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
Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users
Johnson E, Colbert S, Jeffries P, Tillman R, Bigdeli T, Karcher N, Chan G, Kuperman S, Meyers J, Nurnberger J, Plawecki M, Degenhardt L, Martin N, Kamarajan C, Schuckit M, Murray R, Dick D, Edenberg H, D’Souza D, Di Forti M, Porjesz B, Nelson E, Agrawal A. Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users. Schizophrenia Bulletin 2022, 49: 778-787. PMID: 36545904, PMCID: PMC10154717, DOI: 10.1093/schbul/sbac196.Peer-Reviewed Original ResearchConceptsCannabis useAlcohol use disorderCognitive difficultiesSchizophrenia polygenic risk scoresFirst cannabis useDaily cannabis useCannabis usersSocial withdrawalUnusual experiencesCannabis involvementPolygenic risk scoresExpected directionGenetic riskUse disordersIndependent replication sampleLike experiencesGenetic liabilityCannabisSchizophreniaPolygenic riskPolygenic liabilityReplication sampleExperienceAnalytic sampleDisorders
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 levelsIn vivo evidence of lower synaptic vesicle density in schizophrenia
Radhakrishnan R, Skosnik PD, Ranganathan M, Naganawa M, Toyonaga T, Finnema S, Hillmer AT, Esterlis I, Huang Y, Nabulsi N, Carson RE, D’Souza D. In vivo evidence of lower synaptic vesicle density in schizophrenia. Molecular Psychiatry 2021, 26: 7690-7698. PMID: 34135473, DOI: 10.1038/s41380-021-01184-0.Peer-Reviewed Original ResearchMeSH KeywordsBrainHumansNerve Tissue ProteinsPositron-Emission TomographySchizophreniaSynaptic VesiclesConceptsSynaptic vesicle densityHealthy controlsVesicle densityHigh-resolution research tomographySynaptic densitySCZ patientsVivo measuresNovel positron emission tomography (PET) ligandGender-matched healthy controlsCumulative antipsychotic exposurePositron emission tomography (PET) ligandSynaptic spine densityPsychosis symptom severityGray matter volumeJ bindingAntipsychotic exposureSpine densityDisease progressionFrontal cortexOccipital cortexTomography ligandTemporal cortexAnterior cingulateVivo findingsParietal cortexAnalysis of circulating exosomes reveals a peripheral signature of astrocytic pathology in schizophrenia
Ranganathan M, Rahman M, Ganesh S, D’Souza D, Skosnik PD, Radhakrishnan R, Pathania S, Mohanakumar T. Analysis of circulating exosomes reveals a peripheral signature of astrocytic pathology in schizophrenia. The World Journal Of Biological Psychiatry 2021, 23: 33-45. PMID: 33821753, DOI: 10.1080/15622975.2021.1907720.Peer-Reviewed Original ResearchConceptsHealthy controlsSex-matched healthy controlsBlood-brain barrierNovel peripheral biomarkersPlasma-derived exosomesAstroglial pathologyWestern blot analysisPeripheral biomarkersSynaptophysin levelsBrain barrierPeripheral signatureAstrocytic pathologyGFAP concentrationsSchizophrenia patientsExosomal protein expressionNeuropsychiatric disordersNeurodegenerative disordersProtein immunopositivitySchizophreniaProtein expressionGroup differencesDisordersPatientsScarce dataConcentration of exosomes
2020
Association 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 doses
2019
In vivo 5-HT6 and 5-HT2A receptor availability in antipsychotic treated schizophrenia patients vs. unmedicated healthy humans measured with [11C]GSK215083 PET
