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 ResearchMeSH KeywordsAntipsychotic AgentsCognitive TrainingDouble-Blind MethodGlycine Plasma Membrane Transport ProteinsHumansNeuronal PlasticitySchizophreniaConceptsGlycine 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
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 striatumPatientsSchizophreniaEffects of haloperidol on the delta-9-tetrahydrocannabinol response in humans: a responder analysis
Gupta S, De Aquino JP, D’Souza D, Ranganathan M. Effects of haloperidol on the delta-9-tetrahydrocannabinol response in humans: a responder analysis. Psychopharmacology 2019, 236: 2635-2640. PMID: 30919005, PMCID: PMC6697616, DOI: 10.1007/s00213-019-05235-x.Peer-Reviewed Original ResearchConceptsDissociative Symptoms ScalePANSS positive scalePsychotomimetic effectsHuman laboratory studiesRole of dopaminePsychosis-like effectsHaloperidol conditionNegative Syndrome ScalePANSS positive scoreDopaminergic antagonismPositive scalePlacebo conditionResponder analysisSyndrome ScaleSymptom ScaleDouble-blind studyEffects of haloperidolDopaminergic signalingOral haloperidolIndividualsOnly respondersPositive scoreIntravenous administrationHealthy individualsHaloperidol
2018
The 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 Scale
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 abnormalitiesEffect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial
Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, Gleason TC, Vertrees JE, Weingart K, Tal I, Scrymgeour A, Lawrence DD, Planeta B, Thase ME, Huang GD, Zisook S, Rao S, Pilkinton P, Wilcox J, Iranmanesh A, Sapra M, Jurjus G, Michalets J, Aslam M, Beresford T, Anderson K, Fernando R, Ramaswamy S, Kasckow J, Westermeyer J, Yoon G, D’Souza D, Larson G, Anderson W, Klatt M, Fareed A, Thompson S, Carrera C, Williams S, Juergens T, Albers L, Nasdahl C, Villarreal G, Winston J, Nogues C, Connolly K, Tapp A, Jones K, Khatkhate G, Marri S, Suppes T, LaMotte J, Hurley R, Mayeda A, Niculescu A, Fischer B, Loreck D, Rosenlicht N, Lieske S, Finkel M, Little J. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA 2017, 318: 132-145. PMID: 28697253, PMCID: PMC5817471, DOI: 10.1001/jama.2017.8036.Peer-Reviewed Original ResearchConceptsMajor depressive disorderAcute treatment phaseDepressive disorderSwitch groupAdverse effectsTreatment phaseUS Veterans Health Administration medical centersVeterans Health Administration medical centersNonpsychotic major depressive disorderWeeks of treatmentEffects of antidepressantsLikelihood of remissionSignificant treatment differencesBupropion monotherapyRandomized patientsRemission rateBupropion groupSecondary outcomesPrimary outcomeAtypical antipsychoticsDifferent antidepressantsFirst antidepressantClinical trialsCurrent treatmentMedical CenterMinimal 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 cigarettes
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 doses
2015
Reduced 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 ResearchMeSH KeywordsAdultAntipsychotic AgentsHumansMaleMiddle AgedPositron-Emission TomographyRadiopharmaceuticalsReceptor, Cannabinoid, CB1SchizophreniaSmokingYoung AdultConceptsHealthy 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 data
2012
Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia
Gunduz-Bruce H, Oliver S, Gueorguieva R, Forselius-Bielen K, D'Souza DC, Zimolo Z, Tek C, Kaliora S, Ray S, Petrides G. Efficacy of pimozide augmentation for clozapine partial responders with schizophrenia. Schizophrenia Research 2012, 143: 344-347. PMID: 23219861, DOI: 10.1016/j.schres.2012.11.008.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScaleTreatment-resistant schizophreniaClinical trialsNegative symptomsDouble-blind placeboAdequate blood levelsPsychiatric Rating ScaleNeurocognitive measuresAttention/executive functionBPRS totalPartial respondersPartial responseStudy entryQTc intervalBlood levelsClozapine's effectSide effectsNeurocognitive functionPatientsWeekly assessmentsClozapineNeurocognitive testsRating ScaleSchizophreniaTrials
2010
Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study.
