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 ResearchConceptsTreatment 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 doses
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 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 outcome
2012
Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans
Moghaddam B, Krystal JH. Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of NMDA Receptor Antagonists in Animals and Humans. Schizophrenia Bulletin 2012, 38: 942-949. PMID: 22899397, PMCID: PMC3446228, DOI: 10.1093/schbul/sbs075.Peer-Reviewed Original ResearchMeSH KeywordsAllosteric RegulationAnimalsAntipsychotic AgentsBrief Psychiatric Rating ScaleCerebral CortexDisease Models, AnimalDopamineEmotionsGlutamic AcidHumansKetamineNeurosciencesPhencyclidinePsychoses, Substance-InducedReceptor, Metabotropic Glutamate 5Receptors, Dopamine D2Receptors, Metabotropic GlutamateReceptors, N-Methyl-D-AspartateSchizophreniaSynapsesTranslational Research, BiomedicalConceptsNMDA receptor antagonistReceptor antagonistDopamine hypothesisN-methyl-D-aspartate receptor antagonistGlutamate synaptic functionTranslational neuroscience studiesTreatment of schizophreniaPathophysiology of schizophreniaPotential treatment targetPotential new targetsDopamine antagonistsCortical functionAnimal studiesTreatment targetsClinical testingSynaptic functionAntagonistTranslational toolSchizophreniaTranslational research fundingTranslational researchPotential mechanismsNew targetsAngel dustSystems neuroscience
2011
Challenges in the design and conduct of controlled clinical effectiveness trials in schizophrenia
Rosenheck RA, Krystal JH, Lew R, Barnett PG, Thwin SS, Fiore L, Valley D, Huang GD, Neal C, Vertrees JE, Liang MH. Challenges in the design and conduct of controlled clinical effectiveness trials in schizophrenia. Clinical Trials 2011, 8: 196-204. PMID: 21270143, DOI: 10.1177/1740774510392931.Peer-Reviewed Original ResearchConceptsSchizo-affective disorderAntipsychotic medicationUsual careMedication adherenceEffectiveness trialCommon co-morbid illnessesCo-morbid illnessHigh-risk patientsComparative effectiveness trialClinical effectiveness trialVeterans Health AdministrationNew antipsychotic medicationsTreatment of schizophreniaPsychiatric inpatient hospitalizationQuality of lifeHealth care costsElectronic medical recordsLong-term trialsPatient's psychiatristPrimary endpointSecondary endpointsFirst hospitalizationRecent hospitalizationInjectable risperidoneUnstable patients
2010
Contributions of Glutamate and GABA Systems to the Neurobiology and Treatment of Schizophrenia
Krystal J, Moghaddam B. Contributions of Glutamate and GABA Systems to the Neurobiology and Treatment of Schizophrenia. 2010, 433-461. DOI: 10.1002/9781444327298.ch21.Peer-Reviewed Original ResearchThe interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects
Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Machado-de-Sousa JP, Abrão J, Crippa JA, McGuire P, Krystal JH, Baker GB, Zuardi AW. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: Preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects. Progress In Neuro-Psychopharmacology And Biological Psychiatry 2010, 35: 198-202. PMID: 21062637, DOI: 10.1016/j.pnpbp.2010.11.002.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScaleHealthy human subjectsGlutamate receptor systemMale healthy volunteersNMDA receptor antagonistEffects of ketamineTreatment of schizophreniaPsychiatric Rating ScaleHuman subjectsWeak partial agonistNon-significant trendKetamine administrationReceptor antagonistEndocannabinoid systemHealthy volunteersPartial agonistActivation subscalePsychiatric conditionsKetamineRandomized orderReceptor systemBehavioral effectsRating ScaleCannabidiolPreliminary evidencePotential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists
Krystal JH, Mathew SJ, D’Souza D, Garakani A, Gunduz-Bruce H, Charney DS. Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists. CNS Drugs 2010, 24: 669-693. PMID: 20658799, DOI: 10.2165/11533230-000000000-00000.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsPreliminary clinical trialsPositive allosteric modulatorsPsychiatric disordersClinical trialsAnimal modelsAllosteric modulatorsGroup II mGluR agonistGroup IMetabotropic glutamate receptor agonistAnxiety disordersPotential psychiatric applicationsGlutamate receptor agonistsMetabotropic glutamate receptorsTreatment of schizophreniaRole of glutamateForm of depressionMGluR agonistAntidepressant propertiesMGluR5 agonistReceptor agonistGlutamate receptorsMood disordersArea of schizophreniaPromising agentAgonists
2003
NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology 2003, 169: 215-233. PMID: 12955285, DOI: 10.1007/s00213-003-1582-z.Peer-Reviewed Original ResearchConceptsTreatment of schizophreniaReceptor antagonistN-methyl-D-aspartate (NMDA) glutamate receptor antagonistPharmacotherapy of schizophreniaGlutamate receptor antagonistsReceptor antagonist effectsNMDA receptor antagonistNMDA receptor antagonist effectsNMDA receptor contributionTranslational Neuroscience ApproachGlutamatergic activityGlutamatergic functionNew medicationsClinical studiesReceptor contributionTherapeutic implicationsMedication developmentCortical connectivityAntagonist effectsAntagonist responseNew treatment insightsSchizophreniaModel psychosisTreatment insightsAntagonist
1997
The role of serotonin in the pathophysiology and treatment of schizophrenia
Abi-Dargham A, Laruelle M, Aghajanian GK, Charney D, Krystal J. The role of serotonin in the pathophysiology and treatment of schizophrenia. Journal Of Neuropsychiatry 1997, 9: 1-17. PMID: 9017523, DOI: 10.1176/jnp.9.1.1.Peer-Reviewed Original ResearchConceptsRole of serotoninBeneficial effectsSubcortical dopamine activityCerebrospinal fluid studiesCortex of patientsTreatment of schizophreniaBrain tissue analysisSerotonergic hypofunctionDopaminergic antagonistsPharmacological challengeDopamine activityNegative symptomsFluid studiesSchizophreniaPathophysiologySerotoninIllnessTissue analysisTreatmentMore researchAntagonismCompelling evidenceHypofunctionPatientsAntagonist