2023
Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia
Surti T, Ranganathan M, Johannesen J, Gueorguieva R, Deaso E, Kenney J, Krystal J, D'Souza D. Randomized controlled trial of the glycine transporter 1 inhibitor PF-03463275 to enhance cognitive training and neuroplasticity in schizophrenia. Schizophrenia Research 2023, 256: 36-43. PMID: 37141764, PMCID: PMC10257994, DOI: 10.1016/j.schres.2023.04.010.Peer-Reviewed Original ResearchConceptsGlycine transporter 1Cytochrome P450 2D6 extensive metabolizersGlyT1 inhibitorsWeeks of washoutWeeks of CTMedication adherenceReceptor hypofunctionImpaired neuroplasticityPharmacodynamic variabilityNMDAR functionExtensive metabolizersTreatment periodPsychotic symptomsStable outpatientsCognitive impairmentGlyT1 occupancyTransporter 1CTNeuroplasticityCognitive training strategiesSchizophreniaComputerized CTCognitive performanceAugmentation studiesGreater improvement
2022
Illness Phase as a Key Assessment and Intervention Window for Psychosis
Kohler C, Wolf D, Abi-Dargham A, Anticevic A, Cho Y, Fonteneau C, Gil R, Girgis R, Gray D, Grinband J, Javitch J, Kantrowitz J, Krystal J, Lieberman J, Murray J, Ranganathan M, Santamauro N, Van Snellenberg J, Tamayo Z, Group T, D'Souza D, Srihari V, Gueorguieva R, Patel P, Forselius-Bielen K, Lu J, Butler A, Fram G, Afriyie-Agyemang Y, Selloni A, Cadavid L, Gomez-Luna S, Gupta A, Radhakrishnan R, Rashid A, Aker R, Abrahim P, Nia A, Surti T, Kegeles L, Carlson M, Goldberg T, Gangwisch J, Benedict E, Govil P, Brazis S, Mayer M, de la Garrigue N, Fallon N, Baumvoll T, Abeykoon S, Perlman G, Bobchin K, Elliott M, Schmidt L, Rush S, Port A, Heffernan Z, Laney N, Kantor J, Hohing T, Gur R, Gur R, Calkins M. Illness Phase as a Key Assessment and Intervention Window for Psychosis. Biological Psychiatry Global Open Science 2022, 3: 340-350. PMID: 37519466, PMCID: PMC10382701, DOI: 10.1016/j.bpsgos.2022.05.009.Peer-Reviewed Original ResearchIllness phasePotential critical windowsPhase-specific biomarkersDopaminergic abnormalitiesFunctional outcomeSpecialty careSymptom assessmentIllness stageChronic illnessClinical assessmentIllness trajectoryNeurophysiological biomarkersFunctional abnormalitiesClinical careEarly psychosisMemory dysfunctionPsychotic disordersTreatment targetsAllostatic adaptationIntervention windowClinical programsBrain developmentCritical windowDysfunctionIllnessCorrection to: 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
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. Correction to: 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: 1583-1584. PMID: 35545665, PMCID: PMC9205895, DOI: 10.1038/s41386-022-01339-9.Peer-Reviewed Original ResearchDose-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 ResearchConceptsPosttraumatic 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
2021
Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia
Abi-Dargham A, Javitch JA, Slifstein M, Anticevic A, Calkins ME, Cho YT, Fonteneau C, Gil R, Girgis R, Gur RE, Gur RC, Grinband J, Kantrowitz J, Kohler C, Krystal J, Murray J, Ranganathan M, Santamauro N, Van Snellenberg J, Tamayo Z, Wolf D, D’Souza D, Srihari V, Gueorguieva R, Patel P, Forselius-Bielen K, Lu J, Butler A, Fram G, Afriyie-Agyemang Y, Selloni A, Cadavid L, Gomez-Luna S, Gupta A, Radhakrishnan R, Rashid A, Aker R, Abrahim P, Nia A, Surti T, Kegeles L, Carlson M, Goldberg T, Gangwisch J, Benedict E, Govil P, Brazis S, Mayer M, de la Garrigue N, Fallon N, Baumvoll T, Abeykoon S, Perlman G, Bobchin K, Elliott M, Schmidt L, Rush S, Port A, Heffernan Z, Laney N, Kantor J, Hohing T, Gray D, Lieberman J. Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia. Schizophrenia Bulletin 2021, 48: 199-210. PMID: 34423843, PMCID: PMC8781338, DOI: 10.1093/schbul/sbab095.Peer-Reviewed Original ResearchConceptsCortical dopamine neurotransmissionPositive allosteric modulationImportant therapeutic targetPF-06412562Dopaminergic receptorsD1R stimulationDA levelsTolerable dosesLevel of stimulationDopamine neurotransmissionReceptor stimulationTherapeutic targetPartial agonistCognitive deficitsBiased agonismFull agonismTarget engagementAllosteric modulationNew drugsStimulationPoor bioavailabilitySchizophreniaOptimal stimulationDrugsExpression levelsThe effect of ketamine on psychopathology and implications for understanding schizophrenia and its therapeutic use: a meta-analysis
Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, Driesen N, Ranganathan M, D'Souza D, Taylor M, Krystal J, Howes O. The effect of ketamine on psychopathology and implications for understanding schizophrenia and its therapeutic use: a meta-analysis. BJPsych Open 2021, 7: s237-s237. PMCID: PMC8771247, DOI: 10.1192/bjo.2021.634.Peer-Reviewed Original ResearchBrief Psychiatric Rating ScaleEffects of ketaminePlacebo conditionPositive symptomsKetamine administrationKetamine effectsHealthy participantsHealthy volunteersNegative symptomsTherapeutic useAcute ketamine administrationAcute ketamine challengeMagnitude of symptomsStudy-level dataSub-group analysisPsychiatric Rating ScaleSchizophrenia-like symptomatologySchizophrenia-like symptomsMean change scoresNegative Syndrome ScalePositive psychotic symptomsSignificant increaseEffect sizeBolus dosesKetamine challenge
2020
A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants
Abdallah CG, Ahn KH, Averill LA, Nemati S, Averill CL, Fouda S, Ranganathan M, Morgan PT, D’Souza D, Mathalon DH, Krystal JH, Driesen NR. A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants. Neuropsychopharmacology 2020, 46: 478-485. PMID: 32967000, PMCID: PMC7852889, DOI: 10.1038/s41386-020-00864-9.Peer-Reviewed Original ResearchConceptsConnectome fingerprintN-methyl-d-aspartate modulatorsNovel rapid-acting antidepressantsMajor depressive disorder patientsMechanism of antidepressantsWeeks of sertralineRapid-acting antidepressantsMagnetic resonance imaging studyDepressive disorder patientsExecutive networkEffects of ketamineLongitudinal functional magnetic resonance imaging studyResonance imaging studyFunctional magnetic resonance imaging studyBrain functional connectivityCohort AIntravenous infusionSubanesthetic doseClinical trialsNormal salineDisorder patientsConnectomics signaturesBrain circuitryKetamineImaging studiesAssociation of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia
Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, Driesen N, Ranganathan M, D’Souza D, Taylor M, Krystal JH, Howes OD. Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia. JAMA Network Open 2020, 3: e204693. PMID: 32437573, PMCID: PMC7243091, DOI: 10.1001/jamanetworkopen.2020.4693.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScalePlacebo conditionPositive symptomsNegative symptomsHealthy participantsMean differenceKetamine administrationPANSS scoresHealthy volunteersPsychotomimetic symptomsTherapeutic useAcute ketamine administrationAcute ketamine challengePlacebo-controlled studyEffect sizeMagnitude of symptomsStudy-level dataPsychiatric Rating ScaleMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsAssociation of ketamineNegative Syndrome ScaleSignificant increaseAcute administrationBolus dosesSingle-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans
Hu Y, Ranganathan M, Shu C, Liang X, Ganesh S, Osafo-Addo A, Yan C, Zhang X, Aouizerat BE, Krystal JH, D’Souza D, Xu K. Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Scientific Reports 2020, 10: 3450. PMID: 32103029, PMCID: PMC7044203, DOI: 10.1038/s41598-020-59827-1.Peer-Reviewed Original ResearchConceptsSpecific genesCell type-specific genesGene expressionSingle-cell transcriptomic profilingCell typesGene expression correlationsAlters gene expressionTranscriptome mappingTranscriptomic profilingExpression correlationEnrichment analysisCommon genesImportant medical implicationsSignificant genesGenesMajor immune cell typesCell proliferationImmune cell typesImmune responseCell toxicityMedical implicationsCellsImportant insightsExpressionHuman immune cellsModulation 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 ResearchConceptsAntidepressant 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