Kane JM, D'Souza DC, Patkar AA, Youakim JM, Tiller JM, Yang R, Keefe RS. Armodafinil as adjunctive therapy in adults with cognitive deficits associated with schizophrenia: a 4-week, double-blind, placebo-controlled study. The Journal Of Clinical Psychiatry 2010, 71: 1475-81. PMID: 20816042, DOI: 10.4088/jcp.09m05950gry.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntipsychotic AgentsBenzhydryl CompoundsBenzodiazepinesCentral Nervous System StimulantsCognition DisordersDouble-Blind MethodDrug Therapy, CombinationFemaleHumansIsoxazolesMaleMiddle AgedModafinilOlanzapinePaliperidone PalmitatePsychiatric Status Rating ScalesPyrimidinesRisperidoneSchizophreniaTreatment OutcomeConceptsAdjunctive armodafinilAdjunctive therapyFinal visitNegative symptomsTotal scoreIsomer of modafinilTolerability of armodafinilPlacebo-controlled studyPrimary efficacy measureSecondary outcome measuresPANSS total scoreSANS total scoreNegative symptom scoresNegative Syndrome ScaleDaily placeboStable dosesAdverse eventsOral risperidoneSymptom scoresEfficacy measuresSchizophrenia (MATRICS) Consensus Cognitive BatteryOutcome measuresStable schizophreniaSD changeArmodafinilPotential 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 agentAgonistsHigh dose D-serine in the treatment of schizophrenia
Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, D'Souza C, Saksa J, Woods SW, Javitt DC. High dose D-serine in the treatment of schizophrenia. Schizophrenia Research 2010, 121: 125-130. PMID: 20541910, PMCID: PMC3111070, DOI: 10.1016/j.schres.2010.05.012.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnalysis of VarianceAntipsychotic AgentsChi-Square DistributionCognition DisordersDose-Response Relationship, DrugFemaleFollow-Up StudiesHumansMaleMiddle AgedNeuropsychological TestsPsychiatric Status Rating ScalesRegression AnalysisSchizophreniaSerineTreatment OutcomeYoung AdultConceptsD-serineBrain N-methyl-D-aspartate receptorsPlasma D-serine levelsN-methyl-D-aspartate receptorsSafety of dosesSignificant dose-dependent increaseDouble-blind investigationOpen-label trialDose-escalation studyDouble-blind studyLarge effect size improvementsTreatment of schizophreniaD-serine levelsPotential novel treatmentPharmacokinetics/pharmacodynamicsDose-dependent increaseNon-significant improvementEffect size improvementsMedication phasePersistent symptomsEscalation studyBrain levelsPlasma levelsPK analysisNeurocognitive dysfunction
2008
Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans
D’Souza D, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B, Ranganathan M, Bhakta S, Zimolo Z, Cooper T, Perry E. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans. Psychopharmacology 2008, 198: 587-603. PMID: 18228005, PMCID: PMC2878815, DOI: 10.1007/s00213-007-1042-2.Peer-Reviewed Original ResearchConceptsPerceptual alterationsPsychotomimetic effectsCambridge taskRecall deficitsVerbal recallSample taskCognitive effectsMemory impairmentCognitive impairmentSubjective effectsPreclinical literatureBehavioral effectsTaskD2 receptor mechanismsEffects of haloperidolFrequent usersDopaminergic systemHaloperidol pretreatmentImpairmentDistractibilityRecallResultsConsistentSpectrum of effectsRandom orderDeficits
2006
Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects
Neumeister A, Carson R, Henry S, Planeta-Wilson B, Binneman B, Maguire RP, Luckenbaugh DA, D'Souza C, Krystal JH, Frost JJ. Cerebral Metabolic Effects of Intravenous Glycine in Healthy Human Subjects. Journal Of Clinical Psychopharmacology 2006, 26: 595-599. PMID: 17110816, DOI: 10.1097/01.jcp.0000245558.14284.aa.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntipsychotic AgentsBehaviorBrainBrain MappingCluster AnalysisCross-Over StudiesDouble-Blind MethodFemaleFluorodeoxyglucose F18GlycineHumansInfusions, IntravenousMagnetic Resonance ImagingMaleNeuropsychological TestsPositron-Emission TomographyRadiopharmaceuticalsReference ValuesSerineConceptsN-methyl-D-aspartate receptor functionReceptor functionRegional cerebral metabolic rateAdministration of glycineCerebral metabolic effectsMagnetic resonance imaging studyPositron emission tomography studyHealthy control subjectsNMDA receptor functionCerebral metabolic rateEmission tomography studiesTest dayHealthy human subjectsResonance imaging studySignificant reductionPositron emission tomographyDorsolateral prefrontal cortexIntravenous glycinePlacebo infusionCerebral metabolismPatient populationControl subjectsGlycine administrationGlycine infusionIntravenous administration
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
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
1999
Interactive effects of subanesthetic ketamine and haloperidol in healthy humans
Krystal J, D’Souza D, Karper L, Bennett A, Abi-Dargham A, Abi-Saab D, Cassello K, Bowers Jr. M, Vegso S, Heninger G, Charney D, Bowers M. Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology 1999, 145: 193-204. PMID: 10463321, DOI: 10.1007/s002130051049.Peer-Reviewed Original ResearchToward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients
Krystal J, D'Souza D, Madonick S, Petrakis I. Toward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients. Schizophrenia Research 1999, 35: s35-s49. PMID: 10190224, DOI: 10.1016/s0920-9964(98)00162-5.Peer-Reviewed Original ResearchConceptsSchizophrenic patientsSubstance abuseTerms of rehospitalizationComorbid substance abuseExacerbation of symptomsHealth care expensesSelf-medication hypothesisBetter prognosisMedical illnessPharmacotherapeutic approachesRational pharmacotherapyNonschizophrenic populationsPatientsVocational functionIllicit substancesCare expensesAbuseVulnerability hypothesisRehospitalizationExacerbationMedicationsPharmacotherapyPrognosisPsychostimulantsIllness