2024
Ketamine induces multiple individually distinct whole-brain functional connectivity signatures
Moujaes F, Ji J, Rahmati M, Burt J, Schleifer C, Adkinson B, Savic A, Santamauro N, Tamayo Z, Diehl C, Kolobaric A, Flynn M, Rieser N, Fonteneau C, Camarro T, Xu J, Cho Y, Repovs G, Fineberg S, Morgan P, Seifritz E, Vollenweider F, Krystal J, Murray J, Preller K, Anticevic A. Ketamine induces multiple individually distinct whole-brain functional connectivity signatures. ELife 2024, 13: e84173. PMID: 38629811, PMCID: PMC11023699, DOI: 10.7554/elife.84173.Peer-Reviewed Original ResearchConceptsResponse to ketamineAcute ketamineBehavioral effectsQuantified resting-state functional connectivityEffects of acute ketamineSymptom variationResting-state functional connectivityTreatment-resistant depressionFunctional connectivity signaturesGlobal brain connectivitySingle-subject levelInter-individual variabilityPlacebo-controlled studyFunctional connectivityConnectivity signaturesBrain connectivityHealthy participantsSingle-blind placebo-controlled studyNeural variationsTreatment conditionsKetamineGene expression targetsPharmacological biomarkersPilot awardParvalbumin
2022
Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial
Krystal J, Kane J, Correll C, Walling D, Leoni M, Duvvuri S, Patel S, Chang I, Iredale P, Frohlich L, Versavel S, Perry P, Sanchez R, Renger J. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. The Lancet 2022, 400: 2210-2220. PMID: 36528376, DOI: 10.1016/s0140-6736(22)01990-0.Peer-Reviewed Original ResearchConceptsTreatment of schizophreniaPositive allosteric modulatorsAdverse eventsUS sitesAllosteric modulatorsFavorable side effect profileMini International Neuropsychiatric InterviewNovel positive allosteric modulatorReceptor positive allosteric modulatorExtrapyramidal symptom assessmentMultiple ascending dosesCommon adverse eventsPhase 1b trialPlacebo-controlled studySide effect profileInternational Neuropsychiatric InterviewCohort of participantsAscending dosesSafety populationPrimary endpointBlood pressureM4 receptorsTreatment initiationDaily treatmentOral dosesSublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial.
Citrome L, Preskorn SH, Lauriello J, Krystal JH, Kakar R, Finman J, De Vivo M, Yocca FD, Risinger R, Rajachandran L. Sublingual Dexmedetomidine for the Treatment of Acute Agitation in Adults With Schizophrenia or Schizoaffective Disorder: A Randomized Placebo-Controlled Trial. The Journal Of Clinical Psychiatry 2022, 83 PMID: 36198061, DOI: 10.4088/jcp.22m14447.Peer-Reviewed Original ResearchConceptsAcute agitationHours postdoseSchizoaffective disorderTotal scorePrimary efficacy endpointPlacebo-controlled studyAdrenergic receptor agonistFifth Edition criteriaNegative Syndrome ScaleDexmedetomidine groupOral hypoesthesiaStudy medicationDry mouthEfficacy endpointOrthostatic hypotensionRandomized PlaceboAdverse eventsReceptor agonistEdition criteriaDexmedetomidineMean changePEC scoresPlaceboSyndrome ScaleUS sitesValidation 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
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
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
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
2008
Modulation of the cortical processing of novel and target stimuli by drugs affecting glutamate and GABA neurotransmission
Watson TD, Petrakis IL, Edgecombe J, Perrino A, Krystal JH, Mathalon DH. Modulation of the cortical processing of novel and target stimuli by drugs affecting glutamate and GABA neurotransmission. The International Journal Of Neuropsychopharmacology 2008, 12: 357-370. PMID: 18771605, PMCID: PMC2900256, DOI: 10.1017/s1461145708009334.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnalysis of VarianceCerebral CortexDouble-Blind MethodElectroencephalographyEvoked PotentialsFemaleGABA ModulatorsHumansKetamineMalePain MeasurementPattern Recognition, VisualPhotic StimulationReaction TimeReceptors, GABA-BReceptors, N-Methyl-D-AspartateStatistics as TopicThiopentalYoung AdultConceptsPlacebo-controlled studyNMDA receptor systemSubanaesthetic dosesGABA neurotransmissionChallenge sessionsDrug effectsNMDA antagonismHealthy adultsNovel stimuliCortical processingReceptor systemPlaceboDrugsCounterbalanced orderKetaminePotential correlatesNeural correlatesP3a amplitudeNovelty processingP300 componentStandard stimuliStimulus processingStimuliTarget stimuliN2 amplitudeBlunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis
D'Souza DC, Ranganathan M, Braley G, Gueorguieva R, Zimolo Z, Cooper T, Perry E, Krystal J. Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis. Neuropsychopharmacology 2008, 33: 2505-2516. PMID: 18185500, PMCID: PMC3799954, DOI: 10.1038/sj.npp.1301643.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAmnesiaAttentionBrainDose-Response Relationship, DrugDouble-Blind MethodDronabinolDrug Administration ScheduleDrug ToleranceFemaleHallucinationsHallucinogensHumansHydrocortisoneMaleMarijuana AbuseMiddle AgedPerceptual DisordersProlactinPsychoses, Substance-InducedTachycardiaYoung AdultConceptsAmnestic effectsPerceptual alterationsDelta-9-TetrahydrocannabinolCannabis useSubjective effectsFrequent usersCannabisEffects of cannabinoidsIllicit substancesPsychotomimetic effectsEuphoric effectsHealthy controlsHealthy individualsMemoryImpairingPsychosisDose-related effectsIndividualsCortisolPsychotomimeticsAttentionPeopleUsersPlacebo-controlled studyEffect
2005
Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction
D’Souza D, Abi-Saab WM, Madonick S, Forselius-Bielen K, Doersch A, Braley G, Gueorguieva R, Cooper TB, Krystal JH. Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction. Biological Psychiatry 2005, 57: 594-608. PMID: 15780846, DOI: 10.1016/j.biopsych.2004.12.006.Peer-Reviewed Original ResearchMeSH KeywordsAdultAkathisia, Drug-InducedArousalCognitionDose-Response Relationship, DrugDouble-Blind MethodDronabinolEndocrine SystemFemaleHumansInjections, IntravenousMaleMental RecallMiddle AgedMotor ActivityNeuropsychological TestsPerceptionPsychiatric Status Rating ScalesPsychotic DisordersPsychotropic DrugsSchizophreniaVerbal LearningConceptsSchizophrenia patientsAntipsychotic-treated schizophrenia patientsDelta-9-tetrahydrocannabinol effectsLong-term adverse eventsCognitive deficitsPlacebo-controlled studyDelta-9-THCTransient exacerbationAdverse eventsReceptor dysfunctionEndocrine effectsHealthy subjectsStudy participationPsychotic disordersPlasma prolactinSchizophrenia symptomsPatientsSchizophreniaCognitive effectsPerceptual alterationsDeficitsCannabisSubjectsAkathisiaExacerbation
2002
Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients
Stine SM, Southwick SM, Petrakis IL, Kosten TR, Charney DS, Krystal JH. Yohimbine-induced withdrawal and anxiety symptoms in opioid-dependent patients. Biological Psychiatry 2002, 51: 642-651. PMID: 11955464, DOI: 10.1016/s0006-3223(01)01292-6.Peer-Reviewed Original ResearchConceptsOpioid-dependent patientsBlood pressureMethadone patientsOpioid dependenceHPA axis perturbationsPlacebo-controlled studyDiastolic blood pressureSystolic blood pressureMethadone-maintained patientsSymptom scale scoresSynaptic noradrenalineOpioid withdrawalPostsynaptic effectsMHPG levelsAbstinence symptomsAdrenal axisOpioid drugsYohimbine effectNoradrenergic regulationHealthy volunteersHeart ratePhysiologic measuresPatientsCortisol levelsScale score
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
1997
Effect of alpha-methyl-para-tyrosine on response to cocaine challenge
Stine S, Krystal J, Petrakis I, Jatlow P, Heninger G, Kosten T, Chamey D. Effect of alpha-methyl-para-tyrosine on response to cocaine challenge. Biological Psychiatry 1997, 42: 181-190. PMID: 9232210, DOI: 10.1016/s0006-3223(96)00331-9.Peer-Reviewed Original ResearchConceptsDopamine metabolite homovanillic acidCocaine-induced euphoriaNorepinephrine metabolite 3Placebo-controlled studyBlood pressure responseMetabolite homovanillic acidReduced plasma levelsTyrosine hydroxylase inhibitorSerum cocaine levelsTuberoinfundibular dopamine systemAMPT pretreatmentAcute reductionIntranasal administrationPara-tyrosinePlasma levelsProlactin levelsCocaine challengeHomovanillic acidCatecholamine synthesisHeart rateHydroxylase inhibitorAlpha-methylDopamine systemCocaine levelsTherapeutic potential
1995
Opiate Dependence and Withdrawal: Preliminary Assessment Using Single Photon Emission Computerized Tomography (SPECT)
Krystal J, Woods S, Kosten T, Rosen M, Seibyl J, Van Dyck C, Price L, Zubal I, Hoffer P, Charney D. Opiate Dependence and Withdrawal: Preliminary Assessment Using Single Photon Emission Computerized Tomography (SPECT). The American Journal Of Drug And Alcohol Abuse 1995, 21: 47-63. PMID: 7762544, DOI: 10.3109/00952999509095229.Peer-Reviewed Original ResearchConceptsRegional brain functionOpiate withdrawal signsSingle Photon Emission Computerized TomographyHealthy subjectsNaloxone administrationOpiate withdrawalOpiate dependenceBrain functionParietal cortexHexamethylpropyleneamine oximeWithdrawal signsNaloxone effectChronic opiate dependencePlacebo-controlled studyRegional alterationsComparison of patientsMethadone-maintained patientsRegional cerebral perfusionPhoton Emission Computerized TomographyOpiate-dependent patientsRight temporal cortexRight parietal cortexFunctional brain imaging technologiesSingle photon emissionEmission computerized tomography