Radhakrishnan R, Matuskey D, Nabulsi N, Gaiser E, Gallezot JD, Henry S, Planeta B, Lin SF, Ropchan J, Huang Y, Carson RE, D'Souza DC. In vivo 5-HT6 and 5-HT2A receptor availability in antipsychotic treated schizophrenia patients vs. unmedicated healthy humans measured with [11C]GSK215083 PET. Psychiatry Research Neuroimaging 2019, 295: 111007. PMID: 31760336, DOI: 10.1016/j.pscychresns.2019.111007.Peer-Reviewed Original ResearchConceptsHealthy male controlsPositron emission tomographyMultilinear analysis 1Antipsychotic treatmentLower BPFrontal cortexReceptor availabilityAge-matched healthy male controlsDifferent second-generation antipsychoticsSteady-state troughPeak serum levelsSecond-generation antipsychoticsPotential therapeutic targetMale patientsSerum levelsHealthy humansTherapeutic targetSchizophrenia patientsTime-activity curvesMale controlsCognitive impairmentEmission tomographyVentral striatumPatientsSchizophreniaTest-retest reliability of time-frequency measures of auditory steady-state responses in patients with schizophrenia and healthy controls
Roach BJ, D'Souza DC, Ford JM, Mathalon DH. Test-retest reliability of time-frequency measures of auditory steady-state responses in patients with schizophrenia and healthy controls. NeuroImage Clinical 2019, 23: 101878. PMID: 31228795, PMCID: PMC6587022, DOI: 10.1016/j.nicl.2019.101878.Peer-Reviewed Original Research
2018
Herpes simplex virus 1 infection and valacyclovir treatment in schizophrenia: Results from the VISTA study
Breier A, Buchanan RW, D'Souza D, Nuechterlein K, Marder S, Dunn W, Preskorn S, Macaluso M, Wurfel B, Maguire G, Kakar R, Highum D, Hoffmeyer D, Coskinas E, Litman R, Vohs JL, Radnovich A, Francis MM, Metzler E, Visco A, Mehdiyoun N, Yang Z, Zhang Y, Yolken RH, Dickerson FB. Herpes simplex virus 1 infection and valacyclovir treatment in schizophrenia: Results from the VISTA study. Schizophrenia Research 2018, 206: 291-299. PMID: 30478008, DOI: 10.1016/j.schres.2018.11.002.Peer-Reviewed Original ResearchConceptsHSV-1Double-blind efficacy trialHerpes simplex virus 1 (HSV-1) infectionEarly phase schizophreniaSimplex virus 1 infectionVirus-1 infectionPathophysiology of schizophreniaPrimary endpointValacyclovir treatmentNegative subjectsRecent trialsVISTA studyEfficacy trialsLetter-Number Sequencing TestNegative groupPositive groupSevere formHerpes virusPositive symptomsMore impairmentTreatment resultsUS sitesCognitive deficitsNon-activated stateSchizophreniaThe effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial
Boggs DL, Surti T, Gupta A, Gupta S, Niciu M, Pittman B, Schnakenberg Martin AM, Thurnauer H, Davies A, D’Souza D, Ranganathan M. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology 2018, 235: 1923-1932. PMID: 29619533, DOI: 10.1007/s00213-018-4885-9.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAffectAntipsychotic AgentsCannabidiolChronic DiseaseCognitionCognitive DysfunctionDouble-Blind MethodFemaleFollow-Up StudiesHumansMaleMental Status and Dementia TestsMiddle AgedOutpatientsPsychiatric Status Rating ScalesSchizophreniaSchizophrenic PsychologyTreatment OutcomeConceptsMATRICS Consensus Cognitive BatterySide effectsChronic schizophreniaAntipsychotic-treated patientsMovement side effectsFixed-dose studyPlacebo-treated subjectsWeeks of treatmentPANSS total scoreEffects of cannabidiolWorsening of moodNegative Syndrome ScaleAntipsychotic-treated outpatients× time effect× time interactionMCCB composite scoreOral cannabidiolCBD groupClinical trialsParallel groupPANSS scoresMethodsThis studyPsychotic symptomsConsensus Cognitive BatterySyndrome ScaleDose-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
Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia
Hamilton HK, D'Souza DC, Ford JM, Roach BJ, Kort NS, Ahn KH, Bhakta S, Ranganathan M, Mathalon DH. Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia. Schizophrenia Research 2017, 191: 87-94. PMID: 28711472, PMCID: PMC5745273, DOI: 10.1016/j.schres.2017.06.040.Peer-Reviewed Original ResearchConceptsNicotinic acetylcholine receptor agonistAcetylcholine receptor agonistReceptor agonistHealthy volunteersN-methyl-D-aspartate receptor antagonistPathophysiology of schizophreniaAuditory processing abnormalitiesProfile of effectsMMN amplitudeNicotine preventsNicotine administrationReceptor hypofunctionNMDAR hypofunctionNMDAR antagonistsReceptor antagonistMismatch negativity (MMN) event-related potential (ERP) componentPresent doseNicotinic agonistsSchizophrenia patientsCigarette useKetamineDeviant typesNeurophysiological effectsSecondary analysisMMN abnormalitiesMinimal effects of prolonged smoking abstinence or resumption on cognitive performance challenge the “self-medication” hypothesis in schizophrenia
Boggs DL, Surti TS, Esterlis I, Pittman B, Cosgrove K, Sewell RA, Ranganathan M, D'Souza DC. Minimal effects of prolonged smoking abstinence or resumption on cognitive performance challenge the “self-medication” hypothesis in schizophrenia. Schizophrenia Research 2017, 194: 62-69. PMID: 28392208, PMCID: PMC5630481, DOI: 10.1016/j.schres.2017.03.047.Peer-Reviewed Original ResearchConceptsProcessing speedMultiple cognitive domainsCognitive test performancePro-cognitive effectsSelf-medication hypothesisNicotine-dependent smokersVerbal memoryVerbal recallCognitive batteryCognitive domainsExecutive functionVerbal fluencyBehavioral measuresTest batteryCognitive deficitsTest performanceSmoking cessationSmoking abstinenceNegative symptomsConflict resolutionAbstinenceCognitionDepressive symptomsSchizophreniaSmoke cigarettesOpposing Effects of Cannabis Use on Electroencephalographic Measures of Auditory Repetition Suppression in Schizophrenia and Healthy Controls
Skosnik PD, D’Souza D. Opposing Effects of Cannabis Use on Electroencephalographic Measures of Auditory Repetition Suppression in Schizophrenia and Healthy Controls. Biological Psychiatry Cognitive Neuroscience And Neuroimaging 2017, 2: 209-211. PMID: 29528290, DOI: 10.1016/j.bpsc.2017.03.004.Peer-Reviewed Original Research
2016
Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [11C]-(+)-PHNO
Girgis RR, Slifstein M, D’Souza D, Lee Y, Periclou A, Ghahramani P, Laszlovszky I, Durgam S, Adham N, Nabulsi N, Huang Y, Carson RE, Kiss B, Kapás M, Abi-Dargham A, Rakhit A. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [11C]-(+)-PHNO. Psychopharmacology 2016, 233: 3503-3512. PMID: 27525990, PMCID: PMC5035321, DOI: 10.1007/s00213-016-4382-y.Peer-Reviewed Original ResearchConceptsDopamine D3 receptorD2 receptorsD3 receptorsReceptor occupancyPartial agonistPositive symptomsD2 receptor partial agonistNegative symptomsPositron emission tomography scanDose-occupancy relationshipD2 receptor occupancyWeeks of dosingEmission tomography scanWeeks of treatmentExposure-response analysisReceptor partial agonistCerebrospinal fluid samplesDopamine D2 receptorsReward-related behaviorsD2 receptor ligandsTomography scanD2 antagonismPatientsDay 1Low dosesHuman Laboratory Studies on Cannabinoids and Psychosis
Sherif M, Radhakrishnan R, D’Souza D, Ranganathan M. Human Laboratory Studies on Cannabinoids and Psychosis. Biological Psychiatry 2016, 79: 526-538. PMID: 26970363, DOI: 10.1016/j.biopsych.2016.01.011.BooksConceptsCannabinoid agonistsPsychotomimetic effectsAcute psychotomimetic effectsHealthy control subjectsCrossover laboratory studyEffects of ketamineHuman laboratory studiesGamma-aminobutyric acidHealthy human subjectsSelf-medication hypothesisTransient exacerbationAntipsychotic medicationControl subjectsDopamine metabolismGlutamate systemDopamine releasePsychotomimetic drugsCognitive symptomsDrug AdministrationAgonistsMagnitude of effectSymptomsSchizophreniaCannabinoidsLaboratory studies
2015
The early identification of psychosis: can lessons be learnt from cardiac stress testing?
