yoon G. NMDA Glutamate Receptor Antagonism and the Heritable Risk for Alcoholism: New Insights from a Study of Nitrous Oxide. The International Journal Of Neuropsychopharmacology 2017, 20: 351-353. PMID: 28158462, PMCID: PMC5409033, DOI: 10.1093/ijnp/pyw118.Peer-Reviewed Original Research
2016
Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies
Averill LA, Purohit P, Averill CL, Boesl MA, Krystal JH, Abdallah CG. Glutamate dysregulation and glutamatergic therapeutics for PTSD: Evidence from human studies. Neuroscience Letters 2016, 649: 147-155. PMID: 27916636, PMCID: PMC5482215, DOI: 10.1016/j.neulet.2016.11.064.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderPsychiatric disordersStress-related psychiatric disordersAlternative pharmacologic treatmentsPutative neurobiological underpinningsGlutamate-modulating agentsTrauma-related disordersGlutamatergic abnormalitiesGlutamate dysregulationPharmacologic treatmentPharmacologic interventionsGlutamatergic functionGlutamate neurotransmissionMillions of individualsHuman studiesCardinal featuresStress disorderDisordersNeurobiological underpinningsRelated future directionsEvidenceChronicDysfunctionNeurotransmissionSubject data50 Hz hippocampal stimulation in refractory epilepsy: Higher level of basal glutamate predicts greater release of glutamate
Cavus I, Widi GA, Duckrow RB, Zaveri H, Kennard JT, Krystal J, Spencer DD. 50 Hz hippocampal stimulation in refractory epilepsy: Higher level of basal glutamate predicts greater release of glutamate. Epilepsia 2016, 57: 288-297. PMID: 26749134, DOI: 10.1111/epi.13269.Peer-Reviewed Original ResearchConceptsBasal glutamate levelsRefractory epilepsyGlutamate effluxBasal glutamateGlutamate levelsElectrical stimulationEpileptic hippocampusGlutamate releaseSeizure groupHz stimulationBrain glutamate releaseHippocampus of patientsStimulation-induced increaseEpilepsy monitoring unitStimulation-induced changesEpileptogenic hippocampusInduced seizuresSeizure inductionSpontaneous seizuresInterictal levelsGlutamate increaseAtrophic hippocampusElectroencephalography evaluationHippocampal stimulationHippocampal electrodesGlutamate and norepinephrine interaction: Relevance to higher cognitive operations and psychopathology
Abdallah CG, Averill LA, Krystal JH, Southwick SM, Arnsten AF. Glutamate and norepinephrine interaction: Relevance to higher cognitive operations and psychopathology. Behavioral And Brain Sciences 2016, 39: e201. PMID: 28347382, PMCID: PMC5485236, DOI: 10.1017/s0140525x15001727.Peer-Reviewed Original Research
2014
Glutamate Metabolism in Major Depressive Disorder
Abdallah CG, Jiang L, De Feyter HM, Fasula M, Krystal JH, Rothman DL, Mason GF, Sanacora G. Glutamate Metabolism in Major Depressive Disorder. American Journal Of Psychiatry 2014, 171: 1320-1327. PMID: 25073688, PMCID: PMC4472484, DOI: 10.1176/appi.ajp.2014.14010067.Peer-Reviewed Original ResearchKetamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics
Abdallah CG, Sanacora G, Duman RS, Krystal JH. Ketamine and Rapid-Acting Antidepressants: A Window into a New Neurobiology for Mood Disorder Therapeutics. Annual Review Of Medicine 2014, 66: 1-15. PMID: 25341010, PMCID: PMC4428310, DOI: 10.1146/annurev-med-053013-062946.Peer-Reviewed Original ResearchConceptsRapid antidepressant effectsAntidepressant effectsGlutamate-based antidepressantsTolerability of ketamineRapid-acting antidepressantsTreatment-resistant depressionNeurobiology of depressionPotent antidepressant effectsRapid acting antidepressantsBiology of depressionPotential treatment targetHours of treatmentTreatment targetsKetamineAntidepressantsBiomarker studiesDepressionNeurobiologyTolerability
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 receptorsRapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond
Krystal JH, Sanacora G, Duman RS. Rapid-Acting Glutamatergic Antidepressants: The Path to Ketamine and Beyond. Biological Psychiatry 2013, 73: 1133-1141. PMID: 23726151, PMCID: PMC3671489, DOI: 10.1016/j.biopsych.2013.03.026.Peer-Reviewed Original ResearchConceptsAspartate glutamate receptor antagonist ketamineNovel antidepressant mechanismNovel treatment mechanismsSingle subanesthetic doseRapid-acting antidepressantsMeaningful clinical improvementGlutamatergic antidepressantsTraditional antidepressantsAntidepressant mechanismClinical improvementAntidepressant responseAntidepressant researchSubanesthetic doseKetamine studiesTherapeutic effectAntidepressantsKetamineTreatment mechanismsN-methylDoseIncreased brain uptake and oxidation of acetate in heavy drinkers
Jiang L, Gulanski BI, De Feyter HM, Weinzimer SA, Pittman B, Guidone E, Koretski J, Harman S, Petrakis IL, Krystal JH, Mason GF. Increased brain uptake and oxidation of acetate in heavy drinkers. Journal Of Clinical Investigation 2013, 123: 1605-1614. PMID: 23478412, PMCID: PMC3613911, DOI: 10.1172/jci65153.Peer-Reviewed Original ResearchConceptsHeavy drinkersBrain uptakeN-acetylaspartateLight drinkersChronic heavy drinkingNew therapeutic approachesGreater brain uptakeAlcohol detoxificationConsequences of drinkingTherapeutic approachesMagnetic resonance spectroscopyMore brainHeavy drinkingDrinkersBrainWeeksBloodDrinksGlutamateDrinkingResonance spectroscopy
2012
Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans
Moghaddam B, Krystal JH. Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans. Schizophrenia Bulletin 2012, 38: 942-949. PMID: 22899397, PMCID: PMC3446228, DOI: 10.1093/schbul/sbs075.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric RegulationAnimalsAntipsychotic AgentsBrief Psychiatric Rating ScaleCerebral CortexDisease Models, AnimalDopamineEmotionsGlutamic AcidHumansKetamineNeurosciencesPhencyclidinePsychoses, Substance-InducedReceptor, Metabotropic Glutamate 5Receptors, Dopamine D2Receptors, Metabotropic GlutamateReceptors, N-Methyl-D-AspartateSchizophreniaSynapsesTranslational Research, BiomedicalConceptsNMDA receptor antagonistReceptor antagonistDopamine hypothesisN-methyl-D-aspartate receptor antagonistGlutamate synaptic functionTranslational neuroscience studiesTreatment of schizophreniaPathophysiology of schizophreniaPotential treatment targetPotential new targetsDopamine antagonistsCortical functionAnimal studiesTreatment targetsClinical testingSynaptic functionAntagonistTranslational toolSchizophreniaTranslational research fundingTranslational researchPotential mechanismsNew targetsAngel dustSystems neuroscienceKetamine 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