2023
Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia
Surti T, Ranganathan M, Johannesen J, Gueorguieva R, Deaso E, Kenney J, Krystal J, D'Souza D. Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia. Schizophrenia Research 2023, 256: 36-43. PMID: 37141764, PMCID: PMC10257994, DOI: 10.1016/j.schres.2023.04.010.Peer-Reviewed Original ResearchMeSH KeywordsAntipsychotic AgentsCognitive TrainingDouble-Blind MethodGlycine Plasma Membrane Transport ProteinsHumansNeuronal PlasticitySchizophreniaConceptsGlycine transporter 1Cytochrome P450 2D6 extensive metabolizersGlyT1 inhibitorsWeeks of washoutWeeks of CTMedication adherenceReceptor hypofunctionImpaired neuroplasticityPharmacodynamic variabilityNMDAR functionExtensive metabolizersTreatment periodPsychotic symptomsStable outpatientsCognitive impairmentGlyT1 occupancyTransporter 1CTNeuroplasticityCognitive training strategiesSchizophreniaComputerized CTCognitive performanceAugmentation studiesGreater improvementA pilot randomized controlled trial of ketamine in Borderline Personality Disorder
Fineberg S, Choi E, Shapiro-Thompson R, Dhaliwal K, Neustadter E, Sakheim M, Null K, Trujillo-Diaz D, Rondeau J, Pittaro G, Peters J, Corlett P, Krystal J. A pilot randomized controlled trial of ketamine in Borderline Personality Disorder. Neuropsychopharmacology 2023, 48: 991-999. PMID: 36804489, PMCID: PMC10209175, DOI: 10.1038/s41386-023-01540-4.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntidepressive AgentsBorderline Personality DisorderDouble-Blind MethodHumansKetamineMidazolamPilot ProjectsConceptsBorderline personality disorderSecondary outcome measuresOutcome measuresSocio-occupational functioningSuicidal ideationPilot studyTrial of ketaminePersonality disorderInfusion of ketaminePrimary outcome measureEffects of ketamineMidazolam groupAdverse eventsKetamine groupClinical benefitMood symptomsKetamineFDA approvalDrug midazolamInfusionBPD symptomsLarger studyDepressed moodSymptomsChronic mood
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 ResearchMeSH KeywordsAdultCholinergic AgentsDouble-Blind MethodHumansReceptors, CholinergicSchizophreniaTreatment OutcomeConceptsTreatment 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 sitesDose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial
Abdallah CG, Roache JD, Gueorguieva R, Averill LA, Young-McCaughan S, Shiroma PR, Purohit P, Brundige A, Murff W, Ahn KH, Sherif MA, Baltutis EJ, Ranganathan M, D’Souza D, Martini B, Southwick SM, Petrakis IL, Burson RR, Guthmiller KB, López-Roca AL, Lautenschlager KA, McCallin JP, Hoch MB, Timchenko A, Souza SE, Bryant CE, Mintz J, Litz BT, Williamson DE, Keane TM, Peterson AL, Krystal JH. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology 2022, 47: 1574-1581. PMID: 35046508, PMCID: PMC8767037, DOI: 10.1038/s41386-022-01266-9.Peer-Reviewed Original ResearchMeSH KeywordsAntidepressive AgentsDouble-Blind MethodHumansKetamineMilitary PersonnelStress Disorders, Post-TraumaticTreatment OutcomeVeteransConceptsPosttraumatic stress disorderClinical trialsOutcome measuresMontgomery-Åsberg Depression Rating ScaleSelf-report PTSD ChecklistÅsberg Depression Rating ScaleStress disorderPTSD symptomsAntidepressant-resistant symptomsPrevious antidepressant treatmentClinician-Administered PTSD ScaleMulti-center clinical trialRapid antidepressant effectsSecondary outcome measuresPrimary outcome measureSignificant dose-related effectsRole of ketamineDepression Rating ScaleDose-related effectsEffects of ketamineDSM-5Intravenous placeboDose ketamineTreatment discontinuationActive duty military
2020
Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers
Kantrowitz JT, Grinband J, Goff DC, Lahti AC, Marder SR, Kegeles LS, Girgis RR, Sobeih T, Wall MM, Choo TH, Green MF, Yang YS, Lee J, Horga G, Krystal JH, Potter WZ, Javitt DC, Lieberman JA. Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers. Neuropsychopharmacology 2020, 45: 1842-1850. PMID: 32403118, PMCID: PMC7608251, DOI: 10.1038/s41386-020-0706-z.Peer-Reviewed Original ResearchMeSH KeywordsAntipsychotic AgentsDouble-Blind MethodHealthy VolunteersHumansKetaminePharmaceutical PreparationsSchizophreniaSingle-Blind MethodConceptsDorsal anterior cingulate cortexBrief Psychiatric Rating ScaleTS-134Target engagementHealthy volunteersMetabotropic glutamate receptor 2/3 agonistKetamine-induced psychotic symptomsBPRS positive symptomsDouble-blind conditionsProof of mechanismKetamine-induced changesAntipsychotic drug developmentTreatment of schizophreniaPsychiatric Rating ScaleAnterior cingulate cortexPrimary outcomeClinical symptomsGlutamatergic drugsGlutamate neurotransmissionTotal symptomsClinical assessmentLow dosePsychotic symptomsHigh dosePlacebo dataA Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia
Koblan KS, Kent J, Hopkins SC, Krystal JH, Cheng H, Goldman R, Loebel A. A Non–D2-Receptor-Binding Drug for the Treatment of Schizophrenia. New England Journal Of Medicine 2020, 382: 1497-1506. PMID: 32294346, DOI: 10.1056/nejmoa1911772.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAdministration, OralAdultAntipsychotic AgentsDouble-Blind MethodDrug Administration ScheduleFemaleHumansLeast-Squares AnalysisMaleReceptors, Dopamine D2Receptors, G-Protein-CoupledSchizophreniaSchizophrenic PsychologySerotonin 5-HT1 Receptor AgonistsSeverity of Illness IndexTreatment OutcomeConceptsTrace amine-associated receptor 1Week 4Negative Symptom ScaleAcute exacerbationPlacebo groupBrief Negative Symptom ScaleTotal scoreSymptom ScaleClinical Global Impression-Severity ScaleEnd pointPrimary end pointSecondary end pointsSudden cardiac deathPANSS total scoreTreatment of schizophreniaDopamine D2 receptorsTreatment of psychosisType 1A receptorMean total scoreLevels of lipidsGastrointestinal symptomsAdverse eventsCardiac deathExtrapyramidal symptomsPrimary outcomePsilocybin Induces Time-Dependent Changes in Global Functional Connectivity
Preller KH, Duerler P, Burt JB, Ji JL, Adkinson B, Stämpfli P, Seifritz E, Repovš G, Krystal JH, Murray JD, Anticevic A, Vollenweider FX. Psilocybin Induces Time-Dependent Changes in Global Functional Connectivity. Biological Psychiatry 2020, 88: 197-207. PMID: 32111343, DOI: 10.1016/j.biopsych.2019.12.027.Peer-Reviewed Original ResearchConceptsFunctional connectivityBaseline connectivityResting-state functional connectivityGlobal functional connectivityBrain-wide connectivityHealthy human participantsPersonalized medicine approachPeak effectUse of psilocybinMechanism of actionSerotonin 2ATime-dependent mannerCrossover studyPredictive markerPsychedelic treatmentMedicine approachReceptor systemSensory regionsClinical contextTime pointsAssociative regionsDifferent test daysAdministrationTest dayTime-dependent changes
2019
Influence of combined treatment with naltrexone and memantine on alcohol drinking behaviors: a phase II randomized crossover trial
Krishnan-Sarin S, O’Malley S, Franco N, Cavallo DA, Tetrault JM, Shi J, Gueorguieva R, Pittman B, Krystal JH. Influence of combined treatment with naltrexone and memantine on alcohol drinking behaviors: a phase II randomized crossover trial. Neuropsychopharmacology 2019, 45: 319-326. PMID: 31590179, PMCID: PMC6901445, DOI: 10.1038/s41386-019-0536-z.Peer-Reviewed Original ResearchConceptsAlcohol drinking behaviorFirst treatment periodTreatment periodNumber of drinksCrossover trialDrinking behaviorEfficacy of naltrexoneOpioid antagonist naltrexoneNMDA antagonist memantinePositive family historyDay treatment periodSelf-administration periodAlcohol-induced stimulationAd lib accessMemantine treatmentAntagonist naltrexoneOpioid systemFamily historyNTXPriming drinkMemantineNaltrexoneAlcohol cravingHeavy drinkersAlcohol dependenceMaintenance 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 scoreRepeated ketamine infusions for antidepressant-resistant PTSD: Methods of a multicenter, randomized, placebo-controlled clinical trial
