2023
Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments
Krystal J, Kaye A, Jefferson S, Girgenti M, Wilkinson S, Sanacora G, Esterlis I. Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2305772120. PMID: 38011560, PMCID: PMC10710048, DOI: 10.1073/pnas.2305772120.Peer-Reviewed Original ResearchKetamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms
Krystal J, Kavalali E, Monteggia L. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology 2023, 49: 41-50. PMID: 37488280, PMCID: PMC10700627, DOI: 10.1038/s41386-023-01629-w.Peer-Reviewed Original ResearchConceptsMood disordersEffective treatmentN-methyl-D-aspartate receptorsGlutamatergic N-methyl-D-aspartate receptorRapid antidepressant effectsTreatment-resistant depressionKey clinical aspectsRapid antidepressant actionsNovel effective treatmentsSynaptic signaling mechanismsMore effective treatmentsSynaptic plasticity mechanismsOpen channel blockerAntidepressant actionAntidepressant effectsKetamine effectsChannel blockersClinical aspectsClinical practiceNew treatmentsNeuropsychiatric disordersCircuit mechanismsDisordersTreatmentKetamine
2022
Long-term safety of ketamine and esketamine in treatment of depression
Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opinion On Drug Safety 2022, 21: 777-787. PMID: 35416105, DOI: 10.1080/14740338.2022.2066651.Peer-Reviewed Original ResearchConceptsLong-term safetyClinical trialsRacemic ketamineLong-term safety effectsRapid-acting antidepressant effectsLower urinary tract symptomsKetamine/esketamineTreatment-resistant depressionUrinary tract symptomsCommon side effectsTreatment of depressionLong-term impairmentElevated heart ratePhase three clinical trialsTract symptomsAntidepressant effectsBlood pressureIncreased riskBladder pathologyEsketamineHeart ratePsychiatric disordersSide effectsCognitive impairmentHigh dosesmTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression
Averill LA, Averill CL, Gueorguieva R, Fouda S, Sherif M, Ahn KH, Ranganathan M, D'Souza DC, Southwick SM, Sanacora G, Duman RS, Krystal JH, Abdallah CG. mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression. Journal Of Affective Disorders 2022, 303: 91-97. PMID: 35101523, DOI: 10.1016/j.jad.2022.01.104.Peer-Reviewed Original ResearchConceptsAntisuicidal effectsAntidepressant effectsSuicidal ideationKetamine-induced reductionTreatment-resistant depressionLimited treatment optionsCross-over trialMajor depressive episodeOral rapamycinPublic health crisisKetamine administrationTreatment optionsDepressive episodeParent studyOverall severityKetamineTwo weeksBeck ScaleRapamycin complex 1Mechanistic targetPatientsSignificant main effectHealth crisisRobust improvementFuture studies
2021
Mapping data‐driven individualized neurobehavioral phenotypes in heavy alcohol drinkers
DeMartini KS, Gueorguieva R, Pearlson G, Krishnan‐Sarin S, Anticevic A, Ji LJ, Krystal JH, O’Malley S. Mapping data‐driven individualized neurobehavioral phenotypes in heavy alcohol drinkers. Alcohol Clinical And Experimental Research 2021, 45: 841-853. PMID: 33605439, DOI: 10.1111/acer.14580.Peer-Reviewed Original ResearchConceptsConfirmatory factor analysisIncentive salienceNeurofunctional domainsAlcohol use disorderExecutive functionLatent factorsPhysical neglectSelf-report measuresChildhood emotional abuseUse disordersChildhood physical neglectEarly life stressSignificant predictorsMultiple significant predictorsMultiple causes modelCurrent AUDNegative emotionalityAddiction developmentEmotional abuseChildhood neglectFactor structureDrinking frequencySalienceCause modelFactor analysis
2019
Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine’s Antidepressant Effect—Reply
Krystal JH, Yoon G, Petrakis IL. Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine’s Antidepressant Effect—Reply. JAMA Psychiatry 2019, 76: 658-659. PMID: 31042270, DOI: 10.1001/jamapsychiatry.2019.0763.Peer-Reviewed Original ResearchLower synaptic density is associated with depression severity and network alterations
Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, Esterlis I. Lower synaptic density is associated with depression severity and network alterations. Nature Communications 2019, 10: 1529. PMID: 30948709, PMCID: PMC6449365, DOI: 10.1038/s41467-019-09562-7.Peer-Reviewed Original ResearchConceptsMajor depressive disorderPost-traumatic stress disorderLower synaptic densitySynaptic densityPositron emission tomographyFunctional connectivityNetwork alterationsSynaptic vesicle glycoprotein 2ASymptoms of depressionSynaptic lossDepressive disorderHealthy controlsNerve terminalsDepressive symptomsDepression severityUnmedicated individualsSynaptic connectionsEmission tomographyStress disorderVivo evidenceSymptomsDepressionSeverityDisordersAlterations
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 pathologyAntidepressantsNeurobiologyInhibitionActivationPharmacodynamicsPharmacokinetics
2017
Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies
Esterlis I, Holmes SE, Sharma P, Krystal JH, DeLorenzo C. Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies. Biological Psychiatry 2017, 84: 95-105. PMID: 29100629, PMCID: PMC5858955, DOI: 10.1016/j.biopsych.2017.08.025.Peer-Reviewed Original ResearchConceptsMajor depressive disorderPositron emission tomography studyEmission tomography studiesMGluR5 modulationAntidepressant responseStress disorderBipolar disorderStress-related psychiatric disordersTomography studyAntagonism of mGluR5Ketamine’s antidepressant responseSignificant side effectsPromising therapeutic targetReceptor imaging studiesPosttraumatic stress disorderMDD heterogeneityManic mood statesAntidepressant efficacyObsessive-compulsive disorderDepressive disorderSubtype 5Neurotransmitter systemsPsychiatric disordersReceptor 5Side effectsKetamine-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 decreaseAnterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach
Abdallah CG, Wrocklage KM, Averill CL, Akiki T, Schweinsburg B, Roy A, Martini B, Southwick SM, Krystal JH, Scott JC. Anterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach. Translational Psychiatry 2017, 7: e1045-e1045. PMID: 28244983, PMCID: PMC5545643, DOI: 10.1038/tp.2017.12.Peer-Reviewed Original ResearchConceptsGlobal brain connectivityPosttraumatic stress disorderAnterior hippocampusStress disorderPTSD severityTraumatic brain injuryMultimodal approachOverall PTSD severityAnxiety-related behaviorDorsolateral prefrontal connectivityDorsolateral prefrontal cortexElevated PTSD symptomsAnatomical dysconnectivityHippocampal dysconnectivityUS veteransBrain injuryHippocampal volumePTSD subgroupBrain biomarkersClinical valueMedication statusPrefrontal connectivitySignificant associationPrefrontal cortexBrain connectivity
2015
Personalised pharmacotherapy: an interim solution for antidepressant treatment?
Chekroud AM, Krystal JH. Personalised pharmacotherapy: an interim solution for antidepressant treatment? The BMJ 2015, 350: h2502. PMID: 25976040, DOI: 10.1136/bmj.h2502.Peer-Reviewed Original ResearchKetamine as a promising prototype for a new generation of rapid‐acting antidepressants
Abdallah CG, Averill LA, Krystal JH. Ketamine as a promising prototype for a new generation of rapid‐acting antidepressants. Annals Of The New York Academy Of Sciences 2015, 1344: 66-77. PMID: 25727103, PMCID: PMC4412785, DOI: 10.1111/nyas.12718.Peer-Reviewed Original ResearchConceptsOpen-label studyRobust antidepressant effectsRapid-acting antidepressantsNeurobiology of depressionRoute of administrationModerate adverse effectsMechanism of actionTrauma-related disordersTraditional antidepressantsAntidepressant effectsTransient mildChronic treatmentControlled TrialsClinical effectsOptimal dosingPsychopharmacologic interventionsPatient groupPatient populationTreatment targetsKetamineAntidepressantsRelevant biomarkersAdverse effectsNeurobiological underpinningsInfusion
2013
Rapid-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-methylDose
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
Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service–Related PTSD: A Randomized Trial
