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 dependence
2017
Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence
Andersen AM, Pietrzak RH, Kranzler HR, Ma L, Zhou H, Liu X, Kramer J, Kuperman S, Edenberg HJ, Nurnberger JI, Rice JP, Tischfield JA, Goate A, Foroud TM, Meyers JL, Porjesz B, Dick DM, Hesselbrock V, Boerwinkle E, Southwick SM, Krystal JH, Weissman MM, Levinson DF, Potash JB, Gelernter J, Han S. Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. JAMA Psychiatry 2017, 74: 1153-1160. PMID: 28813562, PMCID: PMC5710224, DOI: 10.1001/jamapsychiatry.2017.2269.Peer-Reviewed Original ResearchConceptsMDD polygenic risk scoresMajor depressive disorderPolygenic risk scoresAlcohol dependenceDepressive disorderSignificant public health burdenPublic health burdenAD comorbidityNational HealthHealth burdenMAIN OUTCOMECase-control statusRisk scoreRisk of ADVeterans StudyYale-PennGenetic susceptibilityMDD statusCommon genetic factorsSubstance dependenceMDD casesAD samplesPolygenic riskGenetic factorsHeritable disorderMecamylamine 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 groups
2015
Integrating Acquired Preparedness and Dual Process Models of Risk for Heavy Drinking and Related Problems
Corbin WR, Papova A, Morean ME, O’Malley S, Krishnan-Sarin S, Abi-Dargham A, Anticevic A, Pearlson G, Petrakis I, Pittman BP, Krystal JH. Integrating Acquired Preparedness and Dual Process Models of Risk for Heavy Drinking and Related Problems. Psychology Of Addictive Behaviors 2015, 29: 864-874. PMID: 26348221, PMCID: PMC6223629, DOI: 10.1037/adb0000093.Peer-Reviewed Original ResearchConceptsDual-process modelImpulsive sensationExpectancy challengeDrinking outcomesStronger positive expectanciesAlcohol useIndirect effectsHeavy drinkingExplicit measuresPositive expectanciesAlcohol expectanciesPreparedness modelImplicit influencePersonality traitsNondependent drinkersBehavioral controlTranslational neuroscienceProcess modelAlcohol dependenceHigh levelsExpectancyDrinkingRelated problemsSensationNeuroscienceA New Genomewide Association Meta‐Analysis of Alcohol Dependence
Zuo L, Tan Y, Zhang X, Wang X, Krystal J, Tabakoff B, Zhong C, Luo X. A New Genomewide Association Meta‐Analysis of Alcohol Dependence. Alcohol Clinical And Experimental Research 2015, 39: 1388-1395. PMID: 26173551, PMCID: PMC5587504, DOI: 10.1111/acer.12786.Peer-Reviewed Original ResearchConceptsAfrican American cohortAmerican cohortAlcohol dependenceSingle nucleotide polymorphismsAustralian cohortRisk genesEuropean American cohortRisk single nucleotide polymorphismsRat brainIndependent cohortMeta-AnalysisCohortMouse brainRisk variantsP-valueRNA expression analysisGenomewide association studiesBrainHuman tissuesNucleotide polymorphismsAssociation studiesGenomewide association analysis
2013
Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence
Xie P, Kranzler HR, Krystal JH, Farrer LA, Zhao H, Gelernter J. Deep resequencing of 17 glutamate system genes identifies rare variants in DISC1 and GRIN2B affecting risk of opioid dependence. Addiction Biology 2013, 19: 955-964. PMID: 23855403, PMCID: PMC3815683, DOI: 10.1111/adb.12072.Peer-Reviewed Original ResearchConceptsOpioid dependenceSubstance dependenceRare variantsN-methyl-D-aspartate (NMDA) glutamate receptorsCo-occurring alcohol dependenceHealthy control subjectsControl subjectsNMDA systemOpioid abuseGlutamate receptorsSchizophrenia risk genesSD riskAlcohol dependenceSignificant associationCocaine dependenceAdditional subjectsOD riskRisk genesDISC1African AmericansFirst demonstrationCommon variantsRiskSubjectsMinor allele frequencyExome-wide association study of replicable nonsynonymous variants conferring risk for alcohol dependence.