Abdallah CG, Roache JD, Averill LA, Young-McCaughan S, Martini B, Gueorguieva R, Amoroso T, Southwick SM, Guthmiller K, López-Roca AL, Lautenschlager K, Mintz J, Litz BT, Williamson DE, Keane TM, Peterson AL, Krystal JH, PTSD F. Repeated ketamine infusions for antidepressant-resistant PTSD: Methods of a multicenter, randomized, placebo-controlled clinical trial. Contemporary Clinical Trials 2019, 81: 11-18. PMID: 30999057, DOI: 10.1016/j.cct.2019.04.009.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderStudy drugClinical trialsTherapeutic effectPharmacotherapy of PTSDFirst placebo-controlled trialPlacebo-controlled clinical trialActive duty military populationDose-related efficacyMedication treatment optionsPlacebo-controlled trialDose-related effectsNovel neural mechanismActive duty militaryKetamine infusionSerotonergic antidepressantsEligible participantsTreatment optionsCase reportNew drug developmentOnly trialSustained reductionVeteran populationDrug AdministrationPilot evidence
2018
Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor
Preller KH, Burt JB, Ji JL, Schleifer CH, Adkinson BD, Stämpfli P, Seifritz E, Repovs G, Krystal JH, Murray JD, Vollenweider FX, Anticevic A. Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. ELife 2018, 7: e35082. PMID: 30355445, PMCID: PMC6202055, DOI: 10.7554/elife.35082.Peer-Reviewed Original ResearchConceptsLysergic acid diethylamideLSD effectsResting-state functional connectivityCortical gene expressionHealthy human participantsThalamic connectivityDopamine receptorsReceptor contributionNeurobiological effectsAgonist activityFunctional connectivityBrain connectivityAcid diethylamideReceptorsKetanserinNeuropharmacologyLSD mechanismCritical roleGene expressionAltered statesHuman participantsRational developmentSerotoninDose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
D’Souza D, Carson RE, Driesen N, Johannesen J, Ranganathan M, Krystal JH, Ahn K, Bielen K, Carbuto M, Deaso E, D’Souza D, Ranganathan M, Naganawa M, Ranganathan M, D’Souza D, Nabulsi N, Zheng M, Lin S, Huang Y, Carson R, Driesen N, Ahn K, Morgan P, Suckow R, He G, McCarthy G, Krystal J, Johannesen J, Kenney J, Gelernter J, Gueorguieva R, Pittman B. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biological Psychiatry 2018, 84: 413-421. PMID: 29499855, PMCID: PMC6068006, DOI: 10.1016/j.biopsych.2017.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAdultAzabicyclo CompoundsBrainCognitive DysfunctionDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycine Plasma Membrane Transport ProteinsHumansImidazolesKetamineLong-Term PotentiationMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedPositron-Emission TomographySchizophreniaYoung AdultConceptsHealthy control subjectsLong-term potentiationSchizophrenia patientsControl subjectsCognitive impairmentClinical trialsGlyT1 occupancyN-methyl-D-aspartate receptor functionGlycine transporter-1 inhibitorKetamine-induced disruptionKetamine-induced effectsFunctional magnetic resonance imagingMagnetic resonance imagingPositron emission tomographyMemory-related activationF-MKSubstudy 1Schizophrenia subjectsResonance imagingReceptor functionCortical regionsEmission tomographyTarget engagementPotentiationSchizophrenia
2017
GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose‐Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers
Yang B, Arias AJ, Feinn R, Krystal JH, Gelernter J, Petrakis IL. GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose‐Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. Alcohol Clinical And Experimental Research 2017, 41: 2025-2032. PMID: 29131352, PMCID: PMC5764175, DOI: 10.1111/acer.13516.Peer-Reviewed Original ResearchMecamylamine treatment for alcohol dependence: a randomized controlled trial