Gupta S, Ranganathan M, D’Souza D. The early identification of psychosis: can lessons be learnt from cardiac stress testing? Psychopharmacology 2015, 233: 19-37. PMID: 26566609, PMCID: PMC4703558, DOI: 10.1007/s00213-015-4143-3.Peer-Reviewed Original ResearchMeSH KeywordsEarly DiagnosisExercise TestHumansLearningPsychotic DisordersRisk FactorsSchizophreniaSchizophrenic PsychologyConceptsCardiac stress testingCoronary artery diseaseMyocardial infarctionOutcome measuresPsychotic disordersDetection of CADManagement of schizophreniaStress testingManagement of anginaDiagnosis of schizophreniaStress testArtery diseasePsychotic episodePsychiatric disordersPredictive valueEarly identificationEarly detectionSchizophreniaPsychosisDisordersTarget populationRiskSafe stimuliRange of risksUrgent needReduced Brain Cannabinoid Receptor Availability in Schizophrenia
Ranganathan M, Cortes-Briones J, Radhakrishnan R, Thurnauer H, Planeta B, Skosnik P, Gao H, Labaree D, Neumeister A, Pittman B, Surti T, Huang Y, Carson RE, D’Souza D. Reduced Brain Cannabinoid Receptor Availability in Schizophrenia. Biological Psychiatry 2015, 79: 997-1005. PMID: 26432420, PMCID: PMC4884543, DOI: 10.1016/j.biopsych.2015.08.021.Peer-Reviewed Original ResearchConceptsHealthy control subjectsSCZ subjectsCB1R availabilityECB systemMale healthy control subjectsBody mass indexAge-matched male healthy control subjectsPathophysiology of schizophreniaPositron emission tomographyPosterior cingulate cortexPresence of abnormalitiesMass indexControl subjectsEndocannabinoid systemTobacco useReceptor availabilityCingulate cortexEmission tomography dataBrain regionsEmission tomographySelective radiotracerVivo measuresRegional volumesSchizophreniaPositron emission tomography dataDeficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia: A Positron Emission Tomographic Functional Magnetic Resonance Imaging Study
Slifstein M, van de Giessen E, Van Snellenberg J, Thompson JL, Narendran R, Gil R, Hackett E, Girgis R, Ojeil N, Moore H, D’Souza D, Malison RT, Huang Y, Lim K, Nabulsi N, Carson RE, Lieberman JA, Abi-Dargham A. Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia: A Positron Emission Tomographic Functional Magnetic Resonance Imaging Study. JAMA Psychiatry 2015, 72: 316-324. PMID: 25651194, PMCID: PMC4768742, DOI: 10.1001/jamapsychiatry.2014.2414.Peer-Reviewed Original ResearchMeSH KeywordsAdultAmphetamineCarbon RadioisotopesCase-Control StudiesDopamineDopamine AntagonistsFemaleFunctional NeuroimagingHumansMagnetic Resonance ImagingMaleMemory, Short-TermMesencephalonPositron-Emission TomographyPrefrontal CortexPyrrolidinesSalicylamidesSchizophreniaSchizophrenic PsychologyYoung AdultConceptsLevel-dependent functional magnetic resonanceBlood oxygenation level-dependent functional magnetic resonanceHealthy control individualsFunctional magnetic resonanceDopamine releaseExtrastriatal regionsPrefrontal cortexOutcome measuresAssociative striatumControl individualsAmphetamine-induced dopamine releaseBOLD activationNew York State Psychiatric InstituteDorsolateral PFCMagnetic resonance imaging studyPositron emission tomographic imagingStriatal dopamine releaseDrug-naive patientsFrontal cortical functionEffects of amphetamineExtrastriatal dopamine releaseResonance imaging studyFunctional magnetic resonance imaging studyEmission tomographic imagingMagnetic resonance
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