Zuo L, Saba L, Wang K, Zhang X, Krystal JH, Tabakoff B, Luo X. Exome-wide association study of replicable nonsynonymous variants conferring risk for alcohol dependence. Journal Of Studies On Alcohol And Drugs 2013, 74: 622-5. PMID: 23739027, PMCID: PMC3711352, DOI: 10.15288/jsad.2013.74.622.Peer-Reviewed Original ResearchConceptsApolipoprotein E receptor 2Risk genesNonsynonymous variantsRNA expression analysisExome-wide association studyE receptor 2Expression analysisAssociation studiesGenesWhole exomeProtein 2RNA expressionNsSNPReplicable associationsAlcohol dependenceNonhuman speciesEuropean American sampleReceptor 2UbiquitinVariantsMultiple testingSpeciesExomeBioinformaticsUBAP2
2012
Genome‐Wide Significant Association Signals in IPO11‐HTR1A Region Specific for Alcohol and Nicotine Codependence
Zuo L, Zhang X, Wang F, Li C, Lu L, Ye L, Zhang H, Krystal JH, Deng H, Luo X. Genome‐Wide Significant Association Signals in IPO11‐HTR1A Region Specific for Alcohol and Nicotine Codependence. Alcohol Clinical And Experimental Research 2012, 37: 730-739. PMID: 23216389, PMCID: PMC3610804, DOI: 10.1111/acer.12032.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlcoholismBeta KaryopherinsBlack or African AmericanCase-Control StudiesChromosomes, Human, Pair 5FemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansMaleMiddle AgedPolymorphism, Single NucleotideQuantitative Trait LociReceptor, Serotonin, 5-HT1ATobacco Use DisorderWhite PeopleConceptsGenome-wide significance levelSingle nucleotide polymorphismsReplication cohortDiscovery cohortAlcohol dependenceExpression quantitative loci (eQTL) analysisPeripheral blood mononuclear cell samplesNeuropsychiatric disordersWide significant association signalsMononuclear cell samplesGenome-wide association studiesQuantitative loci analysisGene-disease association analysisCis-eQTL analysisTop single nucleotide polymorphismsCis-acting regulatory effectsSignificant association signalsBrain tissue samplesAmerican controlsEuropean American controlsRisk single nucleotide polymorphismsAfrican-American controlsSevere subtypeGenomic regionsAfrican American casesDifferential brain response to alcohol cue distractors across stages of alcohol dependence
Fryer SL, Jorgensen KW, Yetter EJ, Daurignac EC, Watson TD, Shanbhag H, Krystal JH, Mathalon DH. Differential brain response to alcohol cue distractors across stages of alcohol dependence. Biological Psychology 2012, 92: 282-291. PMID: 23131612, PMCID: PMC3947923, DOI: 10.1016/j.biopsycho.2012.10.004.Peer-Reviewed Original ResearchConceptsAnterior cingulate cortexAlcohol cuesBrain responsesLong-term abstainersAlcohol dependenceDorsal anterior cingulate cortexRecruitment of attentionVentral anterior cingulate cortexCognitive control regionsAlcohol-related cuesCue-reactivity studiesCue-related activationsNon-alcohol cuesAttention-demanding taskDifferential brain responsesTarget detection taskInferior parietal lobuleMedial prefrontal cortexAlcohol-dependent individualsCue exposureAltered attentionDistractor effectNeural responsesParietal lobulePrefrontal cortex
2011
Noradrenergic 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 AdministrationErratum: Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence
Krystal J, Petrakis I, Limoncelli D, Nappi S, Trevisan L, Pittman B, D'Souza D. Erratum: Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence. Neuropsychopharmacology 2011, 36: 911-911. PMCID: PMC3055722, DOI: 10.1038/npp.2011.2.Peer-Reviewed Original ResearchNeuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence
Cosgrove KP, Esterlis I, Mason GF, Bois F, O’Malley S, Krystal JH. Neuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence. Neuropharmacology 2011, 60: 1318-1325. PMID: 21276806, PMCID: PMC3078950, DOI: 10.1016/j.neuropharm.2011.01.020.Peer-Reviewed Original ResearchConceptsAlcohol withdrawalTobacco smokingGABA levelsNeuronal functionNeuronal nicotinic acetylcholine receptorsAlcohol-dependent smokersCortical GABA systemGABA neuronal functionProlonged alcohol withdrawalInfluence of nicotineNicotinic acetylcholine receptorsAlcohol-dependent individualsEffects of alcoholPreclinical evidenceRole of alcoholGABA systemPreclinical modelsTobacco smokeErminio CostaBenzodiazepine receptorsAcetylcholine receptorsAlcohol dependenceSmokingPrimary actionClinical experiments
2010
Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence
Krystal JH, Petrakis IL, Limoncelli D, Nappi SK, Trevisan L, Pittman B, D'Souza DC. Characterization of the Interactive Effects of Glycine and D-Cycloserine in Men: Further Evidence for Enhanced NMDA Receptor Function Associated with Human Alcohol Dependence. Neuropsychopharmacology 2010, 36: 701-710. PMID: 21124304, PMCID: PMC3055693, DOI: 10.1038/npp.2010.203.Peer-Reviewed Original ResearchConceptsNMDA receptor functionAlcohol-dependent patientsHuman alcohol dependenceAntagonist-like effectsReceptor functionReceptor antagonistDCS effectsD-cycloserineAlcohol-like effectsAlcohol dependenceNMDA glutamate receptor functionN-methyl-D-aspartate (NMDA) glutamate receptor antagonistStandard alcohol drinksGlutamate receptor antagonistsChronic alcohol consumptionDouble-blind conditionsNMDA receptor antagonistAlcohol-dependent menGlutamate receptor functionAlcohol-dependent animalsPlasma levelsGlycine administrationGlycine levelsNMDA receptorsCoagonist siteSerotonin 1B Receptor Imaging in Alcohol Dependence
Hu J, Henry S, Gallezot JD, Ropchan J, Neumaier JF, Potenza MN, Sinha R, Krystal JH, Huang Y, Ding YS, Carson RE, Neumeister A. Serotonin 1B Receptor Imaging in Alcohol Dependence. Biological Psychiatry 2010, 67: 800-803. PMID: 20172504, PMCID: PMC3112181, DOI: 10.1016/j.biopsych.2009.12.028.Peer-Reviewed Original ResearchConceptsHealthy control subjectsAlcohol dependencePositron emission tomographyStriatal 5Emission tomographyMagnetic resonance imaging (MRI) scansIndividual magnetic resonance imaging (MRI) scansMultilinear reference tissue modelResonance imaging scansSerotonin 1B receptorReference tissue modelClinical variablesAbstinent patientsControl subjectsImaging scansAnatomical abnormalitiesHC subjectsRodent modelsAntagonist radioligandReceptor imagingAnimal modelsVivo assessmentTomographyFirst evidenceHigh-resolution research tomograph
2009
Population admixture modulates risk for alcohol dependence
Zuo L, Luo X, Listman JB, Kranzler HR, Wang S, Anton RF, Blumberg HP, Stein MB, Pearlson GD, Covault J, Charney DS, van Kammen DP, Price LH, Lappalainen J, Cramer J, Krystal JH, Gelernter J. Population admixture modulates risk for alcohol dependence. Human Genetics 2009, 125: 605-613. PMID: 19306106, PMCID: PMC2777998, DOI: 10.1007/s00439-009-0647-4.Peer-Reviewed Original Research
2008
Positron Emission Tomography Imaging of the Serotonin Transporter and 5-HT1A Receptor in Alcohol Dependence
Martinez D, Slifstein M, Gil R, Hwang DR, Huang Y, Perez A, Frankle WG, Laruelle M, Krystal J, Abi-Dargham A. Positron Emission Tomography Imaging of the Serotonin Transporter and 5-HT1A Receptor in Alcohol Dependence. Biological Psychiatry 2008, 65: 175-180. PMID: 18962444, PMCID: PMC2621104, DOI: 10.1016/j.biopsych.2008.08.034.Peer-Reviewed Original ResearchConceptsType II alcoholismSerotonergic transmissionControl subjectsTransporter levelsAlcohol-dependent subjectsNonspecific partition coefficientEmission Tomography ImagingPositron emission tomography (PET) imagingSeverity of alcoholismDifferent brain regionsTwo-tissue compartment modelSerotonin innervationTransporter availabilityAlcoholic subjectsRodent modelsAlcohol dependenceDisease severitySignificant negative correlationBrain regionsSerotonin transporterSubjects SubjectsAlcoholismTomography imagingSignificant differencesPatientsTreatment implications: using neuroscience to guide the development of new pharmacotherapies for alcoholism.
