2024
Illusory generalizability of clinical prediction models
Chekroud A, Hawrilenko M, Loho H, Bondar J, Gueorguieva R, Hasan A, Kambeitz J, Corlett P, Koutsouleris N, Krumholz H, Krystal J, Paulus M. Illusory generalizability of clinical prediction models. Science 2024, 383: 164-167. PMID: 38207039, DOI: 10.1126/science.adg8538.Peer-Reviewed Original Research
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
A 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 outcomeModulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin
Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, Sherif M, Ahn KH, D’Souza D, Formica R, Southwick SM, Duman RS, Sanacora G, Krystal JH. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 2020, 45: 990-997. PMID: 32092760, PMCID: PMC7162891, DOI: 10.1038/s41386-020-0644-9.Peer-Reviewed Original ResearchMeSH KeywordsAntidepressive AgentsDepressive Disorder, MajorHumansKetamineMechanistic Target of Rapamycin Complex 1SirolimusTreatment OutcomeConceptsAntidepressant effectsKetamine administrationRapamycin pretreatmentMontgomery-Åsberg Depression Rating ScaleDouble-blind cross-over designBenefits of ketamineRobust antidepressant effectsKetamine's antidepressant effectsMajor depressive episodeDepression Rating ScaleCross-over designKetamine exertsOral rapamycinRemission rateDepressive episodePlacebo 2Ketamine 0.5Local blockadeDepressed patientsIntravenous administrationTreatment daysDepression relapseDepression severityKetamineRating Scale
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 scoreEnhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development
Kaffman A, White JD, Wei L, Johnson FK, Krystal JH. Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development. Methods In Molecular Biology 2019, 2011: 3-22. PMID: 31273690, PMCID: PMC6895673, DOI: 10.1007/978-1-4939-9554-7_1.Peer-Reviewed Original ResearchConceptsPreclinical researchAnimal modelsPsychiatric conditionsLower clinical success ratesClinical success rateCommon psychiatric conditionsPsychiatric clinical trialsClinical trialsNew pharmacotherapiesMore effective interventionsPreclinical workPsychiatric disordersPsychiatric pathophysiologyMental illnessSystematic reviewEffective interventionsAnimal experimentsDrug development processSuccess rateDrug developmentHuman psychopathologyPharmaceutical companiesPredictive validityLarge pharmaceutical companiesAnimals
2017
Mecamylamine 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 ScaleReevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach
Chekroud AM, Gueorguieva R, Krumholz HM, Trivedi MH, Krystal JH, McCarthy G. Reevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach. JAMA Psychiatry 2017, 74: 370-378. PMID: 28241180, PMCID: PMC5863470, DOI: 10.1001/jamapsychiatry.2017.0025.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAffectAgedAntidepressive AgentsBupropionCitalopramCluster AnalysisDepressive Disorder, MajorDose-Response Relationship, DrugDrug Therapy, CombinationDuloxetine HydrochlorideFemaleHumansMaleMianserinMiddle AgedMirtazapineRandomized Controlled Trials as TopicSleepSyndromeTreatment OutcomeVenlafaxine HydrochlorideYoung AdultConceptsCore emotional symptomsDepressive severitySymptom clustersHamilton Depression Rating ScaleDepression Outcomes trialDifferent antidepressant medicationsHAM-D scaleHigh-dose duloxetinePhase 3 trialEmotional symptomsPatient-reported dataDepression Rating ScaleSequenced Treatment AlternativesGroup of symptomsCluster of symptomsDepressive symptom checklistMixed-effects regression analysisDepressive Symptomatology ScaleAntidepressant therapyAntidepressant treatmentAntidepressant medicationOutcome trialsCombining MedicationsAtypical symptomsAdditional placeboTrajectories of relapse in randomised, placebo-controlled trials of treatment discontinuation in major depressive disorder: an individual patient-level data meta-analysis