2018
Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
D’Souza D, Carson RE, Driesen N, Johannesen J, Ranganathan M, Krystal JH, Ahn K, Bielen K, Carbuto M, Deaso E, D’Souza D, Ranganathan M, Naganawa M, Ranganathan M, D’Souza D, Nabulsi N, Zheng M, Lin S, Huang Y, Carson R, Driesen N, Ahn K, Morgan P, Suckow R, He G, McCarthy G, Krystal J, Johannesen J, Kenney J, Gelernter J, Gueorguieva R, Pittman B. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biological Psychiatry 2018, 84: 413-421. PMID: 29499855, PMCID: PMC6068006, DOI: 10.1016/j.biopsych.2017.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAdultAzabicyclo CompoundsBrainCognitive DysfunctionDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycine Plasma Membrane Transport ProteinsHumansImidazolesKetamineLong-Term PotentiationMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedPositron-Emission TomographySchizophreniaYoung AdultConceptsHealthy control subjectsLong-term potentiationSchizophrenia patientsControl subjectsCognitive impairmentClinical trialsGlyT1 occupancyN-methyl-D-aspartate receptor functionGlycine transporter-1 inhibitorKetamine-induced disruptionKetamine-induced effectsFunctional magnetic resonance imagingMagnetic resonance imagingPositron emission tomographyMemory-related activationF-MKSubstudy 1Schizophrenia subjectsResonance imagingReceptor functionCortical regionsEmission tomographyTarget engagementPotentiationSchizophrenia
2017
Targeted neural network interventions for auditory hallucinations: Can TMS inform DBS?
Taylor JJ, Krystal JH, D'Souza DC, Gerrard JL, Corlett PR. Targeted neural network interventions for auditory hallucinations: Can TMS inform DBS? Schizophrenia Research 2017, 195: 455-462. PMID: 28969932, PMCID: PMC8141945, DOI: 10.1016/j.schres.2017.09.020.Peer-Reviewed Original ResearchConceptsDeep brain stimulationTranscranial magnetic stimulationAuditory hallucinationsBrain stimulationCombination of TMSTreatment-refractory schizophreniaAberrant neural networksRelevant neural networksNon-invasive formNeuromodulatory interventionsMagnetic stimulationPsychiatric disordersSymptom clusteringTherapeutic interventionsClinical decisionInvasive formNeurophysiological dataCausal evidencePsychiatric constructsStimulationNetwork modulationInterventionNeural networkSafety concernsInvestigational probes67 Ketamine-induced Changes in Neural Noise and their Relationship to Psychosis-like Symptoms
Cortes-Briones J, Skosnik P, D’Souza D, Abdallah C, Petrakis I, Krystal J. 67 Ketamine-induced Changes in Neural Noise and their Relationship to Psychosis-like Symptoms. Biological Psychiatry 2017, 81: s28. DOI: 10.1016/j.biopsych.2017.02.078.Peer-Reviewed Original Research
2016
The role of psychedelics in palliative care reconsidered: A case for psilocybin
Kelmendi B, Corlett P, Ranganathan M, D’Souza C, Krystal JH. The role of psychedelics in palliative care reconsidered: A case for psilocybin. Journal Of Psychopharmacology 2016, 30: 1212-1214. PMID: 27909173, DOI: 10.1177/0269881116675781.Peer-Reviewed Original Research
2015
Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine
Ahn KH, Sewell A, Elander J, Pittman B, Ranganathan M, Gunduz-Bruce H, Krystal J, D'Souza DC. Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine. Neuropsychopharmacology 2015, 40: 2822-2831. PMID: 25953357, PMCID: PMC4864658, DOI: 10.1038/npp.2015.132.Peer-Reviewed Original ResearchConceptsGABA deficitHealthy subjectsPsychotomimetic effectsIntravenous infusionSchizophrenia patientsPANSS positive symptoms subscaleDouble-blind crossover designStriatal dopamine releasePositive symptom subscaleAdministration of drugsDose of AMPHPartial inverse agonistSubclinical responsePharmacokinetic interactionsSubthreshold doseDopamine releaseBenzodiazepine receptorsSymptom subscalesCrossover designCADSS scoresPositive symptomsAMPHInverse agonistSubjective effectsTest day
2014
Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia.