Krystal JH, Rosenheck RA, Cramer JA, Vessicchio JC, Jones KM, Vertrees JE, Horney RA, Huang GD, Stock C, Group F. Adjunctive Risperidone Treatment for Antidepressant-Resistant Symptoms of Chronic Military Service–Related PTSD: A Randomized Trial. JAMA 2011, 306: 493-502. PMID: 21813427, DOI: 10.1001/jama.2011.1080.Peer-Reviewed Original ResearchConceptsMilitary-related posttraumatic stress disorderMontgomery-Asberg Depression Rating ScalePosttraumatic stress disorderClinical Global Impression ScaleClinician-Administered PTSD ScaleHamilton Anxiety ScalePlacebo-controlled multicenter trialCAPS scoresSelf-reported weight gainSecond-generation antipsychotic risperidoneAdjunctive risperidone treatmentAntidepressant-resistant symptomsPrimary outcome measureChronic military-related posttraumatic stress disorderGlobal Impression ScaleOutpatient medical centerDepression Rating ScaleSymptoms of depressionQuality of lifePlacebo groupRisperidone groupVeterans RANDAdverse eventsOngoing symptomsMulticenter trial
2010
A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship
Sen S, Kranzler HR, Krystal JH, Speller H, Chan G, Gelernter J, Guille C. A Prospective Cohort Study Investigating Factors Associated With Depression During Medical Internship. JAMA Psychiatry 2010, 67: 557-565. PMID: 20368500, PMCID: PMC4036806, DOI: 10.1001/archgenpsychiatry.2010.41.Peer-Reviewed Original ResearchMeSH KeywordsAdultCohort StudiesDepressionDepressive DisorderDepressive Disorder, MajorFemaleGenotypeHealth StatusHumansInternship and ResidencyLife Change EventsMaleMedicinePolymorphism, Single NucleotidePrevalenceProspective StudiesRisk FactorsSerotonin Plasma Membrane Transport ProteinsStress, PsychologicalStudents, MedicalSurveys and QuestionnairesConceptsDepressive symptomsPHQ-9 depression scoresProspective cohort studyPrevalence of depressionPatient Health QuestionnaireProportion of participantsMedical internsMedical internshipGreater increasePHQ-9 criteriaCohort studyHealth QuestionnaireMood symptomsGeneral populationDepression scoresUS hospitalsSymptomsSerotonin transporter protein geneGenetic polymorphismsDepressionGenetic factorsLife stressMarked increaseRecent reportsResidency programs
2007
Ketamine and the potential role for rapid-acting antidepressant medications
Krystal JH. Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Medical Weekly 2007, 137: 215-216. PMID: 17525875, DOI: 10.4414/smw.2007.11932.Peer-Reviewed Original ResearchAntiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam
Krupitsky EM, Rudenko AA, Burakov AM, Slavina TY, Grinenko AA, Pittman B, Gueorguieva R, Petrakis IL, Zvartau EE, Krystal JH. Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam. Alcohol Clinical And Experimental Research 2007, 31: 604-611. PMID: 17374039, DOI: 10.1111/j.1530-0277.2007.00344.x.Peer-Reviewed Original ResearchConceptsAlcohol withdrawal symptomsWithdrawal symptomsActive medicationAlcohol withdrawalGlutamatergic activationEthanol detoxificationAspartate glutamate receptor antagonistGlutamate release inhibitorGlutamate receptor antagonistsMale alcohol-dependent inpatientsAdditional diazepamDiazepam administrationClinical evidenceStandard pharmacotherapyReceptor antagonistAlcohol-dependent inpatientsRelease inhibitorEthanol dependenceAlcohol abstinenceGlutamate receptorsReceptor inhibitorsWithdrawal severityPlaceboMedicationsNew treatments
2006
Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children
Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S, Krystal JH, Gelernter J. Brain-Derived Neurotrophic Factor–5-HTTLPR Gene Interactions and Environmental Modifiers of Depression in Children. Biological Psychiatry 2006, 59: 673-680. PMID: 16458264, DOI: 10.1016/j.biopsych.2005.10.026.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentBrain-Derived Neurotrophic FactorCase-Control StudiesChi-Square DistributionChildChild AbuseChild, PreschoolDepressionDNA Mutational AnalysisEnvironmentFemaleGene FrequencyGenetic VariationGenotypeHumansMaleMethioninePredictive Value of TestsPsychiatric Status Rating ScalesRisk FactorsSerotonin Plasma Membrane Transport ProteinsSeverity of Illness IndexSocial SupportSurveys and QuestionnairesValineConceptsBrain-derived neurotrophic factor (BDNF) genotypeNeurotrophic factor genotypeSocial supportHigher depression scoresBDNF genotypeProportion scoreBDNF geneProtective effectDepression scoresComparison subjectsPsychiatric symptomatologyModerate riskEnvironmental modifiersDepressionFactor genotypeChildrenDNA specimensStandard research instrumentsShort alleleRiskMaltreatment historyCurrent dataScoresAncestry informative markersChild abuse