Gueorguieva R, Chekroud AM, Krystal JH. Trajectories of relapse in randomised, placebo-controlled trials of treatment discontinuation in major depressive disorder: an individual patient-level data meta-analysis. The Lancet Psychiatry 2017, 4: 230-237. PMID: 28189575, PMCID: PMC5340978, DOI: 10.1016/s2215-0366(17)30038-x.Peer-Reviewed Original ResearchConceptsActive medicationActive treatmentClinical trialsDepression severityHamilton Depression Rating Scale scoresDepression Rating Scale scoresClinical Global Impression scoresIndividual patient-level dataDouble-blind treatmentPlacebo-controlled trialPatterns of relapseGlobal Impression scoresIndividual patient dataPrevention of relapseTrajectory class membershipTreatment of depressionMajor depressive disorderRating Scale scoresPatient-level dataPost-traumatic stress disorderTreatment discontinuationAntidepressant treatmentClinical responseAlcohol Research CenterAntidepressant medication
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 studyCross-trial prediction of treatment outcome in depression: a machine learning approach
Chekroud AM, Zotti RJ, Shehzad Z, Gueorguieva R, Johnson MK, Trivedi MH, Cannon TD, Krystal JH, Corlett PR. Cross-trial prediction of treatment outcome in depression: a machine learning approach. The Lancet Psychiatry 2016, 3: 243-250. PMID: 26803397, DOI: 10.1016/s2215-0366(15)00471-x.Peer-Reviewed Original ResearchConceptsTreatment outcomesTreatment groupsEscitalopram treatment groupSpecific antidepressantsPatient-reported dataSequenced Treatment AlternativesClinical trial dataIndependent clinical trialsClinical remissionSymptomatic remissionClinical trialsTreatment efficacyPatientsProspective identificationTreatment alternativesTrial dataDepressionRemissionAntidepressantsOutcomesGroupLevel 1CitalopramCohortClinicians
2014
Differences in Treatment Effect Among Clinical Subgroups in a Randomized Clinical Trial of Long-Acting Injectable Risperidone and Oral Antipsychotics in Unstable Chronic Schizophrenia
Leatherman SM, Liang MH, Krystal JH, Lew RA, Valley D, Thwin SS, Rosenheck RA. Differences in Treatment Effect Among Clinical Subgroups in a Randomized Clinical Trial of Long-Acting Injectable Risperidone and Oral Antipsychotics in Unstable Chronic Schizophrenia. The Journal Of Nervous And Mental Disease 2014, 202: 13-17. PMID: 24375206, DOI: 10.1097/nmd.0000000000000069.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntipsychotic AgentsChronic DiseaseDrug Administration ScheduleFemaleHospitalizationHumansInjections, IntramuscularMaleMiddle AgedProportional Hazards ModelsPsychotic DisordersQuality of LifeRisk AssessmentRisperidoneSchizophreniaSchizophrenic PsychologySeverity of Illness IndexSubstance-Related DisordersTreatment OutcomeConceptsQuality of lifeOral antipsychoticsOral treatmentInjectable risperidoneCox regressionTreatment effectsLong-Acting Injectable RisperidoneBody mass indexPsychiatric service useSubstance abuse outcomesSubstance use outcomesLAI risperidonePrimary endpointStudy entryWhite patientsClinical outcomesMass indexUnstable patientsMedication compliancePsychiatric rehospitalizationChronic schizophreniaClinical trialsClinical subgroupsPsychiatric hospitalizationPsychiatric symptoms
2013
Temporal patterns of adherence to medications and behavioral treatment and their relationship to patient characteristics and treatment response
Gueorguieva R, Wu R, Krystal JH, Donovan D, O'Malley SS. Temporal patterns of adherence to medications and behavioral treatment and their relationship to patient characteristics and treatment response. Addictive Behaviors 2013, 38: 2119-2127. PMID: 23435273, PMCID: PMC3595348, DOI: 10.1016/j.addbeh.2013.01.024.Peer-Reviewed Original ResearchConceptsPercent heavy drinking daysAdherence trajectoriesExcellent adherersPercent days abstinentPatient characteristicsMedication adherenceTreatment outcomesMedication adherence trajectoriesPatterns of treatmentHeavy drinking daysPatterns of adherenceExcellent medication adherenceLack of benefitTrajectories of adherenceIntervention main effectsActive medicationAdverse eventsPharmacologic treatmentHigher percent days abstinentTreatment adherenceTreatment modalitiesWorse outcomesTreatment responseDays abstinentDrinking days
2012
Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder
Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C. Effects of Ketamine in Treatment-Refractory Obsessive-Compulsive Disorder. Biological Psychiatry 2012, 72: 964-970. PMID: 22784486, PMCID: PMC3667652, DOI: 10.1016/j.biopsych.2012.05.028.Peer-Reviewed Original ResearchConceptsObsessive-compulsive disorderKetamine infusionDepression symptomsLow-dose ketamine infusionTreatment-refractory obsessive-compulsive disorderOCD symptomsPathogenesis of OCDIncomplete symptom reliefTreatment-Refractory ObsessiveOpen-label trialRapid antidepressant effectsAspartate glutamate receptorsEffects of ketaminePotent noncompetitive antagonistGlutamate abnormalitiesAntidepressant effectsAntidepressant responseSymptom reliefKetamine effectsComorbid depressionAcute effectsGlutamate receptorsDepressive symptomsNoncompetitive antagonistInfusion
2011
Trajectories of Depression Severity in Clinical Trials of Duloxetine: Insights Into Antidepressant and Placebo Responses
Gueorguieva R, Mallinckrodt C, Krystal JH. Trajectories of Depression Severity in Clinical Trials of Duloxetine: Insights Into Antidepressant and Placebo Responses. JAMA Psychiatry 2011, 68: 1227-1237. PMID: 22147842, PMCID: PMC3339151, DOI: 10.1001/archgenpsychiatry.2011.132.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntidepressive AgentsData Interpretation, StatisticalDepressive Disorder, MajorDouble-Blind MethodDuloxetine HydrochlorideFemaleHumansLinear ModelsMalePatient DropoutsPlacebo EffectPsychiatric Status Rating ScalesRandomized Controlled Trials as TopicSelective Serotonin Reuptake InhibitorsSeverity of Illness IndexThiophenesTreatment OutcomeConceptsSelective serotonin reuptake inhibitorsPlacebo-treated patientsComparator selective serotonin reuptake inhibitorsHAM-D scoresClinical trialsAntidepressant treatmentPlacebo responseMajor depressionDouble-blind clinical trialHigh placebo response rateSerotonergic antidepressant treatmentPlacebo response ratesSerotonin reuptake inhibitorsAntidepressant nonrespondersPlacebo armMost patientsAntidepressant respondersMedication risksReuptake inhibitorsSerotonergic antidepressantsResponder statusTreatment responseClinical trajectoriesDepression scoresDepression severityNoradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence
Petrakis IL, Ralevski E, Desai N, Trevisan L, Gueorguieva R, Rounsaville B, Krystal JH. Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence. Neuropsychopharmacology 2011, 37: 996-1004. PMID: 22089316, PMCID: PMC3280636, DOI: 10.1038/npp.2011.283.Peer-Reviewed Original ResearchConceptsPost-traumatic stress disorderSerotonin uptake inhibitorNorepinephrine uptake inhibitorUptake inhibitorAlcohol dependenceMale veteransTreatment of PTSDUse outcomesSymptoms of PTSDDouble-blind conditionsMain outcome measuresEvidence of efficacyComorbid alcohol dependenceCurrent diagnostic criteriaAlcohol use disorderAlcohol use outcomesComorbid conditionsAdjunctive efficacyOutcome measuresOnly FDADiagnostic criteriaUse disordersClinical advantagesAlcohol consumptionDrug AdministrationBaseline trajectories of heavy drinking and their effects on postrandomization drinking in the COMBINE Study: empirically derived predictors of drinking outcomes during treatment
Gueorguieva R, Wu R, Donovan D, Rounsaville BJ, Couper D, Krystal JH, O’Malley S. Baseline trajectories of heavy drinking and their effects on postrandomization drinking in the COMBINE Study: empirically derived predictors of drinking outcomes during treatment. Alcohol 2011, 46: 121-131. PMID: 21925828, PMCID: PMC3266454, DOI: 10.1016/j.alcohol.2011.08.008.Peer-Reviewed Original ResearchConceptsDaily heavy drinkersFrequent heavy drinkersHeavy drinkersHeavy drinkingDrinking outcomesAlcohol-dependent patientsBehavioral intervention studyHeavy drinking trajectoriesSummary drinking measuresBaseline characteristicsActive treatmentSevere baselineCombined PharmacotherapiesWorse outcomesPharmacological interventionsCOMBINE StudyIntervention studiesPatientsTreatment factorsDrinkersOutcomesTrajectory membershipDrinking measuresTreatment effectsDrinking