Krishnan-Sarin S, O'Malley S, Krystal JH. Treatment implications: using neuroscience to guide the development of new pharmacotherapies for alcoholism. Alcohol Research 2008, 31: 400-7. PMID: 23584013, PMCID: PMC3860468.Peer-Reviewed Original ResearchConceptsAlcohol dependenceCurrent treatment optionsAlcohol-drinking behaviorDifferent neurochemical systemsAdjunctive treatmentModest efficacyTreatment optionsNew medicationsNew pharmacotherapiesMedicationsHealth problemsNeurochemical systemsPharmacotherapyTreatmentGreat needCertain genesNaltrexoneAlcoholismDisulfiramDrinkers
2007
Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study
Gelernter J, Gueorguieva R, Kranzler HR, Zhang H, Cramer J, Rosenheck R, Krystal JH, Group T. Opioid Receptor Gene (OPRM1, OPRK1, and OPRD1) Variants and Response to Naltrexone Treatment for Alcohol Dependence: Results From the VA Cooperative Study. Alcohol Clinical And Experimental Research 2007, 31: 555-563. PMID: 17374034, DOI: 10.1111/j.1530-0277.2007.00339.x.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlcoholismConfidence IntervalsDNADouble-Blind MethodExonsFemaleGenetic VariationGenotypeHumansLinear ModelsLogistic ModelsMaleMiddle AgedNaltrexoneNarcotic AntagonistsOdds RatioProportional Hazards ModelsPsychiatric Status Rating ScalesReceptors, Opioid, deltaReceptors, Opioid, kappaReceptors, Opioid, muSmokingTreatment OutcomeUnited StatesUnited States Department of Veterans AffairsConceptsAlcohol dependenceOpioid receptorsTreatment responseVA Cooperative StudyRate of relapsePredictors of responseAlcohol-dependent male subjectsMu-opioid receptorsKappa-opioid receptorsCourse of treatmentShort-term treatmentReceptor gene variantsOpioid receptor geneAsn40Asp polymorphismAvailable medicationsNaltrexone treatmentSpecific pharmacotherapyPretreatment numberDrug naltrexoneNaltrexoneMale subjectsCooperative StudyRelapseHeavy drinkingIndividual single nucleotide polymorphisms
2006
Genetic and Environmental Predictors of Early Alcohol Use
Kaufman J, Yang BZ, Douglas-Palumberi H, Crouse-Artus M, Lipschitz D, Krystal JH, Gelernter J. Genetic and Environmental Predictors of Early Alcohol Use. Biological Psychiatry 2006, 61: 1228-1234. PMID: 17123474, DOI: 10.1016/j.biopsych.2006.06.039.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAlcohol DrinkingAllelesChildChild AbuseChild, PreschoolCohort StudiesDNAFemaleFollow-Up StudiesGenetic VariationGenotypeHumansMaleMental DisordersPredictive Value of TestsPrognosisPsychiatric Status Rating ScalesRiskSerotonin Plasma Membrane Transport ProteinsSocial EnvironmentSocial SupportStress Disorders, Post-TraumaticConceptsEarly alcohol useAlcohol useMaltreated childrenLater alcohol dependenceSubstance use disordersSubstance abuse problemsHigh riskMother-child relationsAlcohol dependenceSeverity of maltreatmentProtective factorsHome careIntervention effortsPotent predictorCommunity controlsAbuse problemsTransporter genotypeChildrenPredictorsMaltreatmentRiskγ-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment
Krystal JH, Staley J, Mason G, Petrakis IL, Kaufman J, Harris RA, Gelernter J, Lappalainen J. γ-Aminobutyric Acid Type A Receptors and Alcoholism: Intoxication, Dependence, Vulnerability, and Treatment. JAMA Psychiatry 2006, 63: 957-968. PMID: 16952998, DOI: 10.1001/archpsyc.63.9.957.Peer-Reviewed Original ResearchConceptsBrain GABA systemsGABA systemAlcohol dependenceWithdrawal symptomsGABA functionGamma-aminobutyric acid (GABA) functionCortical GABA levelsAlcohol withdrawal symptomsΓ-Aminobutyric Acid Type A ReceptorsEnvironmental risk factorsLong-term alcohol effectsType A ReceptorsAlcohol-dependent individualsLong-term sobrietyGABA releaseNeurosteroid levelsAcute withdrawalAlcoholism vulnerabilityGABA neurotransmissionRisk factorsGABA levelsExtrasynaptic locationsLow chloride conductanceReceptor densityTonic component