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 ResearchConceptsDorsal 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 data
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 Administration
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 site
2007
Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors
Trevisan L, Petrakis IL, Pittman B, Gueorguieva R, D’Souza D, Perry E, Limoncelli D, Krystal JH. Absence of Significant Interactive Effects of High‐Dose d‐Cycloserine and Ethanol in Healthy Human Subjects: Preliminary Insights Into Ethanol Actions at the GlycineB Site of NMDA Glutamate Receptors. Alcohol Clinical And Experimental Research 2007, 32: 36-42. PMID: 18028532, DOI: 10.1111/j.1530-0277.2007.00543.x.Peer-Reviewed Original ResearchConceptsCo-agonist siteHealthy human subjectsEthanol administrationD-cycloserineHigh-dose d-cycloserineAlcohol levelsReceptor functionPlacebo 4 hoursDouble-blind conditionsNMDA receptor functionNMDA glutamate receptorsMild sedative effectDoses of ethanolGlutamate receptor functionBreath alcohol levelsHuman subjectsVerbal fluencyGlycineB siteGroups of subjectsEthanol antagonismCombination of ethanolSedative effectsNMDA receptorsClinical significanceGlutamate receptorsEffect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients
Krupitsky EM, Neznanova O, Masalov D, Burakov AM, Didenko T, Romanova T, Tsoy M, Bespalov A, Slavina TY, Grinenko AA, Petrakis IL, Pittman B, Gueorguieva R, Zvartau EE, Krystal JH. Effect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients. American Journal Of Psychiatry 2007, 164: 519-523. PMID: 17329479, DOI: 10.1176/ajp.2007.164.3.519.Peer-Reviewed Original ResearchConceptsNMDA receptor antagonist memantineAlcohol cue-induced cravingEffects of memantineAspartic acid (NMDA) glutamate receptorsDose-related fashionDouble-blind conditionsNMDA receptor functionNMDA receptor antagonistAlcohol-dependent patientsAlcohol cuesCue-induced alcoholTreatment of alcoholismCue-induced cravingEthanol-like effectsReceptor antagonistAlcohol-dependent inpatientsGlutamate receptorsMemantineAlcohol cravingMotivational disturbancesRandomized orderReceptor functionBehavioral effectsSubjective effectsTest day
2002
Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms
Abi-Saab W, Seibyl JP, D'Souza C, Karper LP, Gueorgueva R, Abi-Dargham A, Wong ML, Rajhans S, Erdos JP, Heninger GR, Charney DS, Krystal JH. Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms. Psychopharmacology 2002, 162: 55-62. PMID: 12107618, DOI: 10.1007/s00213-002-1057-7.Peer-Reviewed Original ResearchConceptsReceptor antagonismSchizophrenic patientsNeuroleptic-free schizophrenic patientsBrief Psychiatric Rating ScaleDouble-blind conditionsPsychiatric Rating ScaleTest dayRitanserin pretreatmentIntravenous infusionReceptor modulationAntipsychotic activityMale inpatientsReceptor stimulationPlasma prolactinCortisol levelsSchizoaffective disorderSchizophrenia symptomsPositive symptomsNegative symptomsRandomized orderPatientsRating ScaleBehavioral activationSymptomsRitanserin
2000
IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans
D’Souza D, Gil R, Cassello K, Morrissey K, Abi-Saab D, White J, Sturwold R, Bennett A, Karper L, Zuzarte E, Charney D, Krystal J. IV glycine and oral d-cycloserine effects on plasma and CSF amino acids in healthy humans. Biological Psychiatry 2000, 47: 450-462. PMID: 10704956, DOI: 10.1016/s0006-3223(99)00133-x.Peer-Reviewed Original ResearchMeSH KeywordsAcoustic StimulationAdministration, OralAdultAmino AcidsAntimetabolitesBiological AvailabilityCycloserineDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycineHumansInjections, IntravenousMaleMiddle AgedNeuropsychological TestsPsychiatric Status Rating ScalesReceptors, GlycineReceptors, N-Methyl-D-AspartateReflex, StartleSerineConceptsAcoustic startle responseN-methyl-D-aspartate (NMDA) glutamate receptorsD-cycloserineStartle responseCentral nervous system effectsTest dayCSF glycine levelsOral D-cycloserineCSF amino acidsNervous system effectsDouble-blind conditionsCognitive test performanceD-cycloserine effectsHealthy human subjectsCentral bioavailabilityIntravenous glycineLumbar punctureSecond test dayGlycine administrationModulates neurotransmissionGlycine levelsGlutamate receptorsCoagonist siteCerebrospinal fluidHealthy humansAttenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine: Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists
Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH. Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine: Support for Hyperglutamatergic Effects of N-methyl-D-aspartate Receptor Antagonists. JAMA Psychiatry 2000, 57: 270-276. PMID: 10711913, DOI: 10.1001/archpsyc.57.3.270.Peer-Reviewed Original ResearchMeSH KeywordsAdultAffectBrief Psychiatric Rating ScaleCognition DisordersDouble-Blind MethodExcitatory Amino Acid AntagonistsFemaleGlutamatesHumansKetamineLamotrigineMaleMental DisordersPerceptual DisordersPlacebosPsychiatric Status Rating ScalesReceptors, N-Methyl-D-AspartateSchizophreniaSchizophrenic PsychologyTriazinesVerbal LearningConceptsN-methyl-D-aspartate receptor antagonistNMDA receptor dysfunctionReceptor antagonistNeuropsychiatric effectsGlutamate releaseReceptor dysfunctionSymptom subscalesPlacebo 2 hoursClinician-Administered Dissociative States ScaleAdministration of lamotrigineAdministration of ketamineDouble-blind conditionsNMDA receptor antagonistMood-elevating effectsPositive symptom subscaleBrief Psychiatric RatingNovel therapeutic agentsNegative symptom subscaleHopkins Verbal Learning TestVerbal Learning TestKetamine effectsPsychiatric illnessHealthy subjectsPathophysiologic processesPreclinical studiesAntidepressant effects of ketamine in depressed patients
Berman R, Cappiello A, Anand A, Oren D, Heninger G, Charney D, Krystal J. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry 2000, 47: 351-354. PMID: 10686270, DOI: 10.1016/s0006-3223(99)00230-9.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntidepressive AgentsDepressive Disorder, MajorDose-Response Relationship, DrugDouble-Blind MethodExcitatory Amino Acid AntagonistsFemaleGlutamic AcidHumansInjections, IntravenousKetamineMaleMiddle AgedPsychiatric Status Rating ScalesReceptors, N-Methyl-D-AspartateSeverity of Illness IndexConceptsMajor depressionN-methyl-D-aspartate receptor antagonistBrain glutamate systemDouble-blind trialDouble-blind conditionsTreatment of depressionMechanism of actionPlacebo infusionAntidepressant effectsIntravenous treatmentSingle doseReceptor antagonistDepressed patientsGlutamate systemDepressive symptomsPreclinical researchKetamine hydrochlorideDepressionPotential roleTest dayTreatment effectsPatientsKetamineSaline solutionTreatment
1997
Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-Chlorophenylpiperazine (mCPP)
Krystal J, Webb E, Grillon C, Cooney N, Casal L, Morgan III. C, Southwick S, Davis M, Charney D. Evidence of acoustic startle hyperreflexia in recently detoxified early onset male alcoholics: modulation by yohimbine and m-Chlorophenylpiperazine (mCPP). Psychopharmacology 1997, 131: 207-215. PMID: 9203230, DOI: 10.1007/s002130050285.Peer-Reviewed Original ResearchConceptsHealthy subjectsAcoustic startle responseEthanol withdrawalStartle responseStartle magnitudeStartle amplitudeRandomized orderAcoustic startle magnitudeChronic alcoholic patientsSerotonin partial agonistDouble-blind conditionsAcoustic startle amplitudeNumber of episodesMale healthy subjectsΑ2-adrenergic antagonistTest dayMale patientsPlacebo dayAlcoholic patientsIntravenous infusionNoradrenergic functionYohimbine effectAlcohol detoxificationDrug infusionPreclinical studies
1996
AMPT Effects on Cue‐Induced Craving for Cocaine
Petrakis I, Satel S, Stine S, Kosten T, Namanworth S, Charney D, Krystal J. AMPT Effects on Cue‐Induced Craving for Cocaine. American Journal On Addictions 1996, 5: 313-320. DOI: 10.1111/j.1521-0391.1996.tb00317.x.Peer-Reviewed Original ResearchCue-induced cravingCue exposure sessionsDouble-blind conditionsCocaine-dependent patientsNorepinephrine metaboliteAcute reductionPara-tyrosineDopamine metabolitesPlasma levelsHomovanillic acidSelf-report assessmentsCatecholamine synthesisCocaine cravingCrossover designExposure sessionsCue exposureCravingDiphenhydramineCocaineSerotonergic and noradrenergic dysregulation in alcoholism: m- chlorophenylpiperazine and yohimbine effects in recently detoxified alcoholics and healthy comparison subjects
Krystal JH, Webb E, Cooney NL, Kranzler HR, Southwick SW, Heninger GR, Charney DS. Serotonergic and noradrenergic dysregulation in alcoholism: m- chlorophenylpiperazine and yohimbine effects in recently detoxified alcoholics and healthy comparison subjects. American Journal Of Psychiatry 1996, 153: 83-92. PMID: 8540598, DOI: 10.1176/ajp.153.1.83.Peer-Reviewed Original ResearchConceptsHealthy comparison subjectsAlcoholic patientsComparison subjectsCortisol responseYohimbine infusionPostsynaptic noradrenergic receptorsBlood pressure responseDouble-blind conditionsNoradrenergic reactivitySaline placeboNoradrenergic receptorsMHPG levelsIntravenous infusionYohimbine effectMHPG responsePlasma levelsNoradrenergic systemPersistent alterationsNoradrenergic dysregulationMale inpatientsDrug effectsNeuroendocrine responsivityPatientsPhysiologic responsesPlasma cortisol
1994
Specificity of Ethanollike Effects Elicited by Serotonergic and Noradrenergic Mechanisms
Krystal JH, Webb E, Cooney N, Kranzler HR, Charney DS. Specificity of Ethanollike Effects Elicited by Serotonergic and Noradrenergic Mechanisms. JAMA Psychiatry 1994, 51: 898-911. PMID: 7944878, DOI: 10.1001/archpsyc.1994.03950110058008.Peer-Reviewed Original ResearchConceptsVisual analog scaleAnalog scaleScale scoreVisual analog scale scoreYohimbine hydrochlorideAnalog scale scoreDouble-blind conditionsEffect of mCPPReceptor partial agonistEffects of ethanolNoradrenergic mechanismsIntravenous infusionPlasma levelsSerotonergic systemNoradrenergic systemPlaceboDiscriminative propertiesMale inpatientsYohimbinePlasma prolactinCortisol levelsPartial agonistSerotonergic contributionAlcohol dependenceDays of testing