Boggs DL, Carlson J, Cortes-Briones J, Krystal JH, D'Souza DC. Going up in smoke? A review of nAChRs-based treatment strategies for improving cognition in schizophrenia. Current Pharmaceutical Design 2014, 20: 5077-92. PMID: 24345265, PMCID: PMC4442779, DOI: 10.2174/1381612819666131216121019.Peer-Reviewed Original ResearchConceptsCognitive impairmentStandardized cognitive test batteryCognitive test batteryInformation processing impairmentsNicotinic medicationsProcessing impairmentsCore deficitAttentional deficitsTest batteryCognitive deficitsProximal measuresBrain functionCognitionSchizophreniaDeficitsImpairmentNumber of medicationsNicotinic acetylcholine receptorsCertain symptomsConsistent improvementClinical evidenceTreatment strategiesClinical studiesNicotinic receptorsClinical utility
2013
The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity
Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D'Souza DC, Gueorguieva R, He G, Leung HC, Ramani R, Anticevic A, Suckow RF, Morgan PT, Krystal JH. The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity. Neuropsychopharmacology 2013, 38: 2613-2622. PMID: 23856634, PMCID: PMC3828532, DOI: 10.1038/npp.2013.170.Peer-Reviewed Original ResearchConceptsNMDA-RsRelationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans
Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular Psychiatry 2013, 18: 1199-1204. PMID: 23337947, PMCID: PMC3646075, DOI: 10.1038/mp.2012.194.Peer-Reviewed Original ResearchConceptsFunctional connectivityNegative symptomsGamma-aminobutyric acid (GABA) neuronsNMDA receptor antagonist ketamineAspartate glutamate receptor antagonistContinuous ketamine infusionGlutamate receptor antagonistsNMDA-R antagonistsCortical functional connectivityNMDA-R antagonist ketamineSchizophrenia-like symptomsHealthy human subjectsNegative Syndrome ScaleBrain functional connectivityPrimary samplesRegion-specific mannerFunctional magnetic resonanceKetamine infusionReceptor antagonistPathological increaseSyndrome ScaleSymptomsPreclinical researchKetamineBrain oscillations
2012
Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies
Woods SW, Walsh BC, Hawkins KA, Miller TJ, Saksa JR, D'Souza DC, Pearlson GD, Javitt DC, McGlashan TH, Krystal JH. Glycine treatment of the risk syndrome for psychosis: Report of two pilot studies. European Neuropsychopharmacology 2012, 23: 931-940. PMID: 23089076, PMCID: PMC4028140, DOI: 10.1016/j.euroneuro.2012.09.008.Peer-Reviewed Original ResearchConceptsPilot studyRisk syndromeSyndrome patientsNegative symptomsShort-term pilot studyEffect sizeAdjunctive antipsychotic medicationOpen-label studyPatients meeting criteriaNMDA receptor functionDurability of effectPsychosis risk symptomsGlycine site agonistsGroup effect sizesWeeks of evaluationAntipsychotic medicationSyndrome subjectsPromising effect sizesTreatment needsLarge effect sizesMeeting criteriaCognitive impairmentReduced symptomsReceptor functionSymptoms
2011
Glutamatergic Modulation of Auditory Information Processing in the Human Brain
Gunduz-Bruce H, Reinhart RM, Roach BJ, Gueorguieva R, Oliver S, D'Souza DC, Ford JM, Krystal JH, Mathalon DH. Glutamatergic Modulation of Auditory Information Processing in the Human Brain. Biological Psychiatry 2011, 71: 969-977. PMID: 22036036, PMCID: PMC3290754, DOI: 10.1016/j.biopsych.2011.09.031.Peer-Reviewed Original ResearchConceptsN-acetylcysteineAuditory mismatch negativityReceptor antagonistN-methyl-D-aspartate receptor antagonistAspartate glutamate receptor antagonistOral N-acetylcysteinePlacebo-controlled studyGlutamate receptor antagonistsEffects of ketamineInfusion of salineMismatch negativityTest dayMMN amplitudeCystine-glutamate exchangerAuditory information processingP300 event-related potentialGlutamatergic modulationCognitive enhancing agentsEvent-related potentialsKetamine effectsHealthy volunteersHealthy humansSchizophrenia patientsPositive symptomsKetamine