Petrakis IL, Ralevski E, Gueorguieva R, O'Malley SS, Arias A, Sevarino KA, Jane JS, O'Brien E, Krystal JH. Mecamylamine treatment for alcohol dependence: a randomized controlled trial. Addiction 2017, 113: 6-14. PMID: 28710873, PMCID: PMC5725262, DOI: 10.1111/add.13943.Peer-Reviewed Original ResearchConceptsHeavy drinking daysDrinking daysAlcohol use disorderUse disordersAlcohol consumptionAlcohol dependenceDouble-blind clinical trialNicotinic acetylcholine receptor antagonistWeeks of treatmentAcetylcholine receptor antagonistCurrent alcohol dependenceSignificant differencesTreatment-seeking smokersMecamylamine treatmentPlacebo groupMonth 3Primary outcomeSmoking statusNicotine withdrawalReceptor antagonistNovel pharmacotherapiesClinical trialsManagement therapyMecamylamineTreatment groupsDose-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
2016
RANDOMIZED TRIAL OF D‐CYCLOSERINE ENHANCEMENT OF COGNITIVE‐BEHAVIORAL THERAPY FOR PANIC DISORDER
Otto MW, Pollack MH, Dowd SM, Hofmann SG, Pearlson G, Szuhany KL, Gueorguieva R, Krystal JH, Simon NM, Tolin DF. RANDOMIZED TRIAL OF D‐CYCLOSERINE ENHANCEMENT OF COGNITIVE‐BEHAVIORAL THERAPY FOR PANIC DISORDER. Depression And Anxiety 2016, 33: 737-745. PMID: 27315514, PMCID: PMC5958622, DOI: 10.1002/da.22531.Peer-Reviewed Original ResearchConceptsCognitive behavioral therapyBenzodiazepine usePanic disorderDCS augmentationMulticenter trialD-cycloserineRecent multicenter trialPanic Disorder Severity ScaleExposure-based cognitive-behavioral therapySessions of treatmentStudy pillsPrimary outcomeRandomized trialsBaseline severityPrimary diagnosisAugmentation effectTreatment responseTreatment endpointBooster sessionsSeverity ScaleRole of severityBehavioral therapyDCS efficacyBeneficial effectsPilot studySleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504.
Krystal JH, Pietrzak RH, Rosenheck RA, Cramer JA, Vessicchio J, Jones KM, Huang GD, Vertrees JE, Collins J, Krystal AD. Sleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504. The Journal Of Clinical Psychiatry 2016, 77: 483-91. PMID: 26890894, DOI: 10.4088/jcp.14m09585.Peer-Reviewed Original ResearchConceptsPittsburgh Sleep Quality IndexClinician-Administered PTSD ScaleChronic military-related posttraumatic stress disorderMilitary-related posttraumatic stress disorderPosttraumatic stress disorderSleep disturbancesSleep qualityAdjunctive risperidonePTSD symptom severitySymptom severityDSM-IV-TR Axis I DisordersSecond-generation antipsychotic risperidoneVeterans Affairs Cooperative StudySF-36 v.Placebo-controlled trialTotal PSQI scoreMental health subscaleMulticenter clinical trialSleep Quality IndexStructured Clinical InterviewAxis I DisordersSeverity of nightmaresQuality of lifeMixed model regressionPartial responders
2015
Familial Alcoholism Risk and the Ratio of Stimulant to Sedative Effects of Ketamine
Yoon G, Pittman B, Limoncelli D, Krystal JH, Petrakis IL. Familial Alcoholism Risk and the Ratio of Stimulant to Sedative Effects of Ketamine. Biological Psychiatry 2015, 79: e69-e70. PMID: 26475672, DOI: 10.1016/j.biopsych.2015.09.006.Peer-Reviewed Original ResearchRole of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine
Ahn KH, Sewell A, Elander J, Pittman B, Ranganathan M, Gunduz-Bruce H, Krystal J, D'Souza DC. Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine. Neuropsychopharmacology 2015, 40: 2822-2831. PMID: 25953357, PMCID: PMC4864658, DOI: 10.1038/npp.2015.132.Peer-Reviewed Original ResearchConceptsGABA deficitHealthy subjectsPsychotomimetic effectsIntravenous infusionSchizophrenia patientsPANSS positive symptoms subscaleDouble-blind crossover designStriatal dopamine releasePositive symptom subscaleAdministration of drugsDose of AMPHPartial inverse agonistSubclinical responsePharmacokinetic interactionsSubthreshold doseDopamine releaseBenzodiazepine receptorsSymptom subscalesCrossover designCADSS scoresPositive symptomsAMPHInverse agonistSubjective effectsTest day